{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T20:35:17Z","timestamp":1778186117755,"version":"3.51.4"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R &amp; D Program of China (2020YFC0841400)","award":["2020YFC0841400"],"award-info":[{"award-number":["2020YFC0841400"]}]},{"name":"the Shanghai Municipal Science and Technology Major Project, the National Natural Science Foundation of China","award":["81773634"],"award-info":[{"award-number":["81773634"]}]},{"name":"the National Science and Technology Major Project of the Ministry of Science and Technology of China","award":["2018ZX09711002"],"award-info":[{"award-number":["2018ZX09711002"]}]},{"name":"Strategic Priority Research Program of the Chinese Academy of Sciences","award":["XDPB2505"],"award-info":[{"award-number":["XDPB2505"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The \u201cEPN\u201d motif, \u201cNDD\u201d motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.<\/jats:p>","DOI":"10.3390\/biom11111586","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"1586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study"],"prefix":"10.3390","volume":"11","author":[{"given":"Meina","family":"Gao","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9639-4301","authenticated-orcid":false,"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghao","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Shantou University, Shantou 515063, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaixian","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hualiang","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China"},{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunqian","family":"Yu","sequence":"additional","affiliation":[{"name":"Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0092-8674(00)80694-7","article-title":"DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells","volume":"100","author":"Geijtenbeek","year":"2000","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12780","DOI":"10.1021\/ja072944v","article-title":"Non-carbohydrate inhibitors of the lectin DC-SIGN","volume":"129","author":"Borrok","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_3","unstructured":"Varki, E.E.A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Darvill, A.G., Kinoshita, T., Packer, N.H., and Prestegard, J.H. (2017). Chapter 34 C-Type Lectin, Cold Spring Harbor Laboratory Press (NY)."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1126\/science.1066371","article-title":"Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR","volume":"294","author":"Feinberg","year":"2001","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"28939","DOI":"10.1074\/jbc.M104565200","article-title":"A Novel Mechanism of Carbohydrate Recognition by the C-type Lectins DC-SIGN and DC-signr: Subunit organization and binding to multivalent ligands","volume":"276","author":"Mitchell","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/glycob\/cwg052","article-title":"The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x","volume":"13","author":"Nyame","year":"2003","journal-title":"Glycobiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11314","DOI":"10.1074\/jbc.M111532200","article-title":"Identification of different binding sites in the dendritic cell-specific receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1","volume":"277","author":"Geijtenbeek","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"117350","DOI":"10.1016\/j.carbpol.2020.117350","article-title":"Helicobacter pylori lipopolysaccharide structural domains and their recognition by immune proteins revealed with carbohydrate microarrays","volume":"253","author":"Silva","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15130","DOI":"10.1021\/ja1056714","article-title":"High-affinity glycopolymer binding to human DC-SIGN and disruption of DC-SIGN interactions with HIV envelope glycoprotein","volume":"132","author":"Becer","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1006\/viro.2002.1730","article-title":"DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells","volume":"305","author":"Simmons","year":"2003","journal-title":"Virology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yang, Z.S., Huang, S.W., Wang, W.H., Lin, C.Y., Wang, C.F., Urbina, A.N., Thitithanyanont, A., Tseng, S.P., Lu, P.L., and Chen, Y.H. (2021). Identification of Important N-linked glycosylation sites in the hemagglutinin protein and their functional impact on DC-SIGN mediated avian influenza H5N1 infection. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020743"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.cell.2005.11.042","article-title":"Cryo-EM reconstruction of dengue virus in complex with the carbohydrate recognition domain of DC-SIGN","volume":"124","author":"Pokidysheva","year":"2006","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Amraie, R., Napoleon, M.A., Yin, W., Berrigan, J., Suder, E., Zhao, G., Olejnik, J., Gummuluru, S., Muhlberger, E., and Chitalia, V. (2020). CD209L\/L-SIGN and CD209\/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells. bioRxiv.","DOI":"10.1101\/2020.06.22.165803"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1021\/acs.analchem.0c03173","article-title":"N- and O-Glycosylation of the SARS-CoV-2 Spike Protein","volume":"93","author":"Sanda","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1093\/glycob\/cwaa042","article-title":"Deducing the N- and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2","volume":"30","author":"Shajahan","year":"2020","journal-title":"Glycobiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1126\/science.abb9983","article-title":"Site-specific glycan analysis of the SARS-CoV-2 spike","volume":"369","author":"Watanabe","year":"2020","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/s41422-021-00545-2","article-title":"O-glycosylation pattern of the SARS-CoV-2 spike protein reveals an \u201cO-Follow-N\u201d rule","volume":"31","author":"Tian","year":"2021","journal-title":"Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bagdonaite, I., Thompson, A.J., Wang, X., S\u00f8gaard, M., Fougeroux, C., Frank, M., Diedrich, J.K., Yates, J.R., Salanti, A., and Vakhrushev, S.Y. (2021). Site-specific o-glycosylation analysis of SARS-CoV-2 spike protein produced in insect and human cells. Viruses, 13.","DOI":"10.1101\/2021.02.03.429627"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23763","DOI":"10.1002\/anie.202011015","article-title":"Structural characterization of N-linked glycans in the receptor binding domain of the SARS-CoV-2 spike protein and their interactions with human lectins","volume":"59","author":"Lenza","year":"2020","journal-title":"Angew. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Soh, W.T., Liu, Y., Nakayama, E.E., Ono, C., Torii, S., Nakagami, H., Matsuura, Y., Shioda, T., and Arase, H. (2020). The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN. bioRxiv.","DOI":"10.1101\/2020.11.05.369264"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Th\u00e9paut, M., Luczkowiak, J., Viv\u00e8s, C., Labiod, N., Bally, I., Lasala, F., Grimoire, Y., Fenel, D., Sattin, S., and Thielens, N. (2021). DC\/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist. PLoS Pathog, 17.","DOI":"10.1371\/journal.ppat.1009576"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hoffmann, D., Mereiter, S., Oh, Y.J., Monteil, V., Zhu, R., Canena, D., Hain, L., Laurent, E., Gr\u00fcnwald-Gruber, C., and Novatchkova, M. (2021). Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites. bioRxiv.","DOI":"10.1101\/2021.04.01.438087"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gao, C., Zeng, J., Jia, N., Stavenhagen, K., Matsumoto, Y., Zhang, H., Li, J., Hume, A.J., M\u00fchlberger, E., and van Die, I. (2020). SARS-CoV-2 spike protein interacts with multiple innate immune receptors. bioRxiv.","DOI":"10.1101\/2020.07.29.227462"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lempp, F.A., Soriaga, L., Montiel-Ruiz, M., Benigni, F., Noack, J., Park, Y.-J., Bianchi, S., Walls, A.C., Bowen, J.E., and Zhou, J. (2021). Membrane lectins enhance SARS-CoV-2 infection and influence the neutralizing activity of different classes of antibodies. bioRxiv.","DOI":"10.1101\/2021.04.03.438258"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1021\/jacs.1c00353","article-title":"Heterogeneity of glycan processing on trimeric SARS-CoV-2 spike protein revealed by charge detection mass spectrometry","volume":"143","author":"Miller","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1021\/acscentsci.0c01056","article-title":"Beyond shielding: The roles of glycans in the SARS-CoV-2 spike protein","volume":"6","author":"Casalino","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1002\/jmv.25980","article-title":"DC\/L-SIGNs of hope in the COVID-19 pandemic","volume":"92","author":"Brufsky","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.immuni.2021.05.006","article-title":"SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2","volume":"54","author":"Lu","year":"2021","journal-title":"Immunity"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/jcc.20820","article-title":"GLYCAM06: A generalizable biomolecular force field","volume":"29","author":"Kirschner","year":"2008","journal-title":"Carbohydrates. J. Comput. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1002\/cbic.202000238","article-title":"Molecular Recognition in C-Type Lectins: The Cases of DC-SIGN, Langerin, MGL, and L-Sectin","volume":"21","author":"Valverde","year":"2020","journal-title":"Chembiochem A Eur. J. Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1021\/cb900216e","article-title":"Inhibition of DC-SIGN-mediated HIV infection by a linear trimannoside mimic in a tetravalent presentation","volume":"5","author":"Sattin","year":"2010","journal-title":"ACS Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"33393","DOI":"10.1038\/srep33393","article-title":"Linear biocompatible glyco-polyamidoamines as dual action mode virus infection inhibitors with potential as broad-spectrum microbicides for sexually transmitted diseases","volume":"6","author":"Mauro","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1021\/cb300260p","article-title":"Noncarbohydrate glycomimetics and glycoprotein surrogates as DC-SIGN antagonists and agonists","volume":"7","author":"Prost","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9874","DOI":"10.1002\/chem.200900923","article-title":"Gold manno-glyconanoparticles: Multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN","volume":"15","author":"Hijazi","year":"2009","journal-title":"Chemistry"},{"key":"ref_35","unstructured":"Woods Group (2021, July 15). GLYCAM Web. Available online: http:\/\/glycam.org."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","article-title":"OPLS3e: Extending force field coverage for drug-like small molecules","volume":"15","author":"Roos","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Adzhigirey","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1093\/glycob\/cww076","article-title":"3D implementation of the symbol nomenclature for graphical representation of glycans","volume":"26","author":"Thieker","year":"2016","journal-title":"Glycobiology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3333","DOI":"10.1021\/acs.jctc.5b00159","article-title":"Evaluation of selected classical force fields for alchemical binding free energy calculations of protein-carbohydrate complexes","volume":"11","author":"Mishra","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/0021-9991(83)90014-1","article-title":"Rattle: A \u201cvelocity\u201d version of the shake algorithm for molecular dynamics calculations","volume":"52","author":"Andersen","year":"1983","journal-title":"J. Comput. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1021\/ci4002475","article-title":"MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions","volume":"53","author":"Ylilauri","year":"2013","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1021\/acs.jcim.6b00196","article-title":"Improved Computation of Protein-Protein Relative Binding Energies with the Nwat-MMGBSA Method","volume":"56","author":"Maffucci","year":"2016","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8113","DOI":"10.1021\/acs.jpcb.8b03655","article-title":"Assessing the performance of MM\/PBSA, MM\/GBSA, and QM-MM\/GBSA approaches on protein\/carbohydrate complexes: Effect of implicit solvent models, QM methods, and entropic contributions","volume":"122","author":"Mishra","year":"2018","journal-title":"J. Phys. Chem. B"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: An efficient program for end-state free energy calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"18022","DOI":"10.1021\/jacs.0c06793","article-title":"Glycan-gold nanoparticles as multifunctional probes for multivalent lectin-carbohydrate binding: Implications for blocking virus infection and nanoparticle assembly","volume":"142","author":"Budhadev","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1021\/acs.molpharmaceut.1c00048","article-title":"Characterization of a nanovaccine platform based on an \u03b11,2-mannobiose derivative shows species-non-specific targeting to human, bovine, mouse, and teleost fish dendritic cells","volume":"18","author":"Pappalardo","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1039\/b802144a","article-title":"Docking, synthesis, and NMR studies of mannosyl trisaccharide ligands for DC-SIGN lectin","volume":"6","author":"Reina","year":"2008","journal-title":"Org. Biomol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.chom.2020.08.004","article-title":"Virus-receptor interactions of glycosylated SARS-CoV-2 spike and human ACE2 receptor","volume":"28","author":"Zhao","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eabf6834","DOI":"10.1126\/sciadv.abf6834","article-title":"Differential recognition of oligomannose isomers by glycan-binding proteins involved in innate and adaptive immunity","volume":"7","author":"Gao","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1093\/jmcb\/mjv046","article-title":"E-selectin ligand complexes adopt an extended high-affinity conformation","volume":"8","author":"Preston","year":"2016","journal-title":"J. Mol. Cell Biol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/11\/1586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:12Z","timestamp":1760167272000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/11\/1586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,27]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["biom11111586"],"URL":"https:\/\/doi.org\/10.3390\/biom11111586","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,27]]}}}