{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:06:37Z","timestamp":1791385597957,"version":"4.3.3"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"The Ministry of Education, Culture, Sports, Science and Technology, Japan","doi-asserted-by":"crossref","award":["20H03157"],"award-info":[{"award-number":["20H03157"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to reduce hyperglycemia. The present study investigated the effects of a SGLT2 inhibitor, empagliflozin, on hyperglycemia in a novel rat model of non-obesity type 2 diabetes with enlarged kidney (DEK).<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>Male DEK rats with non-fasting blood glucose concentrations \u2264300 mg\/dl and &gt;300 mg\/dl were classified as nondiabetic and diabetic, respectively. Groups of nondiabetic (control) and diabetic (DM-cont) rats were fed standard chow for 12 weeks, whereas another group of diabetic (DM-empa) rats was fed standard chow containing empagliflozin (300 mg\/kg\/day) for 12 weeks. Blood glucose, body weight, glucose tolerance, food and water intake, urinary volume, plasma and urinary biochemical parameters, and bone mineral density were measured, and their kidneys and pancreas histologically analyzed.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Treatment with empagliflozin reduced blood glucose concentration and food intake in diabetic rats, but inhibited loss of adeps renis and led to body weight gain. Empagliflozin attenuated polyuria and polydipsia but increased plasma concentrations of total cholesterol, sodium and total protein toward normal level. Empagliflozin also significantly reduced urinary excretion of proteins and electrolytes and restored bone mineral density and plasma concentrations of valine and isoleucine to normal levels. Moreover, dilation of renal tubules and kidney enlargement were not attenuated in the DM-empa group.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>The response of DEK rats to empagliflozin differed from that of other diabetic animal models, suggesting that DEK rats have unique characters for studying and evaluating the multiple biological effects of SGLT2 inhibitors. These findings also indicted that empagliflozin could ameliorate systemic metabolism and improve renal tubule function in diabetic condition.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0251135","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T19:48:11Z","timestamp":1620157691000},"page":"e0251135","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Empagliflozin ameliorates symptoms of diabetes and renal tubular dysfunction in a rat model of diabetes with enlarged kidney (DEK)"],"prefix":"10.1371","volume":"16","author":[{"given":"Ayaka","family":"Domon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2859-0423","authenticated-orcid":true,"given":"Kentaro","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Touko","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tochigi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Tazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0177-3158","authenticated-orcid":true,"given":"Hiroetsu","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"pone.0251135.ref001","volume-title":"IDF Diabetes Atlas","author":"International Diabetes Federation","year":"2019","edition":"9"},{"issue":"Suppl 1","key":"pone.0251135.ref002","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.2337\/dc19-S002","article-title":"Classification and Diagnosis of Diabetes. Section 2. Standards of Medical Care in Diabetes-2019","volume":"42","author":"American Diabetes Association","year":"2019","journal-title":"Diabetes Care"},{"issue":"2","key":"pone.0251135.ref003","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Y Zheng","year":"2018","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"pone.0251135.ref004","doi-asserted-by":"crossref","first-page":"10177","DOI":"10.1038\/s41598-017-09243-9","article-title":"Development and validation of a risk prediction model for end-stage renal disease in patients with type 2 diabetes","volume":"7","author":"CC Lin","year":"2017","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0251135.ref005","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1053\/ajkd.2001.26824","article-title":"Quality of life in end-stage renal disease patients","volume":"38","author":"F Valderr\u00e1bano","year":"2001","journal-title":"AM J Kidney Dis"},{"issue":"1","key":"pone.0251135.ref006","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2337\/diaspect.19.1.18","article-title":"Prevention of progression in diabetic nephropathy","volume":"19","author":"PM Hall","year":"2006","journal-title":"Diabetes