{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:53:26Z","timestamp":1781528006807,"version":"3.54.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,4,16]],"date-time":"2019-04-16T00:00:00Z","timestamp":1555372800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,4,16]],"date-time":"2019-04-16T00:00:00Z","timestamp":1555372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HLA078836"],"award-info":[{"award-number":["HLA078836"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["CA206607"],"award-info":[{"award-number":["CA206607"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["CA183379"],"award-info":[{"award-number":["CA183379"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["CA206607"],"award-info":[{"award-number":["CA206607"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["CA183379"],"award-info":[{"award-number":["CA183379"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Disorganized intercellular junctions are critical for maintaining the integrity of solid epithelial tumors and prevent the infiltration of oncological therapies into the bulk of the malignancy. We have developed small, recombinant proteins which bind a critical junction protein, desmoglein 2, triggering the transient and specific opening of tumor tight junctions allowing for infiltration of the tumor with immune cells, oncolytic viruses, drugs, and other therapeutics. Our new molecule, JOC-<jats:italic>x<\/jats:italic>, is a promising candidate for a new class of tumor-targeting agents that accumulate\u00a0both around and within tumors and remodel the tumor microenvironment. Native cysteines were removed from the parental protein, JO-4, followed by addition of\u00a0a single cysteine to allow for convenient attachment of various payloads that can be targeted directly to the tumor. Our tumor-targeting protein exhibits high avidity, minimal aggregation, and is easily purified at good yields from <jats:italic>E. coli<\/jats:italic>. For proof of concept, we demonstrate effective conjugation\u00a0to biotin as a model for flexible co-targeting, addition of metal ion chelators as models for imaging and radiotherapy, and linkage of the TLR3 agonist poly(I:C) as a model immune-oncologic agent. This second-generation cancer co-therapeutic protein is optimized for activity and primed for cGMP manufacture in preparation for upcoming clinical studies.<\/jats:p>","DOI":"10.1038\/s41598-019-42229-3","type":"journal-article","created":{"date-parts":[[2019,4,16]],"date-time":"2019-04-16T10:03:21Z","timestamp":1555409001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Structure-based Design of JOC-x, a Conjugatable Tumor Tight Junction Opener to Enhance Cancer Therapy"],"prefix":"10.1038","volume":"9","author":[{"given":"Ragan","family":"Pitner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenn","family":"Davis-Bergthold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheri","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Vassal-Stermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Ahlgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6698-3367","authenticated-orcid":false,"given":"Pascal","family":"Fender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Lieber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-3402","authenticated-orcid":false,"given":"Darrick","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean A.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,4,16]]},"reference":[{"key":"42229_CR1","first-page":"6891","volume":"62","author":"SK Green","year":"2002","unstructured":"Green, S. K., Karlsson, M. C., Ravetch, J. V. & Kerbel, R. S. Disruption of cell-cell adhesion enhances antibody-dependent cellular cytotoxicity: implications for antibody-based therapeutics of cancer. Cancer Res 62, 6891\u20136900 (2002).","journal-title":"Cancer Res"},{"key":"42229_CR2","doi-asserted-by":"publisher","first-page":"2754","DOI":"10.1242\/jeb.006114","volume":"210","author":"SR Lavin","year":"2007","unstructured":"Lavin, S. R., McWhorter, T. J. & Karasov, W. H. Mechanistic bases for differences in passive absorption. J Exp Biol 210, 2754\u20132764, https:\/\/doi.org\/10.1242\/jeb.006114 (2007).","journal-title":"J Exp Biol"},{"key":"42229_CR3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","volume":"46","author":"CA Lipinski","year":"2001","unstructured":"Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46, 