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Zhang H.,Virginia Polytechnic Institute and State University | Karyala S.V.,Virginia Bioinformatics Institute | Settlage R.,Virginia Bioinformatics Institute | Luo X.M.,Virginia Polytechnic Institute and State University
ISME Journal | Year: 2015

It has long been recognized that the mammalian gut microbiota has a role in the development and activation of the host immune system. Much less is known on how host immunity regulates the gut microbiota. Here we investigated the role of adaptive immunity on the mouse distal gut microbial composition by sequencing 16 S rRNA genes from microbiota of immunodeficient Rag1 -/- mice, versus wild-type mice, under the same housing environment. To detect possible interactions among immunological status, age and variability from anatomical sites, we analyzed samples from the cecum, colon, colonic mucus and feces before and after weaning. High-throughput sequencing showed that Firmicutes, Bacteroidetes and Verrucomicrobia dominated mouse gut bacterial communities. Rag1 - mice had a distinct microbiota that was phylogenetically different from wild-type mice. In particular, the bacterium Akkermansia muciniphila was highly enriched in Rag1 -/- mice compared with the wild type. This enrichment was suppressed when Rag1 -/- mice received bone marrows from wild-type mice. The microbial community diversity increased with age, albeit the magnitude depended on Rag1 status. In addition, Rag1 -/- mice had a higher gain in microbiota richness and evenness with increase in age compared with wild-type mice, possibly due to the lack of pressure from the adaptive immune system. Our results suggest that adaptive immunity has a pervasive role in regulating gut microbiota's composition and diversity. © 2015 International Society for Microbial Ecology All rights reserved.

Firczuk H.,University of Warwick | Kannambath S.,University of Warwick | Pahle J.,University of Manchester | Pahle J.,Virginia Bioinformatics Institute | And 8 more authors.
Molecular Systems Biology | Year: 2013

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNA i to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis. © 2013 EMBO and Macmillan Publishers Limited.

Sun D.,University of Virginia | Lee Y.S.,University of Virginia | Malhotra A.,University of Virginia | Kim H.K.,University of Virginia | And 5 more authors.
Cancer Research | Year: 2011

MicroRNAs (miRNA) have been globally profiled in cancers but there tends to be poor agreement between studies including in the same cancers. In addition, few putative miRNA targets have been validated. To overcome the lack of reproducibility, we profiled miRNAs by next generation sequencing and locked nucleic acid miRNA microarrays and verified concordant changes by quantitative RT-PCR. Notably, miR-125b and the miR-99 family members miR-99a, -99b, and -100 were downregulated in all assays in advanced prostate cancer cell lines relative to the parental cell lines from which they were derived. All four miRNAs were also downregulated in human prostate tumor tissue compared with normal prostate. Transfection of miR-99a, -99b, or -100 inhibited the growth of prostate cancer cells and decreased the expression of prostate-specific antigen (PSA), suggesting potential roles as tumor suppressors in this setting. To identify targets of these miRNAs, we combined computational prediction of potential targets with experimental validation by microarray and polyribosomal loading analysis. Three direct targets of the miR-99 family that were validated in this manner were the chromatin-remodeling factors SMARCA5 and SMARCD1 and the growth regulatory kinase mTOR. We determined that PSA is posttranscriptionally regulated by the miR-99 family members, at least partially, by repression of SMARCA5. Together, our findings suggest key functions and targets of miR-99 family members in prostate cancer suppression and prognosis. ©2011 AACR.

Dyer M.D.,Virginia Bioinformatics Institute | Nef C.,Myriad Genetics | Dufford M.,Myriad Genetics | Rivera C.G.,Virginia Polytechnic Institute and State University | And 4 more authors.
PLoS ONE | Year: 2010

Background: Bacillus anthracis, Francisella tularensis, and Yersinia pestis are bacterial pathogens that can cause anthrax,lethal acute pneumonic disease, and bubonic plague, respectively, and are listed as NIAID Category A priority pathogens forpossible use as biological weapons. However, the interactions between human proteins and proteins in these bacteriaremain poorly characterized leading to an incomplete understanding of their pathogenesis and mechanisms of immuneevasion.Methodology: In this study, we used a high-throughput yeast two-hybrid assay to identify physical interactions betweenhuman proteins and proteins from each of these three pathogens. From more than 250,000 screens performed, weidentified 3,073 human-B. anthracis, 1,383 human-F. tularensis, and 4,059 human-Y. pestis protein-protein interactionsincluding interactions involving 304 B. anthracis, 52 F. tularensis, and 330 Y. pestis proteins that are uncharacterized.Computational analysis revealed that pathogen proteins preferentially interact with human proteins that are hubs andbottlenecks in the human PPI network. In addition, we computed modules of human-pathogen PPIs that are conservedamongst the three networks. Functionally, such conserved modules reveal commonalities between how the differentpathogens interact with crucial host pathways involved in inflammation and immunity.Significance: These data constitute the first extensive protein interaction networks constructed for bacterial pathogens andtheir human hosts. This study provides novel insights into host-pathogen interactions. © 2010 Dyer et al.

