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1.
Genome Med ; 14(1): 46, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35501841

RESUMO

BACKGROUND: Natural killer (NK) cells are innate lymphoid cells that mediate antitumour and antiviral responses. However, very little is known about how ageing influences human NK cells, especially at the single-cell level. METHODS: We applied single-cell sequencing (scRNA-seq) to human lymphocytes and NK cells from 4 young and 4 elderly individuals and then analysed the transcriptome data using Seurat. We detected the proportion and phenotype of NK cell subsets in peripheral blood samples from a total of 62 young and 52 elderly healthy donors by flow cytometry. We also used flow cytometry to examine the effector functions of NK cell subsets upon IFN-α/IL-12+IL-15/K562/IL-2 stimulation in vitro in peripheral blood samples from a total of 64 young and 63 elderly healthy donors. We finally studied and integrated single-cell transcriptomes of NK cells from 15 young and 41 elderly COVID-19 patients with those from 12 young and 6 elderly healthy control individuals to investigate the impacts of ageing on NK cell subsets in COVID-19 disease. RESULTS: We discovered a memory-like NK subpopulation (NK2) exhibiting the largest distribution change between elderly and young individuals among lymphocytes. Notably, we discovered a unique NK subset that was predominantly CD52+ NK2 cells (NK2.1). These memory-like NK2.1 cells accumulated with age, exhibited proinflammatory characteristics, and displayed a type I interferon response state. Integrative analyses of a large-cohort COVID-19 dataset and our datasets revealed that NK2.1 cells from elderly COVID-19 patients are enriched for type I interferon signalling, which is positively correlated with disease severity in COVID-19. CONCLUSIONS: We identified a unique memory-like NK cell subset that accumulates with ageing and correlates with disease severity in COVID-19. Our results identify memory-like NK2.1 cells as a potential target for developing immunotherapies for infectious diseases and for addressing age-related dysfunctions of the immune system.


Assuntos
COVID-19 , Transcriptoma , Idoso , Envelhecimento/genética , Humanos , Imunidade Inata , Células Matadoras Naturais/metabolismo , Índice de Gravidade de Doença
2.
Nat Methods ; 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35577954

RESUMO

Spatial transcriptomics approaches have substantially advanced our capacity to detect the spatial distribution of RNA transcripts in tissues, yet it remains challenging to characterize whole-transcriptome-level data for single cells in space. Addressing this need, researchers have developed integration methods to combine spatial transcriptomic data with single-cell RNA-seq data to predict the spatial distribution of undetected transcripts and/or perform cell type deconvolution of spots in histological sections. However, to date, no independent studies have comparatively analyzed these integration methods to benchmark their performance. Here we present benchmarking of 16 integration methods using 45 paired datasets (comprising both spatial transcriptomics and scRNA-seq data) and 32 simulated datasets. We found that Tangram, gimVI, and SpaGE outperformed other integration methods for predicting the spatial distribution of RNA transcripts, whereas Cell2location, SpatialDWLS, and RCTD are the top-performing methods for the cell type deconvolution of spots. We provide a benchmark pipeline to help researchers select optimal integration methods to process their datasets.

