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A volunteer effort by Artificial Intelligence (AI) researchers has shown it can deliver significant research outcomes rapidly to help tackle COVID-19. Within two months, CLAIRE's self-organising volunteers delivered the World's first comprehensive curated repository of COVID-19-related datasets useful for drug-repurposing, drafted review papers on the role CT/X-ray scan analysis and robotics could play, and progressed research in other areas. Given the pace required and nature of voluntary efforts, the teams faced a number of challenges. These offer insights in how better to prepare for future volunteer scientific efforts and large scale, data-dependent AI collaborations in general. We offer seven recommendations on how to best leverage such efforts and collaborations in the context of managing future crises.
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The advent of Next-Generation Sequencing (NGS) technologies has opened new perspectives in deciphering the genetic mechanisms underlying complex diseases. Nowadays, the amount of genomic data is massive and substantial efforts and new tools are required to unveil the information hidden in the data. The Genomic Data Commons (GDC) Data Portal is a platform that contains different genomic studies including the ones from The Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiatives, accounting for more than 40 tumor types originating from nearly 30000 patients. Such platforms, although very attractive, must make sure the stored data are easily accessible and adequately harmonized. Moreover, they have the primary focus on the data storage in a unique place, and they do not provide a comprehensive toolkit for analyses and interpretation of the data. To fulfill this urgent need, comprehensive but easily accessible computational methods for integrative analyses of genomic data that do not renounce a robust statistical and theoretical framework are required. In this context, the R/Bioconductor package TCGAbiolinks was developed, offering a variety of bioinformatics functionalities. Here we introduce new features and enhancements of TCGAbiolinks in terms of i) more accurate and flexible pipelines for differential expression analyses, ii) different methods for tumor purity estimation and filtering, iii) integration of normal samples from other platforms iv) support for other genomics datasets, exemplified here by the TARGET data. Evidence has shown that accounting for tumor purity is essential in the study of tumorigenesis, as these factors promote confounding behavior regarding differential expression analysis. With this in mind, we implemented these filtering procedures in TCGAbiolinks. Moreover, a limitation of some of the TCGA datasets is the unavailability or paucity of corresponding normal samples. We thus integrated into TCGAbiolinks the possibility to use normal samples from the Genotype-Tissue Expression (GTEx) project, which is another large-scale repository cataloging gene expression from healthy individuals. The new functionalities are available in the TCGAbiolinks version 2.8 and higher released in Bioconductor version 3.7.
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Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias/genética , Carcinogênese , Conjuntos de Dados como Assunto , Genoma Humano , HumanosRESUMO
BACKGROUND & AIMS: Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS: We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS: We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS: We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.
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Técnicas de Apoio para a Decisão , Perfilação da Expressão Gênica/métodos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/genética , Transcriptoma , Corticosteroides/uso terapêutico , Adulto , Área Sob a Curva , Bélgica , Biópsia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Modern high-throughput genomic technologies represent a comprehensive hallmark of molecular changes in pan-cancer studies. Although different cancer gene signatures have been revealed, the mechanism of tumourigenesis has yet to be completely understood. Pathways and networks are important tools to explain the role of genes in functional genomic studies. However, few methods consider the functional non-equal roles of genes in pathways and the complex gene-gene interactions in a network. RESULTS: We present a novel method in pan-cancer analysis that identifies de-regulated genes with a functional role by integrating pathway and network data. A pan-cancer analysis of 7158 tumour/normal samples from 16 cancer types identified 895 genes with a central role in pathways and de-regulated in cancer. Comparing our approach with 15 current tools that identify cancer driver genes, we found that 35.6% of the 895 genes identified by our method have been found as cancer driver genes with at least 2/15 tools. Finally, we applied a machine learning algorithm on 16 independent GEO cancer datasets to validate the diagnostic role of cancer driver genes for each cancer. We obtained a list of the top-ten cancer driver genes for each cancer considered in this study. CONCLUSIONS: Our analysis 1) confirmed that there are several known cancer driver genes in common among different types of cancer, 2) highlighted that cancer driver genes are able to regulate crucial pathways.
