{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:53:48Z","timestamp":1788173628919,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T00:00:00Z","timestamp":1516579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Development and Innovation Office, Hungary","award":["OTKA NK 104846"],"award-info":[{"award-number":["OTKA NK 104846"]}]},{"name":"National Research Development and Innovation Office, Hungary","award":["OTKA NK 105898"],"award-info":[{"award-number":["OTKA NK 105898"]}]},{"name":"National Research Development and Innovation Office, Hungary","award":["OTKA 119459"],"award-info":[{"award-number":["OTKA 119459"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: In rheumatoid arthritis (RA), anti-citrullinated protein\/peptide antibodies (ACPAs) are responsible for disease onset and progression, however, our knowledge is limited on ligand binding affinities of autoantibodies with different citrulline-peptide specificity. Methods: Citrulline-peptide-specific ACPA IgGs were affinity purified and tested by ELISA. Binding affinities of ACPA IgGs and serum antibodies were compared by surface plasmon resonance (SPR) analysis. Bifunctional nanoparticles harboring a multi-epitope citrulline-peptide and a complement-activating peptide were used to induce selective depletion of ACPA-producing B cells. Results: KD values of affinity-purified ACPA IgGs varied between 10\u22126 and 10\u22128 M and inversely correlated with disease activity. Based on their cross-reaction with citrulline-peptides, we designed a novel multi-epitope peptide, containing Cit-Gly and Ala-Cit motifs in two\u2013two copies, separated with a short, neutral spacer. This peptide detected antibodies in RA sera with 66% sensitivity and 98% specificity in ELISA and was recognized by 90% of RA sera, while none of the healthy samples in SPR. When coupled to nanoparticles, the multi-epitope peptide specifically targeted and depleted ACPA-producing B cells ex vivo. Conclusions: The unique multi-epitope peptide designed based on ACPA cross-reactivity might be suitable to develop better diagnostics and novel therapies for RA.<\/jats:p>","DOI":"10.3390\/ijms19010326","type":"journal-article","created":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T13:40:39Z","timestamp":1516628439000},"page":"326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Affinity Purification and Comparative Biosensor Analysis of Citrulline-Peptide-Specific Antibodies in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4756-1502","authenticated-orcid":false,"given":"Eszter","family":"Szarka","sequence":"first","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Aradi","sequence":"additional","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Pozsgay","sequence":"additional","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"V\u00e9gh","sequence":"additional","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1390-6496","authenticated-orcid":false,"given":"Anna","family":"Magyar","sequence":"additional","affiliation":[{"name":"MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Science, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerg\u0151","family":"Gyulai","sequence":"additional","affiliation":[{"name":"Laboratory of Interfaces and Nanostructures, Institute of Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, 3rd Department of Internal Medicine, Semmelweis University, 1125 Budapest, Hungary"},{"name":"Rheumatology, Buda Hospital of the Hospitaller Order of St. John of God, 1023 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Rojkovich","sequence":"additional","affiliation":[{"name":"Rheumatology, Buda Hospital of the Hospitaller Order of St. John of God, 1023 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4757-4437","authenticated-orcid":false,"given":"\u00c9va","family":"Kiss","sequence":"additional","affiliation":[{"name":"Laboratory of Interfaces and Nanostructures, Institute of Chemistry, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferenc","family":"Hudecz","sequence":"additional","affiliation":[{"name":"MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Science, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3066-7768","authenticated-orcid":false,"given":"Gabriella","family":"S\u00e1rmay","sequence":"additional","affiliation":[{"name":"Department of Immunology, E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0889-857X(05)70201-5","article-title":"The Epidemiology of Rheumatoid Arthritis","volume":"27","author":"Gabriel","year":"2001","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2741\/1506","article-title":"Citrullinated Proteins in Rheumatoid Arthritis","volume":"10","author":"Yamada","year":"2005","journal-title":"Front. Biosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1002\/bies.10357","article-title":"Pad, a Growing Family of Citrullinating Enzymes: Genes, Features and Involvement in Disease","volume":"25","author":"Vossenaar","year":"2003","journal-title":"Bioessays"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.molmed.2003.09.010","article-title":"Peptidylarginine Deiminase Type 4: Identification of a Rheumatoid Arthritis-Susceptible Gene","volume":"9","author":"Yamada","year":"2003","journal-title":"Trends Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30709","DOI":"10.1074\/jbc.271.48.30709","article-title":"Protein Unfolding by Peptidylarginine Deiminase. Substrate Specificity and Structural Relationships of the Natural Substrates Trichohyalin and Filaggrin","volume":"271","author":"Tarcsa","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.biocel.2006.03.008","article-title":"Citrullination: A Posttranslational Modification in Health and