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1.
J Mol Biol ; 431(13): 2407-2422, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31075273

RESUMO

Transcription starts at genomic positions called transcription start sites (TSSs), producing RNAs, and is mainly regulated by genomic elements and transcription factors binding around these TSSs. This indicates that TSSs may be a better unit to integrate various data sources related to transcriptional events, including regulation and production of RNAs. However, although several TSS datasets and promoter atlases are available, a comprehensive reference set that integrates all known TSSs is lacking. Thus, we constructed a reference dataset of TSSs (refTSS) for the human and mouse genomes by collecting publicly available TSS annotations and promoter resources, such as FANTOM5, DBTSS, EPDnew, and ENCODE. The data set consists of genomic coordinates of TSS peaks, their gene annotations, quality check results, and conservation between human and mouse. We also developed a web interface to browse the refTSS (http://reftss.clst.riken.jp/). Users can access the resource for collecting and integrating data and information about transcriptional regulation and transcription products.

2.
Nat Commun ; 10(1): 360, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664627

RESUMO

Single-cell transcriptomic profiling is a powerful tool to explore cellular heterogeneity. However, most of these methods focus on the 3'-end of polyadenylated transcripts and provide only a partial view of the transcriptome. We introduce C1 CAGE, a method for the detection of transcript 5'-ends with an original sample multiplexing strategy in the C1TM microfluidic system. We first quantifiy the performance of C1 CAGE and find it as accurate and sensitive as other methods in the C1 system. We then use it to profile promoter and enhancer activities in the cellular response to TGF-ß of lung cancer cells and discover subpopulations of cells differing in their response. We also describe enhancer RNA dynamics revealing transcriptional bursts in subsets of cells with transcripts arising from either strand in a mutually exclusive manner, validated using single molecule fluorescence in situ hybridization.


Assuntos
Elementos Facilitadores Genéticos , Fibroblastos/metabolismo , RNA Mensageiro/genética , Análise de Célula Única/métodos , Sítio de Iniciação de Transcrição , Transcriptoma , Células A549 , Animais , Linhagem Celular , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Camundongos , Técnicas Analíticas Microfluídicas , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Análise de Célula Única/instrumentação , Fator de Crescimento Transformador beta/farmacologia
3.
Sci Data ; 5(1): 2, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538238

RESUMO

The authors regret that Luba M. Pardo was omitted in error from the author list of the original version of this Data Descriptor. This omission has now been corrected in the HTML and PDF versions. The authors also regret that Anemieke Rozemuller was omitted in error from the Acknowledgements of the original version of this Data Descriptor. This omission has now been corrected in the HTML and PDF versions.

4.
Nucleic Acids Res ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407557

RESUMO

The FANTOM web resource (http://fantom.gsc.riken.jp/) was developed to provide easy access to the data produced by the FANTOM project. It contains the most complete and comprehensive sets of actively transcribed enhancers and promoters in the human and mouse genomes. We determined the transcription activities of these regulatory elements by CAGE (Cap Analysis of Gene Expression) for both steady and dynamic cellular states in all major and some rare cell types, consecutive stages of differentiation and responses to stimuli. We have expanded the resource by employing different assays, such as RNA-seq, short RNA-seq and a paired-end protocol for CAGE (CAGEscan), to provide new angles to study the transcriptome. That yielded additional atlases of long noncoding RNAs, miRNAs and their promoters. We have also expanded the CAGE analysis to cover rat, dog, chicken, and macaque species for a limited number of cell types. The CAGE data obtained from human and mouse were reprocessed to make them available on the latest genome assemblies. Here, we report the recent updates of both data and interfaces in the FANTOM web resource.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30420245

RESUMO

OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.

6.
Nucleic Acids Res ; 46(D1): D781-D787, 2018 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-29045713

RESUMO

Published single-cell datasets are rich resources for investigators who want to address questions not originally asked by the creators of the datasets. The single-cell datasets might be obtained by different protocols and diverse analysis strategies. The main challenge in utilizing such single-cell data is how we can make the various large-scale datasets to be comparable and reusable in a different context. To challenge this issue, we developed the single-cell centric database 'SCPortalen' (http://single-cell.clst.riken.jp/). The current version of the database covers human and mouse single-cell transcriptomics datasets that are publicly available from the INSDC sites. The original metadata was manually curated and single-cell samples were annotated with standard ontology terms. Following that, common quality assessment procedures were conducted to check the quality of the raw sequence. Furthermore, primary data processing of the raw data followed by advanced analyses and interpretation have been performed from scratch using our pipeline. In addition to the transcriptomics data, SCPortalen provides access to single-cell image files whenever available. The target users of SCPortalen are all researchers interested in specific cell types or population heterogeneity. Through the web interface of SCPortalen users are easily able to search, explore and download the single-cell datasets of their interests.

