{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:39:03Z","timestamp":1792453143685,"version":"4.5.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T00:00:00Z","timestamp":1573084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T00:00:00Z","timestamp":1573084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["908\/15"],"award-info":[{"award-number":["908\/15"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by\n                    <jats:italic>CCNB1<\/jats:italic>\n                    and\n                    <jats:italic>Ki67<\/jats:italic>\n                    staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-52733-1","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T06:05:29Z","timestamp":1573106729000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis"],"prefix":"10.1038","volume":"9","author":[{"given":"Nurit","family":"Loberman-Nachum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katya","family":"Sosnovski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayelet","family":"Di Segni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilat","family":"Efroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzipi","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"BenShoshan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lait","family":"Anafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Avivi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Barshack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dror S.","family":"Shouval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee A.","family":"Denson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0903-6056","authenticated-orcid":false,"given":"Amnon","family":"Amir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Batia","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2680-1570","authenticated-orcid":false,"given":"Yael","family":"Haberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,7]]},"reference":[{"key":"52733_CR1","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1056\/NEJMcp1113994","volume":"367","author":"A Fasano","year":"2012","unstructured":"Fasano, A. & Catassi, C. Clinical practice. Celiac disease. The New England journal of medicine 367, 2419\u20132426, https:\/\/doi.org\/10.1056\/NEJMcp1113994 (2012).","journal-title":"The New England journal of medicine"},{"key":"52733_CR2","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1056\/NEJMra071600","volume":"357","author":"PH Green","year":"2007","unstructured":"Green, P. H. & Cellier, C. Celiac disease. The New England journal of medicine 357, 1731\u20131743, https:\/\/doi.org\/10.1056\/NEJMra071600 (2007).","journal-title":"The New England journal of medicine"},{"key":"52733_CR3","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1097\/MPG.0000000000001105","volume":"62","author":"H Szajewska","year":"2016","unstructured":"Szajewska, H. et al. Gluten Introduction and the Risk of Coeliac Disease: A Position Paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Journal of pediatric gastroenterology and nutrition 62, 507\u2013513, https:\/\/doi.org\/10.1097\/MPG.0000000000001105 (2016).","journal-title":"Journal of pediatric gastroenterology and nutrition"},{"key":"52733_CR4","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1053\/j.gastro.2009.03.059","volume":"137","author":"A Rubio-Tapia","year":"2009","unstructured":"Rubio-Tapia, A. et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 137, 88\u201393, https:\/\/doi.org\/10.1053\/j.gastro.2009.03.059 (2009).","journal-title":"Gastroenterology"},{"key":"52733_CR5","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3109\/07853890.2010.514285","volume":"42","author":"C Catassi","year":"2010","unstructured":"Catassi, C. et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Annals of medicine 42, 530\u2013538, https:\/\/doi.org\/10.3109\/07853890.2010.514285 (2010).","journal-title":"Annals of medicine"},{"key":"52733_CR6","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1111\/j.1365-2036.2007.03502.x","volume":"26","author":"S Lohi","year":"2007","unstructured":"Lohi, S. et al. Increasing prevalence of coeliac disease over time. Alimentary