3.
J Pharm Biomed Anal ; 215: 114771, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35461164

RESUMO

A metabolomics method based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to study the metabolic changes of liver in db/db mice administered with curcumin. After one week of acclimating to feeding, 20 db/db mice were randomly divided into two groups: curcumin non-treatment group and curcumin treatment group. After eight weeks of treatment, plasma and liver were collected for biochemical analysis and metabolomics analysis, as well as liver oxidative stress and histopathology examination. Serum biochemical indicators such as blood glucose, triglycerides, fasting insulin, and aspartate aminotransferase decreased significantly in the curcumin treatment group compared to the curcumin non-treatment group, whereas hepatic pathological levels and antioxidation levels improved. There were several different potential biomarkers in two groups, including sphingomyelin (SM) (d18:0/20:0), eicosapentaenoic acid (EPA), docosapentaenoic acid (22n-6) (DPAn-6), arachidonic acid (AA), dihomo-gamma- linolenic acid (DGLA), leukotriene C4 (LTC4), lysophosphatidylethanolamine (LysoPE) (16:1(9Z)/0:0), LysoPE (18:1(9Z)/0:0), LysoPE (0:0/18:0), LysoPE (0:0/20:1(11Z)), LysoPE (20:1(11Z)/0:0), 3-sulfinoalanine, alpha-tocotrienol (α-T3) and pantetheine 4'-phosphate (4'-PP). The mechanism might be related to biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, phospholipid metabolism, and taurine and hypotaurine metabolism. The effects of curcumin on type 2 diabetes mellitus (T2DM) include antioxidant, delaying development of T2DM, preventing ß-cell death, decreasing insulin resistance, alleviating hepatic damage, and improving metabolic disturbances. Our results provide novel insights and ideas for prevention and treatment of curcumin on T2DM and its complications.


Assuntos
Curcumina , Diabetes Mellitus Tipo 2 , Animais , Antioxidantes/farmacologia , Ácido Araquidônico/metabolismo , Biomarcadores , Cromatografia Líquida de Alta Pressão , Curcumina/farmacologia , Fígado/metabolismo , Metabolômica/métodos , Camundongos
4.
Sci Adv ; 8(17): eabn2018, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35486718

RESUMO

Clathrin-mediated endocytosis (CME) is the main mechanism by which mammalian cells control their cell surface proteome. Proper operation of the pivotal CME cargo adaptor AP2 requires membrane-localized Fer/Cip4 homology domain-only proteins (FCHO). Here, live-cell enhanced total internal reflection fluorescence-structured illumination microscopy shows that FCHO marks sites of clathrin-coated pit (CCP) initiation, which mature into uniform-sized CCPs comprising a central patch of AP2 and clathrin corralled by an FCHO/Epidermal growth factor potential receptor substrate number 15 (Eps15) ring. We dissect the network of interactions between the FCHO interdomain linker and AP2, which concentrates, orients, tethers, and partially destabilizes closed AP2 at the plasma membrane. AP2's subsequent membrane deposition drives its opening, which triggers FCHO displacement through steric competition with phosphatidylinositol 4,5-bisphosphate, clathrin, cargo, and CME accessory factors. FCHO can now relocate toward a CCP's outer edge to engage and activate further AP2s to drive CCP growth/maturation.

5.
J Exp Med ; 219(5)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35348580

RESUMO

Type 1 innate lymphoid cells (ILC1s) represent the predominant population of liver ILCs and function as important effectors and regulators of immune responses, but the cellular heterogeneity of ILC1s is not fully understood. Here, single-cell RNA sequencing and flow cytometric analysis demonstrated that liver ILC1s could be dissected into Ly49E+ and Ly49E- populations with unique transcriptional and phenotypic features. Genetic fate-mapping analysis revealed that liver Ly49E+ ILC1s with strong cytotoxicity originated from embryonic non-bone marrow hematopoietic progenitor cells (HPCs), persisted locally during postnatal life, and mediated protective immunity against cytomegalovirus infection in newborn mice. However, Ly49E- ILC1s developed from BM and extramedullary HPCs after birth, gradually replaced Ly49E+ ILC1s in the livers with age, and contained the memory subset in recall response to hapten challenge. Thus, our study shows that Ly49E dissects liver ILC1s into two unique subpopulations, with distinct origins and a bias toward neonatal innate or adult immune memory responses.


Assuntos
Células Matadoras Naturais , Linfócitos , Animais , Células-Tronco Hematopoéticas , Imunidade Inata , Fígado , Camundongos
6.
Protein Cell ; 2022 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-35217990

RESUMO

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.

7.
Cell Death Dis ; 12(11): 1023, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716308

RESUMO

Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.