7.
Sci Data ; 4: 170173, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29182598

RESUMO

The promoter landscape of several non-human model organisms is far from complete. As a part of FANTOM5 data collection, we generated 13 profiles of transcription initiation activities in dog and rat aortic smooth muscle cells, mesenchymal stem cells and hepatocytes by employing CAGE (Cap Analysis of Gene Expression) technology combined with single molecule sequencing. Our analyses show that the CAGE profiles recapitulate known transcription start sites (TSSs) consistently, in addition to uncover novel TSSs. Our dataset can be thus used with high confidence to support gene annotation in dog and rat species. We identified 28,497 and 23,147 CAGE peaks, or promoter regions, for rat and dog respectively, and associated them to known genes. This approach could be seen as a standard method for improvement of existing gene models, as well as discovery of novel genes. Given that the FANTOM5 data collection includes dog and rat matched cell types in human and mouse as well, this data would also be useful for cross-species studies.


Assuntos
Transcrição Genética , Animais , Cães , Anotação de Sequência Molecular , Regiões Promotoras Genéticas , Ratos , Sítio de Iniciação de Transcrição
8.
Sci Data ; 4: 170163, 2017 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29087374

RESUMO

Rhesus macaque was the second non-human primate whose genome has been fully sequenced and is one of the most used model organisms to study human biology and disease, thanks to the close evolutionary relationship between the two species. But compared to human, where several previously unknown RNAs have been uncovered, the macaque transcriptome is less studied. Publicly available RNA expression resources for macaque are limited, even for brain, which is highly relevant to study human cognitive abilities. In an effort to complement those resources, FANTOM5 profiled 15 distinct anatomical regions of the aged macaque central nervous system using Cap Analysis of Gene Expression, a high-resolution, annotation-independent technology that allows monitoring of transcription initiation events with high accuracy. We identified 25,869 CAGE peaks, representing bona fide promoters. For each peak we provide detailed annotation, expanding the landscape of 'known' macaque genes, and we show concrete examples on how to use the resulting data. We believe this data represents a useful resource to understand the central nervous system in macaque.


Assuntos
Sistema Nervoso Central , Macaca mulatta , Sítio de Iniciação de Transcrição , Animais , Sistema Nervoso Central/anatomia & histologia , Transcriptoma
9.
Sci Data ; 4: 170147, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28972578

RESUMO

The FANTOM5 expression atlas is a quantitative measurement of the activity of nearly 200,000 promoter regions across nearly 2,000 different human primary cells, tissue types and cell lines. Generation of this atlas was made possible by the use of CAGE, an experimental approach to localise transcription start sites at single-nucleotide resolution by sequencing the 5' ends of capped RNAs after their conversion to cDNAs. While 50% of CAGE-defined promoter regions could be confidently associated to adjacent transcriptional units, nearly 100,000 promoter regions remained gene-orphan. To address this, we used the CAGEscan method, in which random-primed 5'-cDNAs are paired-end sequenced. Pairs starting in the same region are assembled in transcript models called CAGEscan clusters. Here, we present the production and quality control of CAGEscan libraries from 56 FANTOM5 RNA sources, which enhances the FANTOM5 expression atlas by providing experimental evidence associating core promoter regions with their cognate transcripts.


Assuntos
Regiões Promotoras Genéticas , Transcrição Genética , DNA Complementar , Humanos , Especificidade de Órgãos , Análise de Sequência de RNA , Sítio de Iniciação de Transcrição
10.
Nat Biotechnol ; 35(9): 872-878, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28829439

RESUMO

MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.


