{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:00:10Z","timestamp":1768471210505,"version":"3.49.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL153262"],"award-info":[{"award-number":["R01 HL153262"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL150891"],"award-info":[{"award-number":["R01HL150891"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Peripheral atherosclerosis that accumulates in the extracranial carotid and lower extremity arteries can lead to significant morbidity and mortality. However, atherosclerotic disease progression is often not homogenous and is accelerated by diabetes. We previously observed increased phospholipid content in minimally (Min)-diseased arterial segments compared to maximally (Max)-diseased segments. Since Peroxisome Proliferator-Activated Receptor alpha (PPAR\u03b1) is a key regulator of lipid metabolism, we hypothesized that it may have differential expression and signaling in Min vs. Max-diseased peripheral arterial segments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighteen patients who underwent carotid endarterectomy (CEA), and 34 patients who underwent major lower extremity amputation were prospectively enrolled into a vascular tissue biobank. Min and Max-diseased segments were obtained in real-time from CEA plaque and amputated lower extremity arterial segments. mRNA and protein were isolated from specimens and the relative expression of <jats:italic>ppara<\/jats:italic>, and its downstream genes Acyl-CoA Oxidase 1 (<jats:italic>acox1<\/jats:italic>) and Carnitine Palmitoyltransferase 1A (<jats:italic>cpt1a<\/jats:italic>) were also evaluated. We evaluated gene expression and protein content relative to atherosclerotic disease severity and clinical diabetes status. Gene expression was also evaluated relative to Hemoglobin A1c and serum lipid profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In CEA segments of patients with diabetes, we observed significantly higher <jats:italic>ppara<\/jats:italic> and <jats:italic>acox1<\/jats:italic> gene expression (<jats:italic>p<\/jats:italic> &amp;lt; 0.01 and <jats:italic>p<\/jats:italic> &amp;lt; 0.001 respectively), and higher PPAR\u03b1 protein content (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). Hemoglobin A1c significantly correlated with expression of <jats:italic>ppara<\/jats:italic> (R<jats:sup>2<\/jats:sup> = 0.66, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), <jats:italic>acox1<\/jats:italic> (R<jats:sup>2<\/jats:sup> = 0.31, <jats:italic>p<\/jats:italic> &amp;lt; 0.05), and <jats:italic>cpt1a<\/jats:italic> (R<jats:sup>2<\/jats:sup> = 0.4, <jats:italic>p<\/jats:italic> &amp;lt; 0.05). There was no significant difference in gene expression between Min vs. Max-diseased CEA plaque segments. Conversely, in lower extremity arterial segments of patients with diabetes, we observed significantly lower <jats:italic>ppara<\/jats:italic>, <jats:italic>acox1<\/jats:italic>, and <jats:italic>cpt1a<\/jats:italic> expression (<jats:italic>p<\/jats:italic> &amp;lt; 0.05, <jats:italic>p<\/jats:italic> &amp;lt; 0.001, and <jats:italic>p<\/jats:italic> &amp;lt; 0.0001 respectively). Interestingly, CPT1A content was lower in arterial segments of patients with diabetes (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). Hemoglobin A1c and HDL-cholesterol had negative correlations with <jats:italic>ppara<\/jats:italic> (R<jats:sup>2<\/jats:sup> = 0.44, <jats:italic>p<\/jats:italic> &amp;lt; 0.05; R<jats:sup>2<\/jats:sup> = 0.42, <jats:italic>p<\/jats:italic> &amp;lt; 0.05; respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates the significant differential expression of <jats:italic>ppara<\/jats:italic> and its immediate downstream genes in human carotid and lower extremity arteries relative to disease severity and diabetes. These findings highlight that mechanisms that influence atheroprogression in the carotid and lower extremities peripheral arteries are not homogenous and can be impacted by patient diabetes status and serum cholesterol profiles. Further elucidating these differential molecular mechanisms can help improve targeted therapy of atherosclerosis in different peripheral arterial beds.