Disease","volume":"38","author":"Gyorgy","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1002\/eji.200526000","article-title":"Humoral Immune Response to Citrullinated Collagen Type Ii Determinants in Early Rheumatoid Arthritis","volume":"35","author":"Burkhardt","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1002\/eji.200535790","article-title":"Epitopes of Human Fibrin Recognized by the Rheumatoid Arthritis-Specific Autoantibodies to Citrullinated Proteins","volume":"36","author":"Sebbag","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.4049\/jimmunol.166.6.4177","article-title":"The Major Synovial Targets of the Rheumatoid Arthritis-Specific Antifilaggrin Autoantibodies Are Deiminated Forms of the Alpha- and Beta-Chains of Fibrin","volume":"166","author":"Sebbag","year":"2001","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1002\/art.22817","article-title":"Mutation and Citrullination Modifies Vimentin to a Novel Autoantigen for Rheumatoid Arthritis","volume":"56","author":"Bang","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R142","DOI":"10.1186\/ar1149","article-title":"Rheumatoid Arthritis Specific Anti-Sa Antibodies Target Citrullinated Vimentin","volume":"6","author":"Vossenaar","year":"2004","journal-title":"Arthritis Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/ncb898","article-title":"Vimentin Is Secreted by Activated Macrophages","volume":"5","author":"Punturieri","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/art.25036","article-title":"Antibodies to Several Citrullinated Antigens Are Enriched in the Joints of Rheumatoid Arthritis Patients","volume":"62","author":"Snir","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/art.23284","article-title":"Induction of Macrophage Secretion of Tumor Necrosis Factor Alpha through Fcgamma Receptor Iia Engagement by Rheumatoid Arthritis-Specific Autoantibodies to Citrullinated Proteins Complexed with Fibrinogen","volume":"58","author":"Clavel","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/art.30081","article-title":"Immune Complexes Containing Citrullinated Fibrinogen Costimulate Macrophages Via Toll-Like Receptor 4 and Fcgamma Receptor","volume":"63","author":"Sokolove","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1007\/s00296-012-2635-6","article-title":"Anti-Citrullinated Protein Antibodies: Role in Pathogenesis of Ra and Potential as a Diagnostic Tool","volume":"33","author":"Moeez","year":"2013","journal-title":"Rheumatol. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/rheumatology\/ken077","article-title":"Synovial Detection and Autoantibody Reactivity of Processed Citrullinated Isoforms of Vimentin in Inflammatory Arthritides","volume":"47","author":"Tilleman","year":"2008","journal-title":"Rheumatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1093\/rheumatology\/keq419","article-title":"The Relevance of Citrullinated Vimentin in the Production of Antibodies against Citrullinated Proteins and the Pathogenesis of Rheumatoid Arthritis","volume":"50","author":"Tilleman","year":"2011","journal-title":"Rheumatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R1421","DOI":"10.1186\/ar1845","article-title":"Identification of Citrullinated Alpha-Enolase as a Candidate Autoantigen in Rheumatoid Arthritis","volume":"7","author":"Kinloch","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/art.21629","article-title":"Deiminated Epstein-Barr Virus Nuclear Antigen 1 Is a Target of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis","volume":"54","author":"Pratesi","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R135","DOI":"10.1186\/ar2802","article-title":"Diagnostic and Prognostic Value of Antibodies against Chimeric Fibrin\/Filaggrin Citrullinated Synthetic Peptides in Rheumatoid Arthritis","volume":"11","author":"Sanmarti","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.bbagrm.2013.07.003","article-title":"Peptidylarginine Deiminases in Citrullination, Gene Regulation, Health and Pathogenesis","volume":"1829","author":"Wang","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10495-006-3715-4","article-title":"Overexpression of Peptidylarginine Deiminase Iv Features in Apoptosis of Haematopoietic Cells","volume":"11","author":"Liu","year":"2006","journal-title":"Apoptosis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13075-016-1068-0","article-title":"Tumor Necrosis Factor Alpha, Citrullination, and Peptidylarginine Deiminase 4 in Lung and Joint Inflammation","volume":"18","author":"Bawadekar","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R104","DOI":"10.1186\/ar3829","article-title":"Pad4 Is Not Essential for Disease in the K\/Bxn Murine Autoantibody-Mediated Model of Arthritis","volume":"14","author":"Rohrbach","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1136\/ard.2010.131102","article-title":"Anti-Cyclic Citrullinated Peptide Antibodies Are a Collection of Anti-Citrullinated Protein Antibodies and Contain Overlapping and Non-Overlapping Reactivities","volume":"70","author":"Scherer","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrrheum.2011.76","article-title":"Anti-Ccp Antibodies: The Past, the Present and the Future","volume":"7","author":"Pruijn","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1093\/rheumatology\/kes371","article-title":"Monoclonal Anti-Citrullinated Protein Antibodies Selected on Citrullinated Fibrinogen Have Distinct Targets with Different Cross-Reactivity Patterns","volume":"52","author":"Bryde","year":"2013","journal-title":"Rheumatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/cei.12145","article-title":"Fine Specificity of Anti-Citrullinated Peptide Antibodies Discloses a Heterogeneous