{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T01:53:16Z","timestamp":1771465996805,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T00:00:00Z","timestamp":1618272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015077","name":"Wydzia\u0142 Lekarski, Uniwersytet Jagiello\u0144ski Collegium Medicum","doi-asserted-by":"publisher","award":["N41\/DBS\/000208, N41\/DBS\/000211"],"award-info":[{"award-number":["N41\/DBS\/000208, N41\/DBS\/000211"]}],"id":[{"id":"10.13039\/100015077","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Entropy"],"abstract":"<jats:p>The two forms of transthyretin differing slightly in the tertiary structure, despite the presence of five mutations, show radically different properties in terms of susceptibility to the amyloid transformation process. These two forms of transthyretin are the object of analysis. The search for the sources of these differences was carried out by means of a comparative analysis of the structure of these molecules in their native and early intermediate stage forms in the folding process. The criterion for assessing the degree of similarity and differences is the status of the hydrophobic core. The comparison of the level of arrangement of the hydrophobic core and its initial stages is possible thanks to the application of divergence entropy for the early intermediate stage and for the final forms. It was shown that the minimal differences observed in the structure of the hydrophobic core of the forms available in PDB, turned out to be significantly different in the early stage (ES) structure in folding process. The determined values of divergence entropy for both ES forms indicate the presence of the seed of hydrophobic core only in the form resistant to amyloid transformation. In the form of aggressively undergoing amyloid transformation, the structure lacking such a seed is revealed, being a stretched one with a high content of \u03b2-type structure. In the discussed case, the active presence of water in the structural transformation of proteins expressed in the fuzzy oil drop model (FOD) is of decisive importance for the generation of the final protein structure. It has been shown that the resistant form tends to generate a centric hydrophobic core with the possibility of creating a globular structure, i.e., a spherical micelle-like form. The aggressively transforming form reveals in the structure of its early intermediate, a tendency to form the ribbon-like micelle as observed in amyloid.<\/jats:p>","DOI":"10.3390\/e23040458","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T22:55:09Z","timestamp":1618354509000},"page":"458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Divergence Entropy-Based Evaluation of Hydrophobic Core in Aggressive and Resistant Forms of Transthyretin"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-9877","authenticated-orcid":false,"given":"Mateusz","family":"Banach","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Telemedicine, Jagiellonian University\u2014Medical College, 30-688 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3003-6592","authenticated-orcid":false,"given":"Katarzyna","family":"Stapor","sequence":"additional","affiliation":[{"name":"Institute of Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5152-6331","authenticated-orcid":false,"given":"Piotr","family":"Fabian","sequence":"additional","affiliation":[{"name":"Institute of Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leszek","family":"Konieczny","sequence":"additional","affiliation":[{"name":"Chair of Medical Biochemistry\u2014Jagiellonian University\u2014Medical College, 31-034 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3652-9099","authenticated-orcid":false,"given":"Irena","family":"Roterman","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Telemedicine, Jagiellonian University\u2014Medical College, 30-688 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein Misfolding, Functional Amyloid, and Human Disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Ann. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.181.4096.223","article-title":"Principles that Govern the Folding of Protein Chains","volume":"181","author":"Anfinsen","year":"1973","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1515\/bmc-2013-0038","article-title":"Transthyretin: A multifaceted protein","volume":"5","author":"Vieira","year":"2014","journal-title":"Biomol. Concepts"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0074-7742(09)87017-7","article-title":"Transthyretin: An enhancer of nerve regeneration","volume":"87","author":"Fleming","year":"2009","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1586\/eem.12.2","article-title":"Transthyretin: Roles in the nervous system beyond thyroxine and retinol transport","volume":"7","author":"Oliveira","year":"2012","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1007\/PL00000791","article-title":"Transthyretin: A review from a structural perspective","volume":"58","author":"Hamilton","year":"2001","journal-title":"Cell Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1515\/CCLM.2002.223","article-title":"Transthyretin as a thyroid hormone carrier: Function revisited","volume":"40","author":"Palha","year":"2002","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/iub.340","article-title":"Aboard transthyretin: From transport to cleavage","volume":"62","author":"Liz","year":"2010","journal-title":"IUBMB Life"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1007\/s00018-009-0109-0","article-title":"Transthyretin: The servant of many masters","volume":"66","author":"Buxbaum","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Saponaro, F., Kim, J.H., and Chiellini, G. (2020). Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer\u2019s Disease?