Assuntos
Tecido Adiposo/metabolismo , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Animais , Cromatina/genética , Proteínas de Ligação a DNA/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Células HEK293 , Humanos , Inflamação/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Obesidade/etiologia , Obesidade/genética , Células RAW 264.7 , Fatores de Transcrição/genética , Transfecção
8.
Cell Rep ; 37(1): 109793, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587478

RESUMO

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Infecções por HIV/sangue , Leucócitos Mononucleares/metabolismo , SARS-CoV-2/imunologia , Sepse/sangue , Transcriptoma , COVID-19/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Análise de Dados , Conjuntos de Dados como Assunto , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Inflamação/sangue , Leucócitos Mononucleares/imunologia , Sepse/imunologia , Análise de Célula Única
9.
Infect Immun ; 89(12): e0029721, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34491790

RESUMO

Human cystic echinococcosis, caused by the larval stage of Echinococcus granulosus sensu lato, has been reported a near-cosmopolitan zoonotic disease. Various infiltrating immune cells gather around the lesion and produce a lesion microenvironment; however, cellular composition and heterogeneity in hepatic cystic echinococcosis lesion microenvironments are incompletely understood. Here, 81,865 immune cells isolated from peripheral blood, perilesion liver tissue, and adjacent normal liver tissue from four cystic echinococcosis patients were profiled using single-cell RNA sequencing. We identified 23 discrete cell populations and found distinct differences in infiltrating immune cells between tissue environments. Despite the significant similarity between perilesion and adjacent normal liver tissue-resident immune cells, the cellular proportions of type 2 innate lymphoid cells (ILC2s) and plasmacytoid dendritic cells (pDCs) were higher in perilesion liver tissue. Interestingly, the immunosuppressive gene NFKBIA was upregulated in these cells. Seven subsets of CD4+ T cell populations were found, and there were more regulatory-CD4+ T cells (Treg-CD4+) and Th2-CD4+ T cells in perilesion tissue than in adjacent normal tissue. There was close contact between CD4+ T cells and ILC2s and pDCs, which caused upregulation of genes related to positive immune activity in adjacent normal liver tissue. However, expression of genes related to immunosuppression, especially the immune inhibitory checkpoint gene NKG2A/HLA-E, was obviously higher in perilesion tissue, suggesting that cellular interaction resulted in an inhibitory microenvironment in the cystic echinococcosis (CE) lesion. This work offers new insights into the transcriptional heterogeneity of infiltrating immune cells in hepatic cystic echinococcosis lesion microenvironments at a single-cell level and provides potential target signatures for diagnosis and immunotherapies.


Assuntos
Microambiente Celular , Suscetibilidade a Doenças , Equinococose Hepática/etiologia , Equinococose Hepática/patologia , Interações Hospedeiro-Parasita , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Microambiente Celular/imunologia , Células Dendríticas , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Imunidade Inata , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Análise de Célula Única
10.
Science ; 373(6555): 700-704, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34353956

RESUMO

Gag, the primary structural protein of HIV-1, is recruited to the plasma membrane for virus assembly by its matrix (MA) domain. Gag is subsequently cleaved into its component domains, causing structural maturation to repurpose the virion for cell entry. We determined the structure and arrangement of MA within immature and mature HIV-1 through cryo-electron tomography. We found that MA rearranges between two different hexameric lattices upon maturation. In mature HIV-1, a lipid extends out of the membrane to bind with a pocket in MA. Our data suggest that proteolytic maturation of HIV-1 not only assembles the viral capsid surrounding the genome but also repurposes the membrane-bound MA lattice for an entry or postentry function and results in the partial removal of up to 2500 lipids from the viral membrane.


Assuntos
Antígenos HIV/química , Antígenos HIV/metabolismo , HIV-1/química , HIV-1/fisiologia , Envelope Viral/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Capsídeo/química , Capsídeo/fisiologia , Tomografia com Microscopia Eletrônica , HIV-1/ultraestrutura , Bicamadas Lipídicas , Lipídeos de Membrana/metabolismo , Modelos Moleculares , Conformação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Envelope Viral/química , Envelope Viral/ultraestrutura , Vírion/química , Vírion/fisiologia , Vírion/ultraestrutura , Montagem de Vírus , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
11.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33834202

