{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:09:02Z","timestamp":1790680142755,"version":"4.1.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01 HL-118000"],"award-info":[{"award-number":["R01 HL-118000"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["P01 HL-51670"],"award-info":[{"award-number":["P01 HL-51670"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["P01 HL-091842"],"award-info":[{"award-number":["P01 HL-091842"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["T32 GM-008629"],"award-info":[{"award-number":["T32 GM-008629"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001024","name":"Roy J. Carver Charitable Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["P30 DK-54759"],"award-info":[{"award-number":["P30 DK-54759"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cystic fibrosis (CF), caused by mutations to <jats:italic>CFTR<\/jats:italic>, leads to severe and progressive lung disease. The most common mutant, \u0394F508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue \u0394F508-CFTR function yet remain poorly understood. Improved understanding of both the altered state of CF cells and the mechanisms of existing rescue strategies could reveal novel therapeutic strategies. Toward this aim, we measured transcriptional profiles of established temperature, genetic, and chemical interventions that rescue \u0394F508-CFTR and also re-analyzed public datasets characterizing transcription in human CF vs. non-CF samples from airway and whole blood. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these through the lens of prior knowledge, we compiled a \u201cCFTR Gene Set Library\u201d from literature. The core disease signature revealed remarkably strong connections to genes with established effects on CFTR trafficking and function and suggested novel roles of EGR1 and SGK1 in the disease state. Our data also revealed an unexpected mechanistic link between several genetic rescue interventions and the unfolded protein response. Finally, we found that C18, an analog of the CFTR corrector compound Lumacaftor, induces almost no transcriptional perturbation despite its rescue activity.<\/jats:p>","DOI":"10.1038\/s41598-020-76347-0","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T11:03:44Z","timestamp":1606302224000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and \u0394F508-CFTR rescue"],"prefix":"10.1038","volume":"10","author":[{"given":"Rachel A.","family":"Hodos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Strub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Ramachandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Paul B.","family":"McCray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel T.","family":"Dudley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"issue":"6389","key":"76347_CR1","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/358761a0","volume":"358","author":"GM Denning","year":"1992","unstructured":"Denning, G. M. et al. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358(6389), 761\u2013764 (1992).","journal-title":"Nature"},{"issue":"3","key":"76347_CR2","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1056\/NEJMoa1409547","volume":"373","author":"CE Wainwright","year":"2015","unstructured":"Wainwright, C. E. et al. Lumacaftor\u2013Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 373(3), 220\u2013231 (2015).","journal-title":"N. Engl. J. Med."},{"issue":"19","key":"76347_CR3","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","volume":"381","author":"PG Middleton","year":"2019","unstructured":"Middleton, P. G. et al. Elexacaftor\u2013Tezacaftor\u2013Ivacaftor for cystic fibrosis with a single Phe508del allele. N. Engl. J. Med. 381(19), 1809\u20131819 (2019).","journal-title":"N. Engl. J. Med."