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Introduction: The Statistics Canada Biobank (Biobank) is a valuable source of nationally representative health information. It contains biospecimens collected from the Canadian Health Measures Survey (CHMS) and the Canadian COVID-19 Antibody and Health Survey (CCAHS). Both surveys are voluntary and aim to collect a variety of important health information from Canadians to create nationally representative estimates. This information is collected through questionnaires, physical measures, and self-administered sample collection. Biospecimens collected as part of the CHMS and CCAHS from consenting participants include whole blood, plasma, serum, urine, DNA samples, and dried blood spots. These samples are stored as part of the Biobank for future health research. Canadian researchers can apply to the Biobank program to use this nationally representative source of biospecimens. Results obtained from their research can also be combined with a wide variety of health and lifestyle information collected as part of the CHMS and CCAHS, making the Biobank a rich source of health-related information that can fill data gaps on the health concerns that are important to Canadians. This data resource profile provides an overview of the Biobank to inform researchers and data users about the program and how it can be used as a resource for the advancement of health-related research.
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Bancos de Espécimes Biológicos , COVID-19 , Humanos , Canadá/epidemiologia , COVID-19/epidemiologia , Inquéritos Epidemiológicos , Estilo de VidaRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells. However, the mechanisms underlying alterations in energy production have not been identified. METHODS: Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and patients with idiopathic PAH to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from patients with PAH, the downregulation of microRNA-124 (miR-124), determined with a tiered systems biology approach, is responsible for increased expression of the splicing factor PTBP1 (polypyrimidine tract binding protein), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells. RESULTS: Heritable PAH and idiopathic PAH BOECs recapitulated the metabolic abnormalities observed in pulmonary artery endothelial cells from patients with idiopathic PAH, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124 or siRNA silencing of PTPB1 restored normal proliferation and glycolysis in heritable PAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration. BMPR2 knockdown in control BOECs reduced the expression of miR-124, increased PTPB1, and enhanced glycolysis. Moreover, we observed reduced miR-124, increased PTPB1 and PKM2 expression, and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced BMPR2 expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo. CONCLUSIONS: Pulmonary vascular and circulating progenitor endothelial cells isolated from patients with PAH demonstrate downregulation of miR-124, leading to the metabolic and proliferative abnormalities in PAH ECs via PTPB1 and PKM1/PKM2. Therefore, the manipulation of this miRNA or its targets could represent a novel therapeutic approach for the treatment of PAH.
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Hipertensão Pulmonar Primária Familiar/patologia , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , MicroRNAs/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Piruvato Quinase/metabolismo , Animais , Antagomirs/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/metabolismo , Glicólise , Ribonucleoproteínas Nucleares Heterogêneas/antagonistas & inibidores , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Quinases Lim/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/antagonistas & inibidores , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Piruvato Quinase/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Simportadores/metabolismoRESUMO
Clinical evaluation of patients and diagnosis of disorder is crucial to make decisions on appropriate therapies. In addition, in the case of genetic disorders resulting from gene abnormalities, phenotypic effects may guide basic research on the mechanisms of a disorder to find the mutated gene and therefore to propose novel targets for drug therapy. However, this approach is complicated by two facts. First, the relationship between genes and disorders is not simple: one gene may be related to multiple disorders and a disorder may be caused by mutations in different genes. Second, recognizing relevant phenotypes might be difficult for clinicians working with patients of closely related complex disorders. Neuropsychiatric disorders best illustrate these difficulties since phenotypes range from metabolic to behavioral aspects, the latter extremely complex. Based on our clinical expertise on five neurodegenerative disorders, and from the wealth of bibliographical data on neuropsychiatric disorders, we have built a resource to infer associations between genes, chemicals, phenotypes for a total of 31 disorders. An initial step of automated text mining of the literature related to 31 disorders returned thousands of enriched terms. Fewer relevant phenotypic terms were manually selected by clinicians as relevant to the five neural disorders of their expertise and used to analyze the complete set of disorders. Analysis of the data indicates general relationships between neuropsychiatric disorders, which can be used to classify and characterize them. Correlation analyses allowed us to propose novel associations of genes and drugs with disorders. More generally, the results led us to uncovering mechanisms of disease that span multiple neuropsychiatric disorders, for example that genes related to synaptic transmission and receptor functions tend to be involved in many disorders, whereas genes related to sensory perception and channel transport functions are associated with fewer disorders. Our study shows that starting from expertise covering a limited set of neurological disorders and using text and data mining methods, meaningful and novel associations regarding genes, chemicals and phenotypes can be derived for an expanded set of neuropsychiatric disorders. Our results are intended for clinicians to help them evaluate patients, and for basic scientists to propose new gene targets for drug therapies. This strategy can be extended to virtually all diseases and takes advantage of the ever increasing amount of biomedical literature.
