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1.
Nature ; 597(7875): 196-205, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497388

RESUMO

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.


Assuntos
Movimento Celular , Rastreamento de Células , Células/citologia , Biologia do Desenvolvimento/métodos , Embrião de Mamíferos/citologia , Feto/citologia , Disseminação de Informação , Organogênese , Adulto , Animais , Atlas como Assunto , Técnicas de Cultura de Células , Sobrevivência Celular , Visualização de Dados , Feminino , Humanos , Imageamento Tridimensional , Masculino , Modelos Animais , Organogênese/genética , Organoides/citologia , Células-Tronco/citologia
2.
iScience ; : 103115, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34522848

RESUMO

Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity.

3.
Am J Hum Genet ; 108(9): 1765-1779, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450030

RESUMO

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.


Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Locos de Características Quantitativas , Transcriptoma , Bancos de Espécimes Biológicos , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colo/metabolismo , Colo/patologia , Colo/cirurgia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Prognóstico , Medição de Risco , Reino Unido
4.
JCO Clin Cancer Inform ; 5: 881-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34428097

RESUMO

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. This consortium has regularly held topic-focused biannual face-to-face symposiums. These meetings are a place to review cancer informatics and data science priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues that we faced at our respective institutions and cancer centers. Here, we provide meeting highlights from the latest CI4CC Symposium, which was delayed from its original April 2020 schedule because of the COVID-19 pandemic and held virtually over three days (September 24, October 1, and October 8) in the fall of 2020. In addition to the content presented, we found that holding this event virtually once a week for 6 hours was a great way to keep the kind of deep engagement that a face-to-face meeting engenders. This is the second such publication of CI4CC Symposium highlights, the first covering the meeting that took place in Napa, California, from October 14-16, 2019. We conclude with some thoughts about using data science to learn from every child with cancer, focusing on emerging activities of the National Cancer Institute's Childhood Cancer Data Initiative.


Assuntos
COVID-19 , Informática Médica , Neoplasias , Adolescente , Criança , Ciência de Dados , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias , SARS-CoV-2 , Adulto Jovem
5.
JAMA Netw Open ; 4(6): e2112596, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115127

RESUMO

Importance: Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients. Objective: To describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19. Design, Setting, and Participants: This retrospective cohort study included pediatric patients hospitalized between February 2 and October 10, 2020. Patient-level electronic health record (EHR) data were collected across 27 hospitals in France, Germany, Spain, Singapore, the UK, and the US. Patients younger than 21 years who tested positive for COVID-19 and were hospitalized at an institution participating in the Consortium for Clinical Characterization of COVID-19 by EHR were included in the study. Main Outcomes and Measures: Patient characteristics, clinical features, and medication use. Results: There were 347 males (52%; 95% CI, 48.5-55.3) and 324 females (48%; 95% CI, 44.4-51.3) in this study's cohort. There was a bimodal age distribution, with the greatest proportion of patients in the 0- to 2-year (199 patients [30%]) and 12- to 17-year (170 patients [25%]) age range. Trends in hospitalizations for 671 children and youth found discrete surges with variable timing across 6 countries. Data from this cohort mirrored national-level pediatric hospitalization trends for most countries with available data, with peaks in hospitalizations during the initial spring surge occurring within 23 days in the national-level and 4CE data. A total of 27 364 laboratory values for 16 laboratory tests were analyzed, with mean values indicating elevations in markers of inflammation (C-reactive protein, 83 mg/L; 95% CI, 53-112 mg/L; ferritin, 417 ng/mL; 95% CI, 228-607 ng/mL; and procalcitonin, 1.45 ng/mL; 95% CI, 0.13-2.77 ng/mL). Abnormalities in coagulation were also evident (D-dimer, 0.78 ug/mL; 95% CI, 0.35-1.21 ug/mL; and fibrinogen, 477 mg/dL; 95% CI, 385-569 mg/dL). Cardiac troponin, when checked (n = 59), was elevated (0.032 ng/mL; 95% CI, 0.000-0.080 ng/mL). Common complications included cardiac arrhythmias (15.0%; 95% CI, 8.1%-21.7%), viral pneumonia (13.3%; 95% CI, 6.5%-20.1%), and respiratory failure (10.5%; 95% CI, 5.8%-15.3%). Few children were treated with COVID-19-directed medications. Conclusions and Relevance: This study of EHRs of children and youth hospitalized for COVID-19 in 6 countries demonstrated variability in hospitalization trends across countries and identified common complications and laboratory abnormalities in children and youth with COVID-19 infection. Large-scale informatics-based approaches to integrate and analyze data across health care systems complement methods of disease surveillance and advance understanding of epidemiological and clinical features associated with COVID-19 in children and youth.


