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1.
Cell Stem Cell ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34879244

RESUMO

The hypothalamus comprises various nuclei and neuronal subpopulations that control fundamental homeostasis and behaviors. However, spatiotemporal molecular characterization of hypothalamus development in humans is largely unexplored. Here, we revealed spatiotemporal transcriptome profiles and cell-type characteristics of human hypothalamus development and illustrated the molecular diversity of neural progenitors and the cell-fate decision, which is programmed by a combination of transcription factors. Different neuronal and glial fates are sequentially produced and showed spatial developmental asynchrony. Moreover, human hypothalamic gliogenesis occurs at an earlier stage of gestation and displays distinctive transcription profiles compared with those in mouse. Notably, early oligodendrocyte cells in humans exhibit different gene patterns and interact with neuronal cells to regulate neuronal maturation by Wnt, Hippo, and integrin signals. Overall, our study provides a comprehensive molecular landscape of human hypothalamus development at early- and mid-embryonic stages and a foundation for understanding its spatial and functional complexity.

3.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657410

RESUMO

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Assuntos
COVID-19/imunologia , Megacariócitos/imunologia , Monócitos/imunologia , RNA Viral , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Célula Única , Transcriptoma/imunologia , Adulto Jovem
4.
Chem Commun (Camb) ; 56(95): 14984-14987, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33150342

RESUMO

The all-vanadium redox flow battery is considered to be a dispersive and non-perennial energy source due to its grid reliability, high efficiency, standalone modular design, and excellent cycling stability. However, the large vanadium ionic size and relatively high viscosity lead to poor compatibility with most carbon-based microporous electrodes, resulting in sluggish mass diffusion and unsatisfied capacitance retention. Herein, a novel cross-coupled porous graphene aerogel is proposed via the NaNO3-template pore engineering strategy. The microscopic observations and N2 adsorption-desorption isotherms validate the successful regulation of the surface area and porous structure, with the addition of different porogen contents (6.25-25 g L-1). The vanadium redox flow battery delivers a specific capacity of 163.4 mA h g-1 (5.6 A h L-1) at a current density of 25 mA cm-2, surpassing most previously reported batteries with a similar reactor volume. This method holds great promise for the better design and preparation of porous electrodes, and potential suitable applications.

5.
Blood ; 136(24): 2774-2785, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-32750113

RESUMO

Although human B cells have been extensively studied, most reports have used peripheral blood as a source. Here, we used a unique tissue resource derived from healthy organ donors to deeply characterize human B-cell compartments across multiple tissues and donors. These datasets revealed that B cells in the blood are not in homeostasis with compartments in other tissues. We found striking donor-to-donor variability in the frequencies and isotype of CD27+ memory B cells (MBCs). A comprehensive antibody-based screen revealed markers of MBC and allowed identification of novel MBC subsets with distinct functions defined according to surface expression of CD69 and CD45RB. We defined a tissue-resident MBC phenotype that was predominant in the gut but absent in blood. RNA-sequencing of MBC subsets from multiple tissues revealed a tissue-resident MBC gene signature as well as gut- and spleen-specific signatures. Overall, these studies provide novel insights into the nature and function of human B-cell compartments across multiple tissues.


Assuntos
Antígenos CD/imunologia , Subpopulações de Linfócitos B/imunologia , Memória Imunológica , Mucosa Intestinal/imunologia , Humanos
6.
Cell ; 180(4): 749-763.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32059780

RESUMO

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.


Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologia
7.
BMC Mol Cell Biol ; 20(1): 20, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253076

RESUMO

BACKGROUND: Classic dendritic cells (cDCs) play a central role in the immune system by processing and presenting antigens to activate T cells, and consist of two major subsets: CD141+ cDC (cDC1) and CD1c+ cDC (cDC2). A population of migratory precursor cells, the pre-cDCs, is the immediate precursors to both cDC subsets. Previous studies showed that there were two pre-committed pre-cDC subpopulations. However, the key molecular drivers of pre-commitment in human pre-cDCs were not investigated. RESULTS: To identify the key molecular drivers for pre-commitment in human pre-cDCs, we performed single cell RNA sequencing (RNA-Seq) of two cDC subsets and pre-cDCs, and bulk RNA-Seq of pre-cDCs and cDCs from human peripheral blood. We found that pre-DC subpopulations cannot be separated by either variable genes within pre-cDCs or differentially expressed genes between cDC1 and cDC2. In contrast, they were separated by 16 transcription factors that are themselves differentially expressed or have regulated targets enriched in the differentially expressed genes between bulk cDC1 and cDC2, with one subpopulation close to cDC1 and the other close to cDC2. More importantly, these two pre-cDC sub-populations are correlated with ratio of IRF8 to IRF4 expression level more than their individual expression level. We also verified these findings using three recently published datasets. CONCLUSIONS: In this study, we demonstrate that single cell transcriptome profiling can reveal pre-cDCs differentiation map, and our results suggest the concept that combinatorial dose of transcription factors determines cell differentiation fate.