Stewart J.E.,Washington State University | Stewart J.E.,University of Georgia | Timmer L.W.,University of Florida | Lawrence C.B.,Virginia Bioinformatics Institute | And 2 more authors.
BMC Evolutionary Biology | Year: 2014

Background: Traditional morphological and biological species concepts are difficult to apply to closely related, asexual taxa because of the lack of an active sexual phase and paucity of morphological characters. Phylogenetic species concepts such as genealogical concordance phylogenetic species recognition (GCPSR) have been extensively used; however, methods that incorporate gene tree uncertainty into species recognition may more accurately and objectively delineate species. Using a worldwide sample of Alternaria alternata sensu lato, causal agent of citrus brown spot, the evolutionary histories of four nuclear loci including an endo-polygalacturonase gene, two anonymous loci, and one microsatellite flanking region were estimated using the coalescent. Species boundaries were estimated using several approaches including those that incorporate uncertainty in gene genealogies when lineage sorting and non-reciprocal monophyly of gene trees is common. Results: Coalescent analyses revealed three phylogenetic lineages strongly influenced by incomplete lineage sorting and recombination. Divergence of the citrus 2 lineage from the citrus 1 and citrus 3 lineages was supported at most loci. A consensus of species tree estimation methods supported two species of Alternaria causing citrus brown spot worldwide. Based on substitution rates at the endo-polygalacturonase locus, divergence of the citrus 2 and the 1 and 3 lineages was estimated to have occurred at least 5, 400 years before present, predating the human-mediated movement of citrus and associated pathogens out of SE Asia. Conclusions: The number of Alternaria species identified as causing brown spot of citrus worldwide using morphological criteria has been overestimated. Little support was found for most of these morphospecies using quantitative species recognition approaches. Correct species delimitation of plant-pathogenic fungi is critical for understanding the evolution of pathogenicity, introductions of pathogens to new areas, and for regulating the movement of pathogens to enforce quarantines. This research shows that multilocus phylogenetic methods that allow for recombination and incomplete lineage sorting can be useful for the quantitative delimitation of asexual species that are morphologically indistinguishable. Two phylogenetic species of Alternaria were identified as causing citrus brown spot worldwide. Further research is needed to determine how these species were introduced worldwide, how they differ phenotypically and how these species are maintained. © 2014Stewart et al.; licensee BioMed Central Ltd.

Gopaul K.K.,Veterinary Laboratories Agency | Sells J.,Veterinary Laboratories Agency | Bricker B.J.,Bacterial Diseases of Livestock | Crasta O.R.,Virginia Bioinformatics Institute | Whatmore A.M.,Veterinary Laboratories Agency
Journal of Clinical Microbiology | Year: 2010

The reliable differentiation of live Brucella vaccine strains from field isolates is an important element in brucellosis control programs. We describe the design, validation, and implementation of a novel single nucleotide polymorphism (SNP)-based typing platform that offers a rapid, reliable, and robust tool to achieve this with improved diagnostic accuracy compared to existing molecular tests. Furthermore, the assays described are designed such that they supplement, and can be run as an intrinsic part of, a previously described assay identifying Brucella isolates to the species level (K. K. Gopaul, C. J. Smith, M. S. Koylass, and A. M. Whatmore, BMC Microbiol. 8:86), giving a comprehensive molecular typing platform. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Zook J.M.,U.S. National Institute of Standards and Technology | Chapman B.,Harvard University | Wang J.,Arpeggi Inc. | Mittelman D.,Arpeggi Inc. | And 4 more authors.
Nature Biotechnology | Year: 2014

Clinical adoption of human genome sequencing requires methods that output genotypes with known accuracy at millions or billions of positions across a genome. Because of substantial discordance among calls made by existing sequencing methods and algorithms, there is a need for a highly accurate set of genotypes across a genome that can be used as a benchmark. Here we present methods to make high-confidence, single-nucleotide polymorphism (SNP), indel and homozygous reference genotype calls for NA12878, the pilot genome for the Genome in a Bottle Consortium. We minimize bias toward any method by integrating and arbitrating between 14 data sets from five sequencing technologies, seven read mappers and three variant callers. We identify regions for which no confident genotype call could be made, and classify them into different categories based on reasons for uncertainty. Our genotype calls are publicly available on the Genome Comparison and Analytic Testing website to enable real-time benchmarking of any method. © 2014 Nature America, Inc.