Antibody Population in Rheumatoid Arthritis","volume":"174","author":"Goules","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1002\/pro.2178","article-title":"Cross-Reactivity of a Human Igg(1) Anticitrullinated Fibrinogen Monoclonal Antibody to a Citrullinated Profilaggrin Peptide","volume":"21","author":"Trier","year":"2012","journal-title":"Protein Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/imm.12175","article-title":"Recognition of New Citrulline-Containing Peptide Epitopes by Autoantibodies Produced In Vivo and In Vitro by B Cells of Rheumatoid Arthritis Patients","volume":"141","author":"Szarka","year":"2014","journal-title":"Immunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13075-016-0918-0","article-title":"In Vitro Eradication of Citrullinated Protein Specific B-Lymphocytes of Rheumatoid Arthritis Patients by Targeted Bifunctional Nanoparticles","volume":"18","author":"Pozsgay","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1172\/JCI1316","article-title":"Citrulline Is an Essential Constituent of Antigenic Determinants Recognized by Rheumatoid Arthritis-Specific Autoantibodies","volume":"101","author":"Schellekens","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jaut.2011.07.003","article-title":"The Antigen Specificity of the Rheumatoid Arthritis-Associated Acpa Directed to Citrullinated Fibrin Is Very Closely Restricted","volume":"37","author":"Iobagiu","year":"2011","journal-title":"J. Autoimmun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1002\/art.23936","article-title":"Antibodies to Citrullinated Alpha-Enolase Peptide 1 Are Specific for Rheumatoid Arthritis and Cross-React with Bacterial Enolase","volume":"58","author":"Lundberg","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2249.2011.04378.x","article-title":"Antibodies to a New Viral Citrullinated Peptide, VCP2: Fine Specificity and Correlation with Anti-Cyclic Citrullinated Peptide (CCP) and Anti-VCP1 Antibodies","volume":"164","author":"Pratesi","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1021\/bc400073z","article-title":"Role of N- or C-Terminal Biotinylation in Autoantibody Recognition of Citrullin Containing Filaggrin Epitope Peptides in Rheumatoid Arthritis","volume":"24","author":"Babos","year":"2013","journal-title":"Bioconjug. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R167","DOI":"10.1186\/ar4683","article-title":"Affinity Purified Anti-Citrullinated Protein\/Peptide Antibodies Target Antigens Expressed in the Rheumatoid Joint","volume":"16","author":"Ossipova","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1136\/annrheumdis-2012-202615","article-title":"Low-Avidity Anticitrullinated Protein Antibodies (ACPA) Are Associated with a Higher Rate of Joint Destruction in Rheumatoid Arthritis","volume":"73","author":"Suwannalai","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1182\/blood.V87.6.2329.bloodjournal8762329","article-title":"Identification of Complement Activation Sites in Human Immunodeficiency Virus Type-1 Glycoprotein Gp120","volume":"87","author":"Susal","year":"1996","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ab.2014.07.030","article-title":"Biosensor Analysis of Anti-Citrullinated Protein\/Peptide Antibody Affinity","volume":"465","author":"Rossi","year":"2014","journal-title":"Anal. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Trier, N.H., Dam, C.E., Olsen, D.T., Hansen, P.R., and Houen, G. (2015). Contribution of Peptide Backbone to Anti-Citrullinated Peptide Antibody Reactivity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144707"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1136\/annrheumdis-2012-202868","article-title":"The Fibrin-Derived Citrullinated Peptide \u03b260\u201374Cit60,72,74 Bears the Major ACPA Epitope Recognised by the Rheumatoid Arthritis-Specific Anticitrullinated Fibrinogen Autoantibodies and Anti-CCP2 Antibodies","volume":"73","author":"Cornillet","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1177\/0961203314560005","article-title":"Fingerprinting of Anti-Citrullinated Protein Antibodies (ACPA): Specificity, Isotypes and Subclasses","volume":"24","author":"Pratesi","year":"2015","journal-title":"Lupus"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1080\/00365513.2016.1200133","article-title":"The Dependency on Neighboring Amino Acids for Reactivity of Anti-Citrullinated Protein Antibodies to Citrullinated Proteins","volume":"76","author":"Dam","year":"2016","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00281-017-0627-z","article-title":"The Role of Autoantibodies in the Pathophysiology of Rheumatoid Arthritis","volume":"39","author":"Derksen","year":"2017","journal-title":"Semin. Immunopathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0140-6736(09)60008-8","article-title":"Rheumatoid Arthritis","volume":"373","author":"Klareskog","year":"2009","journal-title":"Lancet"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1136\/ard.2010.138461","article-title":"2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology\/European League against Rheumatism Collaborative Initiative","volume":"69","author":"Aletaha","year":"2010","journal-title":"Ann. Rheum. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/326\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:52:05Z","timestamp":1760194325000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/326"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,22]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["ijms19010326"],"URL":"https:\/\/doi.org\/10.3390\/ijms19010326","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201801.0012.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,22]]}}}