Assuntos
Diferenciação Celular/genética , Células Dendríticas/citologia , Fatores Reguladores de Interferon/genética , RNA-Seq , Transcriptoma , Análise de Variância , Antígenos CD1/genética , Glicoproteínas/genética , Humanos , Lectinas Tipo C/genética , Receptores Acoplados a Proteínas G/genética , Receptores Mitogênicos/genética , Análise de Célula Única/métodos , Regulação para Cima/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
8.
Bio Protoc ; 8(10): e2851, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285968

RESUMO

The ability to conduct investigation of cellular transcription, signaling, and function at the single-cell level has opened opportunities to examine heterogeneous populations at unprecedented resolutions. Although methods have been developed to evaluate high-dimensional transcriptomic and proteomic data (relating to cellular mRNA and protein), there has not been a method to evaluate corresponding high-dimensional functionomic data (relating to cellular functions) from single cells. Here, we present a protocol to quantitatively measure the differentiation potentials of single human hematopoietic stem and progenitor cells, and then cluster the cells according to these measurements. High dimensional functionomic analysis of cell potential allows cell function to be linked to molecular mechanisms within the same progenitor population.

10.
Cell Rep ; 20(12): 2921-2934, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930685

RESUMO

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69- TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.


Assuntos
Perfilação da Expressão Gênica , Memória Imunológica , Tecido Linfoide/imunologia , Membrana Mucosa/imunologia , Linfócitos T/imunologia , Transcrição Genética , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linhagem da Célula/genética , Células Clonais , Humanos , Lectinas Tipo C/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Fenótipo , Transcriptoma/genética
11.
Nat Immunol ; 18(8): 877-888, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28650480

RESUMO

The origin and specification of human dendritic cells (DCs) have not been investigated at the clonal level. Through the use of clonal assays, combined with statistical computation, to quantify the yield of granulocytes, monocytes, lymphocytes and three subsets of DCs from single human CD34+ progenitor cells, we found that specification to the DC lineage occurred in parallel with specification of hematopoietic stem cells (HSCs) to the myeloid and lymphoid lineages. This started as a lineage bias defined by specific transcriptional programs that correlated with the combinatorial 'dose' of the transcription factors IRF8 and PU.1, which was transmitted to most progeny cells and was reinforced by upregulation of IRF8 expression driven by the hematopoietic cytokine FLT3L during cell division. We propose a model in which specification to the DC lineage is driven by parallel and inheritable transcriptional programs in HSCs and is reinforced over cell division by recursive interactions between transcriptional programs and extrinsic signals.


Assuntos
Linhagem da Célula , Células Dendríticas/citologia , Células-Tronco Hematopoéticas/citologia , Fatores Reguladores de Interferon/metabolismo , Leucopoese , Células-Tronco Multipotentes/citologia , Animais , Diferenciação Celular , Sangue Fetal , Citometria de Fluxo , Humanos , Fatores Reguladores de Interferon/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Análise de Componente Principal , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Regulação para Cima
12.
Nat Commun ; 7: 12824, 2016 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-27670201

RESUMO

Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression-this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify FGFBP2, LBH, RBFOX2, SGSM1 and ZBTB16 as candidate CHD genes because of significantly altered transcriptional expression.


