{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:37:15Z","timestamp":1788183435860,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T00:00:00Z","timestamp":1604016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1090741"],"award-info":[{"award-number":["1090741"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1200098"],"award-info":[{"award-number":["1200098"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Helsinki Research Foundation","award":["TYH2016251"],"award-info":[{"award-number":["TYH2016251"]}]},{"name":"University of Helsinki Research Foundation","award":["TYH2017251"],"award-info":[{"award-number":["TYH2017251"]}]},{"name":"University of Helsinki Research Foundation","award":["TYH2018229"],"award-info":[{"award-number":["TYH2018229"]}]},{"name":"University of Helsinki Research Foundation","award":["TYH2019319"],"award-info":[{"award-number":["TYH2019319"]}]},{"name":"University of Helsinki Research Foundation","award":["Y1014SL017"],"award-info":[{"award-number":["Y1014SL017"]}]},{"name":"University of Helsinki Research Foundation","award":["Y1014SL018"],"award-info":[{"award-number":["Y1014SL018"]}]},{"name":"University of Helsinki Research Foundation","award":["Y1014SULE1"],"award-info":[{"award-number":["Y1014SULE1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Biomarkers represent promising aids in periodontitis, host-mediate diseases of the tooth-supporting tissues. We assessed the diagnostic potential of matrix metalloproteinase-8 (MMP-8), tartrate-resistant acid phosphatase-5 (TRAP-5), and osteoprotegerin (OPG) to discriminate between healthy patients\u2019, mild and severe periodontitis sites. Thirty-one otherwise healthy volunteers with and without periodontal disease were enrolled at the Faculty of Dentistry, University of Chile. Periodontal parameters were examined and gingival crevicular fluid was sampled from mild periodontitis sites (M; n = 42), severe periodontitis sites (S; n = 59), and healthy volunteer sites (H; n = 30). TRAP-5 and OPG were determined by commercial multiplex assay and MMP-8 by the immunofluorometric (IFMA) method. STATA software was used. All biomarkers showed a good discrimination performance. MMP-8 had the overall best performance in regression models and Receiver Operating Characteristic (ROC) curves, with high discrimination of healthy from periodontitis sites (area under the curve (AUC) = 0.901). OPG showed a very high diagnostic precision (AUC \u2265 0.95) to identify severe periodontitis sites (S versus H + M), while TRAP-5 identified both healthy and severe sites. As conclusions, MMP-8, TRAP-5, and OPG present a high precision potential in the identification of periodontal disease destruction, with MMP-8 as the most accurate diagnostic biomarker.<\/jats:p>","DOI":"10.3390\/biom10111500","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T21:34:47Z","timestamp":1604093687000},"page":"1500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["MMP-8, TRAP-5, and OPG Levels in GCF Diagnostic Potential to Discriminate between Healthy Patients\u2019, Mild and Severe Periodontitis Sites"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8289-7314","authenticated-orcid":false,"given":"Marcela","family":"Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Laboratory of Periodontal Biology, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile"},{"name":"Department of Pathology and Oral Medicine, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Baeza","sequence":"additional","affiliation":[{"name":"Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile"},{"name":"School of Public Health, Faculty of Medicine, University of Chile, Santiago 7510040, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Sorsa","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Diseases, Helsinki University and University Hospital, 00290 Helsinki, Finland"},{"name":"Department of Oral Diseases, Karolinska Institutet, 14152 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8817-896X","authenticated-orcid":false,"given":"Taina","family":"Tervahartiala","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Diseases, Helsinki University and University Hospital, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3791-8881","authenticated-orcid":false,"given":"Macarena","family":"Vald\u00e9s","sequence":"additional","affiliation":[{"name":"School of Public Health, Faculty of Medicine, University of Chile, Santiago 7510040, Chile"},{"name":"Center for Climate and Resilience Research, CR2, University of Chile, Santiago 7510040, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0791-7746","authenticated-orcid":false,"given":"Alejandra","family":"Chaparro","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Centro de Investigaci\u00f3n e Innovaci\u00f3n Biom\u00e9dica (CIIB), Faculty of Dentistry, Universidad de Los Andes, Santiago 7620001, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Hern\u00e1ndez-R\u00edos","sequence":"additional","affiliation":[{"name":"Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380544, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/prd.12344","article-title":"Clinical and public health implications of periodontal and systemic diseases: An overview","volume":"83","author":"Genco","year":"2020","journal-title":"Periodontology 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S159","DOI":"10.1002\/JPER.18-0006","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"89","author":"Tonetti","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S74","DOI":"10.1002\/JPER.17-0719","article-title":"Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"89","author":"Chapple","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1111\/j.1600-051X.2012.01870.x","article-title":"Control of periodontal infections: A randomized controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated sites","volume":"39","author":"Goodson","year":"2012","journal-title":"J. Clin. Periodontol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1034\/j.1600-051X.29.s2.4.x","article-title":"Clinical significance of non-surgical periodontal therapy: An evidence-based perspective of scaling and root planing","volume":"29","author":"Cobb","year":"2002","journal-title":"J. Clin. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1046\/j.0906-6713.2002.003422.x","article-title":"The complete periodontal examination","volume":"34","author":"Armitage","year":"2004","journal-title":"Periodontology 2000"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S149","DOI":"10.1111\/jcpe.12945","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"45","author":"Tonetti","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/jcpe.12223","article-title":"Matrix metalloproteinases and myeloperoxidase in gingival crevicular fluid provide site-specific diagnostic value for chronic periodontitis","volume":"41","author":"Leppilahti","year":"2014","journal-title":"J. Clin. Periodontol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/jcpe.12479","article-title":"Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: An exploratory study","volume":"43","author":"Baeza","year":"2016","journal-title":"J. Clin. Periodontol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1902\/jop.2013.130365","article-title":"Matrix metalloproteinase (MMP)-8 and tissue inhibitor of MMP-1 (TIMP-1) gene polymorphisms in generalized aggressive periodontitis: Gingival crevicular fluid MMP-8 and TIMP-1 levels and outcome of periodontal therapy","volume":"85","author":"Emingil","year":"2014","journal-title":"J. Periodontol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1902\/jop.2015.140421","article-title":"The utility of gingival crevicular fluid matrix metalloproteinase-8 response patterns in prediction of site-level clinical treatment outcome","volume":"86","author":"Leppilahti","year":"2015","journal-title":"J. Periodontol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/jcpe.12194","article-title":"Crevicular fluid biomarkers and periodontal disease progression","volume":"41","author":"Kinney","year":"2014","journal-title":"J. Clin. Periodontol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1600-051X.2010.01670.x","article-title":"Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis","volume":"38","author":"Buduneli","year":"2011","journal-title":"J. Clin. Periodontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/s10753-009-9174-7","article-title":"RANKL and OPG mRNA level after non-surgical periodontal treatment","volume":"33","author":"Dereka","year":"2010","journal-title":"Inflammation"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Franco, C., Patricia, H.R., Timo, S., Claudia, B., and Marcela, H. (2017). Matrix Metalloproteinases as Regulators of Periodontal Inflammation. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020440"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1046\/j.0906-6713.2002.003427.x","article-title":"Analysis of gingival crevice fluid and risk of progression of periodontitis","volume":"34","author":"Armitage","year":"2004","journal-title":"Periodontology 2000"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/prd.12101","article-title":"Analysis of matrix metalloproteinases, especially MMP-8, in gingival creviclular fluid, mouthrinse and saliva for monitoring periodontal diseases","volume":"70","author":"Sorsa","year":"2016","journal-title":"Periodontology 2000"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1902\/jop.2013.130012","article-title":"Total oxidant status and bone resorption biomarkers in serum and gingival crevicular fluid of patients with periodontitis","volume":"85","author":"Baltacioglu","year":"2014","journal-title":"J. Periodontol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1007\/s00784-017-2062-x","article-title":"Bone resorptive activity in symptomatic and asymptomatic apical lesions of endodontic origin","volume":"21","author":"Baeza","year":"2017","journal-title":"Clin. Oral. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1046\/j.1432-1033.2003.03760.x","article-title":"Gelatinase B\/MMP-9 and neutrophil collagenase\/MMP-8 process the chemokines human GCP-2\/CXCL6, ENA-78\/CXCL5 and mouse GCP-2\/LIX and modulate their physiological activities","volume":"270","author":"Wuyts","year":"2003","journal-title":"Eur. J. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1111\/j.1600-051X.2007.01107.x","article-title":"MMP-13 and TIMP-1 determinations in progressive chronic periodontitis","volume":"34","author":"Hernandez","year":"2007","journal-title":"J. Clin. Periodontol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1111\/jcpe.12940","article-title":"Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"45","author":"Chapple","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1111\/j.1600-051X.2009.01488.x","article-title":"Proteolytic roles of matrix metalloproteinase (MMP)-13 during progression of chronic periodontitis: Initial evidence for MMP-13\/MMP-9 activation cascade","volume":"36","author":"Sorsa","year":"2009","journal-title":"J. Clin. Periodontol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/jcpe.12020","article-title":"Salivary type I collagen degradation end-products and related matrix metalloproteinases in periodontitis","volume":"40","author":"Gursoy","year":"2013","journal-title":"J. Clin. Periodontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1600-051X.2010.01563.x","article-title":"Salivary MMP-8, TIMP-1, and ICTP as markers of advanced periodontitis","volume":"37","author":"Gursoy","year":"2010","journal-title":"J. Clin. Periodontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1111\/jcpe.13188","article-title":"Accuracy of single molecular biomarkers in gingival crevicular fluid for the diagnosis of periodontitis: A systematic review and meta-analysis","volume":"46","author":"Nibali","year":"2019","journal-title":"J. Clin. Periodontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1600-051X.2009.01512.x","article-title":"Gingival crevicular fluid levels of MMP-8, MMP-9, TIMP-2, and MPO decrease after periodontal therapy","volume":"37","author":"Marcaccini","year":"2010","journal-title":"J. Clin. Periodontol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sorsa, T., Alassiri, S., Grigoriadis, A., Raisanen, I.T., Parnanen, P., Nwhator, S.O., Gieselmann, D.R., and Sakellari, D. (2020). Active MMP-8 (aMMP-8) as a Grading and Staging Biomarker in the Periodontitis Classification. Diagnostics, 10.","DOI":"10.3390\/diagnostics10020061"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1902\/jop.2009.080480","article-title":"Identification of pathogen and host-response markers correlated with periodontal disease","volume":"80","author":"Ramseier","year":"2009","journal-title":"J. Periodontol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0092-8674(00)81569-X","article-title":"Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation","volume":"93","author":"Lacey","year":"1998","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1600-0765.2006.00946.x","article-title":"Differential expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin mRNA in periodontal diseases","volume":"42","author":"Bostanci","year":"2007","journal-title":"J. Periodontal. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/j.1600-051X.2007.01061.x","article-title":"Gingival crevicular fluid levels of RANKL and OPG in periodontal diseases: Implications of their relative ratio","volume":"34","author":"Bostanci","year":"2007","journal-title":"J. Clin. Periodontol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1177\/154405910408300216","article-title":"Differential expression of RANKL and osteoprotegerin in gingival crevicular fluid of patients with periodontitis","volume":"83","author":"Mogi","year":"2004","journal-title":"J. Dent. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1902\/jop.2009.090106","article-title":"Interleukin-17, RANKL, and osteoprotegerin levels in gingival crevicular fluid from smoking and non-smoking patients with chronic periodontitis during initial periodontal treatment","volume":"80","author":"Buduneli","year":"2009","journal-title":"J. Periodontol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1111\/j.1600-051X.2008.01310.x","article-title":"Saliva concentrations of RANKL and osteoprotegerin in smoker versus non-smoker chronic periodontitis patients","volume":"35","author":"Buduneli","year":"2008","journal-title":"J. Clin. Periodontol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1600-0765.2005.00786.x","article-title":"Longitudinal analysis of metalloproteinases, tissue inhibitors of metalloproteinases and clinical parameters in gingival crevicular fluid from periodontitis-affected patients","volume":"40","author":"Pozo","year":"2005","journal-title":"J. Periodontal. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/j.1600-051X.1996.tb01814.x","article-title":"Matrix metalloproteinases and their inhibitors in gingival crevicular fluid and saliva of periodontitis patients","volume":"23","author":"Ingman","year":"1996","journal-title":"J. Clin. Periodontol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/j.1601-0825.2004.01038.x","article-title":"Matrix metalloproteinases (MMPs) in oral diseases","volume":"10","author":"Sorsa","year":"2004","journal-title":"Oral. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/jre.12495","article-title":"Matrix metalloproteinase-8 levels in periodontal disease patients: A systematic review","volume":"53","author":"Pinheiro","year":"2018","journal-title":"J. Periodontal. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S145","DOI":"10.1111\/jcpe.12683","article-title":"Ageing, dental caries and periodontal diseases","volume":"44","author":"Lopez","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1902\/jop.2010.100148","article-title":"Clinical attachment loss in Chilean adult population: First Chilean National Dental Examination Survey","volume":"81","author":"Gamonal","year":"2010","journal-title":"J. Periodontol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S130","DOI":"10.1111\/jcpe.12944","article-title":"Age-dependent distribution of periodontitis in two countries: Findings from NHANES 2009 to 2014 and SHIP-TREND 2008 to 2012","volume":"45","author":"Billings","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1600-0757.2012.00457.x","article-title":"Risk factors for periodontal disease","volume":"62","author":"Genco","year":"2013","journal-title":"Periodontology 2000"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1902\/jop.2013.130156","article-title":"Gingival crevicular fluid matrix metalloproteinase-8 levels predict treatment outcome among smokers with chronic periodontitis","volume":"85","author":"Leppilahti","year":"2014","journal-title":"J. Periodontol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3758\/BF03196078","article-title":"Assessing absentmindedness: Prospective memory complaint and impairment in middle-aged adults","volume":"31","author":"Mantyla","year":"2003","journal-title":"Mem. Cognit."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/j.1600-051X.2009.01444.x","article-title":"Effect of smoking on concentrations of receptor activator of nuclear factor kappa B ligand and osteoprotegerin in human gingival crevicular fluid","volume":"36","author":"Tang","year":"2009","journal-title":"J. Clin. Periodontol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/jre.12438","article-title":"The effect of smoking on inflammatory and bone remodeling markers in gingival crevicular fluid and subgingival microbiota following periodontal therapy","volume":"52","author":"Bunaes","year":"2017","journal-title":"J. Periodontal. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1834-7819.2010.01261.x","article-title":"Plasma osteoprotegerin levels are decreased in smoker chronic periodontitis patients","volume":"55","author":"Ozcaka","year":"2010","journal-title":"Aust. Dent. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S162","DOI":"10.1111\/jcpe.12946","article-title":"Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"45","author":"Papapanou","year":"2018","journal-title":"J. Clin. Periodontol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:27:18Z","timestamp":1760178438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,30]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["biom10111500"],"URL":"https:\/\/doi.org\/10.3390\/biom10111500","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,30]]}}}