{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:45:43Z","timestamp":1790624743106,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2015,2,19]],"date-time":"2015-02-19T00:00:00Z","timestamp":1424304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,2,19]],"date-time":"2015-02-19T00:00:00Z","timestamp":1424304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Atopic dermatitis is a chronic inflammatory skin disease with defects in the epidermal barrier. In a cohort of African-American children, a <jats:italic>FLG2<\/jats:italic> nonsense mutation has been associated with the disease. In the epidermis of European patients, the expression of filaggrin-2, the filaggrin-related protein encoded by <jats:italic>FLG2<\/jats:italic>, is decreased. To describe the function of filaggrin-2 and evaluate the impact of its deficiency, its expression was downregulated using lentivirus-mediated shRNA interference in a three-dimensional reconstructed human epidermis (RHE) model. This resulted in parakeratosis and a compact <jats:italic>stratum corneum<\/jats:italic>, presence of abnormal vesicles inside the corneocytes, increased pH and reduced amounts of free amino acids at the RHE surface, leading to increased sensitivity to UVB radiations. The expression of differentiation markers was slightly modified. However, we observed reduced proteolytic processing of corneodesmosin, hornerin and filaggrin in parallel with reduced amounts of caspase-14 and bleomycin hydrolase. Our data demonstrated that filaggrin-2 is important for a proper cornification and a functional <jats:italic>stratum corneum<\/jats:italic>. Its downregulation in atopic patients may be involved in the disease-associated epidermis impairment.<\/jats:p>","DOI":"10.1038\/cddis.2015.29","type":"journal-article","created":{"date-parts":[[2015,2,19]],"date-time":"2015-02-19T13:41:39Z","timestamp":1424353299000},"page":"e1656-e1656","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["In a three-dimensional reconstructed human epidermis filaggrin-2 is essential for proper cornification"],"prefix":"10.1038","volume":"6","author":[{"given":"V","family":"Pendaries","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Le Lamer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Cau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Hansmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Malaisse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Kezic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Serre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3655-6329","authenticated-orcid":false,"given":"M","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,2,19]]},"reference":[{"key":"BFcddis201529_CR1","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1111\/j.1398-9995.2012.02845.x","volume":"67","author":"T Bieber","year":"2012","unstructured":"Bieber T . Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012; 67: 1475\u20131482.","journal-title":"Allergy"},{"key":"BFcddis201529_CR2","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/S0065-2776(09)01203-6","volume":"102","author":"MK Oyoshi","year":"2009","unstructured":"Oyoshi MK, He R, Kumar L, Yoon J, Geha RS . Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol 2009; 102: 135\u2013226.","journal-title":"Adv Immunol"},{"key":"BFcddis201529_CR3","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/jid.2011.393","volume":"132","author":"SJ Brown","year":"2012","unstructured":"Brown SJ, McLean WH . One remarkable molecule: filaggrin. J Invest Dermatol 2012; 132: 751\u2013762.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR4","doi-asserted-by":"publisher","first-page":"542","DOI":"10.2741\/4225","volume":"19","author":"S Kezic","year":"2014","unstructured":"Kezic S, Novak N, Jakasa I, Jungersted JM, Simon M, Brandner JM et al. Skin barrier in atopic dermatitis. Front Biosci (Landmark Ed) 2014; 19: 542\u2013556.","journal-title":"Front Biosci (Landmark Ed)"},{"key":"BFcddis201529_CR5","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/j.1749-6632.1985.tb50420.x","volume":"455","author":"BA Dale","year":"1985","unstructured":"Dale BA, Resing KA, Lonsdale-Eccles JD . Filaggrin: a keratin filament associated protein. Ann N Y Acad Sci 1985; 455: 330\u2013342.","journal-title":"Ann N Y Acad Sci"},{"key":"BFcddis201529_CR6","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1038\/jid.2014.259","volume":"134","author":"V Pendaries","year":"2014","unstructured":"Pendaries V, Malaisse J, Pellerin L, Le Lamer M, Nachat R, Kezic S et al. Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation. J Invest Dermatol 2014; 134: 2938\u20132946.