@article {49668, title = {The fruRBA operon is necessary for Group A Streptococcal growth in fructose and for resistance to neutrophil killing during growth in whole human blood.}, journal = {Infect Immun}, year = {2016}, month = {2016 Jan 19}, abstract = {

Bacterial pathogens rely on the availability of nutrients for survival in the host environment. The phosphoenolpyruvate-phosphotransferase system (PTS) is a global regulatory network connecting sugar uptake with signal transduction. Since the fructose PTS has been shown to impact virulence in several Streptococci, including the human pathogen S. pyogenes (the group A Streptococcus, GAS), we characterized its role in carbon metabolism and pathogenesis in the M1T1 strain 5448. Growth in fructose as a sole carbon source resulted in 103 genes affected transcriptionally, where the fru locus (fruRBA) was the most induced. RT-PCR showed that fruRBA formed an operon, which was repressed by FruR in the absence of fructose, in addition to being under carbon catabolic repression. Growth assays and carbon utilization profiles revealed that although the entire fru operon was required for growth in fructose, FruA was the main transporter for fructose and was also involved in the utilization of three additional PTS sugars: cellobiose, mannitol, and N-acetyl-D-galactosamine. Inactivation of sloR, a fruA homolog that was also up regulated in presence of fructose, failed to reveal a role as a secondary fructose transporter. Whereas the ability of both ΔfruR and ΔfruB mutants to survive in the presence of whole human blood or neutrophils was impaired, the phenotype was not reproduced in murine whole blood, nor were those mutants attenuated in a mouse intraperitoneal infection. Since the ΔfruA mutant exhibited no phenotype in the human or mouse assays, we propose that FruR and FruB are important for GAS survival in a human-specific environment.

}, issn = {1098-5522}, doi = {10.1128/IAI.01296-15}, author = {Valdes, Kayla M and Sundar, Ganesh S and Vega, Luis A and Belew, Ashton T and Islam, Emrul and Binet, Rachel and El-Sayed, Najib M and Le Breton, Yoann and McIver, Kevin S} } @article {49731, title = {Functional Alignment of Metabolic Networks.}, journal = {J Comput Biol}, year = {2016}, month = {2016 Jan 13}, abstract = {

Network alignment has become a standard tool in comparative biology, allowing the inference of protein function, interaction, and orthology. However, current alignment techniques are based on topological properties of networks and do not take into account their functional implications. Here we propose, for the first time, an algorithm to align two metabolic networks by taking advantage of their coupled metabolic models. These models allow us to assess the functional implications of genes or reactions, captured by the metabolic fluxes that are altered following their deletion from the network. Such implications may spread far beyond the region of the network where the gene or reaction lies. We apply our algorithm to align metabolic networks from various organisms, ranging from bacteria to humans, showing that our alignment can reveal functional orthology relations that are missed by conventional topological alignments.

}, issn = {1557-8666}, doi = {10.1089/cmb.2015.0203}, author = {Mazza, Arnon and Wagner, Allon and Ruppin, Eytan and Sharan, Roded} } @article {49579, title = {Fumarate induces redox-dependent senescence by modifying glutathione metabolism.}, volume = {6}, year = {2015}, month = {2015}, pages = {6001}, abstract = {

Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

}, issn = {2041-1723}, doi = {10.1038/ncomms7001}, author = {Zheng, Liang and Cardaci, Simone and Jerby, Livnat and MacKenzie, Elaine D and Sciacovelli, Marco and Johnson, T Isaac and Gaude, Edoardo and King, Ayala and Leach, Joshua D G and Edrada-Ebel, RuAngelie and Hedley, Ann and Morrice, Nicholas A and Kalna, Gabriela and Blyth, Karen and Ruppin, Eytan and Frezza, Christian and Gottlieb, Eyal} } @article {49859, title = {A framework for human microbiome research}, journal = {Nature}, volume = {486}, year = {2012}, pages = {215{\textendash}221}, author = {Human Microbiome Project Consortium and Todd Treangen} } @article {38264, title = {A framework for human microbiome research}, journal = {NatureNature}, volume = {486}, year = {2012}, author = {Meth{\'e}, B. A. and Nelson, K. E. and M. Pop and Creasy, H. H. and Giglio, M. G. and Huttenhower, C. and Gevers, D. and Petrosino, J. F. and Abubucker, S. and Badger, J. H. and others,} } @article {38270, title = {Functional Divergence of Gene Duplicates a Domain-centric view}, journal = {BMC Evolutionary BiologyBMC Evolutionary Biology}, year = {2012}, author = {Khaladkar, Mugdha and Sridhar Hannenhalli} } @article {49653, title = {Functional genomics of trypanosomatids.}, journal = {Parasite Immunol}, volume = {34}, year = {2012}, month = {2012 Feb-Mar}, pages = {72-9}, abstract = {