Sun Z.,Virginia Bioinformatics Institute | Errami M.,Collin College | Long T.,Virginia Bioinformatics Institute | Renard C.,Collin College | And 2 more authors.
PLoS ONE | Year: 2010

Background: Computational methods have been used to find duplicate biomedical publications in MEDLINE. Full text articles are becoming increasingly available, yet the similarities among them have not been systematically studied. Here, we quantitatively investigated the full text similarity of biomedical publications in PubMed Central. Methodology/Principal Findings: 72,011 full text articles from PubMed Central (PMC) were parsed to generate three different datasets: full texts, sections, and paragraphs. Text similarity comparisons were performed on these datasets using the text similarity algorithm eTBLAST. We measured the frequency of similar text pairs and compared it among different datasets. We found that high abstract similarity can be used to predict high full text similarity with a specificity of 20.1% (95% CI [17.3%, 23.1%]) and sensitivity of 99.999%. Abstract similarity and full text similarity have a moderate correlation (Pearson correlation coefficient: -0.423) when the similarity ratio is above 0.4. Among pairs of articles in PMC, method sections are found to be the most repetitive (frequency of similar pairs, methods: 0.029, introduction: 0.0076, results: 0.0043). In contrast, among a set of manually verified duplicate articles, results are the most repetitive sections (frequency of similar pairs, results: 0.94, methods: 0.89, introduction: 0.82). Repetition of introduction and methods sections is more likely to be committed by the same authors (odds of a highly similar pair having at least one shared author, introduction: 2.31, methods: 1.83, results: 1.03). There is also significantly more similarity in pairs of review articles than in pairs containing one review and one nonreview paper (frequency of similar pairs: 0.0167 and 0.0023, respectively). Conclusion/Significance: While quantifying abstract similarity is an effective approach for finding duplicate citations, a comprehensive full text analysis is necessary to uncover all potential duplicate citations in the scientific literature and is helpful when establishing ethical guidelines for scientific publications. © 2010 Sun et al.

Viladomiu M.,Virginia Bioinformatics Institute | Viladomiu M.,Virginia Polytechnic Institute and State University | Hontecillas R.,Virginia Bioinformatics Institute | Hontecillas R.,Virginia Polytechnic Institute and State University | And 5 more authors.
Journal of Nutritional Biochemistry | Year: 2013

Inflammatory bowel disease (IBD) is a debilitating and widespread immune-mediated illness characterized by excessive inflammatory and effector mucosal responses leading to tissue destruction at the gastrointestinal tract. Interactions among the immune system, the commensal microbiota and the host genotype are thought to underlie the pathogenesis of IBD. However, the precise etiology of IBD remains unknown. Diet-induced changes in the composition of the gut microbiome can modulate the induction of regulatory versus effector immune responses at the gut mucosa and improve health outcomes. Therefore, manipulation of gut microbiota composition and the local production of microbial-derived metabolites by using prebiotics, probiotics and dietary fibers is being explored as a promising avenue of prophylactic and therapeutic intervention against gut inflammation. Prebiotics and fiber carbohydrates are fermented by resident microflora into short chain fatty acids (SCFAs) in the colon. SCFAs then activate peroxisome proliferator-activated receptor (PPAR)γ, a nuclear transcription factor with widely demonstrated anti-inflammatory efficacy in experimental IBD. The activation of PPARγ by naturally ocurring compounds such as conjugated linoleic acid, pomegranate seed oil-derived punicic acid, eleostearic acid and abscisic acid has been explored as nutritional interventions that suppress colitis by directly modulating the host immune response. The aim of this review is to summarize the status of innovative nutritional interventions against gastrointestinal inflammation, their proposed mechanisms of action, preclinical and clinical efficacy as well as bioinformatics and computational modeling approaches that accelerate discovery in nutritional and mucosal immunology research. © 2013 Elsevier Inc.

Davis B.K.,Franklin And Marshall College | Philipson C.,Virginia Bioinformatics Institute | Hontecillas R.,Virginia Bioinformatics Institute | Eden K.,Virginia Bioinformatics Institute | And 3 more authors.
Inflammatory Bowel Diseases | Year: 2014

Pattern recognition receptors are essential mediators of host defense and inflammation in the gastrointestinal system. Recent data have revealed that toll-like receptors and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) function to maintain homeostasis between the host microbiome and mucosal immunity. The NLR proteins are a diverse class of cytoplasmic pattern recognition receptors. In humans, only about half of the identified NLRs have been adequately characterized. The majority of well-characterized NLRs participate in the formation of a multiprotein complex, termed the inflammasome, which is responsible for the maturation of interleukin-1b and interleukin-18. However, recent observations have also uncovered the presence of a novel subgroup of NLRs that function as positive or negative regulators of inflammation through modulating critical signaling pathways, including NF-kB. Dysregulation of specific NLRs from both proinflammatory and inhibitory subgroups have been associated with the development of inflammatory bowel disease (IBD) in genetically susceptible human populations. Our own preliminary retrospective data mining efforts have identified a diverse range of NLRs that are significantly altered at the messenger RNA level in colons from patients with IBD. Likewise, studies using genetically modified mouse strains have revealed that multiple NLR family members have the potential to dramatically modulate the immune response during IBD. Targeting NLR signaling represents a promising and novel therapeutic strategy. However, significant effort is necessary to translate the current understanding of NLR biology into effective therapies. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.

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