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR7","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1016\/j.jaci.2012.01.068","volume":"129","author":"H Kawasaki","year":"2012","unstructured":"Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 2012; 129: 1538\u20131546.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR8","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1111\/j.1365-2133.2009.09342.x","volume":"161","author":"S Kezic","year":"2009","unstructured":"Kezic S, Kammeyer A, Calkoen F, Fluhr JW, Bos JD . Natural moisturizing factor components in the stratum corneum as biomarkers of filaggrin genotype: evaluation of minimally invasive methods. Br J Dermatol 2009; 161: 1098\u20131104.","journal-title":"Br J Dermatol"},{"key":"BFcddis201529_CR9","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1038\/jid.2010.115","volume":"130","author":"M Mildner","year":"2010","unstructured":"Mildner M, Jin J, Eckhart L, Kezic S, Gruber F, Barresi C et al. Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model. J Invest Dermatol 2010; 130: 2286\u20132294.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR10","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/jid.2011.460","volume":"132","author":"K Yoneda","year":"2012","unstructured":"Yoneda K, Nakagawa T, Lawrence OT, Huard J, Demitsu T, Kubota Y et al. Interaction of the profilaggrin N-terminal domain with loricrin in human cultured keratinocytes and epidermis. J Invest Dermatol 2012; 132: 1206\u20131214.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR11","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1038\/jid.2010.398","volume":"131","author":"R Cascella","year":"2011","unstructured":"Cascella R, Foti Cuzzola V, Lepre T, Galli E, Moschese V, Chini L et al. Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. J Invest Dermatol 2011; 131: 982\u2013984.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR12","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.jaci.2012.12.1566","volume":"131","author":"L Pellerin","year":"2013","unstructured":"Pellerin L, Henry J, Hsu CY, Balica S, Jean-Decoster C, M\u00e9chin MC et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol 2013; 131: 1094\u20131102.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR13","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jaci.2013.09.053","volume":"133","author":"F Thawer-Esmail","year":"2014","unstructured":"Thawer-Esmail F, Jakasa I, Todd G, Wen Y, Brown SJ, Kroboth K et al. South African amaXhosa patients with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. J Allergy Clin Immunol 2014; 133: 280\u2013282.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR14","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1111\/j.1365-2133.2011.10475.x","volume":"165","author":"MC Winge","year":"2011","unstructured":"Winge MC, Bilcha KD, Lieden A, Shibeshi D, Sandilands A, Wahlgren CF et al. Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis. Br J Dermatol 2011; 165: 1074\u20131080.","journal-title":"Br J Dermatol"},{"key":"BFcddis201529_CR15","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1016\/j.jaci.2013.07.005","volume":"132","author":"JP Garrett","year":"2013","unstructured":"Garrett JP, Hoffstad O, Apter AJ, Margolis DJ . Racial comparison of filaggrin null mutations in asthmatic patients with atopic dermatitis in a US population. J Allergy Clin Immunol 2013; 132: 1232\u20131234.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR16","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.jaci.2012.07.008","volume":"130","author":"DJ Margolis","year":"2012","unstructured":"Margolis DJ, Apter AJ, Gupta J, Hoffstad O, Papadopoulos M, Campbell LE et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 2012; 130: 912\u2013917.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR17","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.jaci.2014.05.048","volume":"134","author":"PM Elias","year":"2014","unstructured":"Elias PM, Wakefield JS . Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 2014; 134: 781\u2013791.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR18","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.jaci.2013.09.015","volume":"133","author":"DJ Margolis","year":"2014","unstructured":"Margolis DJ, Gupta J, Apter AJ, Ganguly T, Hoffstad O, Papadopoulos M et al. Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol 2014; 133: 784\u2013789.