},{"issue":"33","key":"76347_CR4","doi-asserted-by":"publisher","first-page":"13362","DOI":"10.1073\/pnas.1210906109","volume":"109","author":"S Ramachandran","year":"2012","unstructured":"Ramachandran, S. et al. A microRNA network regulates expression and biosynthesis of wild-type and \u0394F508 mutant cystic fibrosis transmembrane conductance regulator. Proc. Natl. Acad. Sci. 109(33), 13362\u201313367 (2012).","journal-title":"Proc. Natl. Acad. Sci."},{"issue":"11","key":"76347_CR5","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/gt.2015.56","volume":"22","author":"P Kumar","year":"2015","unstructured":"Kumar, P. et al. miR-16 rescues F508del-CFTR function in native cystic fibrosis epithelial cells. Gene Ther. 22(11), 908 (2015).","journal-title":"Gene Ther."},{"issue":"4","key":"76347_CR6","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.cell.2006.09.043","volume":"127","author":"X Wang","year":"2006","unstructured":"Wang, X. et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127(4), 803\u2013815 (2006).","journal-title":"Cell"},{"key":"76347_CR7","doi-asserted-by":"crossref","unstructured":"Ramachandran, S. et al. SYVN1, NEDD8, and FBXO2 proteins regulate \u0394F508 cystic fibrosis transmembrane conductance regulator (CFTR) ubiquitin-mediated proteasomal degradation. J. Biol. Chem. 291(49), 25489\u201325504 (2016).","DOI":"10.1074\/jbc.M116.754283"},{"issue":"5","key":"76347_CR8","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.chembiol.2014.02.021","volume":"21","author":"DW Eckford Paul","year":"2014","unstructured":"Eckford Paul, D. W. et al. VX-809 and related corrector compounds exhibit secondary activity stabilizing active F508del-CFTR after its partial rescue to the cell surface. Chem. Biol. 21(5), 666\u2013678 (2014).","journal-title":"Chem. Biol."},{"issue":"2","key":"76347_CR9","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1096\/fj.12-216119","volume":"27","author":"L He","year":"2013","unstructured":"He, L. et al. Correctors of \u0394F508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. FASEB J. 27(2), 536\u2013545 (2013).","journal-title":"FASEB J."},{"key":"76347_CR10","doi-asserted-by":"crossref","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B. 57(1), 289\u2013300 (1995).","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"issue":"4","key":"76347_CR11","doi-asserted-by":"publisher","first-page":"C872","DOI":"10.1152\/ajpcell.00507.2010","volume":"301","author":"E Sondo","year":"2011","unstructured":"Sondo, E. et al. Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling. Am. J. Physiol. Cell Physiol. 301(4), C872\u2013C885 (2011).","journal-title":"Am. J. Physiol. Cell Physiol."},{"issue":"7583","key":"76347_CR12","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/nature15729","volume":"528","author":"S Pankow","year":"2015","unstructured":"Pankow, S. et al. \u2206F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528(7583), 510\u2013516 (2015).","journal-title":"Nature"},{"key":"76347_CR13","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/978-1-60761-175-2_18","volume-title":"Protein Networks and Pathway Analysis. Methods in Molecular Biology (Methods and Protocols)","author":"JM Wright","year":"2009","unstructured":"Wright, J. M., Nikolsky, Y., Serebryiskaya, T. & Wetmore, D. R. MetaMiner (CF): A disease-oriented bioinformatics analysis environment. In Protein Networks and Pathway Analysis. Methods in Molecular Biology (Methods and Protocols) Vol. 563 (eds Nikolsky, Y. & Bryant, J.) 353\u2013367 (Humana Press, Totowa, 2009)."},{"issue":"1","key":"76347_CR14","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/1465-9921-14-38","volume":"14","author":"LA Clarke","year":"2013","unstructured":"Clarke, L. A., Sousa, L., Barreto, C. & Amaral, M. D. Changes in transcriptome of native nasal epithelium expressing F508del-CFTR and intersecting data from comparable studies. Respir Res. 14(1), 38 (2013).","journal-title":"Respir Res."