Assuntos
Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Anotação de Sequência Molecular , Regiões Promotoras Genéticas/genética , Animais , Células Cultivadas , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , MicroRNAs/metabolismo
11.
Sci Data ; 4: 170107, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28850105

RESUMO

The FANTOM5 consortium described the promoter-level expression atlas of human and mouse by using CAGE (Cap Analysis of Gene Expression) with single molecule sequencing. In the original publications, GRCh37/hg19 and NCBI37/mm9 assemblies were used as the reference genomes of human and mouse respectively; later, the Genome Reference Consortium released newer genome assemblies GRCh38/hg38 and GRCm38/mm10. To increase the utility of the atlas in forthcoming researches, we reprocessed the data to make them available on the recent genome assemblies. The data include observed frequencies of transcription starting sites (TSSs) based on the realignment of CAGE reads, and TSS peaks that are converted from those based on the previous reference. Annotations of the peak names were also updated based on the latest public databases. The reprocessed results enable us to examine frequencies of transcription initiations on the recent genome assemblies and to refer promoters with updated information across the genome assemblies consistently.


Assuntos
Genoma , Regiões Promotoras Genéticas , Animais , Humanos , Camundongos , Sítio de Iniciação de Transcrição
12.
Methods Mol Biol ; 1611: 199-217, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28451981

RESUMO

The Functional Annotation of the Mammalian Genome 5 (FANTOM5) project conducted transcriptome analysis of various mammalian cell types and provided a comprehensive resource to understand transcriptome and transcriptional regulation in individual cellular states encoded in the genome.FANTOM5 used cap analysis of gene expression (CAGE) with single-molecule sequencing to map transcription start sites (TSS) and measured their expression in a diverse range of samples. The main results from FANTOM5 were published as a promoter-level mammalian expression atlas and an atlas of active enhancers across human cell types. The FANTOM5 dataset is composed of raw experimental data and the results of bioinformatics analyses. In this chapter, we give a detailed description of the content of the FANTOM5 dataset and elaborate on different computing applications developed to publish the data and enable reproducibility and discovery of new findings. We present use cases in which the FANTOM5 dataset has been reused, leading to new findings.


Assuntos
Sítio de Iniciação de Transcrição , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Anotação de Sequência Molecular/métodos , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética
13.
Nature ; 543(7644): 199-204, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28241135

RESUMO

Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters. Incorporating genetic and expression data, we show that lncRNAs overlapping trait-associated single nucleotide polymorphisms are specifically expressed in cell types relevant to the traits, implicating these lncRNAs in multiple diseases. We further demonstrate that lncRNAs overlapping expression quantitative trait loci (eQTL)-associated single nucleotide polymorphisms of messenger RNAs are co-expressed with the corresponding messenger RNAs, suggesting their potential roles in transcriptional regulation. Combining these findings with conservation data, we identify 19,175 potentially functional lncRNAs in the human genome.


Assuntos
Bases de Dados Genéticas , RNA Longo não Codificante/química , RNA Longo não Codificante/genética , Transcriptoma/genética , Células Cultivadas , Sequência Conservada/genética , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Internet , Anotação de Sequência Molecular , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética , Estabilidade de RNA , RNA Mensageiro/genética
14.
Methods Mol Biol ; 1525: 107-121, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27896719

RESUMO

The dynamic structure and functions of genomes are being revealed simultaneously with the progress of technologies and researches in genomics. Evidence indicating genome regional characteristics (genome annotations in a broad sense) provide the basis for further analyses. Target listing and screening can be effectively performed in silico using such data. Here, we describe steps to obtain publicly available genome annotations or to construct new annotations based on your own analyses, as well as an overview of the types of available genome annotations and corresponding resources.


Assuntos
Epigênese Genética/genética , Genômica/métodos , Bases de Dados Genéticas , Software
15.
Nucleic Acids Res ; 45(D1): D737-D743, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-27794045

RESUMO

Upon the first publication of the fifth iteration of the Functional Annotation of Mammalian Genomes collaborative project, FANTOM5, we gathered a series of primary data and database systems into the FANTOM web resource (http://fantom.gsc.riken.jp) to facilitate researchers to explore transcriptional regulation and cellular states. In the course of the collaboration, primary data and analysis results have been expanded, and functionalities of the database systems enhanced. We believe that our data and web systems are invaluable resources, and we think the scientific community will benefit for this recent update to deepen their understanding of mammalian cellular organization. We introduce the contents of FANTOM5 here, report recent updates in the web resource and provide future perspectives.