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR19","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.2741\/4001","volume":"17","author":"J Henry","year":"2012","unstructured":"Henry J, Toulza E, Hsu CY, Pellerin L, Balica S, Mazereeuw-Hautier J et al. Update on the epidermal differentiation complex. Front Biosci (Landmark Ed) 2012; 17: 1517\u20131532.","journal-title":"Front Biosci (Landmark Ed)"},{"key":"BFcddis201529_CR20","doi-asserted-by":"publisher","first-page":"23222","DOI":"10.1074\/jbc.M110.197400","volume":"286","author":"CY Hsu","year":"2011","unstructured":"Hsu CY, Henry J, Raymond AA, M\u00e9chin MC, Pendaries V, Nassar D et al. Deimination of human filaggrin-2 promotes its proteolysis by calpain 1. J Biol Chem 2011; 286: 23222\u201323233.","journal-title":"J Biol Chem"},{"key":"BFcddis201529_CR21","doi-asserted-by":"publisher","first-page":"e5227","DOI":"10.1371\/journal.pone.0005227","volume":"4","author":"Z Wu","year":"2009","unstructured":"Wu Z, Hansmann B, Meyer-Hoffert U, Glaser R, Schroder JM . Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family. PLoS One 2009; 4: e5227.","journal-title":"PLoS One"},{"key":"BFcddis201529_CR22","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1111\/j.1600-0625.2012.01449.x","volume":"21","author":"B Hansmann","year":"2012","unstructured":"Hansmann B, Ahrens K, Wu Z, Proksch E, Meyer-Hoffert U, Schroder JM . Murine filaggrin-2 is involved in epithelial barrier function and down-regulated in metabolically induced skin barrier dysfunction. Exp Dermatol 2012; 21: 271\u2013276.","journal-title":"Exp Dermatol"},{"key":"BFcddis201529_CR23","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/jid.2010.272","volume":"131","author":"C Mathay","year":"2011","unstructured":"Mathay C, Pierre M, Pittelkow MR, Depiereux E, Nikkels AF, Colige A et al. Transcriptional profiling after lipid raft disruption in keratinocytes identifies critical mediators of atopic dermatitis pathways. J Invest Dermatol 2011; 131: 46\u201358.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR24","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.jaci.2010.10.033","volume":"127","author":"CJ Broccardo","year":"2011","unstructured":"Broccardo CJ, Mahaffey S, Schwarz J, Wruck L, David G, Schlievert PM et al. Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization. J Allergy Clin Immunol 2011; 127: 186\u2013193.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR25","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1111\/exd.12020","volume":"21","author":"A Frankart","year":"2012","unstructured":"Frankart A, Malaisse J, De Vuyst E, Minner F, de Rouvroit CL, Poumay Y . Epidermal morphogenesis during progressive in vitro 3D reconstruction at the air-liquid interface. Exp Dermatol 2012; 21: 871\u2013875.","journal-title":"Exp Dermatol"},{"key":"BFcddis201529_CR26","doi-asserted-by":"publisher","first-page":"3471","DOI":"10.1016\/j.bbamcr.2013.06.010","volume":"1833","author":"L Eckhart","year":"2013","unstructured":"Eckhart L, Lippens S, Tschachler E, Declercq W . Cell death by cornification. Biochim Biophys Acta 2013; 1833: 3471\u20133480.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis201529_CR27","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/jid.2012.350","volume":"133","author":"E Hoste","year":"2013","unstructured":"Hoste E, Denecker G, Gilbert B, Van Nieuwerburgh F, van der Fits L, Asselbergh B et al. Caspase-14-deficient mice are more prone to the development of parakeratosis. J Invest Dermatol 2013; 133: 742\u2013750.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR28","doi-asserted-by":"publisher","first-page":"e1181","DOI":"10.1038\/cddis.2014.145","volume":"5","author":"M Yamamoto-Tanaka","year":"2014","unstructured":"Yamamoto-Tanaka M, Makino T, Motoyama A, Miyai M, Tsuboi R, Hibino T . Multiple pathways are involved in DNA degradation during keratinocyte terminal differentiation. Cell Death Dis 2014; 5: e1181.","journal-title":"Cell Death Dis"},{"key":"BFcddis201529_CR29","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.jdermsci.2010.11.018","volume":"61","author":"M Yamamoto","year":"2011","unstructured":"Yamamoto M, Kamata Y, Iida T, Fukushima H, Nomura J, Saito M et al. Quantification of activated and total caspase-14 with newly developed ELISA systems in normal and atopic skin. J Dermatol Sci 2011; 61: 110\u2013117.","journal-title":"J Dermatol Sci"},{"key":"BFcddis201529_CR30","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0923-1811(02)00047-6","volume":"30","author":"K Sakurai","year":"2002","unstructured":"Sakurai K, Sugiura H, Matsumoto M, Uehara M . Occurrence of patchy parakeratosis in normal-appearing skin in patients with active atopic dermatitis and in patients with healed atopic dermatitis: a cause of impaired barrier function of the atopic skin. J Dermatol