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2022.834199","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T04:35:48Z","timestamp":1655267748000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Altered Peroxisome Proliferator-Activated Receptor Alpha Signaling in Variably Diseased Peripheral Arterial Segments"],"prefix":"10.3389","volume":"9","author":[{"given":"Connor","family":"Engel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Meade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolai","family":"Harroun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Penrose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehreen","family":"Shafqat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayan","family":"DeSilva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clay","family":"Semenkovich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Zayed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1161\/01.ATV.0000255310.47940.3b","article-title":"The prevalence and quantification of atherosclerosis in an elderly population assessed by whole-body magnetic resonance angiography.","volume":"27","author":"Hansen","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1161\/01.STR.0000136720.21095.f3","article-title":"Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study.","volume":"35","author":"Mackinnon","year":"2004","journal-title":"Stroke."},{"key":"B3","doi-asserted-by":"publisher","first-page":"297","DOI":"10.2459\/JCM.0b013e328343e962","article-title":"Atherosclerotic burden in coronary and peripheral arteries in patients with first clinical manifestation of coronary artery disease.","volume":"12","author":"Kranjec","year":"2011","journal-title":"J Cardiovasc Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3026","DOI":"10.1161\/01.CIR.94.11.3026","article-title":"Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review.","volume":"94","author":"Weitz","year":"1996","journal-title":"Circulation."},{"key":"B5","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.atherosclerosis.2019.09.012","article-title":"Morbidity and mortality associated with atherosclerotic peripheral artery disease: a systematic review.","volume":"293","author":"Agnelli","year":"2020","journal-title":"Atherosclerosis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e139","DOI":"10.1161\/CIR.0000000000000757","article-title":"Heart disease and stroke statistics\u20142020 update: a report from the American Heart Association.","volume":"141","author":"Virani","year":"2020","journal-title":"Circulation."},{"key":"B7","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1161\/01.STR.23.4.486","article-title":"Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioembolism.","volume":"23","author":"Timsit","year":"1992","journal-title":"Stroke."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1056\/NEJM200006083422302","article-title":"The causes and risk of stroke in patients with asymptomatic internal- carotid-artery stenosis.","volume":"342","author":"Inzitari","year":"2000","journal-title":"N Engl J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1161\/STROKEAHA.108.546150","article-title":"Causes and severity of ischemic stroke in patients with symptomatic intracranial arterial stenosis.","volume":"40","author":"Famakin","year":"2009","journal-title":"Stroke."},{"key":"B10","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.atherosclerosis.2013.12.039","article-title":"Ethnic differences in lower limb revascularisation and amputation rates. Implications for the aetiopathology of atherosclerosis?.","volume":"233","author":"Ahmad","year":"2014","journal-title":"Atherosclerosis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1016\/j.jvs.2017.05.115","article-title":"Association between statin therapy and amputation-free survival in patients with critical limb ischemia in the CRITISCH registry.","volume":"66","author":"Stavroulakis","year":"2017","journal-title":"J Vasc Surg."},{"key":"B12","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1161\/01.STR.0000115752.58601.0B","article-title":"Carotid arterial remodeling. A maladaptive phenomenon in type 2 diabetes but not in impaired glucose metabolism: the hoorn study.","volume":"35","author":"Henry","year":"2004","journal-title":"Stroke."},{"key":"B13","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.pop.2012.11.003","article-title":"Hyperlipidemia as a risk factor for cardiovascular disease.","volume":"40","author":"Nelson","year":"2013","journal-title":"Primary Care."},{"key":"B14","doi-asserted-by":"publisher","first-page":"529","DOI":"10.2337\/dc16-1958","article-title":"Triglyceride and HDL-C dyslipidemia and risks of coronary heart disease and ischemic stroke by glycemic dysregulation status: the strong heart study.","volume":"40","author":"Lee","year":"2017","journal-title":"Diabetes Care."},{"key":"B15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/cr.2010.13","article-title":"PPARs: diverse regulators in energy metabolism and metabolic diseases.","volume":"20","author":"Wang","year":"2010","journal-title":"Cell Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1152\/ajpendo.2001.280.2.e270","article-title":"A potent PPAR\u03b1 agonist stimulates mitochondrial fatty acid \u03b2-oxidation in liver and skeletal muscle.","volume":"280","author":"Minnich","year":"2001","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5336","DOI":"10.1002\/j.1460-2075.1996.tb00918.x","article-title":"PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.","volume":"15","author":"Schoonjans","year":"1996","journal-title":"EMBO J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1016\/j.bbalip.2007.04.021","article-title":"PPAR\u03b1 in atherosclerosis and inflammation.","volume":"1771","author":"Zandbergen","year":"2007","journal-title":"Biochim Biophys Acta."