{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:30:57Z","timestamp":1791415857073,"version":"4.3.3"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2014,2,24]],"date-time":"2014-02-24T00:00:00Z","timestamp":1393200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2014,2,24]],"date-time":"2014-02-24T00:00:00Z","timestamp":1393200000000},"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":["EMBO Mol Med"],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site\u2010specific elimination of pathogenic human mitochondrial DNA (mtDNA). We used mtZFNs to target and cleave mtDNA harbouring the m.8993T&gt;G point mutation associated with neuropathy, ataxia, retinitis pigmentosa (NARP) and the \u201ccommon deletion\u201d (CD), a 4977\u2010bp repeat\u2010flanked deletion associated with adult\u2010onset chronic progressive external ophthalmoplegia and, less frequently, Kearns\u2010Sayre and Pearson's marrow pancreas syndromes. Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild\u2010type mtDNA restored mitochondrial respiratory function in a CD cybrid cell model. This study constitutes proof\u2010of\u2010principle that, through heteroplasmy manipulation, delivery of site\u2010specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species.<\/jats:p>","DOI":"10.1002\/emmm.201303672","type":"journal-article","created":{"date-parts":[[2014,2,24]],"date-time":"2014-02-24T15:09:28Z","timestamp":1393254568000},"page":"458-466","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":303,"title":["Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large\u2010scale deletions or point mutations"],"prefix":"10.1038","volume":"6","author":[{"given":"Payam A","family":"Gammage","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Rorbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna I","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J","family":"Rebar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Minczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,2,24]]},"reference":[{"key":"BFEMMM201303672_CR1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/gt.2008.11","volume":"15","author":"MF Alexeyev","year":"2008","unstructured":"Alexeyev MF, Venediktova N, Pastukh V, Shokolenko I, Bonilla G, Wilson GL (2008) Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther 15: 516\u2013523","journal-title":"Gene Ther"},{"key":"BFEMMM201303672_CR2","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/gt.2011.196","volume":"19","author":"SR Bacman","year":"2012","unstructured":"Bacman SR, Williams SL, Duan D, Moraes CT (2012) Manipulation of mtDNA heteroplasmy in all striated muscles of newborn mice by AAV9\u2010mediated delivery of a mitochondria\u2010targeted restriction endonuclease. Gene Ther 19: 1101\u20131106","journal-title":"Gene Ther"},{"key":"BFEMMM201303672_CR3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/gt.2010.25","volume":"17","author":"SR Bacman","year":"2010","unstructured":"Bacman SR, Williams SL, Garcia S, Moraes CT (2010) Organ\u2010specific shifts in mtDNA heteroplasmy following systemic delivery of a mitochondria\u2010targeted restriction endonuclease. Gene Ther 17: 713\u2013720","journal-title":"Gene Ther"},{"key":"BFEMMM201303672_CR4","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.1093\/nar\/gkp348","volume":"37","author":"SR Bacman","year":"2009","unstructured":"Bacman SR, Williams SL, Moraes CT (2009) Intra\u2010 and inter\u2010molecular recombination of mitochondrial DNA after in vivo induction of multiple double\u2010strand breaks. Nucleic Acids Res 37: 4218\u20134226","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR5","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1038\/nm.3261","volume":"19","author":"SR Bacman","year":"2013","unstructured":"Bacman SR, Williams SL, Pinto M, Peralta S, Moraes CT. Specific elimination of mutant mitochondrial genomes in patient\u2010derived cells by mitoTALENs. Nat Med (2013) 19: 1111\u20131113.","journal-title":"Nat