{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:23:56Z","timestamp":1790263436925,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"am","delay-in-days":366,"URL":"http:\/\/rsc.li\/journals-terms-of-use"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-INBS-08"],"award-info":[{"award-number":["ANR-10-INBS-08"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-10-LABX-49-01"],"award-info":[{"award-number":["ANR-10-LABX-49-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-10-INBS-08"],"award-info":[{"award-number":["ANR-10-INBS-08"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-10-LABX-49-01"],"award-info":[{"award-number":["ANR-10-LABX-49-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Wilson's disease (WD), a rare genetic disease caused by mutations in the ATP7B gene, is associated with altered expression and\/or function of the copper-transporting ATP7B protein, leading to massive toxic accumulation of copper in the liver and brain. The Atp7b\u2212\/\u2212 mouse, a genetic and phenotypic model of WD, was developed to provide new insights into the pathogenic mechanisms of WD. Many plasma proteins are secreted by the liver, and impairment of liver function can trigger changes to the plasma proteome. High standard proteomics workflows can identify such changes. Here, we explored the plasma proteome of the Atp7b\u2212\/\u2212 mouse using a mass spectrometry (MS)-based proteomics workflow combining unbiased discovery analysis followed by targeted quantification. Among the 367 unique plasma proteins identified, 7 proteins were confirmed as differentially abundant between Atp7b\u2212\/\u2212 mice and wild-type littermates, and were directly linked to WD pathophysiology (regeneration of liver parenchyma, plasma iron depletion, etc.). We then adapted our targeted proteomics assay to quantify human orthologues of these proteins in plasma from copper-chelator-treated WD patients. The plasma proteome changes observed in the Atp7b\u2212\/\u2212 mouse were not confirmed in these samples, except for alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals. Plasma ceruloplasmin was investigated in both the Atp7b\u2212\/\u2212 mouse model and human patients; it was significantly decreased in the human form of WD only. In conclusion, MS-based proteomics is a method of choice to identify proteome changes in murine models of disrupted metal homeostasis, and allows their validation in human cohorts.<\/jats:p>","DOI":"10.1039\/c9mt00225a","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T19:46:52Z","timestamp":1575316012000},"page":"249-258","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Comprehensive and comparative exploration of the <i>Atp7b\u2212\/\u2212<\/i> mouse plasma proteome"],"prefix":"10.1093","volume":"12","author":[{"given":"Maud","family":"Lacombe","sequence":"first","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6216-9192","authenticated-orcid":false,"given":"Michel","family":"Jaquinod","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3515-0055","authenticated-orcid":false,"given":"Lucid","family":"Belmudes","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3896-6196","authenticated-orcid":false,"given":"Yohann","family":"Cout\u00e9","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Ramus","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7384-4587","authenticated-orcid":false,"given":"Florence","family":"Combes","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-3564","authenticated-orcid":false,"given":"Thomas","family":"Burger","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"},{"name":"CNRS, BIG-BGE, F-38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Mintz","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, CNRS, IRIG, LCBM, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Barthelon","sequence":"additional","affiliation":[{"name":"Clinique Universitaire d\u2019H\u00e9pato-gastroent\u00e9rologie, Centre Hospitalier Universitaire Grenoble, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Leroy","sequence":"additional","affiliation":[{"name":"Clinique Universitaire d\u2019H\u00e9pato-gastroent\u00e9rologie, Centre Hospitalier Universitaire Grenoble, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lia","family":"Poujois","sequence":"additional","affiliation":[{"name":"National Reference Centre for Wilson's Disease, AP-HP, Lariboisi\u00e8re University Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Lachaux","sequence":"additional","affiliation":[{"name":"National Reference Centre for Wilson's Disease, H\u00f4pital Femme M\u00e8re Enfant, Hospices Civils de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"France","family":"Woimant","sequence":"additional","affiliation":[{"name":"National Reference Centre for Wilson's Disease, AP-HP, Lariboisi\u00e8re University Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-8707","authenticated-orcid":false,"given":"Virginie","family":"Brun","sequence":"additional","affiliation":[{"name":"Univ. Grenoble Alpes, CEA, Inserm, IRIG, BGE, 38000 Grenoble, France. Fax: +33 4 38 78 50 51; Tel: +33 4 38 78 96 57"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,2]]},"reference":[{"issue":"6","key":"2021121004370540100_cit1","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.clinre.2018.03.007","article-title":"Wilson's disease: A 2017 update","volume":"42","author":"Poujois","year":"2018","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"2021121004370540100_cit2","doi-asserted-by":"crossref","first-page":"36041","DOI":"10.1074\/jbc.M112.370403","article-title":"Molecular events initiating exit of a copper-transporting ATPase ATP7B from the trans-Golgi network","volume":"287","author":"Hasan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2021121004370540100_cit3","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1002\/hep.22261","article-title":"Diagnosis and treatment of Wilson disease: an update","volume":"47","author":"Roberts","year":"2008","journal-title":"Hepatology"},{"key":"2021121004370540100_cit4","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1016\/j.cca.2011.08.019","article-title":"Relative exchangeable copper: a new highly sensitive and highly specific biomarker for Wilson's disease diagnosis","volume":"412","author":"El Balkhi","year":"2011","journal-title":"Clin. Chim. Acta"},{"key":"2021121004370540100_cit5","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.jtemb.2018.06.013","article-title":"Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson's disease","volume":"50","author":"Heissat","year":"2018","journal-title":"J. Trace Elem. Med. Biol."