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  • Computational Methods  (62)
  • Biotechnology & Synthetic Biology  (41)
  • Oxford University Press  (103)
  • 1
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    Topology independent comparison of RNA 3D structures using the CLICK algorithm (2017)
    Oxford University Press
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    Publication Date: 2017-01-10
    Description: RNA molecules are attractive therapeutic targets because non-coding RNA molecules have increasingly been found to play key regulatory roles in the cell. Comparing and classifying RNA 3D structures yields unique insights into RNA evolution and function. With the rapid increase in the number of atomic-resolution RNA structures, it is crucial to have effective tools to classify RNA structures and to investigate them for structural similarities at different resolutions. We previously developed the algorithm CLICK to superimpose a pair of protein 3D structures by clique matching and 3D least squares fitting. In this study, we extend and optimize the CLICK algorithm to superimpose pairs of RNA 3D structures and RNA–protein complexes, independent of the associated topologies. Benchmarking Rclick on four different datasets showed that it is either comparable to or better than other structural alignment methods in terms of the extent of structural overlaps. Rclick also recognizes conformational changes between RNA structures and produces complementary alignments to maximize the extent of detectable similarity. Applying Rclick to study Ribonuclease III protein correctly aligned the RNA binding sites of RNAse III with its substrate. Rclick can be further extended to identify ligand-binding pockets in RNA. A web server is developed at http://mspc.bii.a-star.edu.sg/minhn/rclick.html .
    Keywords: Computational Methods
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    OmpF of Pectobacterium carotovorum subsp. carotovorum Pcc3 is required for carocin D sensitivity (2016)
    Oxford University Press
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    Publication Date: 2016-12-23
    Description: Carocin D is a bacteriocin produced by Pectobacterium carotovorum subsp. carotovorum Pcc21. Carocin D inhibits the growth of P . carotovorum subsp. carotovorum and closely related strains. Pectobacterium carotovorum subsp. carotovorum is a causative bacterium for soft rot disease and leads to severe economic losses. Bacteriocins recognize and interact with a specific membrane protein of target bacteria as a receptor. To identify the receptor responsible for carocin D recognition, mutants that underwent a phenotypic change from carocin D sensitivity to carocin D insensitivity were screened. Based on Tn 5 insertions, carocin D sensitivity was dependent on expression of the outer membrane protein OmpF. The insensitivity of the mutant (Pcc3MR) to carocin D was complemented with ompF from carocin D-sensitive strains, not from carocin D-resistant strains. The selectivity between sensitive and resistant strains could be attributed to variation in OmpFs in the cell-surface-exposed regions. Based on sequence analysis and complementation assays, it appears that carocin D uses OmpF as a receptor and is translocated by the TonB system. According to previously reported translocation mechanisms of colicins, OmpF works along with the TolA system rather than the TonB system. Therefore, the current findings suggest that carocin D is imported by a unique colicin-like bacteriocin translocation system.
    Keywords: Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Personalized characterization of diseases using sample-specific networks (2016)
    Oxford University Press
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    Publication Date: 2016-12-17
    Description: A complex disease generally results not from malfunction of individual molecules but from dysfunction of the relevant system or network, which dynamically changes with time and conditions. Thus, estimating a condition-specific network from a single sample is crucial to elucidating the molecular mechanisms of complex diseases at the system level. However, there is currently no effective way to construct such an individual-specific network by expression profiling of a single sample because of the requirement of multiple samples for computing correlations. We developed here with a statistical method, i.e. a sample-specific network (SSN) method, which allows us to construct individual-specific networks based on molecular expressions of a single sample. Using this method, we can characterize various human diseases at a network level. In particular, such SSNs can lead to the identification of individual-specific disease modules as well as driver genes, even without gene sequencing information. Extensive analysis by using the Cancer Genome Atlas data not only demonstrated the effectiveness of the method, but also found new individual-specific driver genes and network patterns for various types of cancer. Biological experiments on drug resistance further validated one important advantage of our method over the traditional methods, i.e. we can even identify such drug resistance genes that actually have no clear differential expression between samples with and without the resistance, due to the additional network information.
