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1.
Sci Rep ; 9(1): 15057, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636323

RESUMO

Lung cancer is the leading cause of cancer-related deaths among men and women in the world, accounting for the 25% of cancer mortality. Early diagnosis is an unmet clinical issue. In this work, we focused to develop a novel approach to identify highly sensitive and specific biomarkers by investigating the use of extracellular vesicles (EVs) isolated from the pleural lavage, a proximal fluid in lung cancer patients, as a source of potential biomarkers. We isolated EVs by ultracentrifuge method from 25 control pleural fluids and 21 pleural lavages from lung cancer patients. Analysis of the expression of EV-associated miRNAs was performed using Taqman OpenArray technology through which we could detect 288 out of the 754 miRNAs that were contained in the OpenArray. The differential expression analysis yielded a list of 14 miRNAs that were significantly dysregulated (adj. p-value < 0.05 and logFC lower or higher than 3). Using Machine Learning approach we discovered the lung cancer diagnostic biomarkers; miRNA-1-3p, miRNA-144-5p and miRNA-150-5p were found to be the best by accuracy. Accordance with our finding, these miRNAs have been related to cancer processes in previous studies. This results opens the avenue to the use of EV-associated miRNA of pleural fluids and lavages as an untapped source of biomarkers, and specifically, identifies miRNA-1-3p, miRNA-144-5p and miRNA 150-5p as promising biomarkers of lung cancer diagnosis.

2.
J Exp Med ; 216(10): 2427-2447, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31324740

RESUMO

Signal strength controls the outcome of αß T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2-/- mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2-/- mice have reduced affinity for MOG/I-Ab tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2-/- mice, suggesting their involvement in autoimmunity.

3.
J Transl Med ; 17(1): 208, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221189

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Current systematic methods for diagnosing have inherent limitations so development of a minimally-invasive diagnosis, based on the identification of sensitive biomarkers in liquid biopsies could therefore facilitate screening among population at risk. METHODS: In this study, we aim to develop a novel approach to identify highly sensitive and specific biomarkers by investigating the use of extracellular vesicles (EVs) isolated from the peritoneal lavage as a source of potential miRNA diagnostic biomarkers. We isolated EVs by ultracentrifugation from 25 ascitic fluids and 25 peritoneal lavages from non-cancer and CRC patients, respectively. Analysis of the expression of EV-associated miRNAs was performed using Taqman OpenArray technology through which we could detect 371 miRNAs. RESULTS: 210 miRNAs were significantly dysregulated (adjusted p value < 0.05 and abs(logFC) ≥ 1). The top-10 miRNAs, which had the AUC value higher than 0.95, were miRNA-199b-5p, miRNA-150-5p, miRNA-29c-5p, miRNA-218-5p, miRNA-99a-3p, miRNA-383-5p, miRNA-199a-3p, miRNA-193a-5p, miRNA-10b-5p and miRNA-181c-5p. CONCLUSIONS: This finding opens the avenue to the use of EV-associated miRNA of peritoneal lavages as an untapped source of biomarkers for CRC.

4.
Nucleic Acids Res ; 47(W1): W600-W604, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31106365

RESUMO

We present a new web application to query and visualize time-series behavioral data: the Pergola web-server. This server provides a user-friendly interface for exploring longitudinal behavioral data taking advantage of the Pergola Python library. Using the server, users can process the data applying some basic operations, such as binning or grouping, while formatting the data into existing genomic formats. Thanks to this repurposing of genomics standards, the application automatically renders an interactive data visualization based on sophisticated genome visualization tools. Our tool allows behavioral scientists to share, display and navigate complex behavioral data comprising multiple individuals and multiple data types, in a scalable and flexible manner. A download option allows for further analysis using genomic tools. The server can be a great resource for the field in a time where behavioral science is entering a data-intensive cycle thanks to high-throughput behavioral phenotyping platforms. Pergola is publicly available at http://pergola.crg.eu/.

5.
Microbiome ; 6(1): 218, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522523

RESUMO

BACKGROUND: The oral cavity comprises a rich and diverse microbiome, which plays important roles in health and disease. Previous studies have mostly focused on adult populations or in very young children, whereas the adolescent oral microbiome remains poorly studied. Here, we used a citizen science approach and 16S profiling to assess the oral microbiome of 1500 adolescents around Spain and its relationships with lifestyle, diet, hygiene, and socioeconomic and environmental parameters. RESULTS: Our results provide a detailed snapshot of the adolescent oral microbiome and how it varies with lifestyle and other factors. In addition to hygiene and dietary habits, we found that the composition of tap water was related to important changes in the abundance of several bacterial genera. This points to an important role of drinking water in shaping the oral microbiota, which has been so far poorly explored. Overall, the microbiome samples of our study can be clustered into two broad compositional patterns (stomatotypes), driven mostly by Neisseria and Prevotella, respectively. These patterns show striking similarities with those found in unrelated populations. CONCLUSIONS: We hypothesize that these stomatotypes represent two possible global optimal equilibria in the oral microbiome that reflect underlying constraints of the human oral niche. As such, they should be found across a variety of geographical regions, lifestyles, and ages.