},{"key":"2021121004370540100_cit6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.livres.2017.08.003","article-title":"Wilson disease: At the crossroads between genetics and epigenetics-A review of the evidence","volume":"1","author":"Kieffer","year":"2017","journal-title":"Liver Res."},{"key":"2021121004370540100_cit7","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.ejmg.2016.08.011","article-title":"Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis","volume":"59","author":"Lv","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"2021121004370540100_cit8","first-page":"35","article-title":"Genetic and environmental modifiers of Wilson disease","volume-title":"Handb. Clin. Neurol.","author":"Medici","year":"2017"},{"key":"2021121004370540100_cit9","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1021\/acs.jproteome.6b00828","article-title":"Quantification of ATP7B Protein in Dried Blood Spots by Peptide Immuno-SRM as a Potential Screen for Wilson's Disease","volume":"16","author":"Jung","year":"2017","journal-title":"J. Proteome Res."},{"key":"2021121004370540100_cit10","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1093\/hmg\/8.9.1665","article-title":"Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation","volume":"8","author":"Buiakova","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"2021121004370540100_cit11","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1042\/BST0361233","article-title":"Atp7b-\/- mice as a model for studies of Wilson's disease","volume":"36","author":"Lutsenko","year":"2008","journal-title":"Biochem. Soc. Trans."},{"key":"2021121004370540100_cit12","doi-asserted-by":"crossref","first-page":"8343","DOI":"10.1074\/jbc.M607496200","article-title":"High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease","volume":"282","author":"Huster","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021121004370540100_cit13","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2353\/ajpath.2006.050312","article-title":"Consequences of copper accumulation in the livers of the Atp7b-\/- (Wilson disease gene) knockout mice","volume":"168","author":"Huster","year":"2006","journal-title":"Am. J. Pathol."},{"key":"2021121004370540100_cit14","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.dib.2017.07.025","article-title":"Data on the impact of the blood sample collection methods on blood protein profiling studies","volume":"14","author":"Ilies","year":"2017","journal-title":"Data Brief"},{"key":"2021121004370540100_cit15","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cca.2017.05.030","article-title":"Impact of blood sample collection methods on blood protein profiling studies","volume":"471","author":"Ilies","year":"2017","journal-title":"Clin. Chim. Acta"},{"key":"2021121004370540100_cit16","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1021\/acs.jproteome.7b00788","article-title":"Systematic Evaluation of the Use of Human Plasma and Serum for Mass-Spectrometry-Based Shotgun Proteomics","volume":"17","author":"Lan","year":"2018","journal-title":"J. Proteome Res."},{"key":"2021121004370540100_cit17","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1021\/ac300006b","article-title":"Consecutive proteolytic digestion in an enzyme reactor increases depth of proteomic and phosphoproteomic analysis","volume":"84","author":"Wisniewski","year":"2012","journal-title":"Anal. Chem."},{"key":"2021121004370540100_cit18","doi-asserted-by":"crossref","first-page":"11033","DOI":"10.1093\/nar\/gkw880","article-title":"2016 update of the PRIDE database and its related tools","volume":"44","author":"Vizcaino","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2021121004370540100_cit19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/bioinformatics\/btw580","article-title":"DAPAR & ProStaR: software to perform statistical analyses in quantitative discovery proteomics","volume":"33","author":"Wieczorek","year":"2017","journal-title":"Bioinformatics"},{"key":"2021121004370540100_cit20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nbt.1524","article-title":"Prediction of high-responding peptides for targeted protein assays by mass spectrometry","volume":"27","author":"Fusaro","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"2021121004370540100_cit21","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1093\/bioinformatics\/btq054","article-title":"Skyline: an open source document editor for creating and analyzing targeted proteomics experiments","volume":"26","author":"MacLean","year":"2010","journal-title":"Bioinformatics"},{"key":"2021121004370540100_cit22","doi-asserted-by":"crossref","first-page":"10073","DOI":"10.1074\/jbc.M110.190546","article-title":"Clusterin (apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B","volume":"286","author":"Materia","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021121004370540100_cit23","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.21037\/atm.2019.02.10","article-title":"Challenges in the diagnosis of Wilson disease","volume":"7","author":"Poujois","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"2021121004370540100_cit24","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1111\/j.1440-1746.2009.06173.x","article-title":"Evidence for a critical role of ceruloplasmin oxidase activity in iron metabolism of Wilson disease gene knockout mice","volume":"25","author":"Merle","year":"2010","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2021121004370540100_cit25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00795-006-0326-7","article-title":"Compound overload of copper and iron in patients with Wilson's disease","volume":"39","author":"Hayashi","year":"2006","journal-title":"Med. Mol. Morphol."