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Mineração de Dados/métodos , Bases de Dados Genéticas , Redes Reguladoras de Genes/genética , Transtornos Mentais/genética , Fenótipo , Bases de Dados Genéticas/normas , HumanosRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by excessive proliferation of pulmonary vascular endothelial cells (ECs). Hereditary PAH (HPAH) is often caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). However, the mechanisms by which these mutations cause PAH remain unclear. Therefore, we screened for dysregulated proteins in blood-outgrowth ECs of HPAH patients with BMPR2 mutations compared with healthy control subjects. METHODS AND RESULTS: A total of 416 proteins were detected with 2-dimensional PAGE in combination with liquid chromatography/tandem mass spectrometry analysis, of which 22 exhibited significantly altered abundance in blood-outgrowth ECs from patients with HPAH. One of these proteins, translationally controlled tumor protein (TCTP), was selected for further study because of its well-established role in promoting tumor cell growth and survival. Immunostaining showed marked upregulation of TCTP in lungs from patients with HPAH and idiopathic PAH, associated with remodeled vessels of complex lesions. Increased TCTP expression was also evident in the SU5416 rat model of severe and irreversible PAH, associated with intimal lesions, colocalizing with proliferating ECs and the adventitia of remodeled vessels but not in the vascular media. Furthermore, silencing of TCTP expression increased apoptosis and abrogated the hyperproliferative phenotype of blood-outgrowth ECs from patients with HPAH, raising the possibility that TCTP may be a link in the emergence of apoptosis-resistant, hyperproliferative vascular cells after EC apoptosis. CONCLUSION: Proteomic screening identified TCTP as a novel mediator of endothelial prosurvival and growth signaling in PAH, possibly contributing to occlusive pulmonary vascular remodeling triggered by EC apoptosis.
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Biomarcadores Tumorais/fisiologia , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Proteômica/métodos , Adulto , Idoso , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Ratos , Ratos Sprague-Dawley , Sobrevida/fisiologia , Proteína Tumoral 1 Controlada por Tradução , Adulto JovemRESUMO
Exogenous 17ß-estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG-LS-TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG-LS-TAg mice. Following intraperitoneal engraftment of two MAS cell lines, MASC1 and MASE2, into SCID mice, exogenous E2 significantly decreased the survival time and increased the tumor burden. Microarray analysis performed on MASE2-derived tumors treated with E2 or placebo showed that E2 treatment caused the upregulation of 197 genes and the downregulation of 55 genes. The expression of gene regulated by estrogen in breast cancer 1 (Greb1) was upregulated in mouse tumors treated with E2 and was overexpressed in human ovarian cancers relative to human ovarian surface epithelium, suggesting a role for GREB1 in human ovarian tumor progression. RNA interference-mediated knockdown of GREB1 in MASE2 cells decreased their proliferation rate in vitro and increased survival time in mice engrafted with the cells. These results emphasize the importance of E2 in ovarian tumor progression and identify Greb1 as a novel gene target for therapeutic intervention.
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Estradiol/farmacologia , Proteínas de Neoplasias/biossíntese , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Carga Tumoral/efeitos dos fármacos , Animais , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos SCID , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Regulação para CimaRESUMO
Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimer's disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways.
