{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:48:06Z","timestamp":1791074886555,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Postoperative neurocognitive disorders (po-NCD), including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in geriatric surgical patients. However, the ideal diagnostic biomarkers to predict individual risks of po-NCDs have not been identified. In this study, proteomic analysis was used to detect dysregulated proteins in three cognitive-related brain regions, the hippocampus, prefrontal cortex, and temporal lobe, of aged dNCR rats. The common affected proteins in these three brain regions were further verified by real-time polymerase chain reaction and western blotting. Furthermore, serum samples from aged rats with dNCR and elderly hip fracture patients with POD were also assessed with enzyme linked immunosorbent assays to investigate the biomarker potential of these dysregulated proteins. The increased expression levels of haptoglobin, caseinolytic protease (ClpP), and alpha-2 macroglobulin (A2M) as well as decreased expression levels of 14-3-3\u03b2\/\u03b1 and biliverdin reductase-A (BVR-A) were validated by proteomic analysis in the hippocampus, prefrontal cortex, and temporal lobe of aged dNCR rats. The increased expression of haptoglobin and decreased expression of 14-3-3\u03b2\/\u03b1 were further demonstrated in the three brain regions by western blotting. Moreover, increased levels of S100A6 and BVR-A in the hippocampus, S100A6 in the prefrontal cortex, and A2M in the temporal lobe were also observed. More intriguingly, both decreased serum 14-3-3\u03b2\/\u03b1 and increased A2M in geriatric POD patients as well as decreased serum ClpP in aged dNCR rats were verified. These results not only indicate potential diagnostic biomarkers for po-NCD but also provide directions for further pathological investigations.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Clinical Trial Registration:<\/jats:bold>\n                    <jats:ext-link>www.ClinicalTrials.gov<\/jats:ext-link>\n                    , identifier [ChiCTR1900027393].\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2021.741263","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T02:52:08Z","timestamp":1632883928000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Potential Serum Biomarkers for Postoperative Neurocognitive Disorders Based on Proteomic Analysis of Cognitive-Related Brain Regions"],"prefix":"10.3389","volume":"13","author":[{"given":"Yitong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengqian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingshu","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixian","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongshen","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jindan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinning","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengyang","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1002\/elps.202000208","article-title":"Recent progress in the LC-MS\/MS analysis of oxidative stress biomarkers","volume":"42","author":"Andries","year":"2021","journal-title":"Electrophoresis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fnagi.2015.00112","article-title":"Biomarkers of postoperative delirium and cognitive dysfunction","volume":"7","author":"Androsova","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1093\/chromsci\/bmw167","article-title":"Proteomics: technologies and their applications","volume":"55","author":"Aslam","year":"2017","journal-title":"J. Chromatogr. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/7854_2018_74","article-title":"Prefrontal contributions to attention and working memory","volume":"41","author":"Bahmani","year":"2019","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1111\/j.1471-4159.2011.07538.x","article-title":"Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease","volume":"120","author":"Barone","year":"2012","journal-title":"J. Neurochem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1038\/nrn1197","article-title":"14-3-3 proteins in the nervous system","volume":"4","author":"Berg","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1093\/brain\/awaa068","article-title":"Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease","volume":"143","author":"Berron","year":"2020","journal-title":"Brain"},{"key":"B8","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.bbamcr.2004.09.011","article-title":"Astrocytic calcium\/zinc binding protein S100A6 over expression in Alzheimer's disease and in PS1\/APP transgenic mice models","volume":"1742","author":"Boom","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e208931","DOI":"10.1001\/jamanetworkopen.2020.8931","article-title":"Economic burden of postoperative neurocognitive disorders among US medicare patients","volume":"3","author":"Boone","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"B10","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.yebeh.2016.04.024","article-title":"Social cognition in temporal lobe epilepsy: a systematic review and meta-analysis","volume":"60","author":"Bora","year":"2016","journal-title":"Epilepsy Behav."},{"key":"B11","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/978-1-4615-8315-8_3","article-title":"Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation","volume":"12","author":"Bowman","year":"1982","journal-title":"Adv. Hum. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1684\/epd.2009.0265","article-title":"Everyday cognition in temporal lobe and frontal lobe epilepsy","volume":"11","author":"Cahn-Weiner","year":"2009","journal-title":"Epileptic Disord."