RESUMO

The low capture rate of expressed RNAs from single-cell sequencing technology is one of the major obstacles to downstream functional genomics analyses. Recently, a number of imputation methods have emerged for single-cell transcriptome data, however, recovering missing values in very sparse expression matrices remains a substantial challenge. Here, we propose a new algorithm, WEDGE (WEighted Decomposition of Gene Expression), to impute gene expression matrices by using a biased low-rank matrix decomposition method. WEDGE successfully recovered expression matrices, reproduced the cell-wise and gene-wise correlations and improved the clustering of cells, performing impressively for applications with sparse datasets. Overall, this study shows a potent approach for imputing sparse expression matrix data, and our WEDGE algorithm should help many researchers to more profitably explore the biological meanings embedded in their single-cell RNA sequencing datasets. The source code of WEDGE has been released at https://github.com/QuKunLab/WEDGE.


Assuntos
Algoritmos , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , RNA-Seq/métodos , Análise de Célula Única/métodos , COVID-19/sangue , COVID-19/genética , COVID-19/virologia , Análise por Conglomerados , Simulação por Computador , Genômica/métodos , Humanos , Leucócitos Mononucleares/classificação , Leucócitos Mononucleares/metabolismo , Reprodutibilidade dos Testes , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
12.
BMC Biol ; 19(1): 79, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863328

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that involves a variety of cell types. However, how the epigenetic dysregulations of peripheral immune cells contribute to the pathogenesis of RA still remains largely unclear. RESULTS: Here, we analysed the genome-wide active DNA regulatory elements of four major immune cells, namely monocytes, B cells, CD4+ T cells and CD8+ T cells, in peripheral blood of RA patients, osteoarthritis (OA) patients and healthy donors using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq). We found a strong RA-associated chromatin dysregulation signature in monocytes, but no other examined cell types. Moreover, we found that serum C-reactive protein (CRP) can induce the RA-associated chromatin dysregulation in monocytes via in vitro experiments. And the extent of this dysregulation was regulated through the transcription factor FRA2. CONCLUSIONS: Together, our study revealed a CRP-induced pathogenic chromatin dysregulation signature in monocytes from RA patients and predicted the responsible signalling pathway as potential therapeutic targets for the disease.


Assuntos
Artrite Reumatoide , Cromatina , Artrite Reumatoide/genética , Linfócitos T CD8-Positivos , Epigenômica , Humanos , Monócitos
13.
G3 (Bethesda) ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33787873

RESUMO

Unsupervised clustering is a fundamental step of single-cell RNA sequencing data analysis. This issue has inspired several clustering methods to classify cells in single-cell RNA sequencing data. However, accurate prediction of the cell clusters remains a substantial challenge. In this study, we propose a new algorithm for single-cell RNA sequencing data clustering based on Sparse Optimization and low-rank matrix factorization (scSO). We applied our scSO algorithm to analyze multiple benchmark datasets and showed that the cluster number predicted by scSO was close to the number of reference cell types and that most cells were correctly classified. Our scSO algorithm is available at https://github.com/QuKunLab/scSO. Overall, this study demonstrates a potent cell clustering approach that can help researchers distinguish cell types in single-cell RNA sequencing data.