pharmacology & therapeutics 26, 1217\u20131225, https:\/\/doi.org\/10.1111\/j.1365-2036.2007.03502.x (2007).","journal-title":"Alimentary pharmacology & therapeutics"},{"key":"52733_CR7","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/S0140-6736(17)31796-8","volume":"391","author":"B Lebwohl","year":"2018","unstructured":"Lebwohl, B., Sanders, D. S. & Green, P. H. R. Coeliac disease. Lancet 391, 70\u201381, https:\/\/doi.org\/10.1016\/S0140-6736(17)31796-8 (2018).","journal-title":"Lancet"},{"key":"52733_CR8","doi-asserted-by":"publisher","first-page":"e98187","DOI":"10.1371\/journal.pone.0098187","volume":"9","author":"J Hedegaard","year":"2014","unstructured":"Hedegaard, J. et al. Next-generation sequencing of RNA and DNA isolated from paired fresh-frozen and formalin-fixed paraffin-embedded samples of human cancer and normal tissue. PloS one 9, e98187, https:\/\/doi.org\/10.1371\/journal.pone.0098187 (2014).","journal-title":"PloS one"},{"key":"52733_CR9","doi-asserted-by":"publisher","first-page":"e0215132","DOI":"10.1371\/journal.pone.0215132","volume":"14","author":"MM Leonard","year":"2019","unstructured":"Leonard, M. M. et al. RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis. PloS one 14, e0215132, https:\/\/doi.org\/10.1371\/journal.pone.0215132 (2019).","journal-title":"PloS one"},{"key":"52733_CR10","doi-asserted-by":"publisher","first-page":"4385","DOI":"10.1007\/s00018-018-2898-5","volume":"75","author":"H Bragde","year":"2018","unstructured":"Bragde, H., Jansson, U., Fredrikson, M., Grodzinsky, E. & Soderman, J. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies. Cellular and molecular life sciences: CMLS 75, 4385\u20134401, https:\/\/doi.org\/10.1007\/s00018-018-2898-5 (2018).","journal-title":"Cellular and molecular life sciences: CMLS"},{"key":"52733_CR11","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1136\/gut.2003.018374","volume":"53","author":"B Diosdado","year":"2004","unstructured":"Diosdado, B. et al. A microarray screen for novel candidate genes in coeliac disease pathogenesis. Gut 53, 944\u2013951 (2004).","journal-title":"Gut"},{"key":"52733_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41424-018-0059-7","volume":"9","author":"P Acharya","year":"2018","unstructured":"Acharya, P. et al. First Degree Relatives of Patients with Celiac Disease Harbour an Intestinal Transcriptomic Signature that Might Protect them from Enterocyte Damage. Clinical and translational gastroenterology 9, 195, https:\/\/doi.org\/10.1038\/s41424-018-0059-7 (2018).","journal-title":"Clinical and translational gastroenterology"},{"key":"52733_CR13","doi-asserted-by":"publisher","first-page":"297","DOI":"10.2147\/CEG.S8315","volume":"4","author":"SA Scanlon","year":"2011","unstructured":"Scanlon, S. A. & Murray, J. A. Update on celiac disease - etiology, differential diagnosis, drug targets, and management advances. Clinical and experimental gastroenterology 4, 297\u2013311, https:\/\/doi.org\/10.2147\/CEG.S8315 (2011).","journal-title":"Clinical and experimental gastroenterology"},{"key":"52733_CR14","doi-asserted-by":"publisher","first-page":"e1005515","DOI":"10.1371\/journal.pcbi.1005515","volume":"13","author":"A Tuerk","year":"2017","unstructured":"Tuerk, A., Wiktorin, G. & Guler, S. Mixture models reveal multiple positional bias types in RNA-Seq data and lead to accurate transcript concentration estimates. PLoS Comput Biol 13, e1005515, https:\/\/doi.org\/10.1371\/journal.pcbi.1005515 (2017).","journal-title":"PLoS Comput Biol"},{"key":"52733_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07841-3","volume":"10","author":"Y Haberman","year":"2019","unstructured":"Haberman, Y. et al. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nature communications 10, 38, https:\/\/doi.org\/10.1038\/s41467-018-07841-3 (2019).","journal-title":"Nature communications"},{"key":"52733_CR16","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","volume":"34","author":"NL Bray","year":"2016","unstructured":"Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nature biotechnology 34, 525\u2013527, https:\/\/doi.org\/10.1038\/nbt.3519 (2016).","journal-title":"Nature biotechnology"},{"key":"52733_CR17","doi-asserted-by":"publisher","first-page":"W305","DOI":"10.1093\/nar\/gkp427","volume":"37","author":"J Chen","year":"2009","unstructured":"Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic acids research 37, W305\u2013311, https:\/\/doi.org\/10.1093\/nar\/gkp427 (2009).","journal-title":"Nucleic acids research"},{"key":"52733_CR18","doi-asserted-by":"publisher","first-page":"W96","DOI":"10.1093\/nar\/gkq418","volume":"38","author":"V Kaimal","year":"2010","unstructured":"Kaimal, V., Bardes, E. E., Tabar, S. C., Jegga, A. G. & Aronow, B. J. ToppCluster: a multiple gene list feature analyzer for comparative enrichment clustering and network-based dissection of biological systems. Nucleic acids research 38, W96\u2013102, https:\/\/doi.org\/10.1093\/nar\/gkq418 (2010).","journal-title":"Nucleic acids research"},{"key":"52733_CR19","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","volume":"25","author":"G Bindea","year":"2009","unstructured":"Bindea, G. et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25, 1091\u20131093, https:\/\/doi.org\/10.1093\/bioinformatics\/btp101 (2009).","journal-title":"Bioinformatics"},{"key":"52733_CR20","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nmeth.2212","volume":"9","author":"R Saito","year":"2012","unstructured":"Saito, R. et al. A travel guide to Cytoscape plugins. Nature methods 9, 1069\u20131076, https:\/\/doi.org\/10.1038\/nmeth.2212 (2012).","journal-title":"Nature methods"},{"key":"52733_CR21","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1021\/ci034160g","volume":"43","author":"V Svetnik","year":"2003","unstructured":"Svetnik, V. et al. Random forest: a classification and regression tool for compound classification and QSAR modeling. J Chem Inf Comput Sci 43, 1947\u20131958, https:\/\/doi.org\/10.1021\/ci034160g (2003).","journal-title":"J Chem Inf Comput Sci"},{"key":"52733_CR22","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1093\/ibd\/izx013","volume":"24","author":"Y Haberman","year":"2018","unstructured":"Haberman, Y. et al. Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease. Inflammatory bowel diseases 24, 346\u2013360, https:\/\/doi.org\/10.1093\/ibd\/izx013 (2018).","journal-title":"Inflammatory bowel diseases"},{"key":"52733_CR23","doi-asserted-by":"publisher","unstructured":"Haberman, Y. et al. Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis. Mucosal immunology, https:\/\/doi.org\/10.1038\/s41385-018-0114-4 (2018).","DOI":"10.1038\/s41385-018-0114-4"},{"key":"52733_CR24","doi-asserted-by":"publisher","first-page":"3617","DOI":"10.1172\/JCI75436","volume":"124","author":"Y Haberman","year":"2014","unstructured":"Haberman, Y. et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. The Journal of clinical investigation 124, 3617\u20133633, https:\/\/doi.org\/10.1172\/JCI75436 (2014).","journal-title":"The Journal of clinical investigation"},{"key":"52733_CR25","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1080\/17474124.2018.1412828","volume":"12","author":"DO Otuya","year":"2018","unstructured":"Otuya, D. O. et al. Non-endoscopic biopsy techniques: a review. Expert review of gastroenterology & hepatology 12, 109\u2013117, https:\/\/doi.org\/10.1080\/17474124.2018.1412828 (2018).","journal-title":"Expert review of gastroenterology & hepatology"},{"key":"52733_CR26","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1136\/gut.36.3.369","volume":"36","author":"TC Savidge","year":"1995","unstructured":"Savidge, T. C., Walker-Smith, J. A. & Phillips, A. D. Novel insights into human intestinal epithelial cell proliferation in health and disease using confocal microscopy. Gut 36, 369\u2013374 (1995).","journal-title":"Gut"},{"key":"52733_CR27","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1136\/gut.14.9.701","volume":"14","author":"N Wright","year":"1973","unstructured":"Wright, N., Watson, A., Morley, A., Appleton, D. & Marks, J. Cell kinetics in flat (avillous) mucosa of the human small intestine. Gut 14, 701\u2013710 (1973).","journal-title":"Gut"},{"key":"52733_CR28","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1136\/gut.14.8.603","volume":"14","author":"N