{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:56:06Z","timestamp":1791212166954,"version":"4.1.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T00:00:00Z","timestamp":1386201600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T00:00:00Z","timestamp":1386201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Cyclophilin A (CypA) is implicated in rheumatoid arthritis (RA) pathogenesis. We studied whether a novel anti-CypA single domain antibody (sdAb) treatment would modulate the severity of the disease in two different animal models of RA.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>A novel sdAb, named sdAbA1, was screened from an immunized camel sdAb library and found to have a high binding affinity (K<jats:sub>D<\/jats:sub>\u2009=\u20096.9\u2009\u00d7\u200910<jats:sup>-9<\/jats:sup>\u00a0M) for CypA. The SCID-HuRAg model and the collagen-induced arthritis (CIA) in mice were used to evaluate the effects of sdAbA1 treatment on inflammation and joint destruction. For <jats:italic>in vitro<\/jats:italic> analysis, monocytes\/macrophages were purified from synovial fluid and peripheral blood of patients with RA and were tested for the effect of anti-CypA sdAb on metalloproteinase (MMP) production. Human monocyte cell line THP-1 cells were selected and western blot analyses were performed to examine the potential signaling pathways.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>In the CIA model of RA, the sdAbA1 treatment resulted in a significant decrease in clinical symptoms as well as of joint damage (<jats:italic>P<\/jats:italic> &lt;0.05). In the SCID-HuRAg model, treatment with anti-CypA antibody sdAbA1 significantly reduced cartilage erosion, inflammatory cell numbers and MMP-9 production in the implanted tissues (<jats:italic>P<\/jats:italic> &lt;0.05). It also significantly reduced the levels of human inflammatory cytokines IL-6 and IL-8 in mouse serum (<jats:italic>P<\/jats:italic> &lt;0.05). No toxic effects were observed in the two animal models. <jats:italic>In vitro<\/jats:italic> results showed that sdAbA1 could counteract CypA-dependent MMP-9 secretion and IL-8 production by interfering with the ERK-NF-\u03baB pathway.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>Blockade of CypA significantly inhibited synovitis and cartilage\/bone erosion in the two tested animal models of RA. Our findings provide evidence that sdAbA1 may be a potential therapeutic agent for RA.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar4401","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T10:04:07Z","timestamp":1386237847000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Inhibition of synovitis and joint destruction by a new single domain antibody specific for cyclophilin A in two different mouse models of rheumatoid arthritis"],"prefix":"10.1186","volume":"15","author":[{"given":"Li","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conghua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenggong","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiguang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangmin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhinan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,12,5]]},"reference":[{"key":"4076_CR1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1136\/annrheumdis-2011-200386","volume":"71","author":"A Korb-Pap","year":"2012","unstructured":"Korb-Pap A, Stratis A, M\u00fchlenberg K, Niederreiter B, Hayer S, Echtermeyer F, Stange R, Zwerina J, Pap T, Pavenst\u00e4dt H, Schett G, Smolen JS, Redlich K: Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis. Ann Rheum Dis. 2012, 71: 1004-1011. 10.1136\/annrheumdis-2011-200386.","journal-title":"Ann Rheum Dis"},{"key":"4076_CR2","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1002\/1529-0131(199808)41:8<1378::AID-ART6>3.0.CO;2-J","volume":"41","author":"G Keyszer","year":"1998","unstructured":"Keyszer G, Redlich A, H\u00e4upl T, Zacher J, Sparmann M, Engeth\u00fcm U, Gay S, Burmester GR: Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Arthritis Rheum. 1998, 41: 1378-1387. 