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Proteínas/metabolismo , Doença de Alzheimer/metabolismo , Biocatálise , Humanos , Fosforilação , Ligação Proteica , Proteoma , Transdução de Sinais , Proteínas Virais/metabolismoRESUMO
INTRODUCTION: The incidence of varicella in Canada has decreased by almost 99% since vaccination was introduced. However, variation in the timing and eligibility of vaccination programs across the country has resulted in some cohorts being under-vaccinated and therefore potentially susceptible to infection. METHODS: We used nationally representative specimens from the Biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) as well as residual specimens from Ontario collected between 2009-2014 to estimate population immunity across age-groups and geography, and identify any groups at increased risk of varicella infection. RESULTS: The weighted proportion of specimens with antibody levels above the threshold of protection was 93.6% (95% CI: 92.4, 95.0). Protection was lowest among those aged 3-5 years (54.3%; 95% CI: 47.3, 61.4), but increased with age. Individuals born outside Canada had more than twice the odds of varicella susceptibility than those born in Canada (aOR: 2.7; 95% CI: 1.4, 5.0; p = 0.004). There were no differences by sex or geography within Canada, and there were no statistically significant differences when Ontario CHMS sera were compared to Ontario residual sera, apart from in participants aged 12-19 year age-group, for whom the CHMS estimate (91.2%; 95% CI: 86.7, 95.7) was significantly higher (p = 0.03) than that from residual specimens (85.9%, 95% CI: 81.1, 90.8). DISCUSSION: Varicella immunity in Canada is changing. Children appear to have low population immunity, placing them at greater risk of infection and at increased risk of severe disease as they age. Our results underscore the importance of performing periodic serosurveys to monitor further population immunity changes as the proportion of vaccine-eligible birth-cohorts increases, and to continually assess the risk of outbreaks.
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Varicela , Humanos , Varicela/epidemiologia , Varicela/imunologia , Varicela/prevenção & controle , Adolescente , Criança , Pré-Escolar , Feminino , Masculino , Canadá/epidemiologia , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Lactente , Vacina contra Varicela/imunologia , Vacinação , Idoso , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Herpesvirus Humano 3/imunologiaRESUMO
BACKGROUND: Gene transcripts specifically expressed in a particular cell type (cell-type specific gene markers) are useful for its detection and isolation from a tissue or other cell mixtures. However, finding informative marker genes can be problematic when working with a poorly characterized cell type, as markers can only be unequivocally determined once the cell type has been isolated. We propose a method that could identify marker genes of an uncharacterized cell type within a mixed cell population, provided that the proportion of the cell type of interest in the mixture can be estimated by some indirect method, such as a functional assay. RESULTS: We show that cell-type specific gene markers can be identified from the global gene expression of several cell mixtures that contain the cell type of interest in a known proportion by their high correlation to the concentration of the corresponding cell type across the mixtures. CONCLUSIONS: Genes detected using this high-throughput strategy would be candidate markers that may be useful in detecting or purifying a cell type from a particular biological context. We present an experimental proof-of-concept of this method using cell mixtures of various well-characterized hematopoietic cell types, and we evaluate the performance of the method in a benchmark that explores the requirements and range of validity of the approach.
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Expressão Gênica , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linhagem Celular Tumoral , Células HL-60 , Humanos , Células Jurkat , Células K562 , TranscriptomaRESUMO
Imitation switch (ISWI) proteins are catalytic subunits of chromatin remodeling complexes that alter nucleosome positioning by hydrolyzing ATP to regulate access to DNA. In mice, there are two paralogs, SNF2-homolog (SNF2H) and SNF2-like (SNF2L), which participate in different complexes and have contrasting patterns of expression. Here we investigate the role of SNF2L in ovaries by characterizing a mouse bearing an inactivating deletion of exon 6 that disrupts the ATPase domain. Snf2l mutant mice produce significantly fewer eggs than control mice when superovulated. Gonadotropin stimulation leads to a significant deficit in secondary follicles and an increase in abnormal antral follicles. Mutant females also failed to induce fibrinogen-like 2 (Fgl2) in response to human chorionic gonadotropin (hCG) stimulation, while overexpression of SNF2L was sufficient to drive its expression in granulosa cells. SNF2L was also shown to directly interact with the nuclear receptor co-activator flightless I (FLI-I) as shown by immunoprecipitation. These results begin to establish a role for SNF2L in the precise coordination of gene expression in granulosa cells during folliculogenesis and its broader implications in fertility.
