-
Science (New York, N.Y.) Jul 2023Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation....
Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting reduced atrial fibrillation in HOMER mice. These results identify SPP1 macrophages as targets for immunotherapy in atrial fibrillation.
Topics: Animals; Humans; Mice; Atrial Fibrillation; Heart Atria; Macrophages; Mitral Valve Insufficiency; Osteopontin; Gene Deletion; Cell Movement; Single-Cell Gene Expression Analysis
PubMed: 37440641
DOI: 10.1126/science.abq3061 -
Nature Oct 2023Multimodal astrocyte-neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control...
Multimodal astrocyte-neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.
Topics: Adult; Humans; Astrocytes; Central Nervous System; Glutamic Acid; Hippocampus; Neurons; Signal Transduction; Synaptic Transmission; Calcium; Exocytosis; Single-Cell Gene Expression Analysis; Vesicular Glutamate Transport Protein 1; Gene Deletion; Cerebral Cortex
PubMed: 37674083
DOI: 10.1038/s41586-023-06502-w -
Nature Jul 2023Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers, but its clinical and biological significance is unknown. Here,...
Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR-Cas9. Y-positive (Y) and Y-negative (Y) tumours grew similarly in vitro, whereas Y tumours were more aggressive than Y tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y tumours promote striking dysfunction or exhaustion of CD8 T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y tumours, Y tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Chromosome Deletion; Chromosomes, Human, Y; Proteomics; Tumor Microenvironment; Urinary Bladder Neoplasms; Tumor Escape; Gene Expression Profiling; Genomics; Prognosis; CRISPR-Cas Systems; Gene Editing; In Vitro Techniques; Immune Checkpoint Inhibitors; Flow Cytometry; Immunotherapy
PubMed: 37344596
DOI: 10.1038/s41586-023-06234-x -
Viruses Jul 2023Due to the high incidence of PRRSV mutation and recombination, PRRSV infection is difficult to prevent and control in China and worldwide. Two species of PRRSV,... (Review)
Review
Due to the high incidence of PRRSV mutation and recombination, PRRSV infection is difficult to prevent and control in China and worldwide. Two species of PRRSV, (PRRSV-1) and (PRRSV-2), exist in China, and PRRSV-1 has always received less attention in China. However, the number of PRRSV-1 strains detected in China has increased recently. To date, PRRSV-1 has spread to more than 23 regions in China. Based on the phylogenetic analysis of ORF5 and the whole genome of PRRSV-1, Chinese PRRSV-1 can be divided into at least seven independent subgroups. Among them, BJEU06-1-like has become the mainstream subgroup in some regions of China. This subgroup of strains has a 5-aa (4 + 1) characteristic discontinuous deletion pattern at aa 357~aa 360 and aa 411 in Nsp2. Previous studies have indicated that the pathogenicity of PRRSV-1 in China is mild, but recent studies found that the pathogenicity of PRRSV-1 was enhanced in China. Therefore, the emergence of PRRSV-1 deserves attention, and the prevention and control of PRRSV-1 infection in China should be strengthened. PRRSV infection is usually prevented and controlled by a combination of virus monitoring, biosafety restrictions, herd management measures and vaccination. However, the use of PRRSV-1 vaccines is currently banned in China. Thus, we should strengthen the monitoring of PRRSV-1 and the biosafety management of pig herds in China. In this review, we summarize the prevalence of PRRSV-1 in China and clarify the genomic characteristics, pathogenicity, vaccine status, and prevention and control management system of PRRSV-1 in China. Consequently, the purpose of this review is to provide a basis for further development of prevention and control measures for PRRSV-1.
Topics: Animals; Swine; Porcine respiratory and reproductive syndrome virus; Porcine Reproductive and Respiratory Syndrome; Phylogeny; Amino Acid Sequence; Genetic Variation; Genome, Viral; China
PubMed: 37515213
DOI: 10.3390/v15071528 -
Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.Acta Neuropathologica Jul 2023Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in...
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2A) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2A meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.
Topics: Humans; Genes, p16; Meningioma; Cyclin-Dependent Kinase Inhibitor p16; Transcriptome; DNA Copy Number Variations; Homozygote; Sequence Deletion; Meningeal Neoplasms
PubMed: 37093270
DOI: 10.1007/s00401-023-02571-3 -
Nature Communications Sep 2023Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we...
Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.
Topics: Humans; Brain Neoplasms; Multiparametric Magnetic Resonance Imaging; Homozygote; Sequence Deletion; Glioma; Magnetic Resonance Imaging; Biological Products
PubMed: 37770427
DOI: 10.1038/s41467-023-41559-1 -
The Journal of Clinical Investigation Sep 2023RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematologic malignancies. We previously reported that coexpression of Sf3b1 mutation...
RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematologic malignancies. We previously reported that coexpression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harboring chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromosomal instability (CIN) remains unclear. Here, we demonstrated that SF3B1 mutation promotes centromeric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromosome segregation, altered spindle architecture, and aneuploidy, which could be alleviated by removal of cen-R-loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlay augmentation of cen-R-loop, as overexpression of the normal isoform, but not the altered form, mitigated mitotic stress in SF3B1-mutant cells. Our study identifies a critical role of splice variants in linking RNA splicing dysregulation and CIN and highlights cen-R-loop augmentation as a key mechanism for leukemogenesis.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; R-Loop Structures; Phosphoproteins; Mutation; RNA Splicing Factors; Ataxia Telangiectasia Mutated Proteins
PubMed: 37463047
DOI: 10.1172/JCI163325 -
Acta Neuropathologica Aug 2023Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in...
Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick's disease. We conclude that MAPT mutation ∆K281 causes Pick's disease.
Topics: Humans; Pick Disease of the Brain; Silver; tau Proteins; Frontotemporal Dementia; Neurons; Mutation
PubMed: 37351604
DOI: 10.1007/s00401-023-02598-6