RESUMEN
The Papillomavirus Episteme (PaVE) is a database of curated papillomavirus genomic sequences, accompanied by web-based sequence analysis tools. This update describes the addition of major new features. The papillomavirus genomes within PaVE have been further annotated, and now includes the major spliced mRNA transcripts. Viral genes and transcripts can be visualized on both linear and circular genome browsers. Evolutionary relationships among PaVE reference protein sequences can be analysed using multiple sequence alignments and phylogenetic trees. To assist in viral discovery, PaVE offers a typing tool; a simplified algorithm to determine whether a newly sequenced virus is novel. PaVE also now contains an image library containing gross clinical and histopathological images of papillomavirus infected lesions. Database URL: https://pave.niaid.nih.gov/.
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Bases de Datos de Ácidos Nucleicos , Genoma Viral , Genómica/métodos , Papillomaviridae/genética , Filogenia , Biología Computacional/métodos , Anotación de Secuencia Molecular , Papillomaviridae/clasificación , Navegador WebRESUMEN
The goal of the Papillomavirus Episteme (PaVE) is to provide an integrated resource for the analysis of papillomavirus (PV) genome sequences and related information. The PaVE is a freely accessible, web-based tool (http://pave.niaid.nih.gov) created around a relational database, which enables storage, analysis and exchange of sequence information. From a design perspective, the PaVE adopts an Open Source software approach and stresses the integration and reuse of existing tools. Reference PV genome sequences have been extracted from publicly available databases and reannotated using a custom-created tool. To date, the PaVE contains 241 annotated PV genomes, 2245 genes and regions, 2004 protein sequences and 47 protein structures, which users can explore, analyze or download. The PaVE provides scientists with the data and tools needed to accelerate scientific progress for the study and treatment of diseases caused by PVs.
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Bases de Datos Genéticas , Papillomaviridae/genética , Genoma Viral , Genómica , Internet , Anotación de Secuencia Molecular , Análisis de Secuencia , Interfaz Usuario-Computador , Proteínas Virales/química , Proteínas Virales/genéticaRESUMEN
BACKGROUND: DAPfinder and DAPview are novel BRB-ArrayTools plug-ins to construct gene coexpression networks and identify significant differences in pairwise gene-gene coexpression between two phenotypes. RESULTS: Each significant difference in gene-gene association represents a Differentially Associated Pair (DAP). Our tools include several choices of filtering methods, gene-gene association metrics, statistical testing methods and multiple comparison adjustments. Network results are easily displayed in Cytoscape. Analyses of glioma experiments and microarray simulations demonstrate the utility of these tools. CONCLUSIONS: DAPfinder is a new friendly-user tool for reconstruction and comparison of biological networks.
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Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Glioma/genética , Programas Informáticos , Humanos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
The mechanisms by which eukaryotic cells sense DNA double-strand breaks (DSBs) in order to initiate checkpoint responses are poorly understood. 53BP1 is a conserved checkpoint protein with properties of a DNA DSB sensor. Here, we solved the structure of the domain of 53BP1 that recruits it to sites of DSBs. This domain consists of two tandem tudor folds with a deep pocket at their interface formed by residues conserved in the budding yeast Rad9 and fission yeast Rhp9/Crb2 orthologues. In vitro, the 53BP1 tandem tudor domain bound histone H3 methylated on Lys 79 using residues that form the walls of the pocket; these residues were also required for recruitment of 53BP1 to DSBs. Suppression of DOT1L, the enzyme that methylates Lys 79 of histone H3, also inhibited recruitment of 53BP1 to DSBs. Because methylation of histone H3 Lys 79 was unaltered in response to DNA damage, we propose that 53BP1 senses DSBs indirectly through changes in higher-order chromatin structure that expose the 53BP1 binding site.
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Daño del ADN , ADN/metabolismo , Histonas/química , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisina/metabolismo , Fosfoproteínas/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Línea Celular Tumoral , Cromatina/química , Cromatina/metabolismo , Secuencia Conservada , Reactivos de Enlaces Cruzados/química , ADN/química , ADN/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Metilación , Metiltransferasas/deficiencia , Metiltransferasas/genética , Metiltransferasas/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Fosfoproteínas/química , Unión Proteica , Estructura Terciaria de Proteína , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
BACKGROUND: Genetic mapping is a powerful method to identify mutations that cause drug resistance and other phenotypic changes in the human malaria parasite Plasmodium falciparum. For efficient mapping of a target gene, it is often necessary to genotype a large number of polymorphic markers. Currently, a community effort is underway to collect single nucleotide polymorphisms (SNP) from the parasite genome. Here we evaluate polymorphism detection accuracy of a high-density 'tiling' microarray with 2.56 million probes by comparing single feature polymorphisms (SFP) calls from the microarray with known SNP among parasite isolates. RESULTS: We found that probe GC content, SNP position in a probe, probe coverage, and signal ratio cutoff values were important factors for accurate detection of SFP in the parasite genome. We established a set of SFP calling parameters that could predict mSFP (SFP called by multiple overlapping probes) with high accuracy (> or = 94%) and identified 121,087 mSFP genome-wide from five parasite isolates including 40,354 unique mSFP (excluding those from multi-gene families) and approximately 18,000 new mSFP, producing a genetic map with an average of one unique mSFP per 570 bp. Genomic copy number variation (CNV) among the parasites was also cataloged and compared. CONCLUSION: A large number of mSFP were discovered from the P. falciparum genome using a high-density microarray, most of which were in clusters of highly polymorphic genes at chromosome ends. Our method for accurate mSFP detection and the mSFP identified will greatly facilitate large-scale studies of genome variation in the P. falciparum parasite and provide useful resources for mapping important parasite traits.