},{"issue":"5","key":"76347_CR15","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.ygeno.2011.06.008","volume":"98","author":"V Ogilvie","year":"2011","unstructured":"Ogilvie, V. et al. Differential global gene expression in cystic fibrosis nasal and bronchial epithelium. Genomics 98(5), 327\u2013336 (2011).","journal-title":"Genomics"},{"issue":"5","key":"76347_CR16","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1093\/bioinformatics\/btp026","volume":"25","author":"A Lachmann","year":"2009","unstructured":"Lachmann, A. & Ma\u2019ayan, A. KEA: Kinase enrichment analysis. Bioinformatics 25(5), 684\u2013686 (2009).","journal-title":"Bioinformatics"},{"issue":"37","key":"76347_CR17","doi-asserted-by":"publisher","first-page":"25241","DOI":"10.1074\/jbc.M109.035345","volume":"284","author":"H Caohuy","year":"2009","unstructured":"Caohuy, H., Jozwik, C. & Pollard, H. B. Rescue of \u0394F508-CFTR by the SGK1\/Nedd4-2 signaling pathway. J. Biol. Chem. 284(37), 25241\u201325253 (2009).","journal-title":"J. Biol. Chem."},{"issue":"3","key":"76347_CR18","doi-asserted-by":"publisher","first-page":"180","DOI":"10.3390\/genes10030180","volume":"10","author":"JE Ideozu","year":"2019","unstructured":"Ideozu, J. E., Zhang, X., McColley, S. & Levy, H. Transcriptome profiling and molecular therapeutic advances in cystic fibrosis: Recent insights. Genes (Basel). 10(3), 180 (2019).","journal-title":"Genes (Basel)."},{"key":"76347_CR19","doi-asserted-by":"publisher","first-page":"12138","DOI":"10.1038\/srep12138","volume":"5","author":"V Tomati","year":"2015","unstructured":"Tomati, V. et al. Genetic inhibition of the ubiquitin ligase Rnf5 attenuates phenotypes associated to F508del cystic fibrosis mutation. Nat. Sci. Rep. 5, 12138 (2015).","journal-title":"Nat. Sci. Rep."},{"issue":"4","key":"76347_CR20","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1074\/mcp.M800268-MCP200","volume":"8","author":"AM Trzci\u0144ska-Daneluti","year":"2009","unstructured":"Trzci\u0144ska-Daneluti, A. M. et al. High-content functional screen to identify proteins that correct F508del-CFTR function. Mol. Cell Proteomics. 8(4), 780\u2013790 (2009).","journal-title":"Mol. Cell Proteomics."},{"issue":"1","key":"76347_CR21","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/ncb2383","volume":"14","author":"JC Christianson","year":"2012","unstructured":"Christianson, J. C. et al. Defining human ERAD networks through an integrative mapping strategy. Nat. Cell Biol. 14(1), 93\u2013105 (2012).","journal-title":"Nat. Cell Biol."},{"key":"76347_CR22","doi-asserted-by":"publisher","first-page":"e10365","DOI":"10.7554\/eLife.10365","volume":"4","author":"RN Hegde","year":"2015","unstructured":"Hegde, R. N. et al. Unravelling druggable signalling networks that control F508del-CFTR proteostasis. Elife. 4, e10365 (2015).","journal-title":"Elife."},{"issue":"5993","key":"76347_CR23","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1126\/science.1191542","volume":"329","author":"T Okiyoneda","year":"2010","unstructured":"Okiyoneda, T. et al. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329(5993), 805\u2013810 (2010).","journal-title":"Science"},{"issue":"4","key":"76347_CR24","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1074\/jbc.M117.816595","volume":"293","author":"V Tomati","year":"2018","unstructured":"Tomati, V. et al. High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel. J. Biol. Chem. 293(4), 1203\u20131217 (2018).","journal-title":"J. Biol. Chem."},{"issue":"6","key":"76347_CR25","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1074\/mcp.M114.046375","volume":"14","author":"AM Trzci\u0144ska-Daneluti","year":"2015","unstructured":"Trzci\u0144ska-Daneluti, A. M. et al. RNA interference screen to identify kinases that suppress rescue of \u0394F508-CFTR. Mol. Cell Proteomics. 14(6), 1569\u20131583 (2015).","journal-title":"Mol. Cell Proteomics."},{"key":"76347_CR26","doi-asserted-by":"crossref","unstructured":"Perkins, L. A. et al. High-content surface and total expression siRNA kinase library screen with VX-809 treatment reveals kinase targets that enhance F508del-CFTR rescue. Mol. Pharm. 