Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 4 939
Page 337 of 494-
DHX15 as a novel immune-related prognostic biomarker in breast cancer: An integrated bioinformatics analysis with in vitro functional validation.
Breast cancer (BC) is a disease that occurs relatively frequently, and its prognosis and treatment outcomes are not optimal at present. Identifying novel BC biomarkers and therapeutic targets is key. DEAH-box helicase 15 (DHX15) is an RNA helicase that exhibits enhanced activity and is closely associated with tumorigenic potential. Alternative splicing is widely dysregulated in BC. However, the biological function of DHX15 in BC, in addition to its underlying molecular mechanisms, remain unclear. DHX15, a key RNA helicase involved in splicing regulation, was therefore selected to explore whether it modulates the malignant progression of BC. The present study therefore analyzed the DHX15 expression profile in BC using the Tumor Immune Estimation Resource database. Kaplan-Meier plotter database was utilized to investigate the prognostic value of DHX15 in BC. The Cancer Genome Atlas-BRCA database was utilized to investigate the association between DHX15 and immune infiltration, as well as the expression of immune biomarkers, within the tumor microenvironment. The potential biological functions of DHX15 in BC were also investigated using Gene Ontology (GO) enrichment analysis, Kyoto encyclopedia of genes and genomes pathway analysis (KEGG) and single-cell functional analysis. GO and KEGG enrichment analyses were performed via the GSEA module embedded in the LinkedOmics database. Single-cell functional analysis was performed using the Human Proteome Atlas database and the CancerSEA database. Concurrently, the expression and function of DHX15 in BC was validated. MDA-MB-231 cells were transfected with a DHX15 knockdown plasmid and MCF-7 cells with an overexpression plasmid, and Transwell assays, plate cloning and scratch assays were performed on the established cell lines. The present findings revealed that the DHX15 expression levels in BC were notably higher compared with those in normal tissues. Furthermore, the expression of DHX15 was associated with immune checkpoints (such as PDCD1, LAG3 and GZMB) and immune cell infiltration (such as T helper cells and central memory T cells) in BC, as determined by single-sample Gene Set Enrichment Analysis and CIBERSORT analyses. In vitro experiments suggested that inhibiting DHX15 notably suppressed the migration, invasion and proliferation of MDA-MB-231 cells. Collectively, these findings suggest that the high expression of DHX15 in BC is associated with worse prognosis and immune cell infiltration, potentially by functionally promoting tumor cell proliferation, migration and invasion.
-
Single-cell analysis of shared signatures and transcriptional diversity during zebrafish development.
During development, animals generate distinct cell populations with specific identities, functions, and morphologies. We mapped transcriptionally distinct populations across 489,686 cells from 62 stages during wild-type zebrafish embryogenesis and early larval development (3-120 hours post-fertilization). Using these data, we identified the limited catalog of gene expression programs reused across multiple tissues and their cell-type-specific adaptations. We also determined the duration each transcriptional state is present during development and suggest new long-term cycling populations. Focused analyses of non-skeletal muscle and the endoderm identified transcriptional profiles of understudied cell types and subpopulations, including the pneumatic duct, individual intestinal smooth muscle layers, spatially distinct pericyte subpopulations, and homologs of recently discovered human best4+ enterocytes. The transcriptional regulators of these populations remain unknown, so we reconstructed gene expression trajectories to suggest candidates. To enable additional discoveries, we make this comprehensive transcriptional atlas of early zebrafish development available through our website, Daniocell.
-
SPAG5 Expression Predicts Poor Prognosis and is Associated With Adverse Immune Infiltration in Lung Adenocarcinomas.
BACKGROUND: Sperm-associated antigen 5 (SPAG5) has been identified as a novel driver oncogene involved in multiple cancers; however, its role in lung adenocarcinoma (LUAD) needs further investigation. Our study aims to elucidate the potential significance of SPAG5 in LUAD prognosis and its implications for the efficacy of immunotherapy. METHODS: In this study, we used bioinformatics analysis and tissue microarray (TMA) staining to examine the potential role of SPAG5 in LUAD survival and response to immunotherapy. We used the Oncomine, TIMER2.0, Gene Expression Profiling Interactive Analysis (GEPIA), Sangerbox, PredicScan, and Kaplan-Meier Plotter databases to examine the expression and prognostic role of SPAG5 in the LUAD of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases. We also used Cancer Single-cell State Atlas (CancerSEA) and Tumor Immune Estimation Resource (TIMER2.0) to analyze the association of SPAG5 with malignant phenotype and tumor immune microenvironment. Furthermore, Immune Cell Abundance Identifier (ImmuCellAI) analysis of TCGA sequencing data was used to predict the role of SPAG5 in determining the response to immune checkpoint blockade (ICB) treatment in LUAD. Co-expression analysis of programmed death-ligand 1 (PD-L1) and SPAG5 was performed using LUAD TMA immunohistochemistry (IHC) analysis. RESULTS: Our findings indicate that SPAG5 is overexpressed in LUAD and is positively correlated with advanced clinical stage, poor overall survival, relapse-free survival, and progression-free survival outcomes. SPAG5 may be involved in regulating the cell cycle, proliferation, invasion, DNA damage and repair, and tumor immunosuppression. Furthermore, TMA IHC analysis showed a positive correlation between PD-L1 expression in LUAD and SPAG5 which suggests that SPAG5 may serve as a potential predictor of response to ICB therapy in LUAD. CONCLUSIONS: Our results highlight the role of SAPG5 in promoting a tumor malignancy phenotype and immunosuppression in LUAD and suggest that SPAG5 may serve as a potential response marker for ICB therapy.