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3125","DOI":"10.1161\/01.CIR.99.24.3125","article-title":"PPAR \u03b1 activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.","volume":"99","author":"Marx","year":"1999","journal-title":"Circulation."},{"key":"B20","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1161\/01.RES.0000014225.20727.8F","article-title":"PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis.","volume":"90","author":"Marx","year":"2002","journal-title":"Circ Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular mechanism of PPAR\u03b1 action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.","volume":"62","author":"Pawlak","year":"2015","journal-title":"J Hepatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1194\/jlr.M081026","article-title":"Diabetes adversely affects phospholipid profiles in human carotid artery endarterectomy plaques.","volume":"59","author":"Zayed","year":"2018","journal-title":"J Lipid Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.2337\/db20-0635","article-title":"CEPT1-mediated phospholipogenesis regulates endothelial cell function and ischemia-induced angiogenesis through PPAR\u03b1.","volume":"70","author":"Zayed","year":"2021","journal-title":"Diabetes."},{"key":"B24","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1161\/01.CIR.0000133317.49796.0E","article-title":"Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.","volume":"110","author":"Grundy","year":"2004","journal-title":"Circulation."},{"key":"B25","first-page":"15","article-title":"Diabetes complications severity index and risk of mortality, hospitalization, and healthcare utilization.","volume":"14","author":"Young","year":"2008","journal-title":"Am J Manag Care."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1007\/s00330-015-4143-z","article-title":"AHA classification of coronary and carotid atherosclerotic plaques by grating-based phase-contrast computed tomography.","volume":"26","author":"Hetterich","year":"2016","journal-title":"Eur Radiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1161\/CIRCRESAHA.107.157586","article-title":"CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis.","volume":"101","author":"Zayed","year":"2007","journal-title":"Circ Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"81","DOI":"10.5551\/jat1994.3.81","article-title":"Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects.","volume":"3","author":"Auwerx","year":"1996","journal-title":"J Atheroscler Thromb."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/435689","article-title":"PPARs: nuclear receptors controlled by, and controlling, nutrient handling through nuclear and cytosolic signaling.","volume":"2010","author":"Moreno","year":"2010","journal-title":"PPAR Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.cmet.2005.04.002","article-title":"\u201cNew\u201d hepatic fat activates PPAR\u03b1 to maintain glucose, lipid, and cholesterol homeostasis.","volume":"1","author":"Chakravarthy","year":"2005","journal-title":"Cell Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"39088","DOI":"10.1074\/jbc.M107073200","article-title":"Peroxisome proliferator-activated receptor-\u03b1 regulates lipid homeostasis, but is not associated with obesity. Studies with congenic mouse lines.","volume":"276","author":"Akiyama","year":"2001","journal-title":"J Biol Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature07413","article-title":"Structure of the intact PPAR-\u03b3-RXR-\u03b1 nuclear receptor complex on DNA.","volume":"456","author":"Chandra","year":"2008","journal-title":"Nature."},{"key":"B33","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1210\/endo.137.1.8536636","article-title":"Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-\u03b1, -\u03b2, and -\u03b3 in the adult rat.","volume":"137","author":"Braissant","year":"1996","journal-title":"Endocrinology."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/612089","article-title":"Peroxisome proliferator-activated receptor alpha target genes.","volume":"2010","author":"Kersten","year":"2010","journal-title":"PPAR Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1161\/CIRCRESAHA.110.226860","article-title":"The PPAR-RXR transcriptional complex in the vasculature: energy in the balance.","volume":"108","author":"Plutzky","year":"2011","journal-title":"Circ Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/j.cell.2009.05.036","article-title":"Identification of a physiologically relevant endogenous ligand for PPAR\u03b1 in liver.","volume":"138","author":"Chakravarthy","year":"2009","journal-title":"Cell."