3\u201326 (2001).","journal-title":"Adv Drug Deliv Rev"},{"key":"42229_CR4","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s10549-009-0412-3","volume":"118","author":"SP Fessler","year":"2009","unstructured":"Fessler, S. P., Wotkowicz, M. T., Mahanta, S. K. & Bamdad, C. MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res Treat 118, 113\u2013124, https:\/\/doi.org\/10.1007\/s10549-009-0412-3 (2009).","journal-title":"Breast Cancer Res Treat"},{"key":"42229_CR5","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/jcb.22952","volume":"112","author":"C Oliveras-Ferraros","year":"2011","unstructured":"Oliveras-Ferraros, C. et al. Stem cell property epithelial-to-mesenchymal transition is a core transcriptional network for predicting cetuximab (Erbitux) efficacy in KRAS wild-type tumor cells. J Cell Biochem 112, 10\u201329, https:\/\/doi.org\/10.1002\/jcb.22952 (2011).","journal-title":"J Cell Biochem"},{"key":"42229_CR6","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-10-255","volume":"10","author":"CM Lee","year":"2010","unstructured":"Lee, C. M. & Tannock, I. F. The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors. BMC Cancer 10, 255, https:\/\/doi.org\/10.1186\/1471-2407-10-255 (2010).","journal-title":"BMC Cancer"},{"key":"42229_CR7","doi-asserted-by":"publisher","first-page":"3340","DOI":"10.1158\/1078-0432.CCR-11-3213","volume":"18","author":"I Beyer","year":"2012","unstructured":"Beyer, I. et al. Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. Clin Cancer Res 18, 3340\u20133351, https:\/\/doi.org\/10.1158\/1078-0432.CCR-11-3213 (2012).","journal-title":"Clin Cancer Res"},{"key":"42229_CR8","doi-asserted-by":"publisher","first-page":"8319","DOI":"10.1158\/0008-5472.CAN-06-0410","volume":"66","author":"JJ Christiansen","year":"2006","unstructured":"Christiansen, J. J. & Rajasekaran, A. K. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66, 8319\u20138326, https:\/\/doi.org\/10.1158\/0008-5472.CAN-06-0410 (2006).","journal-title":"Cancer Res"},{"key":"42229_CR9","doi-asserted-by":"publisher","first-page":"e1003718","DOI":"10.1371\/journal.ppat.1003718","volume":"9","author":"ZZ Lu","year":"2013","unstructured":"Lu, Z. Z. et al. Penton-dodecahedral particles trigger opening of intercellular junctions and facilitate viral spread during adenovirus serotype 3 infection of epithelial cells. PLoS pathogens 9, e1003718, https:\/\/doi.org\/10.1371\/journal.ppat.1003718 (2013).","journal-title":"PLoS pathogens"},{"key":"42229_CR10","doi-asserted-by":"publisher","first-page":"6390","DOI":"10.1128\/JVI.00514-11","volume":"85","author":"H Wang","year":"2011","unstructured":"Wang, H. et al. Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions. J Virol 85, 6390\u20136402, https:\/\/doi.org\/10.1128\/JVI.00514-11 (2011).","journal-title":"J Virol"},{"key":"42229_CR11","doi-asserted-by":"publisher","first-page":"11346","DOI":"10.1128\/JVI.01825-13","volume":"87","author":"H Wang","year":"2013","unstructured":"Wang, H. et al. Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2. J Virol 87, 11346\u201311362, https:\/\/doi.org\/10.1128\/JVI.01825-13 (2013).","journal-title":"J Virol"},{"key":"42229_CR12","doi-asserted-by":"publisher","first-page":"15005","DOI":"10.1038\/mtm.2015.5","volume":"2","author":"M Richter","year":"2015","unstructured":"Richter, M. et al. Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin. Mol Ther Methods Clin Dev 2, 15005, https:\/\/doi.org\/10.1038\/mtm.2015.5 (2015).","journal-title":"Mol Ther Methods Clin Dev"},{"key":"42229_CR13","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1007\/s00262-012-1259-8","volume":"61","author":"K Barrios","year":"2012","unstructured":"Barrios, K. & Celis, E. TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers. Cancer Immunol Immunother 61, 1307\u20131317, https:\/\/doi.org\/10.1007\/s00262-012-1259-8 (2012).","journal-title":"Cancer Immunol Immunother"},{"key":"42229_CR14","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1007\/s00262-012-1382-6","volume":"62","author":"HI Cho","year":"2013","unstructured":"Cho, H. I., Barrios, K., Lee, Y. R., Linowski, A. K. & Celis, E. BiVax: a peptide\/poly-IC subunit vaccine that mimics an acute infection elicits vast and effective anti-tumor CD8 T-cell responses. Cancer Immunol Immunother 62, 787\u2013799, https:\/\/doi.org\/10.1007\/s00262-012-1382-6 (2013).","journal-title":"Cancer Immunol