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Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Genômica/métodos , Neoplasias/genética , Transdução de Sinais , Algoritmos , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
SUMMARY: Identifying molecular cancer subtypes from multi-omics data is an important step in the personalized medicine. We introduce CancerSubtypes, an R package for identifying cancer subtypes using multi-omics data, including gene expression, miRNA expression and DNA methylation data. CancerSubtypes integrates four main computational methods which are highly cited for cancer subtype identification and provides a standardized framework for data pre-processing, feature selection, and result follow-up analyses, including results computing, biology validation and visualization. The input and output of each step in the framework are packaged in the same data format, making it convenience to compare different methods. The package is useful for inferring cancer subtypes from an input genomic dataset, comparing the predictions from different well-known methods and testing new subtype discovery methods, as shown with different application scenarios in the Supplementary Material. AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available under GPL-2 license from the Bioconductor website (http://bioconductor.org/packages/CancerSubtypes/). CONTACT: thuc.le@unisa.edu.au or jiuyong.li@unisa.edu.au. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Neoplasias/classificação , Neoplasias/genética , Software , Gráficos por Computador , Metilação de DNA , Expressão Gênica , Genômica , Humanos , MicroRNAs/metabolismo , Neoplasias/metabolismoRESUMO
The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.
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Biologia Computacional/métodos , Mineração de Dados/métodos , Bases de Dados Genéticas , Genoma Humano/genética , Genômica/métodos , Neoplasias/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Metilação de DNA/genética , Humanos , Neoplasias/classificação , Estatística como Assunto/métodosRESUMO
Like other cancer diseases, prostate cancer (PC) is caused by the accumulation of genetic alterations in the cells that drives malignant growth. These alterations are revealed by gene profiling and copy number alteration (CNA) analysis. Moreover, recent evidence suggests that also microRNAs have an important role in PC development. Despite efforts to profile PC, the alterations (gene, CNA, and miRNA) and biological processes that correlate with disease development and progression remain partially elusive. Many gene signatures proposed as diagnostic or prognostic tools in cancer poorly overlap. The identification of co-expressed genes, that are functionally related, can identify a core network of genes associated with PC with a better reproducibility. By combining different approaches, including the integration of mRNA expression profiles, CNAs, and miRNA expression levels, we identified a gene signature of four genes overlapping with other published gene signatures and able to distinguish, in silico, high Gleason-scored PC from normal human tissue, which was further enriched to 19 genes by gene co-expression analysis. From the analysis of miRNAs possibly regulating this network, we found that hsa-miR-153 was highly connected to the genes in the network. Our results identify a four-gene signature with diagnostic and prognostic value in PC and suggest an interesting gene network that could play a key regulatory role in PC development and progression. Furthermore, hsa-miR-153, controlling this network, could be a potential biomarker for theranostics in high Gleason-scored PC.
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Simulação por Computador , Redes Reguladoras de Genes , MicroRNAs/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adulto , Idoso , Área Sob a Curva , Variações do Número de Cópias de DNA/genética , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Regulação para Cima/genéticaRESUMO
Gene Regulatory Networks (GRNs) control many biological systems, but how such network coordination is shaped is still unknown. GRNs can be subdivided into basic connections that describe how the network members interact e.g., co-expression, physical interaction, co-localization, genetic influence, pathways, and shared protein domains. The important regulatory mechanisms of these networks involve miRNAs. We developed an R/Bioconductor package, namely SpidermiR, which offers an easy access to both GRNs and miRNAs to the end user, and integrates this information with differentially expressed genes obtained from The Cancer Genome Atlas. Specifically, SpidermiR allows the users to: (i) query and download GRNs and miRNAs from validated and predicted repositories; (ii) integrate miRNAs with GRNs in order to obtain miRNA-gene-gene and miRNA-protein-protein interactions, and to analyze miRNA GRNs in order to identify miRNA-gene communities; and (iii) graphically visualize the results of the analyses. These analyses can be performed through a single interface and without the need for any downloads. The full data sets are then rapidly integrated and processed locally.