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Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Fibrinogênio/metabolismo , Células da Granulosa/citologia , Superovulação/metabolismo , Fatores de Transcrição/metabolismo , Animais , Contagem de Células , Núcleo Celular/genética , Núcleo Celular/metabolismo , Células Cultivadas , Gonadotropina Coriônica/farmacologia , Proteínas de Ligação a DNA/genética , Éxons , Feminino , Fibrinogênio/genética , Células da Granulosa/metabolismo , Camundongos , Camundongos Transgênicos , Ovário/citologia , Ovário/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Superovulação/genética , Fatores de Transcrição/genéticaRESUMO
The hedgehog (Hh) signaling pathway is involved in numerous developmental and adult processes with many links to cancer. In vertebrates, the activity of the Hh pathway is mediated primarily through three Gli transcription factors (Gli1, 2 and 3) that can serve as transcriptional activators or repressors. The identification of Gli target genes is essential for the understanding of the Hh-mediated processes. We used a comparative genomics approach using the mouse and human genomes to identify 390 genes that contained conserved Gli binding sites. RT-qPCR validation of 46 target genes in E14.5 and P0.5 retinal explants revealed that Hh pathway activation resulted in the modulation of 30 of these targets, 25 of which demonstrated a temporal regulation. Further validation revealed that the expression of Bok, FoxA1, Sox8 and Wnt7a was dependent upon Sonic Hh (Shh) signaling in the retina and their regulation is under positive and negative controls by Gli2 and Gli3, respectively. We also show using chromatin immunoprecipitation that Gli2 binds to the Sox8 promoter, suggesting that Sox8 is an Hh-dependent direct target of Gli2. Finally, we demonstrate that the Hh pathway also modulates the expression of Sox9 and Sox10, which together with Sox8 make up the SoxE group. Previously, it has been shown that Hh and SoxE group genes promote Müller glial cell development in the retina. Our data are consistent with the possibility for a role of SoxE group genes downstream of Hh signaling on Müller cell development.
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Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Retina/metabolismo , Fatores de Transcrição SOXE/metabolismo , Animais , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Transcrição SOXE/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína GLI1 em Dedos de ZincoRESUMO
Wastewater-based surveillance (WBS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offers a complementary tool for clinical surveillance to detect and monitor coronavirus disease 2019 (COVID-19). Since both symptomatic and asymptomatic individuals infected with SARS-CoV-2 can shed the virus through the fecal route, WBS has the potential to measure community prevalence of COVID-19 without restrictions from healthcare-seeking behaviours and clinical testing capacity. During the Omicron wave, the limited capacity of clinical testing to identify COVID-19 cases in many jurisdictions highlighted the utility of WBS to estimate disease prevalence and inform public health strategies; however, there is a plethora of in-sewage, environmental and laboratory factors that can influence WBS outcomes. The implementation of WBS, therefore, requires a comprehensive framework to outline a pipeline that accounts for these complex and nuanced factors. This article reviews the framework of the national WBS conducted at the Public Health Agency of Canada to present WBS methods used in Canada to track and monitor SARS-CoV-2. In particular, we focus on five Canadian cities-Vancouver, Edmonton, Toronto, Montréal and Halifax-whose wastewater signals are analyzed by a mathematical model to provide case forecasts and reproduction number estimates. The goal of this work is to share our insights on approaches to implement WBS. Importantly, the national WBS system has implications beyond COVID-19, as a similar framework can be applied to monitor other infectious disease pathogens or antimicrobial resistance in the community.
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Circular dichroism (CD) is a spectroscopic technique commonly used to investigate the structure of proteins. Major secondary structure types, alpha-helices and beta-strands, produce distinctive CD spectra. Thus, by comparing the CD spectrum of a protein of interest to a reference set consisting of CD spectra of proteins of known structure, predictive methods can estimate the secondary structure of the protein. Currently available methods, including K2D2, use such experimental CD reference sets, which are very small in size when compared to the number of tertiary structures available in the Protein Data Bank (PDB). Conversely, given a PDB structure, it is possible to predict a theoretical CD spectrum from it. The methodological framework for this calculation was established long ago but only recently a convenient implementation called DichroCalc has been developed. In this study, we set to determine whether theoretically derived spectra could be used as reference set for accurate CD based predictions of secondary structure. We used DichroCalc to calculate the theoretical CD spectra of a nonredundant set of structures representing most proteins in the PDB, and applied a straightforward approach for predicting protein secondary structure content using these theoretical CD spectra as reference set. We show that this method improves the predictions, particularly for the wavelength interval between 200 and 240 nm and for beta-strand content. We have implemented this method, called K2D3, in a publicly accessible web server at http://www. ogic.ca/projects/k2d3.