},{"key":"2021121004370540100_cit26","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1159\/000351207","article-title":"The molecular chaperone apolipoprotein J\/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review","volume":"59","author":"Trougakos","year":"2013","journal-title":"Gerontology"},{"key":"2021121004370540100_cit27","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1074\/jbc.M111.302216","article-title":"Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B","volume":"287","author":"Materia","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2021121004370540100_cit28","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/hep.28472","article-title":"Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice","volume":"63","author":"Li","year":"2016","journal-title":"Hepatology"},{"key":"2021121004370540100_cit29","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.celrep.2016.12.070","article-title":"Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance","volume":"18","author":"Ruby","year":"2017","journal-title":"Cell Rep."},{"key":"2021121004370540100_cit30","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1479-7364-7-22","article-title":"Update of the human and mouse SERPIN gene superfamily","volume":"7","author":"Heit","year":"2013","journal-title":"Hum. Genomics"},{"key":"2021121004370540100_cit31","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.2741\/2275","article-title":"SERPINA3 (aka alpha-1-antichymotrypsin)","volume":"12","author":"Baker","year":"2007","journal-title":"Front. Biosci."},{"key":"2021121004370540100_cit32","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0168-8278(05)80275-2","article-title":"The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease","volume":"18","author":"Faber","year":"1993","journal-title":"J. Hepatol."},{"key":"2021121004370540100_cit33","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1442-200X.2009.02950.x","article-title":"alpha(1)-Antichymotrypsin deficiency associated with liver cirrhosis","volume":"52","author":"Ortega","year":"2010","journal-title":"Pediatr. Int."},{"key":"2021121004370540100_cit34","doi-asserted-by":"crossref","first-page":"46632","DOI":"10.1074\/jbc.M206246200","article-title":"Mechanisms of copper incorporation into human ceruloplasmin","volume":"277","author":"Hellman","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021121004370540100_cit35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/iub.1613","article-title":"The role of insufficient copper in lipid synthesis and fatty-liver disease","volume":"69","author":"Morrell","year":"2017","journal-title":"IUBMB Life"}],"container-title":["Metallomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/metallomics\/article-pdf\/12\/2\/249\/41701899\/c9mt00225a.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/metallomics\/article-pdf\/12\/2\/249\/41701899\/c9mt00225a.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T04:50:06Z","timestamp":1639111806000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/metallomics\/article\/12\/2\/249\/5961852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,2]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2,26]]}},"URL":"https:\/\/doi.org\/10.1039\/c9mt00225a","relation":{},"ISSN":["1756-5901","1756-591X"],"issn-type":[{"value":"1756-5901","type":"print"},{"value":"1756-591X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,2]]},"published":{"date-parts":[[2019,12,2]]},"assertion":[{"value":"This document is Similarity Check deposited","name":"similarity_check","explanation":{"URL":"https:\/\/www.crossref.org\/services\/similarity-check\/"},"group":{"name":"similarity_check","label":"SIMILARITY CHECK"}},{"value":"Supplementary Information","URL":"https:\/\/doi.org\/10.1039\/C9MT00225A","name":"related_data","group":{"name":"related_data","label":"RELATED DATA"}},{"value":"Michel Jaquinod (ORCID)","URL":"http:\/\/orcid.org\/0000-0001-6216-9192","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Lucid Belmudes (ORCID)","URL":"http:\/\/orcid.org\/0000-0002-3515-0055","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Yohann Cout\u00e9 (ORCID)","URL":"http:\/\/orcid.org\/0000-0003-3896-6196","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Florence Combes (ORCID)","URL":"http:\/\/orcid.org\/0000-0001-7384-4587","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Thomas Burger (ORCID)","URL":"http:\/\/orcid.org\/0000-0003-3539-3564","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Virginie Brun (ORCID)","URL":"http:\/\/orcid.org\/0000-0002-9098-8707","name":"identifier","group":{"name":"author_identifiers","label":"IDENTIFIERS"}},{"value":"Single-blind","order":2,"name":"peer_review_method","group":{"name":"peer_review_method","label":"PEER REVIEW METHOD"}},{"value":"Received 9 September 2019; Accepted 2 December 2019;  Accepted Manuscript published 2 December 2019;  Advance Article published 9 December 2019;  Version of Record published 26 February 2020","order":1,"name":"history","group":{"name":"publication_history","label":"PUBLICATION HISTORY"}}]}}