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MicroRNAs/metabolismo , Software , Estatística como Assunto , Neoplasias da Mama/genética , Feminino , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/genética , Ligação ProteicaRESUMO
BACKGROUND: An important challenge in cancer biology is to understand the complex aspects of the disease. It is increasingly evident that genes are not isolated from each other and the comprehension of how different genes are related to each other could explain biological mechanisms causing diseases. Biological pathways are important tools to reveal gene interaction and reduce the large number of genes to be studied by partitioning it into smaller paths. Furthermore, recent scientific evidence has proven that a combination of pathways, instead than a single element of the pathway or a single pathway, could be responsible for pathological changes in a cell. RESULTS: In this paper we develop a new method that can reveal miRNAs able to regulate, in a coordinated way, networks of gene pathways. We applied the method to subtypes of breast cancer. The basic idea is the identification of pathways significantly enriched with differentially expressed genes among the different breast cancer subtypes and normal tissue. Looking at the pairs of pathways that were found to be functionally related, we created a network of dependent pathways and we focused on identifying miRNAs that could act as miRNA drivers in a coordinated regulation process. CONCLUSIONS: Our approach enables miRNAs identification that could have an important role in the development of breast cancer.
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Neoplasias da Mama/genética , Redes Reguladoras de Genes , Genômica/métodos , MicroRNAs/genética , Neoplasias da Mama/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , MicroRNAs/metabolismoRESUMO
Infinium HumanMethylation450 beadarray is a popular technology to explore DNA methylomes in health and disease, and there is a current explosion in the use of this technique. Despite experience acquired from gene expression microarrays, analyzing Infinium Methylation arrays appeared more complex than initially thought and several difficulties have been encountered, as those arrays display specific features that need to be taken into consideration during data processing. Here, we review several issues that have been highlighted by the scientific community, and we present an overview of the general data processing scheme and an evaluation of the different normalization methods available to date to guide the 450K users in their analysis and data interpretation.
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Metilação de DNA , Biologia Computacional , Ilhas de CpG , Interpretação Estatística de Dados , Genoma Humano , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Sondas de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , SoftwareRESUMO
UNLABELLED: The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. CONCLUSION: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.
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Carcinoma Hepatocelular/genética , Lipase/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática Alcoólica/complicações , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , População BrancaRESUMO
Although many methods have been developed for inference of biological networks, the validation of the resulting models has largely remained an unsolved problem. Here we present a framework for quantitative assessment of inferred gene interaction networks using knock-down data from cell line experiments. Using this framework we are able to show that network inference based on integration of prior knowledge derived from the biomedical literature with genomic data significantly improves the quality of inferred networks relative to other approaches. Our results also suggest that cell line experiments can be used to quantitatively assess the quality of networks inferred from tumor samples.
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Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Transcriptoma , Estudos de Validação como AssuntoRESUMO
Type 1 Diabetes (T1D) is an autoimmune disease where local release of cytokines such as IL-1ß and IFN-γ contributes to ß-cell apoptosis. To identify relevant genes regulating this process we performed a meta-analysis of 8 datasets of ß-cell gene expression after exposure to IL-1ß and IFN-γ. Two of these datasets are novel and contain time-series expressions in human islet cells and rat INS-1E cells. Genes were ranked according to their differential expression within and after 24 h from exposure, and characterized by function and prior knowledge in the literature. A regulatory network was then inferred from the human time expression datasets, using a time-series extension of a network inference method. The two most differentially expressed genes previously unknown in T1D literature (RIPK2 and ELF3) were found to modulate cytokine-induced apoptosis. The inferred regulatory network is thus supported by the experimental validation, providing a proof-of-concept for the proposed statistical inference approach.