    Keywords: Computational Methods
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Order restricted inference for oscillatory systems for detecting rhythmic signals (2016)
    Oxford University Press
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    Publication Date: 2016-12-17
    Description: Motivation: Many biological processes, such as cell cycle, circadian clock, menstrual cycles, are governed by oscillatory systems consisting of numerous components that exhibit rhythmic patterns over time. It is not always easy to identify such rhythmic components. For example, it is a challenging problem to identify circadian genes in a given tissue using time-course gene expression data. There is a great potential for misclassifying non-rhythmic as rhythmic genes and vice versa. This has been a problem of considerable interest in recent years. In this article we develop a constrained inference based methodology called Order Restricted Inference for Oscillatory Systems (ORIOS) to detect rhythmic signals. Instead of using mathematical functions (e.g. sinusoidal) to describe shape of rhythmic signals, ORIOS uses mathematical inequalities. Consequently, it is robust and not limited by the biologist's choice of the mathematical model. We studied the performance of ORIOS using simulated as well as real data obtained from mouse liver, pituitary gland and data from NIH3T3, U2OS cell lines. Our results suggest that, for a broad collection of patterns of gene expression, ORIOS has substantially higher power to detect true rhythmic genes in comparison to some popular methods, while also declaring substantially fewer non-rhythmic genes as rhythmic. Availability and Implementation: A user friendly code implemented in R language can be downloaded from http://www.niehs.nih.gov/research/atniehs/labs/bb/staff/peddada/index.cfm . Contact: peddada@niehs.nih.gov
    Keywords: Computational Methods
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The enhanced immune responses induced by Salmonella enteritidis ghosts loaded with Neisseria gonorrhoeae porB against Salmonella in mice (2016)
    Oxford University Press
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    Publication Date: 2016-12-16
    Description: Human health has been seriously endangered by highly prevalent salmonellosis and multidrug-resistant Salmonella strains. Current vaccines suffer from variable immune-protective effects, so more effective ones are needed to control Salmonella infection . Bacterial ghosts have been produced by the expression of lysis gene E from bacteriophage PhiX174 and can be filled with considerable exogenous substances such as DNA or drugs as a novel platform. In this study, Salmonella enteritidis (SE) ghosts were developed and loaded with Neisseria gonorrhoeae porin B (porB) to construct a novel inactive vaccine. Our new studies show that SE ghosts loaded with porB displayed increased production of pro-inflammatory cytokines (IL-1β, IL-6, IL-10 and IL-12p70) in bone marrow-derived dendritic cells (BMDCs), and elicited significantly higher specific systemic and mucosal immune responses to Salmonella than SE ghosts alone. In addition, the novel porB-loaded ghosts conferred higher protective effects on virulent Salmonella challenge. For the first time, we demonstrate that N. gonorrhoeae porB, as a novel adjuvant, can increase the immunogenicity of SE ghosts. Our studies suggested that Salmonella enteritidis ghosts loaded with Neisseria gonorrhoeae porin B might be a useful mucosal Salmonella vaccine candidate for practical use in the future.
    Keywords: Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Expression of biologically active murine interleukin-18 in Lactococcus lactis (2016)
    Oxford University Press
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    Publication Date: 2016-12-12
    Description: The food-grade bacterium Lactococcus lactis is increasingly used for heterologous protein expression in therapeutic and industrial applications. The ability of L. lactis to secrete biologically active cytokines may be used for the generation of therapeutic cytokines. Interleukin (IL)-18 enhances the immune response, especially on mucosal surfaces, emphasizing its therapeutic potential. However, it is produced as an inactive precursor and has to be enzymatically cleaved for maturation. We genetically manipulated L. lactis to secrete murine IL-18. The mature murine IL-18 gene was inserted downstream of a nisin promoter in pNZ8149 plasmid and the construct was used to transform L. lactis NZ3900 . The transformants were selected on Elliker agar and confirmed by restriction enzyme digestion and sequencing. The expression and secretion of IL-18 protein was verified by SDS-PAGE, western blotting and ELISA. The biological activity of recombinant IL-18 was determined by its ability to induce interferon (IFN)- production in L. lactis co-cultured with murine splenic T cells. The amounts of IL-18 in bacterial lysates and supernatants were 3–4 μg mL –1 and 0.6–0.7 ng mL –1 , respectively. The successfully generated L. lactis strain that expressed biologically active murine IL-18 can be used to evaluate the possible therapeutic effects of IL-18 on mucosal surfaces.
    Keywords: Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Localized structural frustration for evaluating the impact of sequence variants (2016)
    Oxford University Press
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    Publication Date: 2016-12-04
    Description: Population-scale sequencing is increasingly uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions of the genome. The rarity of these variants makes it challenging to evaluate their deleteriousness with conventional phenotype–genotype associations. Protein structures provide a way of addressing this challenge. Previous efforts have focused on globally quantifying the impact of SNVs on protein stability. However, local perturbations may severely impact protein functionality without strongly disrupting global stability (e.g. in relation to catalysis or allostery). Here, we describe a workflow in which localized frustration, quantifying unfavorable local interactions, is employed as a metric to investigate such effects. Using this workflow on the Protein Databank, we find that frustration produces many immediately intuitive results: for instance, disease-related SNVs create stronger changes in localized frustration than non-disease related variants, and rare SNVs tend to disrupt local interactions to a larger extent than common variants. Less obviously, we observe that somatic SNVs associated with oncogenes and tumor suppressor genes (TSGs) induce very different changes in frustration. In particular, those associated with TSGs change the frustration more in the core than the surface (by introducing loss-of-function events), whereas those associated with oncogenes manifest the opposite pattern, creating gain-of-function events.