The decoding of the Tritryp reference genomes nearly 7 years ago provided a first peek into the biology of pathogenic trypanosomatids and a blueprint that has paved the way for genome-wide studies. Although 60-70\% of the predicted protein coding genes in Trypanosoma brucei, Trypanosoma cruzi and Leishmania major remain unannotated, the functional genomics landscape is rapidly changing. Facilitated by the advent of next-generation sequencing technologies, improved structural and functional annotation and genes and their products are emerging. Information is also growing for the interactions between cellular components as transcriptomes, regulatory networks and metabolomes are characterized, ushering in a new era of systems biology. Simultaneously, the launch of comparative sequencing of multiple strains of kinetoplastids will finally lead to the investigation of a vast, yet to be explored, evolutionary and pathogenomic space.

}, keywords = {Animals, Genome, Protozoan, Genomics, HUMANS, Proteome, Protozoan Proteins, Transcriptome, Trypanosomatina}, issn = {1365-3024}, doi = {10.1111/j.1365-3024.2011.01347.x}, author = {Choi, J and El-Sayed, N M} } @article {38262, title = {Finding Biologically Accurate Clusterings in Hierarchical Tree Decompositions Using the Variation of Information}, journal = {Journal of Computational BiologyJournal of Computational Biology}, volume = {17}, year = {2010}, type = {10.1089/cmb.2009.0173}, abstract = {Hierarchical clustering is a popular method for grouping together similar elements based on a distance measure between them. In many cases, annotations for some elements are known beforehand, which can aid the clustering process. We present a novel approach for decomposing a hierarchical clustering into the clusters that optimally match a set of known annotations, as measured by the variation of information metric. Our approach is general and does not require the user to enter the number of clusters desired. We apply it to two biological domains: finding protein complexes within protein interaction networks and identifying species within metagenomic DNA samples. For these two applications, we test the quality of our clusters by using them to predict complex and species membership, respectively. We find that our approach generally outperforms the commonly used heuristic methods.}, isbn = {1066-5277, 1557-8666}, author = {Navlakha, Saket and White, James and Nagarajan, Niranjan and M. Pop and Kingsford, Carl} } @article {38263, title = {Finishing genomes with limited resources: lessons from an ensemble of microbial genomes}, journal = {BMC GenomicsBMC Genomics}, volume = {11}, year = {2010}, type = {10.1186/1471-2164-11-242}, abstract = {While new sequencing technologies have ushered in an era where microbial genomes can be easily sequenced, the goal of routinely producing high-quality draft and finished genomes in a cost-effective fashion has still remained elusive. Due to shorter read lengths and limitations in library construction protocols, shotgun sequencing and assembly based on these technologies often results in fragmented assemblies. Correspondingly, while draft assemblies can be obtained in days, finishing can take many months and hence the time and effort can only be justified for high-priority genomes and in large sequencing centers. In this work, we revisit this issue in light of our own experience in producing finished and nearly-finished genomes for a range of microbial species in a small-lab setting. These genomes were finished with surprisingly little investments in terms of time, computational effort and lab work, suggesting that the increased access to sequencing might also eventually lead to a greater proportion of finished genomes from small labs and genomics cores.}, isbn = {1471-2164}, author = {Nagarajan, Niranjan and Cook, Christopher and Di Bonaventura, Maria Pia and Ge, Hong and Richards, Allen and Bishop-Lilly, Kimberly A. and DeSalle, Robert and Read, Timothy D. and M. Pop} } @article {38261, title = {Finding Biologically Accurate Clusterings in Hierarchical Decompositions Using the Variation of Information}, journal = {Lecture Notes in Computer Science: Research in Computational Molecular BiologyLecture Notes in Computer Science: Research in Computational Molecular Biology}, volume = {5541}, year = {2009}, author = {Navlakha, S. and White, J. R. and Nagarajan, N. and M. Pop and Kingsford, Carl} } @article {38260, title = {Figaro: A Novel Statistical Method for Vector Sequence Removal}, journal = {BioinformaticsBioinformaticsBioinformaticsBioinformatics}, volume = {24}, year = {2008}, type = {10.1093/bioinformatics/btm632}, abstract = {Motivation: Sequences produced by automated Sanger sequencing machines frequently contain fragments of the cloning vector on their ends. Software tools currently available for identifying and removing the vector sequence require knowledge of the vector sequence, specific splice sites and any adapter sequences used in the experiment{\textemdash}information often omitted from public databases. Furthermore, the clipping coordinates themselves are missing or incorrectly reported. As an example, within the \~{}1.24 billion shotgun sequences deposited in the NCBI Trace Archive, as many as \~{}735 million (\~{}60\%) lack