Spectr"},{"issue":"1","key":"pone.0251135.ref007","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/MED.0000000000000311","article-title":"An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus","volume":"24","author":"DS Hsia","year":"2017","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"issue":"24","key":"pone.0251135.ref008","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and renal outcomes in type 2 diabetes and nephropathy","volume":"380","author":"V Perkovic","year":"2019","journal-title":"N Engl J Med"},{"issue":"11","key":"pone.0251135.ref009","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1056\/NEJMc1600827","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"374","author":"PA Sarafidis","year":"2016","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0251135.ref010","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"SD Wiviott","year":"2019","journal-title":"N Engl J Med"},{"issue":"Suppl 2","key":"pone.0251135.ref011","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/dom.13650","article-title":"A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors","volume":"21","author":"E Brown","year":"2019","journal-title":"Diabetes Obes Metab"},{"issue":"2","key":"pone.0251135.ref012","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1093\/ndt\/gfz290","article-title":"Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial","volume":"35","author":"HJL Heerspink","journal-title":"Nephrol Dial Transplant. 2020"},{"issue":"1","key":"pone.0251135.ref013","doi-asserted-by":"crossref","first-page":"13009","DOI":"10.1038\/s41598-019-49525-y","article-title":"Effects of sodium-glucose cotransporter 2 inhibitors on renal outcomes in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials","volume":"9","author":"JH Bae","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0251135.ref014","doi-asserted-by":"crossref","first-page":"8153140","DOI":"10.1155\/2019\/8153140","article-title":"Characterization of novel nonobese type 2 diabetes rat model with enlarged kidneys","volume":"2019","author":"A Domon","year":"2019","journal-title":"J Diabetes Res"},{"issue":"2","key":"pone.0251135.ref015","doi-asserted-by":"crossref","first-page":"F194","DOI":"10.1152\/ajprenal.00520.2013","article-title":"SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice","volume":"306","author":"V Vallon","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"pone.0251135.ref016","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2147\/DMSO.S58786","article-title":"Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet","volume":"7","author":"SP Vickers","year":"2014","journal-title":"Diabetes Metab Syndr Obes"},{"issue":"8","key":"pone.0251135.ref017","doi-asserted-by":"crossref","first-page":"e0162131","DOI":"10.1371\/journal.pone.0162131","article-title":"Mouse models of diabetes, obesity and related kidney disease","volume":"11","author":"SJ Glastras","year":"2016","journal-title":"PLoS One"},{"issue":"4","key":"pone.0251135.ref018","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s00726-007-0012-7","article-title":"Application of the Phenomenex EZ:faast\u2122 amino acid analysis kit for rapid gas-chromatographic determination of concentrations of plasma tryptophan and its brain uptake competitors","volume":"34","author":"AA Badawy","year":"2008","journal-title":"Amino Acids"},{"issue":"9","key":"pone.0251135.ref019","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1292\/jvms.19-0194","article-title":"Metabolite profiling in sphere-forming cells from canine mammary adenocarcinoma cell lines using gas chromatography-mass spectrometry","volume":"81","author":"M Michishita","year":"2019","journal-title":"J Vet Med Sci"},{"issue":"1\u20132","key":"pone.0251135.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cca.2006.05.038","article-title":"Urinary fatty acid binding protein in renal disease","volume":"374","author":"A Kamijo-Ikemori","year":"2006","journal-title":"Clin Chim Acta"},{"issue":"2","key":"pone.0251135.ref021","doi-asserted-by":"crossref","first-page":"e14360","DOI":"10.14814\/phy2.14360","article-title":"Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume","volume":"8","author":"T Masuda","year":"2020","journal-title":"Physiol Rep."