15(3), 759\u2013767 (2018).","DOI":"10.1021\/acs.molpharmaceut.7b00928"},{"issue":"8","key":"76347_CR27","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1007\/s00109-016-1403-6","volume":"94","author":"L-C Ho","year":"2016","unstructured":"Ho, L.-C. et al. Egr-1 deficiency protects from renal inflammation and fibrosis. J. Mol. Med. 94(8), 933\u2013942 (2016).","journal-title":"J. Mol. Med."},{"issue":"8","key":"76347_CR28","doi-asserted-by":"publisher","first-page":"e0183526","DOI":"10.1371\/journal.pone.0183526","volume":"12","author":"MS Kormann","year":"2017","unstructured":"Kormann, M. S. et al. Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity. PLoS ONE 12(8), e0183526 (2017).","journal-title":"PLoS ONE"},{"issue":"4","key":"76347_CR29","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1159\/000051935","volume":"11","author":"C Wagner","year":"2001","unstructured":"Wagner, C. et al. Effects of the serine\/threonine kinase SGK1 on the epithelial Na+ channel (ENaC) and CFTR: Implications for cystic fibrosis. Cell Phys. Biochem. 11(4), 209\u2013218 (2001).","journal-title":"Cell Phys. Biochem."},{"issue":"24","key":"76347_CR30","doi-asserted-by":"publisher","first-page":"17142","DOI":"10.1074\/jbc.M114.555599","volume":"289","author":"K Koeppen","year":"2014","unstructured":"Koeppen, K., Coutermarsh, B. A., Madden, D. R. & Stanton, B. A. Serum-and glucocorticoid-induced protein kinase 1 (SGK1) increases the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells by phosphorylating Shank2E protein. J. Biol. Chem. 289(24), 17142\u201317150 (2014).","journal-title":"J. Biol. Chem."},{"issue":"1\u20134","key":"76347_CR31","doi-asserted-by":"publisher","first-page":"091","DOI":"10.1159\/000104157","volume":"20","author":"JD Sato","year":"2007","unstructured":"Sato, J. D., Chapline, M. C., Thibodeau, R., Frizzell, R. A. & Stanton, B. A. Regulation of human cystic fibrosis transmembrane conductance regulator (CFTR) by serum-and glucocorticoid-inducible kinase (SGK1). Cell Phys. Biochem. 20(1\u20134), 091\u2013098 (2007).","journal-title":"Cell Phys. Biochem."},{"issue":"9","key":"76347_CR32","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1080\/15548627.2016.1192752","volume":"12","author":"D Xia","year":"2016","unstructured":"Xia, D. et al. MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling. Autophagy. 12(9), 1614\u20131630 (2016).","journal-title":"Autophagy."},{"issue":"1","key":"76347_CR33","doi-asserted-by":"publisher","first-page":"7642","DOI":"10.1038\/s41598-017-06588-z","volume":"7","author":"R Reilly","year":"2017","unstructured":"Reilly, R. et al. Targeting the PI3K\/Akt\/mTOR signalling pathway in cystic fibrosis. Nat. Sci. Rep. 7(1), 7642 (2017).","journal-title":"Nat. Sci. Rep."},{"issue":"44","key":"76347_CR34","doi-asserted-by":"publisher","first-page":"36762","DOI":"10.1074\/jbc.M508944200","volume":"280","author":"A Swiatecka-Urban","year":"2005","unstructured":"Swiatecka-Urban, A. et al. The short apical membrane half-life of rescued \u0394F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of \u0394F508-CFTR in polarized human airway epithelial cells. J. Biol. Chem. 280(44), 36762\u201336772 (2005).","journal-title":"J. Biol. Chem."},{"issue":"2","key":"76347_CR35","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.jprot.2009.09.001","volume":"73","author":"P Gomes-Alves","year":"2009","unstructured":"Gomes-Alves, P., Neves, S., Coelho, A. V. & Penque, D. Low temperature restoring effect on F508del-CFTR misprocessing: A proteomic approach. J. Proteomics. 73(2), 218\u2013230 (2009).","journal-title":"J. Proteomics."},{"issue":"4","key":"76347_CR36","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1007\/s00418-007-0317-3","volume":"128","author":"E Mart\u00ednez-Alonso","year":"2007","unstructured":"Mart\u00ednez-Alonso, E., Tom\u00e1s, M., Ballesta, J. & Mart\u00ednez-Men\u00e1rguez, J. A. Low temperature (15\u00a0\u00b0C) induces COPII dissociation from membranes and slow exit from the endoplasmic reticulum in HeLa cells. Histochem Cell Bio. 128(4), 379\u2013384 (2007).","journal-title":"Histochem Cell Bio."