6.
iScience ; 9: 244-257, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30419504

RESUMO

The growing appetite of behavioral neuroscience for automated data production is prompting the need for new computational standards allowing improved interoperability, reproducibility, and shareability. We show here how these issues can be solved by repurposing existing genomic formats whose structure perfectly supports the handling of time series. This allows existing genomic analysis and visualization tools to be deployed onto behavioral data. As a proof of principle, we implemented the conversion procedure in Pergola, an open source software, and used genomics tools to reproduce results obtained in mouse, fly, and worm. We also show how common genomics techniques such as principal component analysis, hidden Markov modeling, and volcano plots can be deployed on the reformatted behavioral data. These analyses are easy to share because they depend on the scripting of public software. They are also easy to reproduce thanks to their integration within Nextflow, a workflow manager using containerized software.

7.
Genome Res ; 27(10): 1759-1768, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28855263

RESUMO

Alternative splicing (AS) generates remarkable regulatory and proteomic complexity in metazoans. However, the functions of most AS events are not known, and programs of regulated splicing remain to be identified. To address these challenges, we describe the Vertebrate Alternative Splicing and Transcription Database (VastDB), the largest resource of genome-wide, quantitative profiles of AS events assembled to date. VastDB provides readily accessible quantitative information on the inclusion levels and functional associations of AS events detected in RNA-seq data from diverse vertebrate cell and tissue types, as well as developmental stages. The VastDB profiles reveal extensive new intergenic and intragenic regulatory relationships among different classes of AS and previously unknown and conserved landscapes of tissue-regulated exons. Contrary to recent reports concluding that nearly all human genes express a single major isoform, VastDB provides evidence that at least 48% of multiexonic protein-coding genes express multiple splice variants that are highly regulated in a cell/tissue-specific manner, and that >18% of genes simultaneously express multiple major isoforms across diverse cell and tissue types. Isoforms encoded by the latter set of genes are generally coexpressed in the same cells and are often engaged by translating ribosomes. Moreover, they are encoded by genes that are significantly enriched in functions associated with transcriptional control, implying they may have an important and wide-ranging role in controlling cellular activities. VastDB thus provides an unprecedented resource for investigations of AS function and regulation.


Assuntos
Processamento Alternativo , Bases de Dados de Ácidos Nucleicos , Éxons , Redes Reguladoras de Genes , Isoformas de Proteínas , Animais , Galinhas , Humanos , Camundongos , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética
8.
Eur Respir J ; 49(4)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28404649

RESUMO

The healthy lung has previously been considered to be a sterile organ because standard microbiological culture techniques consistently yield negative results. However, culture-independent techniques report that large numbers of microorganisms coexist in the lung. There are many unknown aspects in the field, but available reports show that the lower respiratory tract microbiota: 1) is similar in healthy subjects to the oropharyngeal microbiota and dominated by members of the Firmicutes, Bacteroidetes and Proteobacteria phyla; 2) shows changes in smokers and well-defined differences in chronic respiratory diseases, although the temporal and spatial kinetics of these changes are only partially known; and 3) shows relatively abundant non-cultivable bacteria in chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and bronchiectasis, with specific patterns for each disease. In all of these diseases, a loss of diversity, paralleled by an over-representation of Proteobacteria (dysbiosis), has been related to disease severity and exacerbations. However, it is unknown whether dysbiosis is a cause or a consequence of the damage to bronchoalveolar surfaces.Finally, little is known about bacterial functionality and the interactions between viruses, fungi and bacteria. It is expected that future research in bacterial gene expressions, metagenomics longitudinal analysis and host-microbiome animal models will help to move towards targeted microbiome interventions in respiratory diseases.