},{"issue":"11","key":"pone.0251135.ref022","doi-asserted-by":"crossref","first-page":"e0165703","DOI":"10.1371\/journal.pone.0165703","article-title":"Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes","volume":"11","author":"SJ Shin","year":"2016","journal-title":"PLos One"},{"issue":"120","key":"pone.0251135.ref023","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1038\/ki.2010.512","article-title":"Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans","author":"JF List","year":"2011","journal-title":"Kidney Int Suppl"},{"issue":"1","key":"pone.0251135.ref024","doi-asserted-by":"crossref","first-page":"4703","DOI":"10.1038\/s41598-019-41253-7","article-title":"Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells","volume":"9","author":"T Maki","year":"2019","journal-title":"Sci Rep"},{"issue":"5","key":"pone.0251135.ref025","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.amjms.2016.08.015","article-title":"Effect of dapagliflozin treatment on fluid and electrolyte balance in diabetic rats","volume":"352","author":"L Chen","year":"2016","journal-title":"Am J Med Sci"},{"issue":"8","key":"pone.0251135.ref026","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00210-015-1134-1","article-title":"A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans","volume":"388","author":"MC Michel","year":"2015","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"issue":"4","key":"pone.0251135.ref027","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/dom.12237","article-title":"Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice","volume":"16","author":"K Tatarkiewicz","year":"2014","journal-title":"Diabetes Obes Metab"},{"issue":"8","key":"pone.0251135.ref028","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/oby.2012.59","article-title":"Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet\u2010induced obese (DIO) rats","volume":"20","author":"JJ Devenny","year":"2012","journal-title":"Obesity (Silver Spring)"},{"issue":"5","key":"pone.0251135.ref029","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1139\/H07-100","article-title":"Non-obese patients with type 2 diabetes and prediabetic subjects: distinct phenotypes requiring special diabetes treatment and (or) prevention?","volume":"32","author":"A Vaag","year":"2007","journal-title":"Appl Physiol Nutr Metab"},{"issue":"2","key":"pone.0251135.ref030","doi-asserted-by":"crossref","first-page":"S165","DOI":"10.2337\/dcS15-3006","article-title":"SGLT2 inhibitors and the diabetic kidney","volume":"39","author":"P Fioretto","year":"2016","journal-title":"Diabetes Care"},{"issue":"5","key":"pone.0251135.ref031","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1248\/bpb.b16-00964","article-title":"The sodium glucose cotransporter 2 inhibitor ipragliflozin promotes preferential loss of fat mass in non-obese diabetic Goto\u2013Kakizaki rats","volume":"40","author":"T Takasu","year":"2017","journal-title":"Biol Pharm Bull"},{"issue":"4","key":"pone.0251135.ref032","doi-asserted-by":"crossref","first-page":"R113","DOI":"10.1530\/EJE-17-0832","article-title":"Mechanisms in endocrinology: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism","volume":"178","author":"RL Esterline","year":"2018","journal-title":"Eur J Endocrinol"},{"issue":"5","key":"pone.0251135.ref033","doi-asserted-by":"crossref","first-page":"e123130","DOI":"10.1172\/jci.insight.123130","article-title":"SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and\u2014independent mechanisms","volume":"4","author":"S Osataphan","year":"2019","journal-title":"JCI Insight"},{"key":"pone.0251135.ref034","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ebiom.2017.05.028","article-title":"SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice","volume":"20","author":"L Xu","year":"2017","journal-title":"EBioMedicine"},{"issue":"2","key":"pone.0251135.ref035","doi-asserted-by":"crossref","first-page":"107","DOI":"10.7570\/jomes.2017.26.2.107","article-title":"Efficacy of body weight reduction on the SGLT2 inhibitor in people with type 2 diabetes mellitus","volume":"26","author":"HA Cho","year":"2017","journal-title":"J Obes Metab Syndr"},{"key":"pone.0251135.ref036","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.diabres.2017.11.016","article-title":"Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment","volume":"135","author":"I Horie","year":"2018","journal-title":"Diabetes Res Clin Pract"},{"issue":"1","key":"pone.0251135.ref037","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1053\/j.jrn.2016.09.002","article-title":"Estimating catabolism: A possible tool for nutritional monitoring of patients with acute kidney injury","volume":"27","author":"MN Bufarah","year":"2017","journal-title":"J Ren Nutr"},{"issue":"3","key":"pone.0251135.ref038","doi-asserted-by":"crossref","first-page":"629","DOI":"10.3390\/ijms20030629","article-title":"Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the renin-angiotensin system","volume":"20","author":"TM Ansary","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0251135.ref039","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s13300-018-0385-5","article-title":"Empagliflozin