},{"key":"B13","doi-asserted-by":"publisher","first-page":"5410657","DOI":"10.1155\/2019\/5410657","article-title":"Alpha-2-macroglobulin, a hypochlorite-regulated chaperone and immune system modulator","volume":"2019","author":"Cater","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1111\/jnc.15436","article-title":"The adenosine A2A receptor alleviates postoperative delirium-like behaviors by restoring blood cerebrospinal barrier permeability in rats","volume":"158","author":"Chen","year":"2021","journal-title":"J. Neurochem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3389\/fnagi.2014.00107","article-title":"Systemic inflammation impairs attention and cognitive flexibility but not associative learning in aged rats: possible implications for delirium","volume":"6","author":"Culley","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1007\/s12031-013-0086-5","article-title":"alpha-Synuclein overexpression represses 14-3-3theta transcription","volume":"51","author":"Ding","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1001\/archneurol.2009.48","article-title":"The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels","volume":"66","author":"Dong","year":"2009","journal-title":"Arch. Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1097\/ALN.0000000000002956","article-title":"Perioperative neurocognitive disorder: state of the preclinical science","volume":"132","author":"Eckenhoff","year":"2020","journal-title":"Anesthesiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/hdy.2010.54","article-title":"Epigenetics and gene expression","volume":"105","author":"Gibney","year":"2010","journal-title":"Heredity"},{"key":"B20","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1212\/CON.0000000000000619","article-title":"Memory dysfunction","volume":"24","author":"Gliebus","year":"2018","journal-title":"Continuum"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.14336\/AD.2020.0106","article-title":"Prebiotics regulation of intestinal microbiota attenuates cognitive dysfunction induced by surgery stimulation in APP\/PS1 Mice","volume":"11","author":"Han","year":"","journal-title":"Aging Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"170","DOI":"10.3389\/fpsyt.2020.00170","article-title":"Proteomic analysis of preoperative CSF reveals risk biomarkers of postoperative delirium","volume":"11","author":"Han","year":"","journal-title":"Front. Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"570210","DOI":"10.3389\/fnagi.2020.570210","article-title":"Metabolomic and lipidomic profiling of preoperative CSF in elderly hip fracture patients with postoperative delirium","volume":"12","author":"Han","year":"","journal-title":"Front. Aging Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"542421","DOI":"10.3389\/fnagi.2020.542421","article-title":"Surgery, anesthesia and intensive care environment induce delirium-like behaviors and impairment of synaptic function-related gene expression in aged mice","volume":"12","author":"Illendula","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.biopsych.2009.05.033","article-title":"SLITRK1 binds 14-3-3 and regulates neurite outgrowth in a phosphorylation-dependent manner","volume":"66","author":"Kajiwara","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.tips.2008.12.003","article-title":"Pleiotropic functions of biliverdin reductase: cellular signaling and generation of cytoprotective and cytotoxic bilirubin","volume":"30","author":"Kapitulnik","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.resmic.2009.08.006","article-title":"Clp chaperone-proteases: structure and function","volume":"160","author":"Kress","year":"2009","journal-title":"Res. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/35051594","article-title":"Identification of the haemoglobin scavenger receptor","volume":"409","author":"Kristiansen","year":"2001","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.ymeth.2005.11.007","article-title":"Western blotting","volume":"38","author":"Kurien","year":"2006","journal-title":"Methods"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1515\/hsz-2017-0125","article-title":"S100A6\u2014focus on recent developments","volume":"398","author":"Lesniak","year":"2017","journal-title":"Biol. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"105","DOI":"10.3389\/fncel.2016.00105","article-title":"Surgery-induced hippocampal angiotensin II elevation causes blood-brain barrier disruption via MMP\/TIMP in aged rats","volume":"10","author":"Li","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"201","DOI":"10.3892\/mmr.2016.5967","article-title":"Calcineurin\/nuclear factor-kappaB signaling mediates isoflurane-induced hippocampal neuroinflammation and subsequent cognitive impairment in aged rats","volume":"15","author":"Li","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s12264-019-00414-4","article-title":"Regional metabolic patterns of abnormal postoperative behavioral performance in aged mice assessed by (1)H-NMR dynamic mapping method","volume":"36","author":"Liu","year":"2020","journal-title":"Neurosci. Bull."},{"key":"B34","doi-asserted-by":"publisher","first-page":"624387","DOI":"10.3389\/fnagi.2021.624387","article-title":"The Non-peptide Angiotensin-(1-7) Mimic AVE 0991 attenuates delayed neurocognitive recovery after laparotomy by reducing neuroinflammation and restoring blood-brain barrier integrity in aged rats","volume":"13","author":"Mi","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/35036228","article-title":"The prefrontal cortex and cognitive control","volume":"1","author":"Miller","year":"2000","journal-title":"Nat. Rev. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1515\/BC.2006.152","article-title":"14-3-3 proteins in membrane protein transport","volume":"387","author":"Mrowiec","year":"2006","journal-title":"Biol. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.bbi.2018.07.016","article-title":"Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats","volume":"73","author":"Netto","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1097\/ACO.0000000000000812","article-title":"Postoperative neurocognitive disorders","volume":"33","author":"Olotu","year":"2020","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"29874","DOI":"10.1038\/srep29874","article-title":"Battery of behavioral tests in mice to study postoperative delirium","volume":"6","author":"Peng","year":"2016","journal-title":"Sci. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.cell.2008.09.050","article-title":"Nature, nurture, or chance: stochastic gene expression and its consequences","volume":"135","author":"Raj","year":"2008","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1523\/JNEUROSCI.4321-06.2007","article-title":"Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation","volume":"27","author":"Rockenstein","year":"2007","journal-title":"J. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1111\/j.1365-2044.2008.05523.x","article-title":"Delirium is associated with early postoperative cognitive dysfunction","volume":"63","author":"Rudolph","year":"2008","journal-title":"Anaesthesia"},{"key":"B43","doi-asserted-by":"publisher","first-page":"S97","DOI":"10.1309\/8GLX5798Y5XHQ0VW","article-title":"Haptoglobin phenotypes in health and disorders","volume":"121","author":"Sadrzadeh","year":"2004","journal-title":"Am. J. Clin. Pathol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1097\/ACO.0000000000000676","article-title":"Biomarkers and postoperative cognitive function: could it be that easy?","volume":"32","author":"Schaefer","year":"2019","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.nbd.2019.02.003","article-title":"Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease","volume":"125","author":"Sharma","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3389\/fnagi.2014.00297","article-title":"Using the Chinese version of memorial delirium assessment scale to describe postoperative delirium after hip surgery","volume":"6","author":"Shi","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1111\/febs.13986","article-title":"Moonlighting chaperone-like activity of the universal regulatory 14-3-3 proteins","volume":"284","author":"Sluchanko","year":"2017","journal-title":"FEBS J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"453","DOI":"10.2169\/internalmedicine.54.2876","article-title":"Association between serum haptoglobin and the pathogenesis of Alzheimer's disease","volume":"54","author":"Song","year":"2015","journal-title":"Intern. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40478-020-01110-5","article-title":"14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model","volume":"9","author":"Underwood","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/nrn.2016.128","article-title":"Lasting impact of general anaesthesia on the brain: mechanisms and relevance","volume":"17","author":"Vutskits","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"8211","DOI":"10.1523\/JNEUROSCI.1134-18.2018","article-title":"14-3-3 Proteins reduce cell-to-cell transfer and propagation of pathogenic alpha-synuclein","volume":"38","author":"Wang","year":"2018","journal-title":"J. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3492","DOI":"10.1016\/j.celrep.2018.05.074","article-title":"Single-molecule characterization of the interactions between extracellular chaperones and toxic alpha-synuclein oligomers","volume":"23","author":"Whiten","year":"2018","journal-title":"Cell Rep."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1126\/science.1128134","article-title":"Learning induces long-term potentiation in the hippocampus","volume":"313","author":"Whitlock","year":"2006","journal-title":"Science"},{"key":"B54","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.febslet.2013.01.020","article-title":"Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms","volume":"587","author":"Wyatt","year":"","journal-title":"FEBS Lett."},{"key":"B55","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s12192-012-0365-z","article-title":"Acute phase proteins are major clients for the chaperone action of alpha(2)-macroglobulin in human plasma","volume":"18","author":"Wyatt","year":"","journal-title":"Cell Stress Chaper."},{"key":"B56","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/(SICI)1096-9861(19990208)404:2<235::AID-CNE8>3.0.CO;2-7","article-title":"Distribution of a specific calcium-binding protein of the S100 protein family, S100A6 (calcyclin), in subpopulations of neurons and glial cells of the adult rat nervous system","volume":"404","author":"Yamashita","year":"1999","journal-title":"J Comp. Neurol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"7262","DOI":"10.18632\/aging.103074","article-title":"Autophagy prevents hippocampal alpha-synuclein oligomerization and early cognitive dysfunction after anesthesia\/surgery in aged rats","volume":"12","author":"Yang","year":"2020","journal-title":"Aging"},{"key":"B58","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.1016\/j.febslet.2007.04.076","article-title":"ClpP: a distinctive family of cylindrical energy-dependent serine proteases","volume":"581","author":"Yu","year":"2007","journal-title":"FEBS Lett."},{"key":"B59","doi-asserted-by":"publisher","first-page":"67","DOI":"10.3389\/fnagi.2020.00067","article-title":"Exosome alpha-synuclein release in plasma may be associated with postoperative delirium in hip fracture patients","volume":"12","author":"Yuan","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"e043720","DOI":"10.1136\/bmjopen-2020-043720","article-title":"Effects of general versus regional anaesthesia on circadian melatonin rhythm and its association with postoperative delirium in elderly patients undergoing hip fracture surgery: study protocol for a prospective cohort clinical trial","volume":"11","author":"Yuan","year":"2021","journal-title":"BMJ Open"},{"key":"B61","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.brainresbull.2018.01.005","article-title":"Serum haptoglobin in Chinese patients with Alzheimer's disease and mild cognitive impairment: a case-control study","volume":"137","author":"Zhu","year":"2018","journal-title":"Brain Res. Bull."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.741263\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T02:52:11Z","timestamp":1632883931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2021.741263\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":61,"alternative-id":["10.3389\/fnagi.2021.741263"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2021.741263","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]},"article-number":"741263"}}