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VectorBase (VectorBase.org) is part of the VEuPathDB Bioinformatics Resource Center, providing free online access to multi-omics and population biology data, focusing on arthropod vectors and invertebrates of importance to human health. VectorBase includes genomics and functional genomics data from bed bugs, biting midges, body lice, kissing bugs, mites, mosquitoes, sand flies, ticks, tsetse flies, stable flies, house flies, fruit flies, and a snail intermediate host. Tools include the Search Strategy system and MapVEu, enabling users to interrogate and visualize diverse 'omics and population-level data using a graphical interface (no programming experience required). Users can also analyze their own private data, such as transcriptomic sequences, exploring their results in the context of other publicly-available information in the database. Help Desk: help@vectorbase.org.
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Biología Computacional , Culicidae , Animales , Genómica , Humanos , Invertebrados/genética , Mosquitos VectoresRESUMEN
MicrobiomeDB (http://microbiomeDB.org) is a data discovery and analysis platform that empowers researchers to fully leverage experimental variables to interrogate microbiome datasets. MicrobiomeDB was developed in collaboration with the Eukaryotic Pathogens Bioinformatics Resource Center (http://EuPathDB.org) and leverages the infrastructure and user interface of EuPathDB, which allows users to construct in silico experiments using an intuitive graphical 'strategy' approach. The current release of the database integrates microbial census data with sample details for nearly 14 000 samples originating from human, animal and environmental sources, including over 9000 samples from healthy human subjects in the Human Microbiome Project (http://portal.ihmpdcc.org/). Query results can be statistically analyzed and graphically visualized via interactive web applications launched directly in the browser, providing insight into microbial community diversity and allowing users to identify taxa associated with any experimental covariate.
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Minería de Datos/métodos , Bases de Datos Genéticas , Microbiota , Biología de Sistemas , Animales , Simulación por Computador , Conjuntos de Datos como Asunto , Microbiología Ambiental , Variación Genética , Humanos , Internet , Aplicaciones Móviles , Interfaz Usuario-Computador , Flujo de TrabajoRESUMEN
The host immune response has a critical role not only in protection from human leishmaniasis but also in promoting disease severity. Although candidate gene approaches in mouse models of leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking. To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out. A signature of the L. braziliensis skin lesion was defined, which includes over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways present in cutaneous lesions, generating a testable 'metapathway' model of immunopathology and providing new insights for treatment of human leishmaniasis.
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Genómica/métodos , Leishmania braziliensis/inmunología , Leishmaniasis Cutánea , Úlcera Cutánea , Adolescente , Adulto , Femenino , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Masculino , Persona de Mediana Edad , Psoriasis/genética , Psoriasis/inmunología , Piel/inmunología , Piel/parasitología , Úlcera Cutánea/genética , Úlcera Cutánea/inmunología , Úlcera Cutánea/parasitología , Transcripción Genética/inmunología , Transcriptoma/inmunología , Adulto JovenRESUMEN
Disease progression in response to infection can be strongly influenced by both pathogen burden and infection-induced immunopathology. While current therapeutics focus on augmenting protective immune responses, identifying therapeutics that reduce infection-induced immunopathology are clearly warranted. Despite the apparent protective role for murine CD8⺠T cells following infection with the intracellular parasite Leishmania, CD8⺠T cells have been paradoxically linked to immunopathological responses in human cutaneous leishmaniasis. Transcriptome analysis of lesions from Leishmania braziliensis patients revealed that genes associated with the cytolytic pathway are highly expressed and CD8⺠T cells from lesions exhibited a cytolytic phenotype. To determine if CD8⺠T cells play a causal role in disease, we turned to a murine model. These studies revealed that disease progression and metastasis in L. braziliensis infected mice was independent of parasite burden and was instead directly associated with the presence of CD8⺠T cells. In mice with severe pathology, we visualized CD8⺠T cell degranulation and lysis of L. braziliensis infected cells. Finally, in contrast to wild-type CD8⺠T cells, perforin-deficient cells failed to induce disease. Thus, we show for the first time that cytolytic CD8⺠T cells mediate immunopathology and drive the development of metastatic lesions in cutaneous leishmaniasis.
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Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Leishmania braziliensis/inmunología , Leishmaniasis Cutánea/inmunología , Piel/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Brasil , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Leishmania braziliensis/aislamiento & purificación , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/patología , Leishmaniasis Cutánea/fisiopatología , Leishmaniasis Cutánea Difusa/etiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Piel/parasitología , Piel/patología , Organismos Libres de Patógenos Específicos , Linfocitos T Citotóxicos/parasitología , Linfocitos T Citotóxicos/patologíaRESUMEN
The new release of SchistoDB (http://SchistoDB.net) provides a rich resource of genomic data for key blood flukes (genus Schistosoma) which cause disease in hundreds of millions of people worldwide. SchistoDB integrates whole-genome sequence and annotation of three species of the genus and provides enhanced bioinformatics analyses and data-mining tools. A simple, yet comprehensive web interface provided through the Strategies Web Development Kit is available for the mining and visualization of the data. Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, gene ontology terms, sequence motifs, protein characteristics and phylogenetic relationships. Search strategies can be saved within a user's profile for future retrieval and may also be shared with other researchers using a unique web address.