},{"issue":"10","key":"76347_CR37","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.tibs.2007.09.003","volume":"32","author":"DT Rutkowski","year":"2007","unstructured":"Rutkowski, D. T. & Kaufman, R. J. That which does not kill me makes me stronger: Adapting to chronic ER stress. Trends Biochem. Sci. 32(10), 469\u2013476 (2007).","journal-title":"Trends Biochem. Sci."},{"issue":"4","key":"76347_CR38","doi-asserted-by":"publisher","first-page":"L473","DOI":"10.1152\/ajplung.00379.2009","volume":"298","author":"TH Hampton","year":"2009","unstructured":"Hampton, T. H. & Stanton, B. A. A novel approach to analyze gene expression data demonstrates that the \u0394F508 mutation in CFTR downregulates the antigen presentation pathway. Am. J. Physiol. Lung Cell Mol. Physiol. 298(4), L473\u2013L482 (2009).","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"issue":"5","key":"76347_CR39","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.ygeno.2015.07.005","volume":"106","author":"LA Clarke","year":"2015","unstructured":"Clarke, L. A., Botelho, H. M., Sousa, L., Falcao, A. O. & Amaral, M. D. Transcriptome meta-analysis reveals common differential and global gene expression profiles in cystic fibrosis and other respiratory disorders and identifies CFTR regulators. Genomics 106(5), 268\u2013277 (2015).","journal-title":"Genomics"},{"issue":"29","key":"76347_CR40","doi-asserted-by":"publisher","first-page":"29ra31","DOI":"10.1126\/scitranslmed.3000928","volume":"2","author":"DA Stoltz","year":"2010","unstructured":"Stoltz, D. A. et al. Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci. Trans. Med. 2(29), 29ra31 (2010).","journal-title":"Sci. Trans. Med."},{"key":"76347_CR41","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1165\/ajrcmb\/8.5.522","volume":"8","author":"K Kunzelmann","year":"1993","unstructured":"Kunzelmann, K. et al. An immortalized cystic fibrosis tracheal epithelial cell line homozygous for the delF508 CFTR mutation. Am. J. Respir. Cell Mol. Bio. 8, 522\u2013529 (1993).","journal-title":"Am. J. Respir. Cell Mol. Bio."},{"issue":"11","key":"76347_CR42","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1111\/j.1600-0854.2008.00806.x","volume":"9","author":"X Wang","year":"2008","unstructured":"Wang, X., Koulov, A. V., Kellner, W. A., Riordan, J. R. & Balch, W. E. Chemical and biological folding contribute to temperature-sensitive \u0394F508 CFTR trafficking. Traffic. 9(11), 1878\u20131893 (2008).","journal-title":"Traffic."},{"key":"76347_CR43","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1038\/nchembio.1253","volume":"9","author":"T Okiyoneda","year":"2013","unstructured":"Okiyoneda, T. et al. Mechanism-based corrector combination restores \u0394F508-CFTR folding and function. Nat. Chem. Biol. 9, 444 (2013).","journal-title":"Nat. Chem. Biol."},{"issue":"2","key":"76347_CR44","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.jcf.2019.08.021","volume":"19","author":"BT Kopp","year":"2020","unstructured":"Kopp, B. T. et al. Whole-blood transcriptomic responses to lumacaftor\/ivacaftor therapy in cystic fibrosis. J. Cyst. Fibr. 19(2), 245\u2013254 (2020).","journal-title":"J. Cyst. Fibr."},{"issue":"2","key":"76347_CR45","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1093\/bioinformatics\/19.2.185","volume":"19","author":"BM Bolstad","year":"2003","unstructured":"Bolstad, B. M., Irizarry, R. A., \u00c5strand, M. & Speed, T. P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19(2), 185\u2013193 (2003).","journal-title":"Bioinformatics"},{"issue":"6","key":"76347_CR46","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","volume":"28","author":"JT Leek","year":"2012","unstructured":"Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E. & Storey, J. D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28(6), 882\u2013883 (2012).","journal-title":"Bioinformatics"},{"key":"76347_CR47","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing: R Foundation for Statistical Computing; 2018. https:\/\/www.R-project.org\/."