vector clipping information. Correct clipping information is essential to scientists attempting to validate, improve and even finish the increasingly large number of genomes released at a {\textquoteleft}draft{\textquoteright} quality level.Results: We present here Figaro, a novel software tool for identifying and removing the vector from raw sequence data without prior knowledge of the vector sequence. The vector sequence is automatically inferred by analyzing the frequency of occurrence of short oligo-nucleotides using Poisson statistics. We show that Figaro achieves 99.98\% sensitivity when tested on \~{}1.5 million shotgun reads from Drosophila pseudoobscura. We further explore the impact of accurate vector trimming on the quality of whole-genome assemblies by re-assembling two bacterial genomes from shotgun sequences deposited in the Trace Archive. Designed as a module in large computational pipelines, Figaro is fast, lightweight and flexible. Availability: Figaro is released under an open-source license through the AMOS package (http://amos.sourceforge.net/Figaro). Contact: mpop@umiacs.umd.edu}, isbn = {1367-4803, 1460-2059}, author = {White, James Robert and Roberts, Michael and Yorke, James A. and M. Pop} } @article {38271, title = {Functional Diversification of Paralogous Transcription Factors via Divergence in DNA Binding Site Motif and in Expression}, journal = {PLoS ONEPLoS ONEPLoS ONEPLoS ONE}, volume = {3}, year = {2008}, type = {10.1371/journal.pone.0002345}, abstract = {Gene duplication is a major driver of evolutionary innovation as it allows for an organism to elaborate its existing biological functions via specialization or diversification of initially redundant gene paralogs. Gene function can diversify in several ways. Transcription factor gene paralogs in particular, can diversify either by changes in their tissue-specific expression pattern or by changes in the DNA binding site motif recognized by their protein product, which in turn alters their gene targets. The relationship between these two modes of functional diversification of transcription factor paralogs has not been previously investigated, and is essential for understanding adaptive evolution of transcription factor gene families.Based on a large set of human paralogous transcription factor pairs, we show that when the DNA binding site motifs of transcription factor paralogs are similar, the expressions of the genes that encode the paralogs have diverged, so in general, at most one of the paralogs is highly expressed in a tissue. Moreover, paralogs with diverged DNA binding site motifs tend to be diverged in their function. Conversely, two paralogs that are highly expressed in a tissue tend to have dissimilar DNA binding site motifs. We have also found that in general, within a paralogous family, tissue-specific decrease in gene expression is more frequent than what is expected by chance. While previous investigations of paralogous gene diversification have only considered coding sequence divergence, by explicitly quantifying divergence in DNA binding site motif, our work presents a new paradigm for investigating functional diversification. Consistent with evolutionary expectation, our quantitative analysis suggests that paralogous transcription factors have survived extinction in part, either through diversification of their DNA binding site motifs or through alterations in their tissue-specific expression levels.}, author = {Singh, Larry N. and Sridhar Hannenhalli} } @article {38258, title = {Features generated for computational splice-site prediction correspond to functional elements}, journal = {BMC BioinformaticsBMC Bioinformatics}, volume = {8}, year = {2007}, type = {10.1186/1471-2105-8-410}, abstract = {BackgroundAccurate selection of splice sites during the splicing of precursors to messenger RNA requires both relatively well-characterized signals at the splice sites and auxiliary signals in the adjacent exons and introns. We previously described a feature generation algorithm (FGA) that is capable of achieving high classification accuracy on human 3{\textquoteright} splice sites. In this paper, we extend the splice-site prediction to 5{\textquoteright} splice sites and explore the generated features for biologically meaningful splicing signals. Results We present examples from the observed features that correspond to known signals, both core signals (including the branch site and pyrimidine tract) and auxiliary signals (including GGG triplets and exon splicing enhancers). We present evidence that features identified by FGA include splicing signals not found by other methods. Conclusion Our generated features capture known biological signals in the expected sequence interval flanking splice sites. The method can be easily applied to other species and to similar classification problems, such as tissue-specific regulatory elements, polyadenylation sites, promoters, etc.}, isbn = {14712105}, author = {Dogan, Rezarta Islamaj and Getoor, Lise and Wilbur, W. John and Stephen M. Mount} } @article {49678, title = {Features generated for computational splice-site prediction correspond to functional elements.}, journal = {BMC Bioinformatics}, volume = {8}, year = {2007}, month = {2007}, pages = {410}, abstract = {