-
Single-cell RNA sequencing and proteomics uncover glycolytic dysregulation linking skin and systemic inflammation in dermatomyositis.
BACKGROUND: Dermatomyositis is a systemic autoimmune disease characterized by progressive muscle weakness and distinctive cutaneous manifestations. While skin involvement is a major clinical feature, the precise cellular and molecular landscape of lesional skin remains poorly defined, limiting our understanding of disease pathogenesis and targeted therapeutic development. OBJECTIVES: To define the systemic and skin lesion landscape of dermatomyositis inflammation, and investigate the underlying pathogenic mechanisms. METHODS: We performed single-cell RNA sequencing (scRNAseq) on skin lesions from adults with classic dermatomyositis in order to construct a high-resolution atlas of the lesional microenvironment. Intercellular communication and trajectory analyses were performed to identify pathogenic cell subpopulations. Proteomic and transcriptomic profiling were integrated to quantify the systemic inflammation burden. Therapeutic validation was conducted in experimental autoimmune myositis (EAM) mouse models. RESULTS: Our study uncovered a unique pathogenic landscape in dermatomyositis, identifying fibroblasts as the dominant signallers, whereas macrophages were dominant in healthy control skin. We characterized a distinct inflammatory fibroblast subset and established type I interferon (IFN-I) signalling as a key immune hallmark. Multi-omics integration revealed aberrant CXCL10 expression with heightened glycolysis as a central inflammatory driver. Therapeutic targeting using the glycolysis inhibitor 2-deoxy-D-glucose (2DG) significantly ameliorated inflammation in EAM mice. CONCLUSIONS: The scRNAseq atlas of dermatomyositis skin lesions delineates a pathogenic cascade centred on inflammatory fibroblasts. We have established the IFN-I signalling pathway and a CXCL10-glycolysis axis as core mechanisms underlying inflammation in dermatomyositis. Therapeutic targeting of glycolytic pathways with 2DG significantly attenuated inflammation in vivo, suggesting potential therapeutic strategies for dermatomyositis.
-
The guinea pig serves as an alternative model to study human preimplantation development.
Preimplantation development is an important window of human embryogenesis. However, ethical constraints and the limitations involved in studying human embryos often necessitate the use of alternative model systems. Here we identify the guinea pig as a promising small animal model to study human preimplantation development. Using single-cell RNA-sequencing, we generated an atlas of guinea pig preimplantation development, revealing its close resemblance to early human embryogenesis in terms of the timing of compaction, early-, mid- and late-blastocyst formation, and implantation, and the spatio-temporal expression of key lineage markers. We also show conserved roles of Hippo, MEK-ERK and JAK-STAT signalling. Furthermore, multi-species analysis highlights the spatio-temporal expression of conserved and divergent genes during preimplantation development and pluripotency. The guinea pig serves as a valuable animal model for advancing preimplantation development and stem cell research, and can be leveraged to better understand the longer-term impact of early exposures on offspring outcomes.
-
Fishing Innate Immune System Properties through the Transcriptomic Single-Cell Data of Teleostei.
The innate immune system is the first line of defense in multicellular organisms. Danio rerio is widely considered a promising model for IIS-related research, with the most amount of scRNAseq data available among Teleostei. We summarized the scRNAseq and spatial transcriptomics experiments related to the IIS for zebrafish and other Teleostei from the GEO NCBI and the Single-Cell Expression Atlas. We found a considerable number of scRNAseq experiments at different stages of zebrafish development in organs such as the kidney, liver, stomach, heart, and brain. These datasets could be further used to conduct large-scale meta-analyses and to compare the IIS of zebrafish with the mammalian one. However, only a small number of scRNAseq datasets are available for other fish (turbot, salmon, cavefish, and dark sleeper). Since fish biology is very diverse, it would be a major mistake to use zebrafish alone in fish immunology studies. In particular, there is a special need for new scRNAseq experiments involving nonmodel Teleostei, e.g., long-lived species, cancer-resistant fish, and various fish ecotypes.
-
A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins.