14.
Genome Med ; 13(1): 49, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771202

RESUMO

BACKGROUND: T cells generated from thymopoiesis are essential for the immune system, and recent single-cell studies have contributed to our understanding of the development of thymocytes at the genetic and epigenetic levels. However, the development of double-positive (DP) T cells, which comprise the majority of thymocytes, has not been well investigated. METHODS: We applied single-cell sequencing to mouse thymocytes and analyzed the transcriptome data using Seurat. By applying unsupervised clustering, we defined thymocyte subtypes and validated DP cell subtypes by flow cytometry. We classified the cell cycle phases of each cell according to expression of cell cycle phase-specific genes. For immune synapse detection, we used immunofluorescent staining and ImageStream-based flow cytometry. We studied and integrated human thymocyte data to verify the conservation of our findings and also performed cross-species comparisons to examine species-specific gene regulation. RESULTS: We classified blast, rearrangement, and selection subtypes of DP thymocytes and used the surface markers CD2 and Ly6d to identify these subtypes by flow cytometry. Based on this new classification, we found that the proliferation of blast DP cells is quite different from that of double-positive cells and other cell types, which tend to exit the cell cycle after a single round. At the DP cell selection stage, we observed that CD8-associated immune synapses formed between thymocytes, indicating that CD8sp selection occurred among thymocytes themselves. Moreover, cross-species comparison revealed species-specific transcription factors (TFs) that contribute to the transcriptional differences of thymocytes from humans and mice. CONCLUSIONS: Our study classified DP thymocyte subtypes of different developmental stages and provided new insight into the development of DP thymocytes at single-cell resolution, furthering our knowledge of the fundamental immunological process of thymopoiesis.


Assuntos
Análise de Célula Única , Timócitos/citologia , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD/metabolismo , Ciclo Celular , Humanos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Especificidade da Espécie , Timócitos/metabolismo , Timo/citologia , Fatores de Transcrição/metabolismo , Transcrição Genética , Transcriptoma/genética
15.
Cell Discov ; 7(1): 1, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33390590

RESUMO

Maintaining homeostasis of the decidual immune microenvironment at the maternal-fetal interface is essential for placentation and reproductive success. Although distinct decidual immune cell subpopulations have been identified under normal conditions, systematic understanding of the spectrum and heterogeneity of leukocytes under recurrent miscarriage in human deciduas remains unclear. To address this, we profiled the respective transcriptomes of 18,646 primary human decidual immune cells isolated from patients with recurrent pregnancy loss (RPL) and healthy controls at single-cell resolution. We discovered dramatic differential distributions of immune cell subsets in RPL patients compared with the normal decidual immune microenvironment. Furthermore, we found a subset of decidual natural killer (NK) cells that support embryo growth were diminished in proportion due to abnormal NK cell development in RPL patients. We also elucidated the altered cellular interactions between the decidual immune cell subsets in the microenvironment and those of the immune cells with stromal cells and extravillous trophoblast under disease state. These results provided deeper insights into the RPL decidual immune microenvironment disorder that are potentially applicable to improve the diagnosis and therapeutics of this disease.

16.
Sci Total Environ ; 753: 142439, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33207477

RESUMO

Cross-regional transport potentially contributes to PM2.5 nitrate (pNO3), and this can occur as indirect transport, through which pNO3 precursors are transported to targeted regions, wherein they subsequently react with locally emitted ones to produce pNO3. However, the process has been rarely studied, which limits its comprehensive understanding. We applied the CMAQ model to study the contributions and mechanisms of pNO3 transport during autumn in the Pearl River Delta (PRD), a metropolitan region under the growing influence of cross-regional transport on PM2.5 pollution. Results showed that cross-regional transport contributed to 58% pNO3 monthly in the PRD, and this mostly occurred as indirect transport contributions (accounting for 43% among all contributions). For the first time, we identified the mechanism of indirect pNO3 transport in the PRD, which mainly involves transported O3 and locally emitted NOx reacting to produce pNO3 through N2O5 heterogeneous hydrolysis. pNO3 contributions in different periods and regions indicated differences in the indirect transport contributions to N2O5 heterogeneous hydrolysis under varying O3 availability conditions, which are determined by wind fields and the intensity of NOx emissions. On the regional scale, the pNO3 level is controlled by both transported O3 and local NOx emissions, but pNO3 sensitivity to these two precursors varies among cities. This study demonstrates the notable effect and complex process of cross-regional pNO3 transport in the PRD. Considering the important role of transported O3 for pNO3, O3 reduction within a larger scale is required to achieve PM2.5 pollution control target.

18.
Nat Commun ; 11(1): 5843, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203843

RESUMO

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.