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Citocinas/metabolismo , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Células Secretoras de Insulina/fisiologia , Animais , Citocinas/farmacologia , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 1 , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Interferon gama/metabolismo , Interferon gama/farmacologia , Ilhotas Pancreáticas/fisiologia , Proteínas Proto-Oncogênicas c-ets/genética , Ratos , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Reprodutibilidade dos Testes , Fatores de Transcrição/genéticaRESUMO
MOTIVATION: Feature selection is one of the main challenges in analyzing high-throughput genomic data. Minimum redundancy maximum relevance (mRMR) is a particularly fast feature selection method for finding a set of both relevant and complementary features. Here we describe the mRMRe R package, in which the mRMR technique is extended by using an ensemble approach to better explore the feature space and build more robust predictors. To deal with the computational complexity of the ensemble approach, the main functions of the package are implemented and parallelized in C using the openMP Application Programming Interface. RESULTS: Our ensemble mRMR implementations outperform the classical mRMR approach in terms of prediction accuracy. They identify genes more relevant to the biological context and may lead to richer biological interpretations. The parallelized functions included in the package show significant gains in terms of run-time speed when compared with previously released packages. AVAILABILITY: The R package mRMRe is available on Comprehensive R Archive Network and is provided open source under the Artistic-2.0 License. The code used to generate all the results reported in this application note is available from Supplementary File 1. CONTACT: bhaibeka@ircm.qc.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Genômica/métodos , Software , Algoritmos , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Resistencia a Medicamentos Antineoplásicos , IrinotecanoRESUMO
Genomics provided us with an unprecedented quantity of data on the genes that are activated or repressed in a wide range of phenotypes. We have increasingly come to recognize that defining the networks and pathways underlying these phenotypes requires both the integration of multiple data types and the development of advanced computational methods to infer relationships between the genes and to estimate the predictive power of the networks through which they interact. To address these issues we have developed Predictive Networks (PN), a flexible, open-source, web-based application and data services framework that enables the integration, navigation, visualization and analysis of gene interaction networks. The primary goal of PN is to allow biomedical researchers to evaluate experimentally derived gene lists in the context of large-scale gene interaction networks. The PN analytical pipeline involves two key steps. The first is the collection of a comprehensive set of known gene interactions derived from a variety of publicly available sources. The second is to use these 'known' interactions together with gene expression data to infer robust gene networks. The PN web application is accessible from http://predictivenetworks.org. The PN code base is freely available at https://sourceforge.net/projects/predictivenets/.
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Bases de Dados Genéticas , Redes Reguladoras de Genes , Genômica , Humanos , Internet , Fenótipo , Interface Usuário-ComputadorRESUMO
Myoelectric prostheses have recently shown significant promise for restoring hand function in individuals with upper limb loss or deficiencies, driven by advances in machine learning and increasingly accessible bioelectrical signal acquisition devices. Here, we first introduce and validate a novel experimental paradigm using a virtual reality headset equipped with hand-tracking capabilities to facilitate the recordings of synchronized EMG signals and hand pose estimation. Using both the phasic and tonic EMG components of data acquired through the proposed paradigm, we compare hand gesture classification pipelines based on standard signal processing features, convolutional neural networks, and covariance matrices with Riemannian geometry computed from raw or xDAWN-filtered EMG signals. We demonstrate the performance of the latter for gesture classification using EMG signals. We further hypothesize that introducing physiological knowledge in machine learning models will enhance their performances, leading to better myoelectric prosthesis control. We demonstrate the potential of this approach by using the neurophysiological integration of the "move command" to better separate the phasic and tonic components of the EMG signals, significantly improving the performance of sustained posture recognition. These results pave the way for the development of new cutting-edge machine learning techniques, likely refined by neurophysiology, that will further improve the decoding of real-time natural gestures and, ultimately, the control of myoelectric prostheses.
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The musculoskeletal system (MSS) is essential to allow us performing every-day tasks, being able to have a professional life or developing social interactions with our entourage. MSS pathologies have a significant impact on our daily life. It is therefore not surprising to find MSS-related health problems at the top of global statistics on professional absenteeism or societal health costs. The MSS is also involved in central nervous conditions, such as cerebral palsy (CP). Such conditions show complex etiology that complicates the interpretation of the observable clinical signs and the establishment of a wide consensus on the best practices to adopt for clinical monitoring and patient follow-up. These elements justify the organization of fundamental and applied research projects aiming to develop new methods to help clinicians to cope with the complexity of some MSS disorders. The ICT4Rehab project (www.ict4rehab.org) developed an integrated platform providing tools that enable easier management and visualization of clinical information related to the MSS of CP patients. This platform is opened to every interested clinical centre.