Assuntos
Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Mamíferos/genética , Software , Navegador , Animais , Biologia Computacional , Humanos , Ferramenta de Busca
16.
Artigo em Inglês | MEDLINE | ID: mdl-27402679

RESUMO

The Functional Annotation of the Mammalian Genome project (FANTOM5) mapped transcription start sites (TSSs) and measured their activities in a diverse range of biological samples. The FANTOM5 project generated a large data set; including detailed information about the profiled samples, the uncovered TSSs at high base-pair resolution on the genome, their transcriptional initiation activities, and further information of transcriptional regulation. Data sets to explore transcriptome in individual cellular states encoded in the mammalian genomes have been enriched by a series of additional analysis, based on the raw experimental data, along with the progress of the research activities. To make the heterogeneous data set accessible and useful for investigators, we developed a web-based database called Semantic catalog of Samples, Transcription initiation And Regulators (SSTAR). SSTAR utilizes the open source wiki software MediaWiki along with the Semantic MediaWiki (SMW) extension, which provides flexibility to model, store, and display a series of data sets produced during the course of the FANTOM5 project. Our use of SMW demonstrates the utility of the framework for dissemination of large-scale analysis results. SSTAR is a case study in handling biological data generated from a large-scale research project in terms of maintenance and growth alongside research activities.Database URL: http://fantom.gsc.riken.jp/5/sstar/.


Assuntos
Bases de Dados de Ácidos Nucleicos , Genoma Humano , Software , Sítio de Iniciação de Transcrição , Transcriptoma , Animais , Humanos , Semântica
18.
Genome Biol ; 16: 22, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25723102

RESUMO

The FANTOM5 project investigates transcription initiation activities in more than 1,000 human and mouse primary cells, cell lines and tissues using CAGE. Based on manual curation of sample information and development of an ontology for sample classification, we assemble the resulting data into a centralized data resource (http://fantom.gsc.riken.jp/5/). This resource contains web-based tools and data-access points for the research community to search and extract data related to samples, genes, promoter activities, transcription factors and enhancers across the FANTOM5 atlas.


Assuntos
Genômica/métodos , Regiões Promotoras Genéticas , Software , Iniciação da Transcrição Genética , Animais , Biologia Computacional/métodos , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Camundongos , Transcriptoma , Interface Usuário-Computador
19.
J Transl Med ; 12 Suppl 2: S4, 2014 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-25471042

RESUMO

BACKGROUND AND HYPOTHESIS: Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. OBJECTIVE AND METHOD: Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. RESULTS: In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. CONCLUSIONS: The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Biomarcadores/metabolismo , Comorbidade , Simulação por Computador , Metabolismo Energético , Humanos , Músculo Esquelético/patologia , Oxigênio/química , Espécies Reativas de Oxigênio , Pesquisa Médica Translacional/métodos
20.
PLoS One ; 9(9): e104382, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25203647

RESUMO

Translational medicine is becoming increasingly dependent upon data generated from health care, clinical research, and molecular investigations. This increasing rate of production and diversity in data has brought about several challenges, including the need to integrate fragmented databases, enable secondary use of patient clinical data from health care in clinical research, and to create information systems that clinicians and biomedical researchers can readily use. Our case study effectively integrates requirements from the clinical and biomedical researcher perspectives in a translational medicine setting. Our three principal achievements are (a) a design of a user-friendly web-based system for management and integration of clinical and molecular databases, while adhering to proper de-identification and security measures; (b) providing a real-world test of the system functionalities using clinical cohorts; and (c) system integration with a clinical decision support system to demonstrate system interoperability. We engaged two active clinical cohorts, 747 psoriasis patients and 2001 rheumatoid arthritis patients, to demonstrate efficient query possibilities across the data sources, enable cohort stratification, extract variation in antibody patterns, study biomarker predictors of treatment response in RA patients, and to explore metabolic profiles of psoriasis patients. Finally, we demonstrated system interoperability by enabling integration with an established clinical decision support system in health care. To assure the usefulness and usability of the system, we followed two approaches. First, we created a graphical user interface supporting all user interactions. Secondly we carried out a system performance evaluation study where we measured the average response time in seconds for active users, http errors, and kilobits per second received and sent. The maximum response time was found to be 0.12 seconds; no server or client errors of any kind were detected. In conclusion, the system can readily be used by clinicians and biomedical researchers in a translational medicine setting.


Assuntos
Informática Médica/métodos , Pesquisa Médica Translacional/métodos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/terapia , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos de Coortes , Bases de Dados Factuais , Sistemas de Apoio a Decisões Clínicas , Frequência do Gene , Genótipo , Humanos , Internet , Metaboloma , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/terapia , Sorologia , Fatores de Tempo , Resultado do Tratamento , Interface Usuário-Computador
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