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006796","article-title":"Comparative analysis of gene regulation by the transcription factor PPAR\u03b1 between mouse and human.","volume":"4","author":"Rakhshandehroo","year":"2009","journal-title":"PLoS One."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1432-1033.1997.00001.x","article-title":"The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.","volume":"244","author":"McGarry","year":"1997","journal-title":"Eur J Biochem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1016\/S0140-6736(09)60698-X","article-title":"Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial.","volume":"373","author":"Rajamani","year":"2009","journal-title":"Lancet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1111\/j.1744-1609.2012.00275.x","article-title":"Use of fibrates in clinical practice: queensland lipid group consensus recommendations.","volume":"10","author":"Hamilton-Craig","year":"2012","journal-title":"Int J Evid Based Healthc."},{"key":"B41","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1210\/jc.2009-1487","article-title":"Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome.","volume":"95","author":"Belfort","year":"2010","journal-title":"J Clin Endocrinol Metab."},{"key":"B42","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1161\/STROKEAHA.110.591065","article-title":"Carotid plaque and candidate genes related to inflammation and endothelial function in hispanics from Northern Manhattan.","volume":"42","author":"Gardener","year":"2011","journal-title":"Stroke."},{"key":"B43","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.atherosclerosis.2005.12.005","article-title":"Association between well-characterized lipoprotein-related genetic variants and carotid intimal medial thickness and stenosis: the Framingham Heart Study.","volume":"189","author":"Elosua","year":"2006","journal-title":"Atherosclerosis."},{"key":"B44","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.atherosclerosis.2006.02.036","article-title":"Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: in vivo demonstration by high-resolution MRI.","volume":"190","author":"Corti","year":"2007","journal-title":"Atherosclerosis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.diabres.2018.05.006","article-title":"Fenofibrate effects on carotid artery intima-media thickness in adults with type 2 diabetes mellitus: a FIELD substudy.","volume":"141","author":"Harmer","year":"2018","journal-title":"Diabetes Res Clin Prac."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-98479-7","article-title":"Prevalence of elevated serum fatty acid synthase in chronic limb - threatening ischemia.","volume":"11","author":"Tay","year":"2021","journal-title":"Sci Rep."},{"key":"B47","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.atherosclerosis.2019.05.016","article-title":"Circulating serum fatty acid synthase is elevated in patients with diabetes and carotid artery stenosis and is LDL-associated.","volume":"287","author":"De Silva","year":"2019","journal-title":"Atherosclerosis."},{"key":"B48","doi-asserted-by":"publisher","first-page":"12830","DOI":"10.1016\/s0021-9258(18)42970-5","article-title":"Source of arachidonic acid for prostaglandin synthesis in Madin-Darby canine kidney cells.","volume":"256","author":"Daniel","year":"1981","journal-title":"J Biol Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1007\/s00726-010-0772-3","article-title":"Lipid glycation and protein glycation in diabetes and atherosclerosis.","volume":"42","author":"Miyazawa","year":"2012","journal-title":"Amino Acids."},{"key":"B50","first-page":"654","article-title":"Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody.","volume":"147","author":"Kume","year":"1995","journal-title":"Am J Pathol."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20143561","article-title":"The atherogenic role of circulating modified lipids in atherosclerosis.","volume":"20","author":"Summerhill","year":"2019","journal-title":"Int J Mol Sci."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.834199\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T13:58:19Z","timestamp":1655474299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.834199\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":51,"alternative-id":["10.3389\/fcvm.2022.834199"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.834199","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]},"article-number":"834199"}}