Med"},{"key":"BFEMMM201303672_CR6","doi-asserted-by":"crossref","first-page":"14392","DOI":"10.1073\/pnas.0502896102","volume":"102","author":"MP Bayona\u2010Bafaluy","year":"2005","unstructured":"Bayona\u2010Bafaluy MP, Blits B, Battersby BJ, Shoubridge EA, Moraes CT (2005) Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease. Proc Natl Acad Sci USA 102: 14392\u201314397","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM201303672_CR7","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.mito.2011.05.004","volume":"11","author":"PJ Carling","year":"2011","unstructured":"Carling PJ, Cree LM, Chinnery PF (2011) The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion 11: 686\u2013692","journal-title":"Mitochondrion"},{"key":"BFEMMM201303672_CR8","doi-asserted-by":"crossref","unstructured":"Carroll D, Morton JJ, Beumer KJ, Segal DJ. Design, construction and in vitro testing of zinc finger nucleases. Nat Protoc 2006;1:1329\u20131341.","DOI":"10.1038\/nprot.2006.231"},{"key":"BFEMMM201303672_CR9","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.ab.2009.08.006","volume":"395","author":"J Carroll","year":"2009","unstructured":"Carroll J, Fearnley IM, Wang Q, Walker JE Measurement of the molecular masses of hydrophilic and hydrophobic subunits of ATP synthase and complex I in a single experiment. Anal Biochem 2009;395:249\u2013255.","journal-title":"Anal Biochem"},{"key":"BFEMMM201303672_CR10","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/1531-8249(200008)48:2<188::AID-ANA8>3.0.CO;2-P","volume":"48","author":"PF Chinnery","year":"2000","unstructured":"Chinnery PF, Johnson MA, Wardell TM, Singh\u2010Kler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM (2000) The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48: 188\u2013193","journal-title":"Ann Neurol"},{"key":"BFEMMM201303672_CR11","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nmeth.1539","volume":"8","author":"Y Doyon","year":"2011","unstructured":"Doyon Y, Vo TD, Mendel MC, Greenberg SG, Wang J, Xia DF, Miller JC, Urnov FD, Gregory PD, Holmes MC Enhancing zinc\u2010finger\u2010nuclease activity with improved obligate heterodimeric architectures. Nat Methods 2011;8:74\u201379.","journal-title":"Nat Methods"},{"key":"BFEMMM201303672_CR12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/gt.2011.211","volume":"20","author":"BL Ellis","year":"2013","unstructured":"Ellis BL, Hirsch ML, Porter SN, Samulski RJ, Porteus MH (2013) Zinc\u2010finger nuclease\u2010mediated gene correction using single AAV vector transduction and enhancement by Food and Drug Administration\u2010approved drugs. Gene Ther 20: 35\u201342","journal-title":"Gene Ther"},{"key":"BFEMMM201303672_CR13","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.jmb.2003.09.072","volume":"334","author":"J Fernandez\u2010Martinez","year":"2003","unstructured":"Fernandez\u2010Martinez J, Brown CV, Diez E, Tilburn J, Arst HN Jr, Penalva MA, Espeso EA Overlap of nuclear localisation signal and specific DNA\u2010binding residues within the zinc finger domain of PacC. J Mol Biol 2003;334:667\u2013684.","journal-title":"J Mol Biol"},{"key":"BFEMMM201303672_CR14","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.tibtech.2013.04.004","volume":"31","author":"T Gaj","year":"2013","unstructured":"Gaj T, Gersbach CA, Barbas CF 3rd. ZFN, TALEN, and CRISPR\/Cas\u2010based methods for genome engineering. Trends Biotechnol 2013;31:397\u2013405.","journal-title":"Trends Biotechnol"},{"key":"BFEMMM201303672_CR15","doi-asserted-by":"publisher","unstructured":"Grady JP, Campbell G, Ratnaike T, Blakely EL, Falkous G, Nesbitt V, Schaefer AM, McNally RJ, Gorman GS, Taylor RW et\u00a0al Disease progression in patients with single, large\u2010scale mitochondrial DNA deletions. Brain DOI https:\/\/doi.org\/10.1093\/brain\/awt321","DOI":"10.1093\/brain\/awt321"},{"key":"BFEMMM201303672_CR16","first-page":"428","volume":"46","author":"IJ Holt","year":"1990","unstructured":"Holt IJ, Harding AE, Petty RK, Morgan\u2010Hughes