10.1002\/1529-0131(199808)41:8<1378::AID-ART6>3.0.CO;2-J.","journal-title":"Arthritis Rheum"},{"key":"4076_CR3","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nri2094","volume":"7","author":"IB McInnes","year":"2007","unstructured":"McInnes IB, Schett G: Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007, 7: 429-442. 10.1038\/nri2094.","journal-title":"Nat Rev Immunol"},{"key":"4076_CR4","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1161\/01.RES.87.9.789","volume":"87","author":"ZG Jin","year":"2000","unstructured":"Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC: Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res. 2000, 87: 789-796. 10.1161\/01.RES.87.9.789.","journal-title":"Circ Res"},{"key":"4076_CR5","doi-asserted-by":"publisher","first-page":"517","DOI":"10.4049\/jimmunol.175.1.517","volume":"175","author":"K Arora","year":"2005","unstructured":"Arora K, Gwinn WM, Bower MA, Watson A, Okwumabua I, MacDonald HR, Bukrinsky MI, Constant SL: Extracellular cyclophilins contribute to the regulation of inflammatory responses. J Immunol. 2005, 175: 517-522.","journal-title":"J Immunol"},{"key":"4076_CR6","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1007\/s00268-004-7812-7","volume":"29","author":"QZ Yao","year":"2005","unstructured":"Yao QZ, Li M, Yang H, Handschumacher RE, Lyttle CR: Roles of cyclophilins in cancers and other organ systems. World J Surg. 2005, 29: 276-280. 10.1007\/s00268-004-7812-7.","journal-title":"World J Surg"},{"key":"4076_CR7","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.clim.2005.05.004","volume":"116","author":"H Kim","year":"2005","unstructured":"Kim H, Kim WJ, Jeon ST, Koh EM, Cha HS, Ahn KS, Lee WH: Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages. Clin Immunol. 2005, 116: 217-224. 10.1016\/j.clim.2005.05.004.","journal-title":"Clin Immunol"},{"key":"4076_CR8","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1093\/rheumatology\/ken225","volume":"47","author":"Y Yang","year":"2008","unstructured":"Yang Y, Lu N, Zhou J, Chen ZN, Zhu P: Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes\/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford). 2008, 47: 1299-1310. 10.1093\/rheumatology\/ken225.","journal-title":"Rheumatology (Oxford)"},{"key":"4076_CR9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1007\/s10875-009-9329-1","volume":"30","author":"L Wang","year":"2010","unstructured":"Wang L, Wang CH, Jia JF, Ma XK, Li Y, Zhu HB, Tang H, Chen ZN, Zhu P: Contribution of cyclophilin A to the regulation of inflammatory processes in rheumatoid arthritis. J Clin Immunol. 2010, 30: 24-33.","journal-title":"J Clin Immunol"},{"key":"4076_CR10","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1038\/nri802","volume":"2","author":"M Feldmann","year":"2002","unstructured":"Feldmann M: Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002, 2: 364-371. 10.1038\/nri802.","journal-title":"Nat Rev Immunol"},{"key":"4076_CR11","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1002\/art.21827","volume":"54","author":"K Coppieters","year":"2006","unstructured":"Coppieters K, Dreier T, Silence K, de Haard H, Lauwereys M, Casteels P, Beirnaert E, Jonckheere H, Van de Wiele C, Staelens L, Hostens J, Revets H, Remaut E, Elewaut D, Rottiers P: Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis. Arthritis Rheum. 2006, 54: 1856-1866. 10.1002\/art.21827.","journal-title":"Arthritis Rheum"},{"key":"4076_CR12","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s00430-009-0116-7","volume":"198","author":"J Wesolowski","year":"2009","unstructured":"Wesolowski J, Alzogaray V, Reyelt J, Unger M, Juarez K, Urrutia M, Cauerhff A, Danquah W, Rissiek B, Scheuplein F, Schwarz N, Adriouch S, Boyer O, Seman M, Licea A, Serreze DV, Goldbaum FA, Haag F, Koch-Nolte F: Single domain antibodies: promising experimental and therapeutic tools in infection and immunity. Med Microbiol Immunol. 2009, 198: 157-174. 10.1007\/s00430-009-0116-7.","journal-title":"Med Microbiol Immunol"},{"key":"4076_CR13","unstructured":"Ablynx Annual report. 