BACKGROUND: Accurate selection of splice sites during the splicing of precursors to messenger RNA requires both relatively well-characterized signals at the splice sites and auxiliary signals in the adjacent exons and introns. We previously described a feature generation algorithm (FGA) that is capable of achieving high classification accuracy on human 3{\textquoteright} splice sites. In this paper, we extend the splice-site prediction to 5{\textquoteright} splice sites and explore the generated features for biologically meaningful splicing signals.

RESULTS: We present examples from the observed features that correspond to known signals, both core signals (including the branch site and pyrimidine tract) and auxiliary signals (including GGG triplets and exon splicing enhancers). We present evidence that features identified by FGA include splicing signals not found by other methods.

CONCLUSION: Our generated features capture known biological signals in the expected sequence interval flanking splice sites. The method can be easily applied to other species and to similar classification problems, such as tissue-specific regulatory elements, polyadenylation sites, promoters, etc.

}, keywords = {Computational Biology, HUMANS, Predictive Value of Tests, RNA Splice Sites, RNA, Messenger}, issn = {1471-2105}, doi = {10.1186/1471-2105-8-410}, author = {Dogan, Rezarta Islamaj and Getoor, Lise and Wilbur, W John and Mount, Stephen M} } @article {38269, title = {Functional Analysis of Hes-1 in Preadipocytes}, journal = {Molecular EndocrinologyMolecular EndocrinologyMolecular EndocrinologyMolecular Endocrinology}, volume = {20}, year = {2006}, type = {10.1210/me.2005-0325}, abstract = {Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1. Although considered initially to function only as a repressor, recent evidence indicates that Hes-1 can also activate transcription. We show here that the domains of Hes-1 needed to block adipogenesis coincide with those necessary for transcriptional repression. HRT1, another basic-helix-loop-helix protein and potential Hes-1 partner, was also induced by Notch in 3T3-L1 cells but did not block adipogenesis, suggesting that Hes-1 functions primarily as a homodimer or possibly as a heterodimer with an unknown partner. Purification of Hes-1 identified the Groucho/transducin-like enhancer of split family of corepressors as the only significant Hes-1 interacting proteins in vivo. An evaluation of global gene expression in preadipocytes identified approximately 200 Hes-1-responsive genes comprising roughly equal numbers of up-regulated and down-regulated genes. However, promoter analyses indicated that the down-regulated genes were significantly more likely to contain Hes-1 binding sites, indicating that Hes-1 is more likely to repress transcription of its direct targets. We conclude that Notch most likely blocks adipogenesis through the induction of Hes-1 homodimers, which repress transcription of key target genes.}, isbn = {0888-8809, 1944-9917}, author = {Ross, David A. and Sridhar Hannenhalli and Tobias, John W. and Cooch, Neil and Shiekhattar, Ramin and Kadesch, Tom} } @article {38265, title = {A framework for set-oriented computation in inductive logic programming and its application in generalizing inverse entailment}, journal = {Inductive Logic ProgrammingInductive Logic Programming}, year = {2005}, author = {H{\'e}ctor Corrada Bravo and Page, D. and Ramakrishnan, R. and Shavlik, J. and Costa, V. S.} } @article {38259, title = {Few amino acid positions in {\i}t rpoB are associated with most of the rifampin resistance in {\i}t Mycobacterium tuberculosis}, journal = {BMC BioinformaticsBMC Bioinformatics}, volume = {5}, year = {2004}, type = {10.1186/1471-2105-5-137}, abstract = {BACKGROUND: Mutations in rpoB, the gene encoding the beta subunit of DNA-dependent RNA polymerase, are associated with rifampin resistance in Mycobacterium tuberculosis. Several studies have been conducted where minimum inhibitory concentration (MIC, which is defined as the minimum concentration of the antibiotic in a given culture medium below which bacterial growth is not inhibited) of rifampin has been measured and partial DNA sequences have been determined for rpoB in different isolates of M. tuberculosis. However, no model has been constructed to predict rifampin resistance based on sequence information alone. Such