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  1. Article ; Online: Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome

    Deepak Mav / Dhiral P Phadke / Michele R Balik-Meisner / B Alex Merrick / Scott Auerbach / Marije Niemeijer / Suzanna Huppelschoten / Audrey Baze / Celine Parmentier / Lysiane Richert / Bob van de Water / Ruchir R Shah / Richard S Paules

    Bioinformatics and Biology Insights, Vol

    Tunicamycin Case Study

    2020  Volume 14

    Abstract: The TempO-Seq S1500+ platform(s), now available for human, mouse, rat, and zebrafish, measures a discrete number of genes that are representative of biological and pathway co-regulation across the entire genome in a given species. While measurement of ... ...

    Abstract The TempO-Seq S1500+ platform(s), now available for human, mouse, rat, and zebrafish, measures a discrete number of genes that are representative of biological and pathway co-regulation across the entire genome in a given species. While measurement of these genes alone provides a direct assessment of gene expression activity, extrapolating expression values to the whole transcriptome (~26 000 genes in humans) can estimate measurements of non-measured genes of interest and increases the power of pathway analysis algorithms by using a larger background gene expression space. Here, we use data from primary hepatocytes of 54 donors that were treated with the endoplasmic reticulum (ER) stress inducer tunicamycin and then measured on the human S1500+ platform containing ~3000 representative genes. Measurements for the S1500+ genes were then used to extrapolate expression values for the remaining human transcriptome. As a case study of the improved downstream analysis achieved by extrapolation, the “measured only” and “whole transcriptome” (measured + extrapolated) gene sets were compared. Extrapolation increased the number of significant genes by 49%, bringing to the forefront many that are known to be associated with tunicamycin exposure. The extrapolation procedure also correctly identified established tunicamycin-related functional pathways reflected by coordinated changes in interrelated genes while maintaining the sample variability observed from the “measured only” genes. Extrapolation improved the gene- and pathway-level biological interpretations for a variety of downstream applications, including differential expression analysis, gene set enrichment pathway analysis, DAVID keyword analysis, Ingenuity Pathway Analysis, and NextBio correlated compound analysis. The extrapolated data highlight the role of metabolism/metabolic pathways, the ER, immune response, and the unfolded protein response, each of which are key activities associated with tunicamycin exposure that were unrepresented or underrepresented in ...
    Keywords Biology (General) ; QH301-705.5
    Subject code 572 ; 570
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds

    Angela Oppelt / Daniel Kaschek / Suzanna Huppelschoten / Rowena Sison-Young / Fang Zhang / Marie Buck-Wiese / Franziska Herrmann / Sebastian Malkusch / Carmen L. Krüger / Mara Meub / Benjamin Merkt / Lea Zimmermann / Amy Schofield / Robert P. Jones / Hassan Malik / Marcel Schilling / Mike Heilemann / Bob van de Water / Christopher E. Goldring /
    B. Kevin Park / Jens Timmer / Ursula Klingmüller

    npj Systems Biology and Applications, Vol 4, Iss 1, Pp 1-

    2018  Volume 16

    Abstract: Drug-induced liver injury: mathematical model quantifies impact of liver-damaging drugs Drug-induced liver injury (DILI) is one of the most important obstacles during drug development. More than 1000 drugs have been identified to damage the liver, but ... ...

    Abstract Drug-induced liver injury: mathematical model quantifies impact of liver-damaging drugs Drug-induced liver injury (DILI) is one of the most important obstacles during drug development. More than 1000 drugs have been identified to damage the liver, but the current test systems are poor in predicting DILI. A team of cell biologists, theoretical physicists, and clinical pharmacologists combined experimental data generated in cultured liver cells with mathematical modeling to quantify the impact of the anti-inflammatory drug diclofenac. The analysis demonstrated that diclofenac induces multiple changes in the signal transduction network activated by the tumor necrosis factor alpha (TNFα), one of the known factors to amplify liver toxicity. Data of other liver injury-causing compounds were integrated into the mathematical model and their impact was quantified, thereby demonstrating the potential use of the mathematical model for the further analysis of other compounds in order to improve DILI test systems.
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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