Assuntos
Bacteroidetes/classificação , Pulmão/microbiologia , Microbiota , Proteobactérias/classificação , Pneumologia , Animais , Bronquiectasia/microbiologia , Fibrose Cística/microbiologia , Disbiose , Interações Hospedeiro-Patógeno , Humanos , Pneumonias Intersticiais Idiopáticas/microbiologia , Camundongos , Doença Pulmonar Obstrutiva Crônica/microbiologia , Fatores de Risco , Terminologia como Assunto
9.
PLoS Comput Biol ; 13(3): e1005341, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28253259

RESUMO

CRISPR-Cas9 technology can be used to engineer precise genomic deletions with pairs of single guide RNAs (sgRNAs). This approach has been widely adopted for diverse applications, from disease modelling of individual loci, to parallelized loss-of-function screens of thousands of regulatory elements. However, no solution has been presented for the unique bioinformatic design requirements of CRISPR deletion. We here present CRISPETa, a pipeline for flexible and scalable paired sgRNA design based on an empirical scoring model. Multiple sgRNA pairs are returned for each target, and any number of targets can be analyzed in parallel, making CRISPETa equally useful for focussed or high-throughput studies. Fast run-times are achieved using a pre-computed off-target database. sgRNA pair designs are output in a convenient format for visualisation and oligonucleotide ordering. We present pre-designed, high-coverage library designs for entire classes of protein-coding and non-coding elements in human, mouse, zebrafish, Drosophila melanogaster and Caenorhabditis elegans. In human cells, we reproducibly observe deletion efficiencies of ≥50% for CRISPETa designs targeting an enhancer and exonic fragment of the MALAT1 oncogene. In the latter case, deletion results in production of desired, truncated RNA. CRISPETa will be useful for researchers seeking to harness CRISPR for targeted genomic deletion, in a variety of model organisms, from single-target to high-throughput scales.


Assuntos
Proteínas Associadas a CRISPR/genética , Deleção de Genes , Edição de Genes/métodos , Técnicas de Silenciamento de Genes/métodos , Edição de RNA/genética , RNA Guia/genética
10.
Sci Rep ; 7: 44138, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28281571

RESUMO

Opitz trigonocephaly C syndrome (OTCS) is a rare genetic disorder characterized by craniofacial anomalies, variable intellectual and psychomotor disability, and variable cardiac defects with a high mortality rate. Different patterns of inheritance and genetic heterogeneity are known in this syndrome. Whole exome and genome sequencing of a 19-year-old girl (P7), initially diagnosed with OTCS, revealed a de novo nonsense mutation, p.Q638*, in the MAGEL2 gene. MAGEL2 is an imprinted, maternally silenced, gene located at 15q11-13, within the Prader-Willi region. Patient P7 carried the mutation in the paternal chromosome. Recently, mutations in MAGEL2 have been described in Schaaf-Yang syndrome (SHFYNG) and in severe arthrogryposis. Patient P7 bears resemblances with SHFYNG cases but has other findings not described in this syndrome and common in OTCS. We sequenced MAGEL2 in nine additional OTCS patients and no mutations were found. This study provides the first clear molecular genetic basis for an OTCS case, indicates that there is overlap between OTCS and SHFYNG syndromes, and confirms that OTCS is genetically heterogeneous. Genes encoding MAGEL2 partners, either in the retrograde transport or in the ubiquitination-deubiquitination complexes, are promising candidates as OTCS disease-causing genes.


Assuntos
Craniossinostoses , Deficiência Intelectual , Mutação de Sentido Incorreto , Proteínas , Adulto , Craniossinostoses/genética , Craniossinostoses/metabolismo , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Proteínas/genética , Proteínas/metabolismo
12.
PLoS One ; 10(5): e0127108, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26001197

RESUMO

Human RSV is one of the most prevalent viral pathogens of early childhood for which no vaccine is available. Herein we provide an analysis of RSV epitope data to examine its application to vaccine design and development. Our objective was to provide an overview of antigenic coverage, identify critical antibody and T cell determinants, and then analyze the cumulative RSV epitope data from the standpoint of functional responses using a combinational approach to characterize antigenic structure and epitope location. A review of the cumulative data revealed, not surprisingly, that the vast majority of epitopes have been defined for the two major surface antigens, F and G. Antibody and T cell determinants have been reported from multiple hosts, including those from human subjects following natural infection, however human data represent a minority of the data. A structural analysis of the major surface antigen, F, showed that the majority of epitopes defined for functional antibodies (neutralizing and/or protective) were either shown to bind pre-F or to be accessible in both pre- and post-F forms. This finding may have has implications for on-going vaccine design and development. These interpretations are in agreement with previous work and can be applied in the larger context of functional epitopes on the F protein. It is our hope that this work will provide the basis for further RSV-specific epitope discovery and investigation into the nature of antigen conformation in immunogenicity.