Assuntos
Cromatina/metabolismo , Células de Langerhans/patologia , Escleroderma Sistêmico/patologia , Pele/patologia , Estudos de Casos e Controles , Comunicação Celular , Cromatina/genética , Epigenoma , Fibrose , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Pele/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição
19.
BMC Med Genomics ; 13(1): 163, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33138824

RESUMO

BACKGROUND: The goal of our study is to investigate whether the methylation levels of AHCY and CBS promoters are related to the risk of cerebral infarction by detecting the methylation level of AHCY and CBS genes. METHODS: We extracted peripheral venous blood from 152 patients with cerebral infarction and 152 gender- and age-matched healthy controls, and determined methylation levels of AHCY and CBS promoters using quantitative methylation-specific polymerase chain reaction. We used the percentage of methylation reference (PMR) to indicate gene methylation level. RESULTS: We compared the promoter methylation levels of two genes (AHCY and CBS) in peripheral blood DNA between the cerebral infarction case group and the control group. Our study showed no significant difference in AHCY promoter methylation between case and control. Subgroup analysis by gender showed that the methylation level of AHCY in males in the case group was lower than that in the control group, but the difference was not statistically significant in females. In a subgroup analysis by age, there was no significant difference in the AHCY methylation level between the case and control in the young group (≤44 years old). However, the level of AHCY gene methylation in the middle-aged group (45-59 years old) was significantly higher and the aged group (≥60 years old) was significantly lower than that in the control groups. However, CBS promoter methylation levels were significantly lower in the case group than in the control group (median PMR: 70.20% vs 104.10%, P = 3.71E-10). In addition, the CBS methylation levels of males and females in the case group were significantly lower than those in the control group (male: 64.33% vs 105%, P = 2.667E-08; female: 78.05% vs 102.8%, P = 0.003). We also found that the CBS levels in the young (23-44), middle-aged (45-59), and older (60-90) groups were significantly lower than those in the control group (young group: 69.97% vs 114.71%; P = 0.015; middle-aged group: 56.04% vs 91.71%; P = 6.744E-06; older group: 81.6% vs 119.35%; P = 2.644E-04). Our ROC curve analysis of CBS hypomethylation showed an area under the curve of 0.713, a sensitivity of 67.4%, and a specificity of 74.0%. CONCLUSION: Our study suggests that hypomethylation of the CBS promoter may be closely related to the risk of cerebral infarction and may be used as a non-invasive diagnostic biomarker for cerebral infarction.


Assuntos
Adenosil-Homocisteinase/genética , Infarto Cerebral/diagnóstico , Cistationina beta-Sintase/genética , Metilação de DNA , Regiões Promotoras Genéticas , Adulto , Estudos de Casos e Controles , Infarto Cerebral/epidemiologia , Infarto Cerebral/genética , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC
20.
Nature ; 587(7834): 495-498, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32908308

RESUMO

Influenza A virus causes millions of severe cases of disease during annual epidemics. The most abundant protein in influenza virions is matrix protein 1 (M1), which mediates virus assembly by forming an endoskeleton beneath the virus membrane1. The structure of full-length M1, and how it oligomerizes to mediate the assembly of virions, is unknown. Here we determine the complete structure of assembled M1 within intact virus particles, as well as the structure of M1 oligomers reconstituted in vitro. We find that the C-terminal domain of M1 is disordered in solution but can fold and bind in trans to the N-terminal domain of another M1 monomer, thus polymerizing M1 into linear strands that coat the interior surface of the membrane of the assembling virion. In the M1 polymer, five histidine residues-contributed by three different monomers of M1-form a cluster that can serve as the pH-sensitive disassembly switch after entry into a target cell. These structures therefore reveal mechanisms of influenza virus assembly and disassembly.


Assuntos
Microscopia Crioeletrônica , Vírus da Influenza A Subtipo H3N2/química , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/ultraestrutura , Animais , Cães , Células HEK293 , Histidina , Humanos , Concentração de Íons de Hidrogênio , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A Subtipo H3N2/ultraestrutura , Células Madin Darby de Rim Canino , Modelos Moleculares , Proteínas da Matriz Viral/metabolismo , Vírion/química , Vírion/metabolismo , Vírion/ultraestrutura
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