{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:04:41Z","timestamp":1792173881562,"version":"4.4.0"},"reference-count":50,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["A-14814"],"award-info":[{"award-number":["A-14814"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"publisher","award":["Momentum 2017"],"award-info":[{"award-number":["Momentum 2017"]}],"id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["A-11582"],"award-info":[{"award-number":["A-11582"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS100802"],"award-info":[{"award-number":["R01 NS100802"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","award":["PIIF"],"award-info":[{"award-number":["PIIF"]}],"id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington\u2019s disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in\n                    <jats:italic>Drd1<\/jats:italic>\n                    -expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs.\n                  <\/jats:p>","DOI":"10.7554\/elife.64984","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T19:00:20Z","timestamp":1614020420000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64984","source":"Crossref","is-referenced-by-count":17,"title":["Shape deformation analysis reveals the temporal dynamics of cell-type-specific homeostatic and pathogenic responses to mutant huntingtin"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6835-6033","authenticated-orcid":true,"given":"Lucile","family":"Megret","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gris","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique, Laboratoire Jacques-Louis Lyons (LJLL), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Sasidharan Nair","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Cevost","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Wertz","sequence":"additional","affiliation":[{"name":"MIT, Broad Institute, MIT, Picower Institute for Learning and Memory, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Aaronson","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Rosinski","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F","family":"Vogt","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"CHDI Foundation, Princeton, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Heiman","sequence":"additional","affiliation":[{"name":"MIT, Broad Institute, MIT, Picower Institute for Learning and Memory, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-2978","authenticated-orcid":true,"given":"Christian","family":"Neri","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Centre National de la Recherche Scientifique UMR 8256, INSERM ERL U1164, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,2,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"3481","DOI":"10.1093\/hmg\/ddv099","article-title":"Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington's disease mice","volume":"24","author":"Achour","year":"2015","journal-title":"Human Molecular Genetics"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-019-0581-9","article-title":"The caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal Huntington's disease brain","volume":"12","author":"Agus","year":"2019","journal-title":"BMC Medical Genomics"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-0880-6","article-title":"Single-nucleus RNA-seq identifies Huntington disease astrocyte states","volume":"8","author":"Al-Dalahmah","year":"2020","journal-title":"Acta Neuropathologica Communications"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.cels.2018.05.010","article-title":"High-Throughput functional analysis distinguishes pathogenic, Nonpathogenic, and compensatory transcriptional changes in neurodegeneration","volume":"7","author":"Al-Ramahi","year":"2018","journal-title":"Cell Systems"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.1523\/JNEUROSCI.5409-05.2006","article-title":"CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity","volume":"26","author":"Arango","year":"2006","journal-title":"Journal of Neuroscience"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.matpur.2015.02.004","article-title":"Shape deformation analysis from the optimal control viewpoint","volume":"104","author":"Arguill\u00e8re","year":"2015","journal-title":"Journal De Math\u00e9matiques Pures Et Appliqu\u00e9es"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1093\/bioinformatics\/btz514","article-title":"Genetic cooperativity in multi-layer networks implicates cell survival and senescence in the striatum of Huntington\u2019s disease mice synchronous to symptoms","volume":"36","author":"Bigan","year":"2020","journal-title":"Bioinformatics"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075099","article-title":"Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6\/2 mouse model of Huntington's disease","volume":"8","author":"Bissonnette","year":"2013","journal-title":"PLOS ONE"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1242\/dmm.017368","article-title":"Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane","volume":"7","author":"Brandstaetter","year":"2014","journal-title":"Disease Models & Mechanisms"},{"key":"bib10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12675-y","article-title":"Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control Cancer cell proliferation","volume":"7","author":"Chowdhury","year":"2017","journal-title":"Scientific Reports"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.nbd.2018.08.010","article-title":"A role for autophagy in Huntington's disease","volume":"122","author":"Croce","year":"2019","journal-title":"Neurobiology of Disease"},{"key":"bib13","doi-asserted-by":"publisher","DOI":"10.3389\/fnsys.2014.00198","article-title":"Differential loss of thalamostriatal and corticostriatal input to striatal projection neuron types prior to overt motor symptoms in the Q140 knock-in mouse model of Huntington's disease","volume":"8","author":"Deng","year":"2014","journal-title":"Frontiers in Systems Neuroscience"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.cell.2008.10.029","article-title":"Application of a translational profiling approach for the comparative analysis of CNS cell types","volume":"135","author":"Doyle","year":"2008","journal-title":"Cell"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/S1474-4422(18)30029-2","article-title":"Cognitive and neuroimaging features and brain \u03b2-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study","volume":"17","author":"Dubois","year":"2018","journal-title":"The Lancet Neurology"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1002\/jnr.24493","article-title":"Phenotype onset in Huntington's disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene","volume":"97","author":"Franich","year":"2019","journal-title":"Journal of Neuroscience Research"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.cell.2019.06.036","article-title":"CAG repeat not polyglutamine length determines timing of Huntington's Disease Onset","volume":"178","author":"Genetic Modifiers of Huntington\u2019s Disease (GeM-HD) Consortium","year":"2019","journal-title":"Cell"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1093\/brain\/awy122","article-title":"Testing a longitudinal compensation model in Premanifest Huntington's disease","volume":"141","author":"Gregory","year":"2018","journal-title":"Brain"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1137\/16M1076733","article-title":"A Sub-Riemannian modular framework for Diffeomorphism-Based analysis of shape ensembles","volume":"11","author":"Gris","year":"2018","journal-title":"SIAM Journal on Imaging Sciences"},{"key":"bib20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050717","article-title":"Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease","volume":"7","author":"Heikkinen","year":"2012","journal-title":"PLOS