Assuntos
Anticorpos Antivirais/imunologia , Epitopos/imunologia , Imunidade/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Humanos
13.
Nucleic Acids Res ; 43(Database issue): D405-12, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25300482

RESUMO

The IEDB, www.iedb.org, contains information on immune epitopes--the molecular targets of adaptive immune responses--curated from the published literature and submitted by National Institutes of Health funded epitope discovery efforts. From 2004 to 2012 the IEDB curation of journal articles published since 1960 has caught up to the present day, with >95% of relevant published literature manually curated amounting to more than 15,000 journal articles and more than 704,000 experiments to date. The revised curation target since 2012 has been to make recent research findings quickly available in the IEDB and thereby ensure that it continues to be an up-to-date resource. Having gathered a comprehensive dataset in the IEDB, a complete redesign of the query and reporting interface has been performed in the IEDB 3.0 release to improve how end users can access this information in an intuitive and biologically accurate manner. We here present this most recent release of the IEDB and describe the user testing procedures as well as the use of external ontologies that have enabled it.


Assuntos
Bases de Dados de Proteínas , Epitopos/química , Proteínas/química , Proteínas/imunologia , Internet
14.
J Immunol ; 192(7): 3121-32, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24591377

RESUMO

The transcription factor NF-κB is a regulator of inflammatory and adaptive immune responses, yet only IκBα was shown to limit NF-κB activation and inflammatory responses. We investigated another negative feedback regulator, IκBε, in the regulation of B cell proliferation and survival. Loss of IκBε resulted in increased B cell proliferation and survival in response to both antigenic and innate stimulation. NF-κB activity was elevated during late-phase activation, but the dimer composition was stimulus specific. In response to IgM, cRel dimers were elevated in IκBε-deficient cells, yet in response to LPS, RelA dimers also were elevated. The corresponding dimer-specific sequences were found in the promoters of hyperactivated genes. Using a mathematical model of the NF-κB-signaling system in B cells, we demonstrated that kinetic considerations of IκB kinase-signaling input and IκBε's interactions with RelA- and cRel-specific dimers could account for this stimulus specificity. cRel is known to be the key regulator of B cell expansion. We found that the RelA-specific phenotype in LPS-stimulated cells was physiologically relevant: unbiased transcriptome profiling revealed that the inflammatory cytokine IL-6 was hyperactivated in IκBε(-/-) B cells. When IL-6R was blocked, LPS-responsive IκBε(-/-) B cell proliferation was reduced to near wild-type levels. Our results provide novel evidence for a critical role for immune-response functions of IκBε in B cells; it regulates proliferative capacity via at least two mechanisms involving cRel- and RelA-containing NF-κB dimers. This study illustrates the importance of kinetic considerations in understanding the functional specificity of negative-feedback regulators.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Quinase I-kappa B/imunologia , Proteínas Proto-Oncogênicas c-rel/imunologia , Fator de Transcrição RelA/imunologia , Algoritmos , Animais , Linfócitos B/metabolismo , Western Blotting , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Retroalimentação Fisiológica/efeitos dos fármacos , Citometria de Fluxo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-6/metabolismo , Cinética , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Multimerização Proteica/imunologia , Proteínas Proto-Oncogênicas c-rel/química , Proteínas Proto-Oncogênicas c-rel/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Fator de Transcrição RelA/química , Fator de Transcrição RelA/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/imunologia
15.
PLoS Curr ; 62014 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-25642381

RESUMO

BACKGROUND: Several monoclonal antibodies (mAb) are being evaluated as treatment options for the current 2014 Ebola outbreak. But they were derived from and tested for protection against the older 1976 Mayinga or 1995 Kikwit Zaire Ebolaviruses (EBOV). The EBOV sequences reported for the current outbreak contain several mutations whose significance remained to be established. METHODS: We analyzed sequence and structural conservation of the Ebolavirus glycoprotein (GP) epitopes for all experimentally identified protective mAbs published to date. RESULTS: The conservancy analysis of protective mAb epitopes in the Ebolavirus glycoprotein sequences spanning all Ebola virus lineages since 1976 showed that conservancy within the Zaire EBOV lineage was high, with only one immunodominant epitope of mAb 13F6-1-2 acquiring two novel mutations in the 2014 outbreak that might potentially change the antibody specificity and neutralization activity. However, the conservation to other Ebola viruses was unexpectedly low. CONCLUSION: Low conservancy of Zaire EBOV mAb epitopes to other EBOV lineages suggests that these epitopes are not indispensable for viral fitness, and that alternative mAbs could be developed to broadly target all EBOV. However, average percent sequence identity of the epitopes for mAbs used in current cocktails to the Zaire EBOV is high with only one epitope differing in the 2014 outbreak. These data bode well for general usefulness of these antibodies in the context of the current outbreak.