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Paralisia Cerebral/reabilitação , Registros de Saúde Pessoal , HumanosRESUMO
Cytokines produced by islet-infiltrating immune cells induce ß-cell apoptosis in type 1 diabetes. The IFN-γ-regulated transcription factors STAT1/IRF-1 have apparently divergent effects on ß-cells. Thus, STAT1 promotes apoptosis and inflammation, whereas IRF-1 down-regulates inflammatory mediators. To understand the molecular basis for these differential outcomes within a single signal transduction pathway, we presently characterized the gene networks regulated by STAT1 and IRF-1 in ß-cells. This was done by using siRNA approaches coupled to microarray analysis of insulin-producing cells exposed or not to IL-1ß and IFN-γ. Relevant microarray findings were further studied in INS-1E cells and primary rat ß-cells. STAT1, but not IRF-1, mediates the cytokine-induced loss of the differentiated ß-cell phenotype, as indicated by decreased insulin, Pdx1, MafA, and Glut2. Furthermore, STAT1 regulates cytokine-induced apoptosis via up-regulation of the proapoptotic protein DP5. STAT1 and IRF-1 have opposite effects on cytokine-induced chemokine production, with IRF-1 exerting negative feedback inhibition on STAT1 and downstream chemokine expression. The present study elucidates the transcriptional networks through which the IFN-γ/STAT1/IRF-1 axis controls ß-cell function/differentiation, demise, and islet inflammation.
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Apoptose/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Pancreatite/imunologia , Pancreatite/patologia , Fator de Transcrição STAT1/imunologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Retroalimentação Fisiológica/fisiologia , Técnicas de Silenciamento de Genes , Fator Regulador 1 de Interferon/imunologia , Fator Regulador 1 de Interferon/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-1beta/farmacologia , Masculino , Neuropeptídeos/genética , Neuropeptídeos/imunologia , RNA Interferente Pequeno , Ratos , Ratos Wistar , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transcrição Gênica/imunologiaRESUMO
Illumina Infinium DNA Methylation (5mC) arrays are a popular technology for low-cost, high-throughput, genome-scale measurement of 5mC distribution, especially in cancer and other complex diseases. After the success of its HumanMethylation450 array (450k), Illumina released the MethylationEPIC array (850k) featuring increased coverage of enhancers. Despite the widespread use of 850k, analysis of the corresponding data remains suboptimal: it still relies mostly on Illumina's default annotation, which underestimates enhancerss and long noncoding RNAs. Results: We have thus developed an approach, based on the ENCODE and LNCipedia databases, which greatly improves upon Illumina's default annotation of enhancers and long noncoding transcripts. We compared the re-annotated 850k with both 450k and reduced-representation bisulphite sequencing (RRBS), another high-throughput 5mC profiling technology. We found 850k to cover at least three times as many enhancers and long noncoding RNAs as either 450k or RRBS. We further investigated the reproducibility of the three technologies, applying various normalization methods to the 850k data. Most of these methods reduced variability to a level below that of RRBS data. We then used 850k with our new annotation and normalization to profile 5mC changes in breast cancer biopsies. 850k highlighted aberrant enhancer methylation as the predominant feature, in agreement with previous reports. Our study provides an updated processing approach for 850k data, based on refined probe annotation and normalization, allowing for improved analysis of methylation at enhancers and long noncoding RNA genes. Our findings will help to further advance understanding of the DNA methylome in health and disease.
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Metilação de DNA , RNA Longo não Codificante , Humanos , Ilhas de CpG , RNA Longo não Codificante/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Benchmarking , Reprodutibilidade dos TestesRESUMO
The number of daily credit card transactions is inexorably growing: the e-commerce market expansion and the recent constraints for the Covid-19 pandemic have significantly increased the use of electronic payments. The ability to precisely detect fraudulent transactions is increasingly important, and machine learning models are now a key component of the detection process. Standard machine learning techniques are widely employed, but inadequate for the evolving nature of customers behavior entailing continuous changes in the underlying data distribution. his problem is often tackled by discarding past knowledge, despite its potential relevance in the case of recurrent concepts. Appropriate exploitation of historical knowledge is necessary: we propose a learning strategy that relies on diversity-based ensemble learning and allows to preserve past concepts and reuse them for a faster adaptation to changes. In our experiments, we adopt several state-of-the-art diversity measures and we perform comparisons with various other learning approaches. We assess the effectiveness of our proposed learning strategy on extracts of two real datasets from two European countries, containing more than 30 M and 50 M transactions, provided by our industrial partner, Worldline, a leading company in the field.