Assuntos
Cardiopatias Congênitas/metabolismo , RNA/metabolismo , Adolescente , Adulto , Idoso , Alelos , Aorta/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Feto , Expressão Gênica , Estudos de Associação Genética , Impressão Genômica , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Miocárdio/metabolismo , Artéria Pulmonar/metabolismo , Adulto Jovem
13.
Tsinghua Sci Technol ; 19(6): 559-567, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-26221066

RESUMO

Protein structure Quality Assessment (QA) is an essential component in protein structure prediction and analysis. The relationship between protein sequence and structure often serves as a basis for protein structure QA. In this work, we developed a new Hidden Markov Model (HMM) to assess the compatibility of protein sequence and structure for capturing their complex relationship. More specifically, the emission of the HMM consists of protein local structures in angular space, secondary structures, and sequence profiles. This model has two capabilities: (1) encoding local structure of each position by jointly considering sequence and structure information, and (2) assigning a global score to estimate the overall quality of a predicted structure, as well as local scores to assess the quality of specific regions of a structure, which provides useful guidance for targeted structure refinement. We compared the HMM model to state-of-art single structure quality assessment methods OPUSCA, DFIRE, GOAP, and RW in protein structure selection. Computational results showed our new score HMM.Z can achieve better overall selection performance on the benchmark datasets.

14.
J Comput Biol ; 20(10): 765-79, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24093228

RESUMO

Conformational changes frequently occur when proteins interact with other proteins. How to detect such changes in silico is a major problem. Existing methods for docking with conformational changes remain time-consuming, and they solve only a small portion of protein complexes accurately. This work presents a more accurate method (FlexDoBi) for docking with conformational changes. FlexDoBi generates the possible conformational changes of the interface residues that transform the proteins from their unbound states to bound states. Based on the generated conformational changes, multidimensional scaling is performed to construct candidates for the bound structure. We develop a new energy item for determining the orientation of docking subunits and selecting of plausible conformational changes. Experimental results illustrate that FlexDoBi achieves better results. On 20 complexes, we obtained an average iRMSD of 1.55Å, which compares favorably with the average iRMSD of 1.94Å for FiberDock. Compared to ZDOCK, our results are of 0.27Å less in average iRMSD of the medium difficulty group.


Assuntos
Simulação de Acoplamento Molecular , Subunidades Proteicas/química , Software , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Termodinâmica
15.
Biochim Biophys Acta ; 1824(12): 1418-24, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22771297

RESUMO

With the development of high-throughput methods for identifying protein-protein interactions, large scale interaction networks are available. Computational methods to analyze the networks to detect functional modules as protein complexes are becoming more important. However, most of the existing methods only make use of the protein-protein interaction networks without considering the structural limitations of proteins to bind together. In this paper, we design a new protein complex prediction method by extending the idea of using domain-domain interaction information. Here we formulate the problem into a maximum matching problem (which can be solved in polynomial time) instead of the binary integer linear programming approach (which can be NP-hard in the worst case). We also add a step to predict domain-domain interactions which first searches the database Pfam using the hidden Markov model and then predicts the domain-domain interactions based on the database DOMINE and InterDom which contain confirmed DDIs. By adding the domain-domain interaction prediction step, we have more edges in the DDI graph and the recall value is increased significantly (at least doubled) comparing with the method of Ozawa et al. (2010) [1] while the average precision value is slightly better. We also combine our method with three other existing methods, such as COACH, MCL and MCODE. Experiments show that the precision of the combined method is improved. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction.


Assuntos
Complexos Multiproteicos/química , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas/métodos , Algoritmos , Biologia Computacional , Cadeias de Markov , Proteínas/química
16.
Artigo em Inglês | MEDLINE | ID: mdl-22025760

RESUMO

The fundamental problem in linkage analysis is to identify regions whose allele is shared by all or almost all affected members but by none or few unaffected members. Almost all the existing methods for linkage analysis are for families with clearly given pedigrees. Little work has been done for the case where the sampled individuals are closely related, but their pedigree is not known. This situation occurs very often when the individuals share a common ancestor at least six generations ago. Solving this case will tremendously extend the use of linkage analysis for finding genes that cause genetic diseases. In this paper, we propose a mathematical model (the shared center problem) for inferring the allele-sharing status of a given set of individuals using a database of confirmed haplotypes as reference. We show the NP-completeness of the shared center problem and present a ratio-2 polynomial-time approximation algorithm. We then convert the approximation algorithm into a heuristic algorithm for the shared center problem. Based on this heuristic, we finally design a heuristic algorithm for mutation region detection. We further implement the algorithms to obtain a software package. Our experimental data shows that the software works very well. The package is available at http://www.cs.cityu.edu.hk/~lwang/software/LDWP/index.html for non-commercial use.


Assuntos
Algoritmos , Biologia Computacional/métodos , Ligação Genética/genética , Haplótipos/genética , Mutação/genética , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Software
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