JA A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990;46:428\u2013433.","journal-title":"Am J Hum Genet"},{"key":"BFEMMM201303672_CR17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nmeth0111-7a","volume":"8","author":"S Kim","year":"2011","unstructured":"Kim S, Lee MJ, Kim H, Kang M, Kim JS (2011) Preassembled zinc\u2010finger arrays for rapid construction of ZFNs. Nat Methods 8: 7","journal-title":"Nat Methods"},{"key":"BFEMMM201303672_CR18","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1073\/pnas.93.3.1156","volume":"93","author":"YG Kim","year":"1996","unstructured":"Kim YG, Cha J, Chandrasegaran S (1996) Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci USA 93: 1156\u20131160","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM201303672_CR19","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/embor.2011.93","volume":"12","author":"RN Lightowlers","year":"2011","unstructured":"Lightowlers RN (2011) Mitochondrial transformation: time for concerted action. EMBO Rep 12: 480\u2013481","journal-title":"EMBO Rep"},{"key":"BFEMMM201303672_CR20","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.molcel.2008.06.016","volume":"31","author":"ML Maeder","year":"2008","unstructured":"Maeder ML, Thibodeau\u2010Beganny S, Osiak A, Wright DA, Anthony RM, Eichtinger M, Jiang T, Foley JE, Winfrey RJ, Townsend JA et\u00a0al (2008) Rapid \u201copen\u2010source\u201d engineering of customized zinc\u2010finger nucleases for highly efficient gene modification. Mol Cell 31: 294\u2013301","journal-title":"Mol Cell"},{"key":"BFEMMM201303672_CR21","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.1093\/nar\/gkh921","volume":"32","author":"K Maniura\u2010Weber","year":"2004","unstructured":"Maniura\u2010Weber K, Goffart S, Garstka HL, Montoya J, Wiesner RJ Transient overexpression of mitochondrial transcription factor A (TFAM) is sufficient to stimulate mitochondrial DNA transcription, but not sufficient to increase mtDNA copy number in cultured cells. Nucleic Acids Res 2004;32:6015\u20136027.","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR22","doi-asserted-by":"crossref","first-page":"8176","DOI":"10.1016\/S0021-9258(17)37177-6","volume":"269","author":"C Matheny","year":"1994","unstructured":"Matheny C, Day ML, Milbrandt J The nuclear localization signal of NGFI\u2010A is located within the zinc finger DNA binding domain. J Biol Chem 1994;269:8176\u20138181.","journal-title":"J Biol Chem"},{"key":"BFEMMM201303672_CR23","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/nbt1319","volume":"25","author":"JC Miller","year":"2007","unstructured":"Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, Beausejour CM, Waite AJ, Wang NS, Kim KA et\u00a0al (2007) An improved zinc\u2010finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25: 778\u2013785","journal-title":"Nat Biotechnol"},{"key":"BFEMMM201303672_CR24","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/978-1-60761-753-2_16","volume":"649","author":"M Minczuk","year":"2010","unstructured":"Minczuk M (2010) Engineered zinc finger proteins for manipulation of the human mitochondrial genome. Methods Mol Biol 649: 257\u2013270","journal-title":"Methods Mol Biol"},{"key":"BFEMMM201303672_CR25","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.1093\/nar\/gkq1224","volume":"39","author":"M Minczuk","year":"2011","unstructured":"Minczuk M, He J, Duch AM, Ettema TJ, Chlebowski A, Dzionek K, Nijtmans LG, Huynen MA, Holt IJ TEFM (c17orf42) is necessary for transcription of human mtDNA. Nucleic Acids Res 2011;39:4284\u20134299.","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR26","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nprot.2009.245","volume":"5","author":"M Minczuk","year":"2010","unstructured":"Minczuk M, Kolasinska\u2010Zwierz P, Murphy MP, Papworth MA Construction and testing of engineered zinc\u2010finger proteins for sequence\u2010specific modification of mtDNA. Nat Protoc 2010;5:342\u2013356.","journal-title":"Nat Protoc"},{"key":"BFEMMM201303672_CR27","doi-asserted-by":"crossref","first-page":"19689","DOI":"10.1073\/pnas.0609502103","volume":"103","author":"M Minczuk","year":"2006","unstructured":"Minczuk M, Papworth MA, Kolasinska P, Murphy MP, Klug A Sequence\u2010specific modification of mitochondrial DNA using a chimeric zinc finger methylase. Proc Natl Acad Sci USA 2006;103:19689\u201319694.