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Genoma de Protozoos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Plasmodium falciparum/genética , Polimorfismo de Nucleótido Simple , Animales , Composición de Base , Mapeo Cromosómico , Biología Computacional , Sondas de ADN , ADN Protozoario/genética , Dosificación de Gen , Variación Genética , Curva ROC , Sensibilidad y Especificidad , Análisis de Secuencia de ADNRESUMEN
The Mob protein family comprises a group of highly conserved eukaryotic proteins whose founding member functions in the mitotic exit network. At the molecular level, Mob proteins act as kinase-activating subunits. We cloned a human Mob1 family member, Mob1A, and determined its three-dimensional structure by X-ray crystallography. The core of Mob1A consists of a four-helix bundle that is stabilized by a bound zinc atom. The N-terminal helix of the bundle is solvent exposed and together with adjacent secondary structure elements forms an evolutionarily conserved surface with a strong negative electrostatic potential. Several conditional mutant alleles of S. cerevisiae MOB1 target this surface and decrease its net negative charge. Interestingly, the kinases with which yeast Mob proteins interact have two conserved basic regions within their N-terminal lobe. Thus, Mob proteins may regulate their target kinases through electrostatic interactions mediated by conserved charged surfaces.
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Ciclo Celular , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Secuencia de Aminoácidos , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cristalografía por Rayos X , Humanos , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Conformación Proteica , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Homología de Secuencia de Aminoácido , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
The DNA binding domains of human p53 and Cep-1, its C. elegans ortholog, recognize essentially identical DNA sequences despite poor sequence similarity. We solved the three-dimensional structure of the Cep-1 DNA binding domain in the absence of DNA and compared it to that of human p53. The two domains have similar overall folds. However, three loops, involved in DNA and Zn binding in human p53, contain small alpha helices in Cep-1. The alpha helix in loop L3 of Cep-1 orients the side chains of two conserved arginines toward DNA; in human p53, both arginines are mutation hotspots, but only one contacts DNA. The alpha helix in loop L1 of Cep-1 repositions the entire loop, making it unlikely for residues of this loop to contact bases in the major groove of DNA, as occurs in human p53. Thus, during evolution there have been considerable changes in the structure of the p53 DNA binding domain.
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Proteínas de Caenorhabditis elegans/química , Caenorhabditis elegans/metabolismo , Proteína p53 Supresora de Tumor/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Proteínas de Caenorhabditis elegans/metabolismo , Cristalización , Recolección de Datos , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homología Estructural de Proteína , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The Chfr mitotic checkpoint protein is frequently inactivated in human cancer. We determined the three-dimensional structure of its FHA domain in its native form and in complex with tungstate, an analog of phosphate. The structures revealed a beta sandwich fold similar to the previously determined folds of the Rad53 N- and C-terminal FHA domains, except that the Rad53 domains were monomeric, whereas the Chfr FHA domain crystallized as a segment-swapped dimer. The ability of the Chfr FHA domain to recognize tungstate suggests that it shares the ability with other FHA domains to bind phosphoproteins. Nevertheless, differences in the sequence and structure of the Chfr and Rad53 FHA domains suggest that FHA domains can be divided into families with distinct binding properties.
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Proteínas de Ciclo Celular/química , Proteínas de Neoplasias , Compuestos de Tungsteno/química , Secuencia de Aminoácidos , Secuencia Conservada , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas de Unión a Poli-ADP-Ribosa , Estructura Terciaria de Proteína , Ubiquitina-Proteína LigasasRESUMEN
The ATM (mutated in Ataxia-Telangiectasia) protein kinase is an important player in signaling the presence of DNA double strand breaks (DSBs) in higher eukaryotes. Recent studies suggest that ATM monitors the presence of DNA DSBs indirectly, through DNA DSB-induced changes in chromatin structure. One of the proteins that sense these chromatin structure changes is 53BP1, a DNA damage checkpoint protein conserved in all eukaryotes and the putative ortholog of the S. cerevisiae RAD9 protein. We review here the mechanisms by which ATM is activated in response to DNA DSBs, as well as key ATM substrates that control cell cycle progression, apoptosis and DNA repair.