Assuntos
COVID-19/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Pandemias , SARS-CoV-2 , Adolescente , Criança , Pré-Escolar , Feminino , Saúde Global , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
6.
Sci Rep ; 11(1): 9905, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972602

RESUMO

The COVID-19 pandemic has affected African American populations disproportionately with respect to prevalence, and mortality. Expression profiles represent snapshots of combined genetic, socio-environmental (including socioeconomic and environmental factors), and physiological effects on the molecular phenotype. As such, they have potential to improve biological understanding of differences among populations, and provide therapeutic biomarkers and environmental mitigation strategies. Here, we undertook a large-scale assessment of patterns of gene expression between African Americans and European Americans, mining RNA-Seq data from 25 non-diseased and diseased (tumor) tissue-types. We observed the widespread enrichment of pathways implicated in COVID-19 and integral to inflammation and reactive oxygen stress. Chemokine CCL3L3 expression is up-regulated in African Americans. GSTM1, encoding a glutathione S-transferase that metabolizes reactive oxygen species and xenobiotics, is upregulated. The little-studied F8A2 gene is up to 40-fold more highly expressed in African Americans; F8A2 encodes HAP40 protein, which mediates endosome movement, potentially altering the cellular response to SARS-CoV-2. African American expression signatures, superimposed on single cell-RNA reference data, reveal increased number or activity of esophageal glandular cells and lung ACE2-positive basal keratinocytes. Our findings establish basal prognostic signatures that can be used to refine approaches to minimize risk of severe infection and improve precision treatment of COVID-19 for African Americans. To enable dissection of causes of divergent molecular phenotypes, we advocate routine inclusion of metadata on genomic and socio-environmental factors for human RNA-sequencing studies.


Assuntos
Afro-Americanos/genética , COVID-19/genética , Grupo com Ancestrais do Continente Europeu/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , COVID-19/epidemiologia , COVID-19/virologia , Quimiocina CCL3/genética , Redes Reguladoras de Genes , Glutationa Transferase/genética , Humanos , Neoplasias/classificação , Neoplasias/etnologia , Proteínas Nucleares/genética , Pandemias , Prognóstico , RNA-Seq/métodos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Fatores Socioeconômicos , Estados Unidos/epidemiologia
7.
Proc Natl Acad Sci U S A ; 118(22)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34035170

RESUMO

Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and additionally predispose to multiple other neurodevelopmental disorders. Engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multicenter effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. Using neurons transdifferentiated from induced pluripotent stem cells that were derived from schizophrenia patients carrying heterozygous NRXN1 deletions, we observed the same synaptic impairment as in engineered NRXN1-deficient neurons. This impairment manifested as a large decrease in spontaneous synaptic events, in evoked synaptic responses, and in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. Human NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene-expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

8.
Dev Med Child Neurol ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33768551

RESUMO

AIM: To characterize the patterns of care of children with cerebral palsy (CP) in a tertiary healthcare system. METHOD: Electronic health record data from 2009 to 2019 were extracted for children with CP. Machine learning hierarchical clustering was used to identify clusters of care. The ratio of in-person to care coordination visits was calculated for each specialty. RESULTS: The sample included 6369 children with CP (55.7% males, 44.3% females, 76.2% white, 94.7% non-Hispanic; with a mean age of 8y 2mo [SD 5y 10mo; range 0-21y; median 7y 1mo]) at the time of diagnosis. A total of 3.7 million in-person visits and care coordination notes were identified across 34 specialties. The duration of care averaged 5 years 5 months with five specialty interactions and 21.8 in-person visits per year per child. Seven clusters of care were identified, including: musculoskeletal and function; neurological; high-frequency/urgent care services; procedures; comorbid diagnoses; development and behavioral; and primary care. Network analysis showed shared membership among several clusters. INTERPRETATION: Coordination of care is a central element for children with CP. Medical informatics, machine learning, and big data approaches provide unique insights into care delivery to inform approaches to improve outcomes for children with CP.