2012, [http:\/\/www.ablynx.com\/wp-content\/uploads\/2013\/03\/Ablynx_Annual-Report-2012_EN_FINAL.pdf]"},{"key":"4076_CR14","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1084\/jem.158.6.2007","volume":"158","author":"N Kaibara","year":"1983","unstructured":"Kaibara N, Hotokebuchi T, Takagishi K, Katsuki I: Paradoxical effects of cyclosporin A on collagen arthritis in rats. J Exp Med. 1983, 158: 2007-2015. 10.1084\/jem.158.6.2007.","journal-title":"J Exp Med"},{"key":"4076_CR15","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/art.1780310302","volume":"31","author":"FC Arnett","year":"1988","unstructured":"Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002\/art.1780310302.","journal-title":"Arthritis Rheum"},{"key":"4076_CR16","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.toxicon.2005.10.017","volume":"47","author":"RA Harrison","year":"2006","unstructured":"Harrison RA, Hasson SS, Harmsen M, Laing GD, Conrath K, Theakston RDG: Neutralisation of venom-induced haemorrhage by IgG from camels and llamas immunised with viper venom and also by endogenous, non-IgG components in camelid sera. Toxicon. 2006, 47: 364-368. 10.1016\/j.toxicon.2005.10.017.","journal-title":"Toxicon"},{"key":"4076_CR17","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S0014-5793(97)01062-4","volume":"414","author":"GM Arbabi","year":"1997","unstructured":"Arbabi GM, Desmyter A, Wyns L, Hamers R, Muyldermans S: Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett. 1997, 414: 521-526. 10.1016\/S0014-5793(97)01062-4.","journal-title":"FEBS Lett"},{"key":"4076_CR18","doi-asserted-by":"publisher","first-page":"6127","DOI":"10.1021\/bi00239a007","volume":"30","author":"JL Kofron","year":"1991","unstructured":"Kofron JL, Kuzmic P, Kishore V, Colon-Bonilla E, Rich DH: Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry. 1991, 30: 6127-6134. 10.1021\/bi00239a007.","journal-title":"Biochemistry"},{"key":"4076_CR19","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/nprot.2007.173","volume":"2","author":"DD Brand","year":"2007","unstructured":"Brand DD, Latham KA, Rosloniec EF: Collagen-induced arthritis. Nat Protoc. 2007, 2: 1269-1275. 10.1038\/nprot.2007.173.","journal-title":"Nat Protoc"},{"key":"4076_CR20","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/ar3119","volume":"12","author":"S Seeuws","year":"2010","unstructured":"Seeuws S, Jacques P, Van Praet J, Drennan M, Coudenys J, Decruy T, Deschepper E, Lepescheux L, Pujuguet P, Oste L, Vandeghinste N, Brys R, Verbruggen G, Elewaut D: A multiparameter approach to monitor disease activity in collagen-induced arthritis. Arthritis Res Ther. 2010, 12: 160-10.1186\/ar3119.","journal-title":"Arthritis Res Ther"},{"key":"4076_CR21","doi-asserted-by":"publisher","first-page":"3311","DOI":"10.1002\/art.27689","volume":"62","author":"YH Hsu","year":"2010","unstructured":"Hsu YH, Chang MS: Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. Arthritis Rheum. 2010, 62: 3311-3321. 10.1002\/art.27689.","journal-title":"Arthritis Rheum"},{"key":"4076_CR22","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1002\/art.1780371116","volume":"37","author":"T Geiler","year":"1994","unstructured":"Geiler T, Kriegsmann J, Keyszer GM, Gay RE, Gay S: A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum. 1994, 37: 1664-1671. 10.1002\/art.1780371116.","journal-title":"Arthritis Rheum"},{"key":"4076_CR23","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1016\/S0002-9440(10)64289-7","volume":"162","author":"CA Seemayer","year":"2003","unstructured":"Seemayer CA, Kuchen S, Kuenzler P, Rihoskov\u00e1 V, Rethage J, Aicher WK, Michel BA, Gay RE, Kyburz D, Neidhart M, Gay S: Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. Am J Pathol. 2003, 162: 1549-1557. 10.1016\/S0002-9440(10)64289-7.","journal-title":"Am J Pathol"},{"key":"4076_CR24","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.molcel.2007.02.005","volume":"25","author":"LK Nicholson","year":"2007","unstructured":"Nicholson LK, Lu KP: Prolyl cis\u2013trans isomerization as a molecular timer in Crk signaling. Mol Cell. 2007, 25: 483-485. 