16.
Nat Immunol ; 13(12): 1162-70, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23086447

RESUMO

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Linfocitária , NF-kappa B/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Quinase I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Multimerização Proteica , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Fator de Transcrição RelB/genética
17.
Nucleic Acids Res ; 40(Web Server issue): W525-30, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22610854

RESUMO

The immune epitope database analysis resource (IEDB-AR: http://tools.iedb.org) is a collection of tools for prediction and analysis of molecular targets of T- and B-cell immune responses (i.e. epitopes). Since its last publication in the NAR webserver issue in 2008, a new generation of peptide:MHC binding and T-cell epitope predictive tools have been added. As validated by different labs and in the first international competition for predicting peptide:MHC-I binding, their predictive performances have improved considerably. In addition, a new B-cell epitope prediction tool was added, and the homology mapping tool was updated to enable mapping of discontinuous epitopes onto 3D structures. Furthermore, to serve a wider range of users, the number of ways in which IEDB-AR can be accessed has been expanded. Specifically, the predictive tools can be programmatically accessed using a web interface and can also be downloaded as software packages.


Assuntos
Epitopos de Linfócito B/química , Epitopos de Linfócito T/química , Software , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Internet , Peptídeos/imunologia , Homologia Estrutural de Proteína
18.
BMC Genomics ; 13: 35, 2012 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-22260095

RESUMO

BACKGROUND: With the growth of biological data in volume and heterogeneity, web search engines become key tools for researchers. However, general-purpose search engines are not specialized for the search of biological data. DESCRIPTION: Here, we present an approach at developing a biological web search engine based on the Semantic Web technologies and demonstrate its implementation for retrieving gene- and protein-centered knowledge. The engine is available at http://www.integromedb.org. CONCLUSIONS: The IntegromeDB search engine allows scanning data on gene regulation, gene expression, protein-protein interactions, pathways, metagenomics, mutations, diseases, and other gene- and protein-related data that are automatically retrieved from publicly available databases and web pages using biological ontologies. To perfect the resource design and usability, we welcome and encourage community feedback.


Assuntos
Biologia Computacional/métodos , Bases de Dados Factuais , Expressão Gênica , Internet , Metagenômica , Mapeamento de Interação de Proteínas , Proteínas/genética , Ferramenta de Busca , Software
19.
PLoS One ; 7(12): e52836, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285197

RESUMO

BACKGROUND: Gene regulatory networks (GRNs) provide insight into the mechanisms of differential gene expression at a system level. However, the methods for inference, functional analysis and visualization of gene regulatory modules and GRNs require the user to collect heterogeneous data from many sources using numerous bioinformatics tools. This makes the analysis expensive and time-consuming. RESULTS: In this work, the BiologicalNetworks application-the data integration and network based research environment-was extended with tools for inference and analysis of gene regulatory modules and networks. The backend database of the application integrates public data on gene expression, pathways, transcription factor binding sites, gene and protein sequences, and functional annotations. Thus, all data essential for the gene regulation analysis can be mined publicly. In addition, the user's data can either be integrated in the database and become public, or kept private within the application. The capabilities to analyze multiple gene expression experiments are also provided. CONCLUSION: The generated modular networks, regulatory modules and binding sites can be visualized and further analyzed within this same application. The developed tools were applied to the mouse model of asthma and the OCT4 regulatory network in embryonic stem cells. Developed methods and data are available through the Java application from BiologicalNetworks program at http://www.biologicalnetworks.org.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Animais , Asma/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Internet , Camundongos , Fator 3 de Transcrição de Octâmero/genética , Software
20.
Sci Signal ; 4(161): ra11, 2011 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-21343618

RESUMO

The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. Members of the nuclear factor κB (NF-κB) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the κB site and the IFN response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-κB p50 homodimer as a regulator of IRF responses. Unbiased genome-wide expression and biochemical and structural analyses revealed that the p50 homodimer repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences. Mathematical modeling predicted that the p50 homodimer might enforce the stimulus specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-ß was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE-containing IFNß enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-ß in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-κB p50 homodimer in enforcing the specificity of the cellular response to pathogens by binding to a subset of IRE sequences alters our understanding of how the NF-κB and IRF signaling systems cooperate to regulate antimicrobial immunity.


Assuntos
Imunidade Inata , Interferons/metabolismo , Subunidade p50 de NF-kappa B/fisiologia , Animais , Sequência de Bases , Linhagem Celular , Sondas de DNA , Humanos , Camundongos , Camundongos Endogâmicos C57BL
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