Immunother"},{"key":"42229_CR15","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1080\/15384047.2017.1373220","volume":"18","author":"F Bianchi","year":"2017","unstructured":"Bianchi, F., Pretto, S., Tagliabue, E., Balsari, A. & Sfondrini, L. Exploiting poly(I:C) to induce cancer cell apoptosis. Cancer Biol Ther 18, 747\u2013756, https:\/\/doi.org\/10.1080\/15384047.2017.1373220 (2017).","journal-title":"Cancer Biol Ther"},{"key":"42229_CR16","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.3389\/fimmu.2017.01383","volume":"8","author":"E Muller","year":"2017","unstructured":"Muller, E. et al. Toll-Like Receptor Ligands and Interferon-gamma Synergize for Induction of Antitumor M1 Macrophages. Frontiers in immunology 8, 1383, https:\/\/doi.org\/10.3389\/fimmu.2017.01383 (2017).","journal-title":"Frontiers in immunology"},{"key":"42229_CR17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1159\/000355126","volume":"6","author":"H Shime","year":"2014","unstructured":"Shime, H. et al. Myeloid-derived suppressor cells confer tumor-suppressive functions on natural killer cells via polyinosinic:polycytidylic acid treatment in mouse tumor models. J Innate Immun 6, 293\u2013305, https:\/\/doi.org\/10.1159\/000355126 (2014).","journal-title":"J Innate Immun"},{"key":"42229_CR18","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1073\/pnas.1113099109","volume":"109","author":"H Shime","year":"2012","unstructured":"Shime, H. et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proceedings of the National Academy of Sciences of the United States of America 109, 2066\u20132071, https:\/\/doi.org\/10.1073\/pnas.1113099109 (2012).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"42229_CR19","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1006\/viro.2001.0967","volume":"285","author":"C Durmort","year":"2001","unstructured":"Durmort, C. et al. Structure of the fiber head of Ad3, a non-CAR-binding serotype of adenovirus. Virology 285, 302\u2013312, https:\/\/doi.org\/10.1006\/viro.2001.0967 (2001).","journal-title":"Virology"},{"key":"42229_CR20","doi-asserted-by":"publisher","first-page":"10841","DOI":"10.1128\/JVI.01425-15","volume":"89","author":"H Wang","year":"2015","unstructured":"Wang, H. et al. Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1. J Virol 89, 10841\u201310859, https:\/\/doi.org\/10.1128\/JVI.01425-15 (2015).","journal-title":"J Virol"},{"key":"42229_CR21","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1111\/jam.12492","volume":"116","author":"V Lausch","year":"2014","unstructured":"Lausch, V., Hermann, P., Laue, M. & Bannert, N. Silicon nitride grids are compatible with correlative negative staining electron microscopy and tip-enhanced Raman spectroscopy for use in the detection of micro-organisms. J Appl Microbiol 116, 1521\u20131530, https:\/\/doi.org\/10.1111\/jam.12492 (2014).","journal-title":"J Appl Microbiol"},{"key":"42229_CR22","doi-asserted-by":"publisher","first-page":"5380","DOI":"10.1128\/JVI.07127-11","volume":"86","author":"P Fender","year":"2012","unstructured":"Fender, P., Hall, K., Schoehn, G. & Blair, G. E. Impact of human adenovirus type 3 dodecahedron on host cells and its potential role in viral infection. J Virol 86, 5380\u20135385, https:\/\/doi.org\/10.1128\/JVI.07127-11 (2012).","journal-title":"J Virol"},{"issue":"33-38","key":"42229_CR23","first-page":"27","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J Mol Graph 14(33-38), 27\u201338 (1996).","journal-title":"J Mol Graph"},{"key":"42229_CR24","first-page":"131","volume":"41","author":"HB Breitz","year":"2000","unstructured":"Breitz, H. B. et al. Clinical optimization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and 90Y-DOTA-biotin. J Nucl Med 41, 131\u2013140 (2000).","journal-title":"J Nucl Med"},{"key":"42229_CR25","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1097\/00006231-200001000-00015","volume":"21","author":"RJ Domingo","year":"2000","unstructured":"Domingo, R. J. & Reilly, R. M. Pre-targeted radioimmunotherapy of human colon cancer xenografts in athymic mice using streptavidin-CC49 monoclonal antibody and 90Y-DOTA-biotin. Nucl Med Commun 21, 89\u201396 (2000).","journal-title":"Nucl Med Commun"},{"issue":"22","key":"42229_CR26","doi-asserted-by":"publisher","first-page":"6669","DOI":"10.1158\/0008-5472.CAN-16-0571","volume":"76","author":"Damian J. Green","year":"2016","unstructured":"Green, D. J. et al. Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers. Cancer Res, https:\/\/doi.org\/10.1158\/0008-5472.CAN-16-0571 (2016).","journal-title":"Cancer Research"},{"key":"42229_CR27","doi-asserted-by":"publisher","first-page":"971","DOI":"10.2174\/0929867003374516","volume":"7","author":"A Heppeler","year":"2000","unstructured":"Heppeler, A., Froidevaux, S., Eberle, A. N. & Maecke, H. R. Receptor targeting for tumor localisation and therapy with radiopeptides. Curr Med Chem 7, 971\u2013994 (2000).","journal-title":"Curr Med Chem"},{"key":"42229_CR28","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1089\/cbr.2004.19.399","volume":"19","author":"M Janssen","year":"2004","unstructured":"Janssen, M. et al. Improved tumor targeting of radiolabeled RGD peptides using rapid dose fractionation. Cancer Biother Radiopharm 19, 399\u2013404, https:\/\/doi.org\/10.1089\/cbr.2004.19.399 (2004).","journal-title":"Cancer Biother Radiopharm"},{"key":"42229_CR29","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1111\/j.1742-4658.2012.08550.x","volume":"279","author":"WJ Zhang","year":"2012","unstructured":"Zhang, W. J. et al. Design, recombinant expression and convenient A-chain N-terminal europium-labelling of a fully active human relaxin-3 analogue. FEBS J 279, 1505\u20131512, https:\/\/doi.org\/10.1111\/j.1742-4658.2012.08550.x (2012).","journal-title":"FEBS J"},{"key":"42229_CR30","unstructured":"DeNardo, S. J. et al. Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts. J Nucl Med 39, 842-849 (1998)."},{"key":"42229_CR31","first-page":"473","volume":"31","author":"SV Deshpande","year":"1990","unstructured":"Deshpande, S. V. et al. Yttrium-90-labeled monoclonal antibody for therapy: labeling by a new macrocyclic bifunctional chelating agent. J Nucl Med 31, 473\u2013479 (1990).","journal-title":"J Nucl Med"},{"key":"42229_CR32","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1021\/bc049974x","volume":"15","author":"MF Giblin","year":"2004","unstructured":"Giblin, M. F. et al. In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties. Bioconjug Chem 15, 872\u2013880, https:\/\/doi.org\/10.1021\/bc049974x (2004).","journal-title":"Bioconjug Chem"},{"key":"42229_CR33","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1038\/nprot.2006.175","volume":"1","author":"JK Sosabowski","year":"2006","unstructured":"Sosabowski, J. K. & Mather, S. J. Conjugation of DOTA-like chelating agents to peptides and radiolabeling with trivalent metallic isotopes. Nat Protoc 1, 972\u2013976, https:\/\/doi.org\/10.1038\/nprot.2006.175 (2006).","journal-title":"Nat Protoc"},{"key":"42229_CR34","doi-asserted-by":"publisher","first-page":"344","DOI":"10.5732\/cjc.010.10456","volume":"30","author":"A Hasimu","year":"2011","unstructured":"Hasimu, A., Ge, L., Li, Q. Z., Zhang, R. P. & Guo, X. Expressions of Toll-like receptors 3, 4, 7, and 9 in cervical lesions and their correlation with HPV16 infection in Uighur women. Chin J Cancer 30, 344\u2013350 (2011).","journal-title":"Chin J Cancer"},{"key":"42229_CR35","doi-asserted-by":"publisher","first-page":"7080","DOI":"10.1158\/0008-5472.CAN-11-2009","volume":"71","author":"I Beyer","year":"2011","unstructured":"Beyer, I. et al. Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer. Cancer Res 71, 7080\u20137090, https:\/\/doi.org\/10.1158\/0008-5472.CAN-11-2009 (2011).","journal-title":"Cancer Res"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-42229-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-42229-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-42229-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T08:48:26Z","timestamp":1671266906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-42229-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,16]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["42229"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-42229-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,16]]},"assertion":[{"value":"11 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 March 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"R.P., J.K., J.D-B., C.T., E.V-S., H.W., J.A., L.C., J.A.A., P.F. and S.A.G. declare no competing interests.\u00a0D.C. and A.L. are co-owners of Compliment Corp., a start-up company that is involved with the clinical development of the JO technology.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"6169"}}