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Algoritmos , Dicroísmo Circular , Estrutura Secundária de Proteína , Proteínas/química , Bases de Dados de Proteínas , InternetRESUMO
PURPOSE: During mammalian eye development, the restriction of Wnt/ß-catenin signaling at the junction of the neural retina and the retinal pigment epithelium in the peripheral eyecup is required for the development of the ciliary margin, a non-neural region of the eyecup that is the precursor of the ciliary body and iris of the adult eye. METHODS: To identify genes that are modulated by ß-catenin activity in the embryonic retina, we performed gene expression profiling in Li(+)-treated retinal explants, a pharmacological model of ß-catenin activation. The Li(+)-modulated gene data set was searched for ß-catenin/T-cell specific transcription factor binding sites. RESULTS: Functional annotations of this data set revealed significant enrichments for genes involved in chromatin organization, neurogenesis, and cell motion/migration. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed the modulation of 12 genes in Li(+)-treated explants and retinas of mice with Cre-mediated induction of constitutively active ß-catenin (ß-cat(act)). In situ hybridization revealed ß-catenin-specific upregulation of cyclin-dependent kinase inhibitor 1A (P21) [Cdkn1a] and tumor necrosis factor receptor superfamily, member 19 (Tnfrsf19) in the developing retina consistent with the antineurogenic and proliferation changes associated with ectopic Wnt/ß-catenin signaling in the eyecup. CONCLUSIONS: This data set of Li(+)-modulated genes provides a valuable resource for characterizing the Wnt/ ß-catenin regulated gene network in eyecup patterning.
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Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Embrião de Mamíferos , Feminino , Perfilação da Expressão Gênica , Cloreto de Lítio/farmacologia , Camundongos , Camundongos Transgênicos , Receptores do Fator de Necrose Tumoral/genética , Epitélio Pigmentado da Retina/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Regulação para Cima , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , Quinases Ativadas por p21/genéticaRESUMO
We aimed to determine population immunity to measles in Canada, and to assess the risk of future outbreaks. We tested 11,176 sera from Cycles 2 (2009-2011) and 3 (2011-2013) cohorts from the biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) using the BioPlex 2220 MMRV IgG assay. We then tested all BioPlex negative and equivocal samples using a more sensitive Plaque Reduction Neutralization Test (PRNT). We determined the weighted proportion of positive, equivocal, and negative samples by age, sex, region and whether individuals were born in Canada. We found that 90.0% (95% confidence interval (CI): 88.2, 91.9) of samples were positive, 4.5% (95% CI: 3.4, 5.5) were equivocal and 5.5% (95% CI: 4.3, 6.7) were negative. Individuals in the 12-19 year age band had the lowest proportion positive at 78.7% (95% CI: 74.2, 83.2) and the highest proportion of positive samples was found in those 60-79 years (99.6%, 95% CI: 99.3, 99.9). Seropositivity was consistently <90% across a broad range of pediatric and adult age bands (6-39 years). We found that a slightly higher proportion of females were positive (91.9%, 95% CI: 90.1, 93.6) compared to males (88.3%, 95% CI: 85.8, 90.7). When taking into account interaction between age and born in Canada status, we found individuals born in Canada aged 19 and under were less susceptible (OR = 0.6 (95% CI: 0.4, 0.95)) compared to those born outside Canada whereas, those aged 20 and over were more susceptible (OR = 1.7 (95% CI: 1.1, 2.8)). Our findings indicate that measles immunity in Canada is below the 95% immunity threshold required to sustain measles elimination, underscoring the importance of maintaining high vaccine coverage to prevent future measles outbreaks and sustain Canada's elimination status.
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Sarampo , Adulto , Anticorpos Antivirais , Canadá/epidemiologia , Criança , Feminino , Humanos , Imunização , Masculino , Sarampo/epidemiologia , Sarampo/prevenção & controle , Vacina contra Sarampo , Estudos SoroepidemiológicosAssuntos
Biologia Computacional/tendências , Direitos Autorais/tendências , Mineração de Dados/tendências , Publicações Periódicas como Assunto/tendências , Biologia Computacional/legislação & jurisprudência , Direitos Autorais/legislação & jurisprudência , Mineração de Dados/legislação & jurisprudência , Humanos , Publicações Periódicas como Assunto/legislação & jurisprudênciaRESUMO
The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch+/- mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche.