    Keywords: Computational Methods
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 8
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    Function-driven discovery of disease genes in zebrafish using an integrated genomics big data resource (2016)
    Oxford University Press
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    Publication Date: 2016-12-01
    Description: Whole exome sequencing (WES) accelerates disease gene discovery using rare genetic variants, but further statistical and functional evidence is required to avoid false-discovery. To complement variant-driven disease gene discovery, here we present function-driven disease gene discovery in zebrafish ( Danio rerio ), a promising human disease model owing to its high anatomical and genomic similarity to humans. To facilitate zebrafish-based function-driven disease gene discovery, we developed a genome-scale co-functional network of zebrafish genes, DanioNet ( www.inetbio.org/danionet ), which was constructed by Bayesian integration of genomics big data. Rigorous statistical assessment confirmed the high prediction capacity of DanioNet for a wide variety of human diseases. To demonstrate the feasibility of the function-driven disease gene discovery using DanioNet, we predicted genes for ciliopathies and performed experimental validation for eight candidate genes. We also validated the existence of heterozygous rare variants in the candidate genes of individuals with ciliopathies yet not in controls derived from the UK10K consortium, suggesting that these variants are potentially involved in enhancing the risk of ciliopathies. These results showed that an integrated genomics big data for a model animal of diseases can expand our opportunity for harnessing WES data in disease gene discovery.
    Keywords: Computational Methods
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Enterotoxigenic Escherichia coli heat-stable toxin and heat-labile toxin toxoid fusion 3xSTaN12S-dmLT induces neutralizing anti-STa antibodies in subcutaneously immunized mice (2016)
    Oxford University Press
    Details
    Publication Date: 2016-11-17
    Description: Enterotoxigenic Escherichia coli (ETEC) bacteria producing heat-stable toxin (STa) and/or heat-labile toxin (LT) are among top causes of children's diarrhea and travelers’ diarrhea. Currently no vaccines are available for ETEC associated diarrhea. A major challenge in developing ETEC vaccines is the inability to stimulate protective antibodies against the key STa toxin that is potently toxic and also poorly immunogenic. A recent study suggested toxoid fusion 3xSTa N12S -dmLT, which consists of a monomer LT toxoid (LT R192G/L211A ) and three copies of STa toxoid STa N12S , may represent an optimal immunogen inducing neutralizing antibodies against STa toxin [IAI 2014, 82(5):1823-32]. In this study, we immunized mice with this fusion protein following a different parenteral route and using different adjuvants to further characterize immunogenicity of this toxoid fusion. Data from this study showed that 3xSTa N12S -dmLT toxoid fusion induced neutralizing anti-STa antibodies in the mice following subcutaneous immunization, as effectively as in the mice under intraperitoneal route. Data also indicated that double mutant LT (dmLT) can be an effective adjuvant for this toxoid fusion in mice subcutaneous immunization. Results from this study affirmed that toxoid fusion 3xSTa N12S -dmLT induces neutralizing antibodies against STa toxin, suggesting this toxoid fusion is potentially a promising immunogen for ETEC vaccine development.
    Keywords: Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Recombineering and I-SceI-mediated Pseudomonas putida KT2440 scarless gene deletion (2016)
    Oxford University Press
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    Publication Date: 2016-11-17
    Description: Pseudomonas putida KT2440 is a saprophytic and generally recognized as safe microorganism that plays important roles in the biodegradation and production of value-added chemicals. Chromosomal gene deletion of P. putida KT2440 usually involves time-consuming gene cloning, conjugal transfer and counterselection. Recently, we developed a P. putida KT2440 markerless gene deletion method based on recombineering and Cre/ loxP site-specific recombination. PCR-based Red recombineering circumvents the tedious cloning steps and is more amenable to high-throughput manipulation. Here we report an improved scarless gene deletion strategy based on recombineering and intron-encoded homing endonuclease I-SceI-mediated double-strand break repair. Sixteen drug exporter gene(s) were deleted and the minimal inhibition concentrations of the mutants to a variety of antibiotics were determined. The robustness of the procedure was also demonstrated by sequential deletion of five large genomic regions. Up to 59% recombination efficiency was achieved for a 54.8 kb deletion, and the efficiency of RecA-mediated double-strand break repair, which was boosted by Red recombinase, was nearly 100%. The strain with a 3.76% genome reduction showed an improved growth rate and transformation efficiency. The straightforward, time-saving and highly efficient scarless deletion approach has the potential to facilitate the genetic study, and biotechnological and environmental applications of P. putida KT2440.
    Keywords: Biotechnology & Synthetic Biology
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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