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Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada , ADN/metabolismo , Daño del ADN , Reparación del ADN , Activación Enzimática , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
The advent of Next Generation Sequencing (NGS) technologies has opened new possibilities for researchers. However, the more biology becomes a data-intensive field, the more biologists have to learn how to process and analyze NGS data with complex computational tools. Even with the availability of common pipeline specifications, it is often a time-consuming and cumbersome task for a bench scientist to install and configure the pipeline tools. We believe that a unified, desktop and biologist-friendly front end to NGS data analysis tools will substantially improve productivity in this field. Here we present NGS pipelines "Variant Calling with SAMtools", "Tuxedo Pipeline for RNA-seq Data Analysis" and "Cistrome Pipeline for ChIP-seq Data Analysis" integrated into the Unipro UGENE desktop toolkit. We describe the available UGENE infrastructure that helps researchers run these pipelines on different datasets, store and investigate the results and re-run the pipelines with the same parameters. These pipeline tools are included in the UGENE NGS package. Individual blocks of these pipelines are also available for expert users to create their own advanced workflows.
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The National Institutes of Health (NIH) has launched the NIH 3D Print Exchange, an online portal for discovering and creating bioscientifically relevant 3D models suitable for 3D printing, to provide both researchers and educators with a trusted source to discover accurate and informative models. There are a number of online resources for 3D prints, but there is a paucity of scientific models, and the expertise required to generate and validate such models remains a barrier. The NIH 3D Print Exchange fills this gap by providing novel, web-based tools that empower users with the ability to create ready-to-print 3D files from molecular structure data, microscopy image stacks, and computed tomography scan data. The NIH 3D Print Exchange facilitates open data sharing in a community-driven environment, and also includes various interactive features, as well as information and tutorials on 3D modeling software. As the first government-sponsored website dedicated to 3D printing, the NIH 3D Print Exchange is an important step forward to bringing 3D printing to the mainstream for scientific research and education.
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The era of "big data" presents immense opportunities for scientific discovery and technological progress, with the potential to have enormous impact on research and development in the public sector. In order to capitalize on these benefits, there are significant challenges to overcome in data analytics. The National Institute of Allergy and Infectious Diseases held a symposium entitled "Data Science: Unlocking the Power of Big Data" to create a forum for big data experts to present and share some of the creative and innovative methods to gleaning valuable knowledge from an overwhelming flood of biological data. A significant investment in infrastructure and tool development, along with more and better-trained data scientists, may facilitate methods for assimilation of data and machine learning, to overcome obstacles such as data security, data cleaning, and data integration.
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INTRODUCTION: Meningococcal infections are major causes of death in children globally. In Belarus, the incidence of cases and fatality rate of meningococcal infections are low and comparable to the levels in other European countries. AIM: In the present study, the molecular and epidemiological traits of Neisseria meningitidis strains circulating in Belarus were characterized and compared to isolates from other European countries. MATERIALS AND METHODS: Twenty N. meningitidis strains isolated from patients (n = 13) and healthy contacts (n = 7) during 20062012 in Belarus were selected for multilocus sequence typing (MLST), genosubtyping and FetA typing. TheSTs of the Belarusian strains were phylogenetically compared to the STs of 110 selected strains from 22 other European countries. RESULTS: Overall, eleven different genosubtypes were observed, there were seven variants of variable region of the fet Agene detected. The majority of the STs (95%) found in Belarus were novel and allthose were submitted to the Neisseria MLST database for assignment. Several newly discovered alleles of fumC (allele 451) and gdh (allele 560 and 621) appeared to be descendants of alleles which are widespread in Europe, and single aroE alleles (602 and 603) occurred as a result of separate evolution. CONCLUSIONS: N. meningitidis strains circulating in Belarus are heterogeneous and include sequence types, possibly, locally evolved in Belarus as well as representatives of widespread European hyperinvasive clonal complexes.
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Evolución Molecular , Neisseria meningitidis/genética , Alelos , Humanos , Tipificación de Secuencias Multilocus , Neisseria meningitidis/clasificación , Filogenia , Polimorfismo de Nucleótido Simple , República de BelarúsRESUMEN
The variable regions (VR) of the surface-exposed PorA protein of Meningococci are used for subtyping and are considered the most abundant epitopes of outer membrane vesicle-based vaccine preparations. We have developed both a database that maintains all the known VR3 alleles and a web-based application for the rapid identification and submission of new VR3 variants based on sequence comparison.