To understand functional duality of the complement system in host defense and lung injury, a more comprehensive view of its localized production in the lung, and the impact of age on complement production are essential. Here, we explored the expression of complement genes through computational analysis of preexisting single cell RNA sequencing data from lung transcriptomes of healthy young (3 months) and old C57BL/6 mice (24 months), and humans. We characterized the distribution of 48 complement genes. Across 28 distinct immune and non-immune cell types in mice, mesothelial cells expressed the greatest number of complement genes (e.g., C1ra, C2, C3), and regulators (e.g., Serping1, Cfh). C5 was abundant in type II alveolar epithelial cells and C1q in interstitial lung macrophages. There were only moderate differences in gene expression between young and old mice. Among 57 human lung cell types, mesothelial cells showed abundant complement expression. A few differences in gene expression (e.g., FCN1, CFI, C6, C7) were also evident between mice and human lung cells. Our findings present a novel perspective on the expression patterns of complement genes in normal lungs. These findings highlight the potential functions of complement in tissue-specific homeostasis and immunity and may foster a mechanistic understanding of its role in lung health and disease.
-
Comparative analysis of cell-cell communication at single-cell resolution.
Inference of cell-cell communication from single-cell RNA sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell-level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease.
-
An NRIP1-Centric Monocyte Immunogenetic Bridge Between Heart Failure and Ischemic Stroke.
BACKGROUND: Heart failure (HF) and ischemic stroke (IS) frequently co-occur and worsen each other. Circulating immune cells may act as a cross-organ inflammatory bridge, but the key immune lineage, genetically supported mediators, and druggable targets remain unclear. OBJECTIVE: To identify the immune-cell lineage, candidate gene, and tractable intervention target linking HF and IS. METHODS: Bidirectional Mendelian randomization (MR) of genome-wide association study summary statistics was used to assess causal links between HF and IS. Mouse single-cell transcriptomic datasets from HF and IS models were integrated to define a shared immune/stromal atlas and characterize Ly6C⁺ monocyte expansion. Ly6C⁺ monocyte marker genes were mapped to human orthologs and evaluated using peripheral-blood expression quantitative trait locus data for gene-level MR, followed by expression validation, colocalization, summary-data-based MR, and spatial transcriptomics. In HF single-cell data, Ly6C⁺ monocytes were stratified by Nrip1 expression for cell-cell communication, pathway enrichment, and pseudotime analyses. Candidate-drug prediction, druggability evaluation, molecular docking, molecular dynamics simulation, and in vitro validation were then performed. RESULTS: MR supported a bidirectional positive association between HF and IS. Both diseases showed expansion of inflammatory Ly6C⁺ monocytes at single-cell resolution. Among MR-implicated genes, NRIP1 was prioritized as a key gene associated with reduced IS risk, and genetic and spatial evidence supported its monocyte-mediated role in HF-IS coupling. Nrip1-stratified and pseudotime analyses suggested a homeostatic role through modulation of inflammatory thresholds and communication patterns. Drug prediction and in silico analyses indicated that retinoic acid-related small molecules may bind NRIP1 and exhibit preliminary druggability. In vitro, tretinoin alleviated ischemia-like HMC3 cell injury and inflammation by modulating monocyte NRIP1. CONCLUSION: An NRIP1-centered monocyte network may represent a tractable immune bridge in HF-IS comorbidity, and tretinoin provides an entry point for NRIP1-targeted intervention.
-
Single-cell transcriptomics reveals the impact of sex and age in the healthy human liver.
BACKGROUND & AIMS: The liver is a vital organ composed of parenchymal, non-parenchymal, and immune cell populations. Single-cell sequencing approaches now provide the opportunity to understand how sex and age influence gene expression and cellular function across cell types within the liver. METHODS: We analyzed the cellular composition and intercellular interactions of the human liver through single-nucleus RNA sequencing, incorporating insights from 37 healthy liver samples. The dataset contains cells from female and male donors spanning more than seven decades of life, and analysis was performed to evaluate the impact of sex and age on differential gene expression, pathway enrichment, and predicted ligand-receptor and protein-protein interactions. RESULTS: Excluding the X and Y chromosomes, we identified 374 genes uniquely enriched in cells of the female liver and 520 genes enriched in cells of the male liver. Differential expression analysis defined unique circuitries enriched within each cell type between females and males and their impact on cell-cell communication and response to external signals, including enrichment of cholesterol metabolism (p <1.64 x 10-3), TGF-β receptor signaling (p <5.69 x 10-3), and fibronectin production (p <1.04 x 10-8) in female cells and bone morphogenic protein signaling (p <7.62 × 10-6) in male cells. With increasing age, we observe a greater diversity in gene expression, including enrichment of genes that regulate neuregulin signaling (p <7.81 × 10-3) at older ages, while genes regulating insulin growth factor signaling (p <2.44 × 10-3) are enriched at younger ages. Senescence signatures were also identified for each cell type within the liver. CONCLUSIONS: These results define the activities of healthy cell types within the liver across sex and age, providing a foundation for studies to examine how ancestry, geography, and disease states influence liver function within these contexts. IMPACT AND IMPLICATIONS: Our study provides a comprehensive single-cell analysis of 37 healthy human liver samples, revealing how sex and age influence gene expression profiles, cellular interactions, and signaling responses across liver cell types and subtypes. These insights are of particular significance for researchers investigating the influence of sex and age on cellular responses to injury and treatment of injury. Furthermore, this dataset serves as a healthy reference, enabling future studies to understand how ancestry, geography, and disease states shape liver biology in the context of age and sex.