},{"issue":"1","key":"76347_CR48","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.febslet.2004.07.055","volume":"573","author":"R Breitling","year":"2004","unstructured":"Breitling, R., Armengaud, P., Amtmann, A. & Herzyk, P. Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett. 573(1), 83\u201392 (2004).","journal-title":"FEBS Lett."},{"key":"76347_CR49","doi-asserted-by":"crossref","unstructured":"Hong, F. et al. RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis. Bioinformatics 22, 2825\u20132827 (2006).","DOI":"10.1093\/bioinformatics\/btl476"},{"issue":"12","key":"76347_CR50","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15(12), 550 (2014).","journal-title":"Genome Biol."},{"issue":"3","key":"76347_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","volume":"36","author":"W Viechtbauer","year":"2010","unstructured":"Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36(3), 1\u201348 (2010).","journal-title":"J. Stat. Softw."},{"key":"76347_CR52","unstructured":"Dabney A, Storey JD, Warnes G. qvalue: Q-value estimation for false discovery rate control. R package version 2010."},{"issue":"6","key":"76347_CR53","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1093\/bioinformatics\/btr028","volume":"27","author":"X Wang","year":"2011","unstructured":"Wang, X., Terfve, C., Rose, J. C. & Markowetz, F. HTSanalyzeR: An R\/Bioconductor package for integrated network analysis of high-throughput screens. Bioinformatics 27(6), 879\u2013880 (2011).","journal-title":"Bioinformatics"},{"issue":"6","key":"76347_CR54","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The molecular signatures database hallmark gene set collection. Cell Sys. 1(6), 417\u2013425 (2015).","journal-title":"Cell Sys."},{"issue":"1","key":"76347_CR55","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner, M. et al. Gene ontology: Tool for the unification of biology. Nat. Genet. 25(1), 25\u201329 (2000).","journal-title":"Nat. Genet."},{"issue":"Database issue","key":"76347_CR56","doi-asserted-by":"publisher","first-page":"D331","DOI":"10.1093\/nar\/gkw1108","volume":"45","author":"The Gene Ontology Consortium","year":"2017","unstructured":"The Gene Ontology Consortium. Expansion of the gene ontology knowledgebase and resources. Nucleic Acids Res. 45(Database issue), D331\u2013D338 (2017).","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"76347_CR57","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28(1), 27\u201330 (2000).","journal-title":"Nucleic Acids Res."},{"issue":"19","key":"76347_CR58","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.1093\/bioinformatics\/btq466","volume":"26","author":"A Lachmann","year":"2010","unstructured":"Lachmann, A. et al. ChEA: Transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 26(19), 2438\u20132444 (2010).","journal-title":"Bioinformatics"},{"issue":"43","key":"76347_CR59","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. 102(43), 15545\u201315550 (2005).","journal-title":"Proc. Natl. Acad. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76347-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76347-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76347-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T23:56:23Z","timestamp":1670370983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-76347-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,25]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["76347"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-76347-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,25]]},"assertion":[{"value":"26 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"20553"}}