a model might provide the basis for quantifying rifampin resistance status based exclusively on DNA sequence data and thus eliminate the requirements for time consuming culturing and antibiotic testing of clinical isolates. RESULTS: Sequence data for amino acid positions 511-533 of rpoB and associated MIC of rifampin for different isolates of M. tuberculosis were taken from studies examining rifampin resistance in clinical samples from New York City and throughout Japan. We used tree-based statistical methods and random forests to generate models of the relationships between rpoB amino acid sequence and rifampin resistance. The proportion of variance explained by a relatively simple tree-based cross-validated regression model involving two amino acid positions (526 and 531) is 0.679. The first partition in the data, based on position 531, results in groups that differ one hundredfold in mean MIC (1.596 micrograms/ml and 159.676 micrograms/ml). The subsequent partition based on position 526, the most variable in this region, results in a > 354-fold difference in MIC. When considered as a classification problem (susceptible or resistant), a cross-validated tree-based model correctly classified most (0.884) of the observations and was very similar to the regression model. Random forest analysis of the MIC data as a continuous variable, a regression problem, produced a model that explained 0.861 of the variance. The random forest analysis of the MIC data as discrete classes produced a model that correctly classified 0.942 of the observations with sensitivity of 0.958 and specificity of 0.885. CONCLUSIONS: Highly accurate regression and classification models of rifampin resistance can be made based on this short sequence region. Models may be better with improved (and consistent) measurements of MIC and more sequence data.}, author = {Michael P. Cummings and Segal, M. R.} } @inbook {38266, title = {Free-Living to Freewheeling: The Evolution of Vibrio cholerae from Innocence to Infamy}, booktitle = {Infectious Disease and Host-Pathogen EvolutionInfectious Disease and Host-Pathogen Evolution}, year = {2004}, publisher = {Cambridge University Press}, organization = {Cambridge University Press}, isbn = {9780521820660}, author = {Rita R. Colwell and Faruque, S. M. and Nair, G. B.}, editor = {Dronamraju, Krishna R.} } @article {38267, title = {From terabytes to insights}, journal = {Communications of the ACMCommunications of the ACM}, volume = {46}, year = {2003}, type = {10.1145/792704.792724}, abstract = {For scientists and engineers tapping the NSF{\textquoteright}s high-performance cyberinfrastructure, the path to wisdom follows a route both miraculous and familiar.}, isbn = {0001-0782}, author = {Rita R. Colwell} } @inbook {38268, title = {Fulfilling the promise of marine biotechnology}, booktitle = {Marine biotechnology in the twenty-first century: problems, promise, and productsMarine biotechnology in the twenty-first century: problems, promise, and products}, year = {2002}, note = {(U S. )}, publisher = {National Academies Press}, organization = {National Academies Press}, isbn = {9780309083423}, author = {Rita R. Colwell}, editor = {National Research Council Committee on Marine Biotechnology: Biomedical Applications of Marine Natural, Products} } @inbook {38257, title = {Fast sorting by reversal}, booktitle = {Combinatorial Pattern MatchingCombinatorial Pattern Matching}, series = {Lecture Notes in Computer Science}, volume = {1075}, year = {1996}, publisher = {Springer Berlin / Heidelberg}, organization = {Springer Berlin / Heidelberg}, abstract = {Analysis of genomes evolving by inversions leads to a combinatorial problem of sorting by reversals studied in detail recently. Following a series of work recently, Hannenhalli and Pevzner developed the first polynomial algorithm for the problem of sorting signed permutations by reversals and proposed an O(n 4 ) implementation of the algorithm. In this paper we exploit a few combinatorial properties of the cycle graph of a permutation and propose an O(n 2 (n)) implementation of the algorithm where is the inverse Ackerman function. Besides making this algorithm practical, our technique improves implementations of the other rearrangement distance problems.}, isbn = {978-3-540-61258-2}, author = {Berman, Piotr and Sridhar Hannenhalli}, editor = {Hirschberg, Dan and Myers, Gene} }