9.
J Med Internet Res ; 23(3): e22219, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33600347

RESUMO

Coincident with the tsunami of COVID-19-related publications, there has been a surge of studies using real-world data, including those obtained from the electronic health record (EHR). Unfortunately, several of these high-profile publications were retracted because of concerns regarding the soundness and quality of the studies and the EHR data they purported to analyze. These retractions highlight that although a small community of EHR informatics experts can readily identify strengths and flaws in EHR-derived studies, many medical editorial teams and otherwise sophisticated medical readers lack the framework to fully critically appraise these studies. In addition, conventional statistical analyses cannot overcome the need for an understanding of the opportunities and limitations of EHR-derived studies. We distill here from the broader informatics literature six key considerations that are crucial for appraising studies utilizing EHR data: data completeness, data collection and handling (eg, transformation), data type (ie, codified, textual), robustness of methods against EHR variability (within and across institutions, countries, and time), transparency of data and analytic code, and the multidisciplinary approach. These considerations will inform researchers, clinicians, and other stakeholders as to the recommended best practices in reviewing manuscripts, grants, and other outputs from EHR-data derived studies, and thereby promote and foster rigor, quality, and reliability of this rapidly growing field.


Assuntos
COVID-19/epidemiologia , Coleta de Dados/métodos , Registros Eletrônicos de Saúde , Coleta de Dados/normas , Humanos , Revisão da Pesquisa por Pares/normas , Editoração/normas , Reprodutibilidade dos Testes , SARS-CoV-2/isolamento & purificação
10.
Clin Transl Sci ; 14(2): 518-528, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33048460

RESUMO

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFß1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFß1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.

11.
J Crohns Colitis ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770196

RESUMO

BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

12.
Proc Natl Acad Sci U S A ; 117(9): 4921-4930, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071223

RESUMO

Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2 -) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Ácido Edético/farmacologia , Nitrito de Sódio/farmacologia , Animais , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Farmacorresistência Bacteriana/efeitos dos fármacos , Ácido Edético/química , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Redes e Vias Metabólicas , Camundongos , Nitritos/química , Nitritos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos
13.
Blood Adv ; 3(9): 1519-1532, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31076408

RESUMO

Sickle cell anemia (SCA) is caused by a point mutation in the ß-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative organ damage resulting in death. SCA patients show coagulation activation and inflammation even in the absence of vascular occlusion. The coagulation factor fibrinogen is not only central to hemostasis but also plays important roles in pathologic inflammatory processes, in part by engaging neutrophils/macrophages through the αMß2 integrin receptor. To determine whether fibrin(ogen)-mediated inflammation is a driver of SCA-associated pathologies, hematopoietic stem cells from Berkeley sickle mice were transplanted into homozygous Fibγ390-396A mice that express normal levels of a mutant form of fibrin(ogen) that does not engage αMß2 Fibγ390-396A mice with SCA displayed an impressive reduction of reactive oxygen species (ROS) in white blood cells (WBCs), decreased circulating inflammatory cytokines/chemokines, and significantly improved SCA-associated glomerular pathology highlighted by reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hypercellularity, and glomerular enlargement. In addition, Fibγ390-396A mice with SCA had improved glomerular protective responses and podocyte/mesangial transcriptional signatures that resulted in reduced albuminuria. Interestingly, the fibrinogen γ390-396A mutation had a negligible effect on cardiac, lung, and liver functions and pathologies in the context of SCA over a year-long observation period. Taken together, our data support that fibrinogen significantly contributes to WBC-driven inflammation and ROS production, which is a key driver of SCA-associated glomerulopathy, and may represent a novel therapeutic target against irreversible kidney damage in SCA.


Assuntos
Anemia Falciforme/patologia , Fibrinogênio/metabolismo , Rim/patologia , Antígeno de Macrófago 1/metabolismo , Motivos de Aminoácidos , Animais , Sítios de Ligação , Transplante de Medula Óssea , Quimiocinas/sangue , Creatinina/sangue , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Fibrinogênio/química , Fibrinogênio/genética , Leucócitos/citologia , Leucócitos/metabolismo , Antígeno de Macrófago 1/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese , Espécies Reativas de Oxigênio/metabolismo
14.
Nature ; 569(7755): E3, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31019298

RESUMO

In this Letter, the first name of author Virendra K. Chaudhri was incorrectly spelled 'Viren'; author Meenakshi Venkatasubramanian should also be associated with 'Department of Electrical Engineering and Computer Science, University of Cincinnati, Cincinnati, Ohio 45221, USA'; authors Bruce J. Aronow, Nathan Salomonis, Harinder Singh and H. Leighton Grimes should also be associated with 'Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA'. The Letter has not been corrected online.

15.
Dev Cell ; 49(1): 10-29, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30930166

RESUMO

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.


Assuntos
Desenvolvimento Embrionário/genética , Redes Reguladoras de Genes/genética , Pediatria/tendências , Análise de Célula Única/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Distribuição Tecidual/genética
16.
Cell Stem Cell ; 24(5): 707-723.e8, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982771

RESUMO

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.