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Bases de Datos Genéticas , Genoma de los Helmintos , Schistosoma haematobium/genética , Schistosoma japonicum/genética , Schistosoma mansoni/genética , Animales , Genómica , InternetRESUMEN
The TDR Targets Database (http://tdrtargets.org) has been designed and developed as an online resource to facilitate the rapid identification and prioritization of molecular targets for drug development, focusing on pathogens responsible for neglected human diseases. The database integrates pathogen specific genomic information with functional data (e.g. expression, phylogeny, essentiality) for genes collected from various sources, including literature curation. This information can be browsed and queried using an extensive web interface with functionalities for combining, saving, exporting and sharing the query results. Target genes can be ranked and prioritized using numerical weights assigned to the criteria used for querying. In this report we describe recent updates to the TDR Targets database, including the addition of new genomes (specifically helminths), and integration of chemical structure, property and bioactivity information for biological ligands, drugs and inhibitors and cheminformatic tools for querying and visualizing these chemical data. These changes greatly facilitate exploration of linkages (both known and predicted) between genes and small molecules, yielding insight into whether particular proteins may be druggable, effectively allowing the navigation of chemical space in a genomics context.
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Bases de Datos Factuales , Descubrimiento de Drogas , Enfermedades Desatendidas/tratamiento farmacológico , Genoma de los Helmintos , Genómica , Humanos , Enfermedades Desatendidas/microbiología , Enfermedades Desatendidas/parasitología , Preparaciones Farmacéuticas/química , Proteínas/química , Proteínas/genéticaRESUMEN
UNLABELLED: Toxoplasma gondii is a common parasite of animals that also causes a zoonotic infection in humans. Previous studies have revealed a strongly clonal population structure that is shared between North America and Europe, while South American strains show greater genetic diversity and evidence of sexual recombination. The common inheritance of a monomorphic version of chromosome Ia (referred to as ChrIa*) among three clonal lineages from North America and Europe suggests that inheritance of this chromosome might underlie their recent clonal expansion. To further examine the diversity and distribution of ChrIa, we have analyzed additional strains with greater geographic diversity. Our findings reveal that the same haplotype of ChrIa* is found in the clonal lineages from North America and Europe and in older lineages in South America, where sexual recombination is more common. Although lineages from all three continents harbor the same conserved ChrIa* haplotype, strains from North America and Europe are genetically separate from those in South America, and these respective geographic regions show limited evidence of recent mixing. Genome-wide, array-based profiling of polymorphisms provided evidence for an ancestral flow from particular older southern lineages that gave rise to the clonal lineages now dominant in the north. Collectively, these data indicate that ChrIa* is widespread among nonclonal strains in South America and has more recently been associated with clonal expansion of specific lineages in North America and Europe. These findings have significant implications for the spread of genetic loci influencing transmission and virulence in pathogen populations. IMPORTANCE: Understanding parasite population structure is important for evaluating the potential spread of pathogenicity determinants between different geographic regions. Examining the genetic makeup of different isolates of Toxoplasma gondii from around the world revealed that chromosome Ia is highly homogeneous among lineages that predominate on different continents and within genomes that were otherwise quite divergent. This pattern of recent shared ancestry is highly unusual and suggests that some gene(s) found on this chromosome imparts an unusual fitness advantage that has resulted in its recent spread. Although the basis for the conservation of this particularly homogeneous chromosome is unknown, it may have implications for the transmission of infection and spread of human disease.
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Cromosomas , Variación Genética , Toxoplasma/genética , Toxoplasma/patogenicidad , Toxoplasmosis/epidemiología , Toxoplasmosis/parasitología , Animales , Análisis por Conglomerados , ADN Protozoario/genética , Europa (Continente)/epidemiología , Evolución Molecular , Genotipo , Haplotipos , Humanos , Análisis por Micromatrices , Epidemiología Molecular , Tipificación Molecular , América del Norte/epidemiología , Filogeografía , América del Sur/epidemiología , Toxoplasmosis/transmisiónRESUMEN
The increasing availability of genomic data for pathogens that cause tropical diseases has created new opportunities for drug discovery and development. However, if the potential of such data is to be fully exploited, the data must be effectively integrated and be easy to interrogate. Here, we discuss the development of the TDR Targets database (http://tdrtargets.org), which encompasses extensive genetic, biochemical and pharmacological data related to tropical disease pathogens, as well as computationally predicted druggability for potential targets and compound desirability information. By allowing the integration and weighting of this information, this database aims to facilitate the identification and prioritization of candidate drug targets for pathogens.
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Enfermedades Transmisibles , Bases de Datos Genéticas , Diseño de Fármacos , Genoma , Animales , Enfermedades Transmisibles/tratamiento farmacológico , Enfermedades Transmisibles/microbiología , Enfermedades Transmisibles/parasitología , Enfermedades Transmisibles/virología , HumanosRESUMEN
Two replicative forms characterize the asexual cycle of the protozoan parasite Toxoplasma gondii: rapidly growing tachyzoites and slowly dividing encysted bradyzoites. The mechanisms that regulate the transition between these two stages are not clearly understood. However, stress inducers that also activate heat shock protein expression can trigger formation of bradyzoites in vitro. Here, we studied the association of the T.gondii Hsp90 with modulation of parasite differentiation and response to stress stimuli using RH DeltaUPRT parasites and the cystogenic strain ME49 and a clone derivative of that strain, PK. Our results show that Hsp90 transcript and protein levels increase under stress or bradyzoite differentiation conditions. Moreover, fluorescence microscopy studies revealed that Hsp90 is present in the cytosol of tachyzoites and both in the nucleus and cytosol of mature bradyzoites, suggesting a correlation between its subcellular organization and these two developmental stages. To further characterize the role for Hsp90 in bradyzoite differentiation, T.gondii tachyzoite mutants that are defective in differentiation showed the same staining pattern as tachyzoites under differentiation conditions. In addition, geldanamycin, a benzoquinone ansamycin antibiotic capable of binding and disrupting the function of Hsp90, blocked conversion both from the tachyzoite to bradyzoite and the bradyzoite to tachyzoite stage, suggesting an essential role for this protein in the regulation of stage interconversion. These results thus suggest Hsp90 may play a role in stage switch.