ONE"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.cell.2008.10.028","article-title":"A translational profiling approach for the molecular characterization of CNS cell types","volume":"135","author":"Heiman","year":"2008","journal-title":"Cell"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1073\/pnas.98.4.1811","article-title":"The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis","volume":"98","author":"Holbert","year":"2001","journal-title":"PNAS"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-357","article-title":"An integrative approach to ortholog prediction for disease-focused and other functional studies","volume":"12","author":"Hu","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nn.4256","article-title":"Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice","volume":"19","author":"Langfelder","year":"2016","journal-title":"Nature Neuroscience"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1002\/1531-8249(200004)47:4<493::AID-ANA13>3.0.CO;2-4","article-title":"In vivo positron emission tomographic evidence for compensatory changes in Presynaptic dopaminergic nerve terminals in Parkinson's disease","volume":"47","author":"Lee","year":"2000","journal-title":"Annals of Neurology"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.neuron.2020.06.021","article-title":"Cell Type-Specific transcriptomics reveals that mutant huntingtin leads to mitochondrial RNA release and neuronal innate immune activation","volume":"107","author":"Lee","year":"2020","journal-title":"Neuron"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-13-91","article-title":"Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons","volume":"13","author":"Lejeune","year":"2012","journal-title":"BMC Genomics"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1126\/science.aav9776","article-title":"Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis","volume":"364","author":"Maniatis","year":"2019","journal-title":"Science"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/j.1474-9726.2011.00768.x","article-title":"New genes that extend Caenorhabditis elegans' lifespan in response to reproductive signals","volume":"11","author":"McCormick","year":"2012","journal-title":"Aging Cell"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-020-3418-9","article-title":"Combining feature selection and shape analysis uncovers precise rules for miRNA regulation in Huntington's disease mice","volume":"21","author":"M\u00e9gret","year":"2020","journal-title":"BMC Bioinformatics"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/cne.10776","article-title":"Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats","volume":"465","author":"Menalled","year":"2003","journal-title":"The Journal of Comparative Neurology"},{"key":"bib33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049838","article-title":"Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175","volume":"7","author":"Menalled","year":"2012","journal-title":"PLOS ONE"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/S1474-4422(17)30161-8","article-title":"Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study","volume":"16","author":"Moss","year":"2017","journal-title":"The Lancet Neurology"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00127","article-title":"Multiple aspects of gene dysregulation in Huntington's Disease","volume":"4","author":"Moumn\u00e9","year":"2013","journal-title":"Frontiers in Neurology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"16889","DOI":"10.1073\/pnas.1420103111","article-title":"Potential function for the huntingtin protein as a scaffold for selective autophagy","volume":"111","author":"Ochaba","year":"2014","journal-title":"PNAS"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1093\/hmg\/ddn385","article-title":"Altered serotonin receptor expression is associated with depression-related behavior in the R6\/1 transgenic mouse model of Huntington's disease","volume":"18","author":"Pang","year":"2009","journal-title":"Human Molecular Genetics"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/ng1534","article-title":"Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons","volume":"37","author":"Parker","year":"2005","journal-title":"Nature Genetics"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1080\/01621459.1971.10482356","article-title":"Objective criteria for the evaluation of clustering methods","volume":"66","author":"Rand","year":"1971","journal-title":"Journal of the American Statistical Association"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"5733","DOI":"10.1073\/pnas.85.15.5733","article-title":"Differential loss of striatal projection neurons in Huntington disease","volume":"85","author":"Reiner","year":"1988","journal-title":"PNAS"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/ncb3101","article-title":"Huntingtin functions as a scaffold for selective macroautophagy","volume":"17","author":"Rui","year":"2015","journal-title":"Nature Cell Biology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1073\/pnas.1717877115","article-title":"Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease","volume":"115","author":"Sbodio","year":"2018","journal-title":"PNAS"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.nbd.2017.05.011","article-title":"Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease","volume":"105","author":"Sebastianutto","year":"2017","journal-title":"Neurobiology of Disease"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Research"},{"key":"bib45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001895","article-title":"The wnt receptor ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity","volume":"12","author":"Tourette","year":"2014","journal-title":"PLOS Biology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1016\/j.bmc.2011.02.047","article-title":"Using small molecules to target protein phosphatases","volume":"19","author":"Vintonyak","year":"2011","journal-title":"Bioorganic & Medicinal Chemistry"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13226","article-title":"FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase","volume":"19","author":"Voisin","year":"2020","journal-title":"Aging Cell"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.neuron.2020.01.004","article-title":"Genome-wide in\u00a0Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity","volume":"106","author":"Wertz","year":"2020","journal-title":"Neuron"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/hmg\/8.1.115","article-title":"Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse","volume":"8","author":"Wheeler","year":"1999","journal-title":"Human Molecular Genetics"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1152\/physrev.00041.2009","article-title":"Molecular mechanisms and potential therapeutical targets in Huntington's disease","volume":"90","author":"Zuccato","year":"2010","journal-title":"Physiological Reviews"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/64984\/elife-64984-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/64984\/elife-64984-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/64984","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:07:39Z","timestamp":1697058459000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/64984"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,23]]},"references-count":50,"alternative-id":["10.7554\/eLife.64984"],"URL":"https:\/\/doi.org\/10.7554\/elife.64984","archive":["CLOCKSS"],"relation":{"references":[{"id-type":"accession","id":"GPL24247","asserted-by":"subject"},{"id-type":"accession","id":"GSE152058","asserted-by":"subject"},{"id-type":"accession","id":"GPL13112","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.64984.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.64984.sa2","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,23]]},"article-number":"e64984"}}