Assuntos
Glioma/genética , Células-Tronco Neoplásicas/fisiologia , Neuroglia/fisiologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Células-Tronco/fisiologia , Transcriptoma/genética , Animais , Biodiversidade , Fator 1 de Resposta a Butirato/genética , Carcinogênese , Diferenciação Celular , Reprogramação Celular , Desenvolvimento Fetal , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout
17.
J Clin Invest ; 129(5): 2014-2028, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30958799

RESUMO

T cell heterogeneity is highly relevant to allergic disorders. We resolved the heterogeneity of human tissue CD3+ T cells during allergic inflammation, focusing on a tissue-specific allergic disease, eosinophilic esophagitis (EoE). We investigated 1088 single T cells derived from patients with a spectrum of disease activity. Eight disparate tissue T cell subtypes (designated T1-T8) were identified, with T7 and T8 enriched in the diseased tissue. The phenotypes of T7 and T8 resemble putative Treg (FOXP3+) and effector Th2-like (GATA3+) cells, respectively. Prodigious levels of IL-5 and IL-13 were confined to HPGDS+ CRTH2+IL-17RB+FFAR3+CD4+ T8 effector Th2 cells. EoE severity closely paralleled a lipid/fatty acid-induced activation node highlighted by the expression of the short-chain fatty acid receptor FFAR3. Ligands for FFAR3 induced Th2 cytokine production from human and murine T cells, including in an in vivo allergy model. Therefore, we elucidated the defining characteristics of tissue-residing CD3+ T cells in EoE, a specific enrichment of CD4+ Treg and effector Th2 cells, confinement of type 2 cytokine production to the CD4+ effector population, a highly likely role for FFAR3 in amplifying local Th2 responses in EoE, and a resource to further dissect tissue lymphocytes and allergic responses.


Assuntos
Esofagite Eosinofílica/genética , Esofagite Eosinofílica/imunologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Linfócitos T/imunologia , Adolescente , Animais , Biópsia , Complexo CD3/análise , Separação Celular , Criança , Pré-Escolar , Biologia Computacional , Endoscopia , Feminino , Citometria de Fluxo , Fator de Transcrição GATA3/imunologia , Humanos , Inflamação , Interleucina-13/imunologia , Interleucina-5/imunologia , Ligantes , Pulmão/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fenótipo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
18.
Nat Commun ; 10(1): 38, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604764

RESUMO

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4ß7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.


Assuntos
Colite Ulcerativa/genética , Genes Mitocondriais/genética , Mucosa Intestinal/metabolismo , Doenças Mitocondriais/genética , Transcriptoma/genética , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Fezes/microbiologia , Feminino , Perfilação da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Integrinas/antagonistas & inibidores , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Microbiota , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/microbiologia , Doenças Mitocondriais/patologia , Medicina de Precisão/métodos , Estudos Prospectivos , Reto/metabolismo , Reto/microbiologia , Reto/patologia , Indução de Remissão/métodos , Análise de Sequência de RNA , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
19.
Data Brief ; 22: 365-372, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30596133

RESUMO

This data is a curated collection of visual images of gene expression patterns from the pre- and post-natal mouse lung, accompanied by associated mRNA probe sequences and RNA-Seq expression profiles. Mammalian lungs undergo significant growth and cellular differentiation before and after the transition to breathing air. Documenting normal lung development is an important step in understanding abnormal lung development, as well as the challenges faced during a preterm birth. Images in this dataset indicate the spatial distribution of mRNA transcripts for over 500 different genes that are active during lung development, as initially determined via RNA-Seq. Images were systematically acquired using high-throughput in situ hybridization with non-radioactive digoxigenin-labeled mRNA probes across mouse lungs from developmental time points E16.5, E18.5, P7, and P28. The dataset was produced as part of The Molecular Atlas of Lung Development Program (LungMAP) and is hosted at https://lungmap.net. This manuscript describes the nature of the data and the protocols for generating the dataset.

20.
Inflamm Bowel Dis ; 25(3): 547-560, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30124884

RESUMO

BACKGROUND: Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS: Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS: We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS: Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.


Assuntos
Doença de Crohn/patologia , Subunidade beta Comum dos Receptores de Citocinas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Mutação de Sentido Incorreto , Neutrófilos/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/genética , Doença de Crohn/metabolismo , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Lactente , Masculino , Neutrófilos/metabolismo , Prognóstico , Adulto Jovem
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