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228672"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1074\/jbc.M708028200","article-title":"Human-Murine Transthyretin Heterotetramers Are Kinetically Stable and Non-amyloidogenic\u2014A lesson in the generation of transgenic models of diseases involving oligomeric proteins","volume":"283","author":"Reixach","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27207","DOI":"10.1074\/jbc.M101024200","article-title":"Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants","volume":"276","author":"Quintas","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/978-94-007-5416-4_9","article-title":"Mechanisms of transthyretin aggregation and toxicity","volume":"65","author":"Gasperini","year":"2012","journal-title":"Subcell Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1006\/jmbi.1998.1937","article-title":"Protein subunit interactions and structural integrity of amyloidogenic transthyretins: Evidence from electrospray mass spectrometry","volume":"281","author":"Nettleton","year":"1998","journal-title":"J. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/s41467-019-08609-z","article-title":"A molecular mechanism for transthyretin amyloidogenesis","volume":"10","author":"Yee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1016\/j.bpj.2020.08.043","article-title":"Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions","volume":"119","author":"Childers","year":"2020","journal-title":"Biophys. J."},{"key":"ref_17","first-page":"75","article-title":"The \u2018edge strand\u2019 hypothesis: Prediction and test of a mutational \u2018hot-spot\u2019 on the transthyretin molecule associated with FAP amyloidogenesis","volume":"3","author":"Serpell","year":"1996","journal-title":"Amyloid Int. J. Exp. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5699","DOI":"10.1074\/jbc.M310605200","article-title":"Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy","volume":"279","author":"Olofsson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8654","DOI":"10.1021\/bi00151a036","article-title":"Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro","volume":"31","author":"Wilfredo","year":"1992","journal-title":"Biochemistry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/78980","article-title":"A glimpse of a possible amyloidogenic intermediate of transthyretin","volume":"7","author":"Liu","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0065-3233(08)60321-6","article-title":"Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid","volume":"50","author":"Kelly","year":"1997","journal-title":"Adv. Protein Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1529\/biophysj.105.059642","article-title":"Initial conformational changes of human transthyretin under partially denaturing conditions","volume":"89","author":"Yang","year":"2005","journal-title":"Biophys. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/pro.289","article-title":"Potentially amyloidogenic conformational intermediates populate the\n            unfolding landscape of transthyretin: Insights from molecular dynamics simulations","volume":"19","author":"Rodrigues","year":"2010","journal-title":"Protein Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1021\/acs.biochem.7b00658","article-title":"Pathogenic Mutations Induce Partial Structural Changes in the Native beta-Sheet Structure of Transthyretin and Accelerate Aggregation","volume":"56","author":"Lim","year":"2017","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16612","DOI":"10.1021\/bi0511484","article-title":"Partitioning conformational intermediates between competing refolding and aggregation pathways: Insights into transthyretin amyloid disease","volume":"44","author":"Wiseman","year":"2005","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"36948","DOI":"10.1074\/jbc.M204168200","article-title":"Kinetic studies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization","volume":"277","author":"Fezoui","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1021\/bm049841e","article-title":"Amyloid fibril formation by peptide LYS (11-36) in aqueous trifluoroethanol","volume":"5","author":"Liu","year":"2004","journal-title":"Biomacromolecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9290","DOI":"10.1021\/bi050249z","article-title":"The effect of iodide and chloride on transthyretin structure and stability","volume":"44","author":"Hultdin","year":"2005","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.bbapap.2018.10.013","article-title":"Two distinct aggregation pathways in transthyretin misfolding and amyloid formation","volume":"1867","author":"Dasari","year":"2019","journal-title":"Biochim. Biophys. Acta Proteins Proteom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4408","DOI":"10.1021\/acs.biochem.9b00769","article-title":"Drivers of alpha-Sheet Formation in Transthyretin under Amyloidogenic Conditions","volume":"58","author":"Childers","year":"2019","journal-title":"Biochemistry."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.2174\/092986712800269344","article-title":"Computational studies on transthyretin","volume":"19","author":"Ortore","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dongmo Foumthuim, C.J., Corazza, A., Berni, R., Esposito, G., and Fogolari, F. (2018). Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations. Biomed. Res. Int., 7480749.","DOI":"10.1155\/2018\/7480749"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28932","DOI":"10.1074\/jbc.M115.659912","article-title":"Uncovering the mechanism of aggregation of human transthyretin","volume":"290","author":"Saelices","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1002\/pro.3420","article-title":"Crystal structures of amyloidogenic segments of human transthyretin","volume":"27","author":"Saelices","year":"2018","journal-title":"Protein Sci."},{"key":"ref_35","first-page":"411","article-title":"Cloning of Human Prealbumin Complementary DNA. Localization of the Gene to Chromosome 18 and Detection of a Variant Prealbumin Allele in a Family with Familial Amyloid Polyneuropathy","volume":"2","author":"Whitehead","year":"1984","journal-title":"Mol. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1111\/j.1469-1809.2008.00439.x","article-title":"On the Origin of the Transthyretin Val30Met Familial Amyloid Polyneuropathy","volume":"72","author":"Zaros","year":"2008","journal-title":"Ann. Human Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.jmb.2006.12.007","article-title":"Early Kinetics of Amyloid Fibril Formation Reveals Conformational Reorganisation of Initial Aggregates","volume":"366","author":"Serrano","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21057","DOI":"10.1073\/pnas.1112197108","article-title":"Experimental free energy surfaces reveal the mechanisms of maintenance of protein solubility","volume":"108","author":"Dhulesia","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1021\/ar050067x","article-title":"Sequence and Structural Determinants of Amyloid Fibril Formation","volume":"39","author":"Bemporad","year":"2006","journal-title":"Acc. Chem. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/S1097-2765(00)00117-9","article-title":"The \u03b2-Slip","volume":"6","author":"Eneqvist","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11442","DOI":"10.1021\/bi011194d","article-title":"An Engineered Transthyretin Monomer that Is Nonamyloidogenic, Unless It Is Partially Denatured","volume":"40","author":"Jiang","year":"2001","journal-title":"Biochemistry"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Banach, M., Konieczny, L., and Roterman, I. (2019). The Amyloid as a Ribbon-Like Micelle in Contrast to Spherical Micelles Represented by Globular Proteins. Molecules, 24.","DOI":"10.3390\/molecules24234395"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Roterman-Konieczna, I. (2012). The early-stage intermediate. Protein Folding in Silico, Woodhead Publishing.","DOI":"10.1533\/9781908818256"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Roterman-Konieczna, I. (2020). Description of the fuzzy oil drop model. From Globular Proteins to Amyloids. From Globular Proteins to Amyloids, Elsevier.","DOI":"10.1016\/B978-0-08-102981-7.00001-4"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7077","DOI":"10.1021\/bi200750k","article-title":"Native-State Interconversion of a Metamorphic Protein Requires Global Unfolding","volume":"50","author":"Tyler","year":"2011","journal-title":"Biochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nsb768","article-title":"Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme","volume":"9","author":"Canet","year":"2002","journal-title":"Nat. Struct. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Roterman-Konieczna, I. (2020). Information encoded in protein structure. From Globular Proteins to Amyloids, Elsevier.","DOI":"10.1016\/B978-0-08-102981-7.00003-8"},{"key":"ref_48","first-page":"15","article-title":"Gauss-function-Based model of hydrophobicity density in proteins","volume":"6","author":"Konieczny","year":"2006","journal-title":"Silico Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Fabian, P., Stapor, K., and Roterman, I. (2019). Model of Early Stage Intermediate in Respect to Its Final Structure. Biomolecules, 9.","DOI":"10.3390\/biom9120866"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/prot.20002","article-title":"Conformational subspace in simulation of early-stage protein folding","volume":"55","author":"Jurkowski","year":"2004","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1006\/jtbi.1995.0245","article-title":"Modelling the Optimal Simulation Path in the Peptide Chain Folding\u2013Studies Based on Geometry of Alanine Heptapeptide","volume":"177","author":"Roterman","year":"1995","journal-title":"J. Theoret. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/0300-9084(96)88126-0","article-title":"The geometrical analysis of peptide backbone structure and its local deformations","volume":"77","author":"Roterman","year":"1995","journal-title":"Biochimie"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.3390\/e17031477","article-title":"Application of Divergence Entropy to Characterize the Structure of the Hydrophobic Core in DNA Interacting Proteins","volume":"17","author":"Kalinowska","year":"2015","journal-title":"Entropy"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0022-2836(76)90004-8","article-title":"A simplified representation of protein conformations for rapid simulation of protein folding","volume":"104","author":"Levitt","year":"1976","journal-title":"J. Mol. Biol"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1214\/aoms\/1177729694","article-title":"On Information and Sufficiency","volume":"22","author":"Kullback","year":"1951","journal-title":"Ann. Math. Stat."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Banach, M., Fabian, P., Stapor, K., Konieczny, L., and Roterman, I. (2020). Structure of the Hydrophobic Core Determines the 3D Protein Structure\u2014Verification by Single Mutation Proteins. Biomolecules, 10.","DOI":"10.3390\/biom10050767"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"D289","DOI":"10.1093\/nar\/gkw1098","article-title":"CATH: An expanded resource to predict protein function through structure and sequence","volume":"45","author":"Dawson","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_59","unstructured":"(2015). The PyMOL Molecular Graphics System, Version 2.0, Schr\u00f6dinger LLC."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D Graphics Environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Banach, M., Banach, M., Fabian, P., Stapor, K., Konieczny, L., Ptak-Kaczor, M., and Roterman, I. (2020). The Status of Edge Strands in Ferredoxin-Like Fold. Symmetry, 12.","DOI":"10.3390\/sym12061032"},{"key":"ref_62","unstructured":"Roterman-Konieczna, I. (2020). Anti-amyloid drug design. From Globular Proteins to Amyloids, Elsevier."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Fabian, P., Banach, M., Stapor, K., Konieczny, L., Ptak-Kaczor, M., and Roterman, I. (2020). Structure of amyloid versus structure of globular proteins. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134683"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.jmb.2008.12.044","article-title":"Structural alphabets for protein structure classification: A comparison study","volume":"387","author":"Le","year":"2008","journal-title":"J. Mol. Biol."}],"container-title":["Entropy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1099-4300\/23\/4\/458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:47:42Z","timestamp":1760161662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1099-4300\/23\/4\/458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,13]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["e23040458"],"URL":"https:\/\/doi.org\/10.3390\/e23040458","relation":{},"ISSN":["1099-4300"],"issn-type":[{"value":"1099-4300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,13]]}}}