Wright","year":"1973","unstructured":"Wright, N. et al. The cell cycle time in the flat (avillous) mucosa of the human small intestine. Gut 14, 603\u2013606 (1973).","journal-title":"Gut"},{"key":"52733_CR29","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.3389\/fimmu.2018.01270","volume":"9","author":"C Andrews","year":"2018","unstructured":"Andrews, C., McLean, M. H. & Durum, S. K. Cytokine Tuning of Intestinal Epithelial Function. Frontiers in immunology 9, 1270, https:\/\/doi.org\/10.3389\/fimmu.2018.01270 (2018).","journal-title":"Frontiers in immunology"},{"key":"52733_CR30","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/nature16460","volume":"528","author":"CA Lindemans","year":"2015","unstructured":"Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560\u2013564, https:\/\/doi.org\/10.1038\/nature16460 (2015).","journal-title":"Nature"},{"key":"52733_CR31","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.4049\/jimmunol.1601066","volume":"199","author":"EM Bradford","year":"2017","unstructured":"Bradford, E. M. et al. Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease. J Immunol 199, 1886\u20131897, https:\/\/doi.org\/10.4049\/jimmunol.1601066 (2017).","journal-title":"J Immunol"},{"key":"52733_CR32","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.immuni.2010.03.001","volume":"32","author":"P Nava","year":"2010","unstructured":"Nava, P. et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity 32, 392\u2013402, https:\/\/doi.org\/10.1016\/j.immuni.2010.03.001 (2010).","journal-title":"Immunity"},{"key":"52733_CR33","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000000136","author":"T Braun","year":"2019","unstructured":"Braun, T. et al. Individualized Dynamics in the Gut Microbiota Precede Crohn\u2019s Disease Flares. The American journal of gastroenterology. https:\/\/doi.org\/10.14309\/ajg.0000000000000136 (2019).","journal-title":"The American journal of gastroenterology"},{"key":"52733_CR34","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1053\/j.gastro.2016.06.041","volume":"151","author":"A Caminero","year":"2016","unstructured":"Caminero, A. et al. Duodenal Bacteria From Patients With Celiac Disease and Healthy Subjects Distinctly Affect Gluten Breakdown and Immunogenicity. Gastroenterology 151, 670\u2013683, https:\/\/doi.org\/10.1053\/j.gastro.2016.06.041 (2016).","journal-title":"Gastroenterology"},{"key":"52733_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-018-0415-6","volume":"6","author":"M Olivares","year":"2018","unstructured":"Olivares, M. et al. Gut microbiota trajectory in early life may predict development of celiac disease. Microbiome 6, 36, https:\/\/doi.org\/10.1186\/s40168-018-0415-6 (2018).","journal-title":"Microbiome"},{"key":"52733_CR36","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3109\/00365521.2013.775666","volume":"48","author":"TG de Meij","year":"2013","unstructured":"de Meij, T. G. et al. Composition and diversity of the duodenal mucosa-associated microbiome in children with untreated coeliac disease. Scandinavian journal of gastroenterology 48, 530\u2013536, https:\/\/doi.org\/10.3109\/00365521.2013.775666 (2013).","journal-title":"Scandinavian journal of gastroenterology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52733-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52733-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52733-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T10:27:15Z","timestamp":1671272835000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52733-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,7]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["52733"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-52733-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,7]]},"assertion":[{"value":"15 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All authors have no financial and non-financial conflict of interests or competing interests associated with this work. Funding for this work was in part from the Israel Science Foundation, European Research Council, and Crohn's & Colitis Foundation.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16163"}}