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Carcinogênese , Proteínas do Olho/metabolismo , Receptores Frizzled/metabolismo , Meduloblastoma/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , CamundongosRESUMO
Many cytoplasmic substrates degraded by autophagy have been identified; however, the impact of RNA degradation by autophagy remains uncertain. Retrotransposons comprise 40% of the human genome and are a major source of genetic variation among species, individuals and cells. Retrotransposons replicate via a copy-paste mechanism involving a cytoplasmic RNA intermediate. Here we report that autophagy degrades retrotransposon RNA from both long and short interspersed elements, preventing new retrotransposon insertions into the genome. Retrotransposon RNA localizes to RNA granules, whose selective degradation is facilitated by the autophagy receptors NDP52 and p62. Accordingly, NDP52 and p62 control retrotransposon insertion in the genome. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. Thus, autophagy physiologically buffers genetic variegation by degrading retrotransposon RNA. This may contribute to the increased tumorigenesis occuring when autophagy is inhibited and suggest a role for autophagy in tempering evolutionary change.
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Elementos Alu , Autofagia , Elementos Nucleotídeos Longos e Dispersos , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Instabilidade Genômica , Células HEK293 , Células HeLa , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Fagossomos/metabolismo , RNA/metabolismoRESUMO
A major goal of cell therapy for vascular diseases is to promote revascularization through the injection of endothelial stem/progenitor cells. The gene regulatory mechanisms that underlie endothelial progenitor-mediated vascular repair, however, remain elusive. Here, we identify the transcription factor TAL1/SCL as a key mediator of the vascular repair function of primary human endothelial colony-forming cells (ECFCs). Genome-wide analyses in ECFCs demonstrate that TAL1 activates a transcriptional program that promotes cell adhesion and migration. At the mechanistic level, we show that TAL1 upregulates the expression of migratory and adhesion genes through recruitment of the histone acetyltransferase p300. Based on these findings, we establish a strategy that enhances the revascularization efficiency of ECFCs after ischemia through ex vivo priming with the histone deacetylase inhibitor TSA. Thus, small molecule epigenetics drugs are effective tools for modifying the epigenome of stem/progenitor cells prior to transplantation as a means to enhance their therapeutic potential.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Ácidos Hidroxâmicos/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Imunoprecipitação da Cromatina , Células Progenitoras Endoteliais/citologia , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Proteínas Proto-Oncogênicas/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células TRESUMO
Alpha-solenoids are flexible protein structural domains formed by ensembles of alpha-helical repeats (Armadillo and HEAT repeats among others). While homology can be used to detect many of these repeats, some alpha-solenoids have very little sequence homology to proteins of known structure and we expect that many remain undetected. We previously developed a method for detection of alpha-helical repeats based on a neural network trained on a dataset of protein structures. Here we improved the detection algorithm and updated the training dataset using recently solved structures of alpha-solenoids. Unexpectedly, we identified occurrences of alpha-solenoids in solved protein structures that escaped attention, for example within the core of the catalytic subunit of PI3KC. Our results expand the current set of known alpha-solenoids. Application of our tool to the protein universe allowed us to detect their significant enrichment in proteins interacting with many proteins, confirming that alpha-solenoids are generally involved in protein-protein interactions. We then studied the taxonomic distribution of alpha-solenoids to discuss an evolutionary scenario for the emergence of this type of domain, speculating that alpha-solenoids have emerged in multiple taxa in independent events by convergent evolution. We observe a higher rate of alpha-solenoids in eukaryotic genomes and in some prokaryotic families, such as Cyanobacteria and Planctomycetes, which could be associated to increased cellular complexity. The method is available at http://cbdm.mdc-berlin.de/~ard2/.
Assuntos
Genômica , Proteínas/fisiologia , Conformação Proteica , Proteínas/química , Proteínas/genéticaRESUMO
BACKGROUND: Reviewer and editor selection for peer review is getting harder for authors and publishers due to the specialization onto narrower areas of research carried by the progressive growth of the body of knowledge. Examination of the literature facilitates finding appropriate reviewers but is time consuming and complicated by author name ambiguities. RESULTS: We have developed a method called peer2ref to support authors and editors in selecting suitable reviewers for scientific manuscripts. Peer2ref works from a text input, usually the abstract of the manuscript, from which important concepts are extracted as keywords using a fuzzy binary relations approach. The keywords are searched on indexed profiles of words constructed from the bibliography attributed to authors in MEDLINE. The names of these scientists have been previously disambiguated by coauthors identified across the whole MEDLINE. The methods have been implemented in a web server that automatically suggests experts for peer-review among scientists that have authored manuscripts published during the last decade in more than 3,800 journals indexed in MEDLINE. CONCLUSION: peer2ref web server is publicly available at http://www.ogic.ca/projects/peer2ref/.