Sci 2002; 30: 37\u201342.","journal-title":"J Dermatol Sci"},{"key":"BFcddis201529_CR31","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/026119291103900508","volume":"39","author":"S Kuchler","year":"2011","unstructured":"Kuchler S, Henkes D, Eckl KM, Ackermann K, Plendl J, Korting HC et al. Hallmarks of atopic skin mimicked in vitro by means of a skin disease model based on FLG knock-down. Altern Lab Anim 2011; 39: 471\u2013480.","journal-title":"Altern Lab Anim"},{"key":"BFcddis201529_CR32","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1038\/jid.2008.370","volume":"129","author":"Z Wu","year":"2009","unstructured":"Wu Z, Meyer-Hoffert U, Reithmayer K, Paus R, Hansmann B, He Y et al. Highly complex peptide aggregates of the S100 fused-type protein hornerin are present in human skin. J Invest Dermatol 2009; 129: 1446\u20131458.","journal-title":"J Invest Dermatol"},{"key":"BFcddis201529_CR33","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jdermsci.2013.05.004","volume":"72","author":"S Igawa","year":"2013","unstructured":"Igawa S, Kishibe M, Honma M, Murakami M, Mizuno Y, Suga Y et al. Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). J Dermatol Sci 2013; 72: 54\u201360.","journal-title":"J Dermatol Sci"},{"key":"BFcddis201529_CR34","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1016\/j.jaci.2014.07.056","volume":"134","author":"L Pellerin","year":"2014","unstructured":"Pellerin L, Paul C, Schmitt AM, Serre G, Simon M . Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis patients is independent of FLG gene mutations. J Allergy Clin Immunol 2014; 134: 1459\u20131461.","journal-title":"J Allergy Clin Immunol"},{"key":"BFcddis201529_CR35","first-page":"26","volume":"176","author":"M Fartasch","year":"1992","unstructured":"Fartasch M, Diepgen TL . The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm Venereol Suppl (Stockh) 1992; 176: 26\u201331.","journal-title":"Acta Derm Venereol Suppl (Stockh)"},{"key":"BFcddis201529_CR36","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1080\/000155500750042943","volume":"80","author":"B Eberlein-Konig","year":"2000","unstructured":"Eberlein-Konig B, Schafer T, Huss-Marp J, Darsow U, M\u00f6hrenschlager M, Herbert O et al. Skin surface pH, stratum corneum hydration, trans-epidermal water loss and skin roughness related to atopic eczema and skin dryness in a population of primary school children. Acta Derm Venereol 2000; 80: 188\u2013191.","journal-title":"Acta Derm Venereol"},{"key":"BFcddis201529_CR37","first-page":"242","volume":"19","author":"T Knor","year":"2011","unstructured":"Knor T, Meholjic-Fetahovic A, Mehmedagic A . Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermato Venerol Croat 2011; 19: 242\u2013247.","journal-title":"Acta Dermato Venerol Croat"},{"key":"BFcddis201529_CR38","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1097\/DER.0000000000000045","volume":"25","author":"J Bandier","year":"2014","unstructured":"Bandier J, Johansen JD, Petersen LJ, Carlsen BC . Skin pH, atopic dermatitis, and filaggrin mutations. Dermatitis 2014; 25: 127\u2013129.","journal-title":"Dermatitis"},{"key":"BFcddis201529_CR39","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1080\/00032719.2013.789881","volume":"46","author":"I Dapic","year":"2013","unstructured":"Dapic I, Jakasaa I, Yaub NLH, Kezic S, Kammeyerc A . Evaluation of an HPLC method for the determination of natural moisturizing factors in the human stratum corneum. Analyt Lett 2013; 46: 2133\u20132144.","journal-title":"Analyt Lett"},{"key":"BFcddis201529_CR40","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1016\/j.jaci.2009.09.031","volume":"124","author":"E Guttman-Yassky","year":"2009","unstructured":"Guttman-Yassky E, Suarez-Farinas M, Chiricozzi A, Nograles KE, Shemer A, Fuentes-Duculan J et al. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol 2009; 124: 1235\u20131244.","journal-title":"J Allergy Clin Immunol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis201529.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis201529","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis201529.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T10:11:45Z","timestamp":1672913505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis201529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2,19]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,2]]}},"alternative-id":["BFcddis201529"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2015.29","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,2,19]]},"assertion":[{"value":"20 October 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}