Induces Transient Diuresis Without Changing Long-Term Overall Fluid Balance in Japanese Patients With Type 2 Diabetes","volume":"9","author":"A Yasui","year":"2018","journal-title":"Diabetes Ther"},{"key":"pone.0251135.ref040","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bone.2015.07.025","article-title":"SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA\/2J male mice","volume":"82","author":"KM Thrailkill","year":"2016","journal-title":"Bone"},{"issue":"5","key":"pone.0251135.ref041","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/BF00852550","article-title":"Hyperlipidemia in childhood nephrotic syndrome","volume":"7","author":"MA Thabet","year":"1993","journal-title":"Pediatr Nephrol"},{"key":"pone.0251135.ref042","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.3389\/fphys.2019.01140","article-title":"BCAA catabolic defect alters glucose metabolism in lean mice","volume":"10","author":"J Wang","year":"2019","journal-title":"Front Physiol"},{"issue":"4","key":"pone.0251135.ref043","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1113\/JP275075","article-title":"Restoration of metabolic health by decreased consumption of branched-chain amino acids","volume":"596","author":"NE Cummings","year":"2018","journal-title":"J Physiol"},{"issue":"12","key":"pone.0251135.ref044","doi-asserted-by":"crossref","first-page":"e15234","DOI":"10.1371\/journal.pone.0015234","article-title":"Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women","volume":"5","author":"O Fiehn","year":"2010","journal-title":"PLoS One"},{"issue":"12","key":"pone.0251135.ref045","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nrendo.2014.171","article-title":"Branched-chain amino acids in metabolic signalling and insulin resistance","volume":"10","author":"CJ Lynch","year":"2014","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"pone.0251135.ref046","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00726-017-2508-0","article-title":"Insulin resistance and glycine metabolism in humans","volume":"50","author":"M Adeva-Andany","year":"2018","journal-title":"Amino Acids"},{"issue":"24","key":"pone.0251135.ref047","doi-asserted-by":"crossref","first-page":"16768","DOI":"10.1074\/jbc.M601876200","article-title":"Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption","volume":"281","author":"T Soga","year":"2006","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0251135.ref048","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jphs.2018.08.005","article-title":"Glycine mitigates renal oxidative stress by suppressing Nox4expression in rats with streptozotocin-induced diabetes","volume":"137","author":"Z Wang","year":"2018","journal-title":"J Pharmacol Sci"},{"issue":"8","key":"pone.0251135.ref049","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1111\/dom.13301","article-title":"Effects of the SGLT\u20102 inhibitor dapagliflozin on glomerular and tubular injury markers","volume":"20","author":"CCJ Dekkers","year":"2018","journal-title":"Diabetes Obes Metab"},{"issue":"4","key":"pone.0251135.ref050","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2337\/db18-0090","article-title":"Proximal tubular cell-specific ablation of carnitine acetyltransferase causes tubular disease and secondary glomerulosclerosis","volume":"68","author":"C Kruger","year":"2019","journal-title":"Diabetes"},{"issue":"1","key":"pone.0251135.ref051","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/s41598-018-22229-5","article-title":"Coprehensive renoprotective effects of ipragliflozin on early diabetic nephropathy in mice","volume":"8","author":"M Kamezaki","year":"2018","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0251135.ref052","doi-asserted-by":"crossref","first-page":"e33942","DOI":"10.1371\/journal.pone.0033942","article-title":"Diabetic kidney disease in FVB\/NJ Akita mice: Temporal pattern of kidney injury and urinary nephrin excretion","volume":"7","author":"JH Chang","year":"2012","journal-title":"PLoS One"},{"issue":"8","key":"pone.0251135.ref053","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00210-015-1134-1","article-title":"A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans","volume":"388","author":"MC Michel","year":"2015","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251135","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T07:34:00Z","timestamp":1698996840000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251135"}},"subtitle":[],"editor":[{"given":"Michael","family":"Bader","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":53,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0251135","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}