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      Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response

      research-article
      1 , 2 , 1 , 1 , 3 , 4 , 5 , 1 , 2 , 6 , 1 , 7 , 1 , 8 , 1 , 1 , 9 , 9 , 1 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 1 , 12 , 22 , 8 , 9 , 25 , 6 , 4 , 3 , 26 , 3 , 27 , 28 , 1 ,
      Nature Communications
      Nature Publishing Group UK

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          Abstract

          Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α 4β 7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

          Abstract

          The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.

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          Most cited references59

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          Near-optimal probabilistic RNA-seq quantification.

          We present kallisto, an RNA-seq quantification program that is two orders of magnitude faster than previous approaches and achieves similar accuracy. Kallisto pseudoaligns reads to a reference, producing a list of transcripts that are compatible with each read while avoiding alignment of individual bases. We use kallisto to analyze 30 million unaligned paired-end RNA-seq reads in <10 min on a standard laptop computer. This removes a major computational bottleneck in RNA-seq analysis.
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            xCell: digitally portraying the tissue cellular heterogeneity landscape

            Tissues are complex milieus consisting of numerous cell types. Several recent methods have attempted to enumerate cell subsets from transcriptomes. However, the available methods have used limited sources for training and give only a partial portrayal of the full cellular landscape. Here we present xCell, a novel gene signature-based method, and use it to infer 64 immune and stromal cell types. We harmonized 1822 pure human cell type transcriptomes from various sources and employed a curve fitting approach for linear comparison of cell types and introduced a novel spillover compensation technique for separating them. Using extensive in silico analyses and comparison to cytometry immunophenotyping, we show that xCell outperforms other methods. xCell is available at http://xCell.ucsf.edu/. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1349-1) contains supplementary material, which is available to authorized users.
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              ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

              Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in. Availability: http://www.ici.upmc.fr/cluego/cluegoDownload.shtml Contact: jerome.galon@crc.jussieu.fr Supplementary information: Supplementary data are available at Bioinformatics online.
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                Author and article information

                Contributors
                lee.denson@cchmc.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                3 January 2019
                3 January 2019
                2019
                : 10
                : 38
                Affiliations
                [1 ]Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH USA
                [2 ]ISNI 0000 0004 1937 0546, GRID grid.12136.37, Sheba Medical Center, , Tel Hashomer, affiliated with the Tel Aviv University, ; Tel Aviv, 5265601 Israel
                [3 ]GRID grid.66859.34, Broad Institute of MIT and Harvard University, ; Cambridge, 02142 MA USA
                [4 ]ISNI 0000000121102151, GRID grid.6451.6, Faculty of Medicine, , Technion, ; Haifa, 3109601 Israel
                [5 ]ISNI 0000 0004 1937 0562, GRID grid.18098.38, Department of Information Systems, , University of Haifa, ; Haifa, 3498838 Israel
                [6 ]ISNI 0000 0000 9753 0008, GRID grid.239553.b, Children’s Hospital of Pittsburgh, ; Pittsburgh, 15224 PA USA
                [7 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Pediatrics, , University of California at San Diego, ; La Jolla, 92162 CA USA
                [8 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, Georgia Institute of Technology, ; Atlanta, 30332 GA USA
                [9 ]ISNI 0000 0001 1034 1720, GRID grid.410711.2, Collaborative Studies Coordinating Center, , University of North Carolina, ; Chapel Hill, 27516 NC USA
                [10 ]Harvard—Children’s Hospital Boston, Boston, 02115 MA USA
                [11 ]ISNI 0000 0000 9958 7286, GRID grid.413993.5, Women & Children’s Hospital of Buffalo WCHOB, ; Buffalo, 14222 NY USA
                [12 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Emory University, ; Atlanta, 30322 GA USA
                [13 ]GRID grid.415338.8, Cohen Children’s Medical Center of New York, ; 11040, New Hyde Park, NY USA
                [14 ]ISNI 0000 0000 9682 4709, GRID grid.414923.9, Riley Hospital for Children, ; Indianapolis, 46202 IN USA
                [15 ]Goryeb Children’s Hospital—Atlantic Health, Morristown, 07960 NJ USA
                [16 ]ISNI 0000 0004 0392 3476, GRID grid.240344.5, Nationwide Children’s Hospital, ; Columbus, 43205 OH USA
                [17 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Children’s Hospital of East Ontario, Ottawa, ; Ontario, K1P 1J1 Canada
                [18 ]ISNI 0000 0001 0680 8770, GRID grid.239552.a, The Children’s Hospital of Philadelphia, ; Philadelphia, 19104 PA USA
                [19 ]ISNI 0000 0000 9753 0008, GRID grid.239553.b, Children’s Hospital of Pittsburgh of UPMC, ; Pittsburgh, 15224 PA USA
                [20 ]ISNI 0000 0004 0443 4957, GRID grid.414169.f, Hasbro Children’s Hospital, ; Providence, 02903 RI USA
                [21 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, University of California at San Francisco, ; San Francisco, 94143 CA USA
                [22 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Hospital for Sick Children, ; Toronto, M5G 1X8 Canada
                [23 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, UT Southwestern, ; Dallas, 75390 TX USA
                [24 ]ISNI 0000 0001 2111 8460, GRID grid.30760.32, Medical College of Wisconsin, ; Milwaukee, 53226 WI USA
                [25 ]ISNI 0000000100301493, GRID grid.62562.35, RTI International, ; Research Triangle Park, 27709 NC USA
                [26 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard School of Public Health, ; Boston, 02115 MA USA
                [27 ]ISNI 000000041936754X, GRID grid.38142.3c, Massachusetts General Hospital, , Harvard Medical School, ; Boston, 02114 MA USA
                [28 ]ISNI 0000 0001 0440 7332, GRID grid.414666.7, Connecticut Children’s Medical Center, ; Hartford, 06106 CT USA
                Author information
                http://orcid.org/0000-0003-2680-1570
                http://orcid.org/0000-0003-3965-6894
                http://orcid.org/0000-0002-0756-5974
                http://orcid.org/0000-0003-4798-1347
                http://orcid.org/0000-0001-7988-0220
                http://orcid.org/0000-0002-8686-4189
                http://orcid.org/0000-0002-5352-5877
                http://orcid.org/0000-0002-6991-7736
                http://orcid.org/0000-0002-1110-0096
                http://orcid.org/0000-0002-5630-5167
                http://orcid.org/0000-0001-8045-7198
                Article
                7841
                10.1038/s41467-018-07841-3
                6318335
                30604764
                fa9f1570-0c9b-44ef-96cd-28c93e80065e
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 October 2018
                : 28 November 2018
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