10.1016\/j.molcel.2007.02.005.","journal-title":"Mol Cell"},{"key":"4076_CR25","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nsb927","volume":"10","author":"BR Howard","year":"2003","unstructured":"Howard BR, Vajdos FF, Li S, Sundquist WI, Hill CP: Structural insights into the catalytic mechanism of cyclophilin A. Nat Struct Biol. 2003, 10: 475-481. 10.1038\/nsb927.","journal-title":"Nat Struct Biol"},{"key":"4076_CR26","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/j.1365-2567.2008.02877.x","volume":"126","author":"JM Damsker","year":"2009","unstructured":"Damsker JM, Okwumabua I, Pushkarsky T, Arora K, Bukrinsky MI, Constant SL: Targeting the chemotactic function of CD147 reduces collagen-induced arthritis. Immunology. 2009, 126: 55-62. 10.1111\/j.1365-2567.2008.02877.x.","journal-title":"Immunology"},{"key":"4076_CR27","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1111\/j.1365-2249.2010.04115.x","volume":"160","author":"V Yurchenko","year":"2010","unstructured":"Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M: Cyclophilin\u2013CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol. 2010, 160: 305-317. 10.1111\/j.1365-2249.2010.04115.x.","journal-title":"Clin Exp Immunol"},{"key":"4076_CR28","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.nbd.2006.08.012","volume":"25","author":"S Boulos","year":"2007","unstructured":"Boulos S, Meloni BP, Arthur PG, Majda B, Bojarski C, Knuckey NW: Evidence that intracellular cyclophilin A and cyclophilin A\/CD147 receptor-mediated ERK1\/2 signalling can protect neurons against in vitro oxidative and ischemic injury. Neurobiol Dis. 2007, 25: 54-64. 10.1016\/j.nbd.2006.08.012.","journal-title":"Neurobiol Dis"},{"key":"4076_CR29","doi-asserted-by":"publisher","first-page":"22959","DOI":"10.1074\/jbc.M201593200","volume":"277","author":"V Yurchenko","year":"2002","unstructured":"Yurchenko V, Zybarth G, O\u2019Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M: Active site residues of cyclophilin A are crucial for its signaling activity via CD147. J Biol Chem. 2002, 277: 22959-22965. 10.1074\/jbc.M201593200.","journal-title":"J Biol Chem"},{"key":"4076_CR30","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/1476-9255-9-44","volume":"9","author":"T Nishioku","year":"2012","unstructured":"Nishioku T, Dohgu S, Koga M, Machida T, Watanabe T, Miura T, Tsumagari K, Terasawa M, Yamauchi A, Kataoka Y: Cyclophilin A secreted from fibroblast-like synoviocytes is involved in the induction of CD147 expression in macrophages of mice with collagen-induced arthritis. J Inflamm (Lond). 2012, 9: 44-10.1186\/1476-9255-9-44.","journal-title":"J Inflamm (Lond)"},{"key":"4076_CR31","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1186\/ar1778","volume":"7","author":"P Zhu","year":"2005","unstructured":"Zhu P, Ding J, Zhou J, Dong WJ, Fan CM, Chen ZN: Expression of CD147 on monocytes\/macrophages in rheumatoid arthritis: its potential role in monocyte accumulation and matrix metallopro-teinase production. Arthritis Res Ther. 2005, 7: 1023-1033. 10.1186\/ar1778.","journal-title":"Arthritis Res Ther"},{"key":"4076_CR32","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1475-2867-12-19","volume":"12","author":"K Bahmed","year":"2012","unstructured":"Bahmed K, Henry C, Holliday M, Redzic J, Ciobanu M, Zhang F, Weekes C, Sclafani R, Degregori J, Eisenmesser E: Extracellular cyclophilin-A stimulates ERK1\/2 phosphorylation in a cell-dependent manner but broadly stimulates nuclear factor kappa B. Cancer Cell Int. 2012, 12: 19-10.1186\/1475-2867-12-19.","journal-title":"Cancer Cell Int"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4401.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar4401\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4401.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T10:06:56Z","timestamp":1728382016000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar4401"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,5]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["4076"],"URL":"https:\/\/doi.org\/10.1186\/ar4401","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,5]]},"assertion":[{"value":"17 July 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R208"}}