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMMM201303672_CR28","doi-asserted-by":"crossref","first-page":"3926","DOI":"10.1093\/nar\/gkn313","volume":"36","author":"M Minczuk","year":"2008","unstructured":"Minczuk M, Papworth MA, Miller JC, Murphy MP, Klug A Development of a single\u2010chain, quasi\u2010dimeric zinc\u2010finger nuclease for the selective degradation of mutated human mitochondrial DNA. Nucleic Acids Res 2008;36:3926\u20133938.","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/gt.2012.2","volume":"20","author":"NJ Palpant","year":"2013","unstructured":"Palpant NJ, Dudzinski D (2013) Zinc finger nucleases: looking toward translation. Gene Ther 20: 121\u2013127","journal-title":"Gene Ther"},{"key":"BFEMMM201303672_CR30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.gene.2005.09.011","volume":"366","author":"M Papworth","year":"2006","unstructured":"Papworth M, Kolasinska P, Minczuk M (2006) Designer zinc\u2010finger proteins and their applications. Gene 366: 27\u201338","journal-title":"Gene"},{"key":"BFEMMM201303672_CR31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/455160a","volume":"455","author":"H Pearson","year":"2008","unstructured":"Pearson H (2008) Protein engineering: the fate of fingers. Nature 455: 160\u2013164","journal-title":"Nature"},{"key":"BFEMMM201303672_CR32","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/nrneurol.2013.129","volume":"9","author":"G Pfeffer","year":"2013","unstructured":"Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu\u2010Wai\u2010Man P et\u00a0al (2013) New treatments for mitochondrial disease\u2010no time to drop our standards. Nat Rev Neurol 9: 474\u2013481","journal-title":"Nat Rev Neurol"},{"key":"BFEMMM201303672_CR33","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1046\/j.1432-1327.1998.2570192.x","volume":"257","author":"WK Porteous","year":"1998","unstructured":"Porteous WK, James AM, Sheard PW, Porteous CM, Packer MA, Hyslop SJ, Melton JV, Pang CY, Wei YH, Murphy MP (1998) Bioenergetic consequences of accumulating the common 4977\u2010bp mitochondrial DNA deletion. Eur J Biochem 257: 192\u2013201","journal-title":"Eur J Biochem"},{"key":"BFEMMM201303672_CR34","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1093\/nar\/gkr1282","volume":"40","author":"J Rorbach","year":"2012","unstructured":"Rorbach J, Gammage PA, Minczuk M (2012) C7orf30 is necessary for biogenesis of the large subunit of the mitochondrial ribosome. Nucleic Acids Res 40: 4097\u20134109","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nmeth.1542","volume":"8","author":"JD Sander","year":"2011","unstructured":"Sander JD, Dahlborg EJ, Goodwin MJ, Cade L, Zhang F, Cifuentes D, Curtin SJ, Blackburn JS, Thibodeau\u2010Beganny S, Qi Y et\u00a0al (2011) Selection\u2010free zinc\u2010finger\u2010nuclease engineering by context\u2010dependent assembly (CoDA). Nat Methods 8: 67\u201369","journal-title":"Nat Methods"},{"key":"BFEMMM201303672_CR36","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/ana.21217","volume":"63","author":"AM Schaefer","year":"2008","unstructured":"Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63: 35\u201339","journal-title":"Ann Neurol"},{"key":"BFEMMM201303672_CR37","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1093\/nar\/28.17.3361","volume":"28","author":"J Smith","year":"2000","unstructured":"Smith J, Bibikova M, Whitby FG, Reddy AR, Chandrasegaran S, Carroll D (2000) Requirements for double\u2010strand cleavage by chimeric restriction enzymes with zinc finger DNA\u2010recognition domains. Nucleic Acids Res 28: 3361\u20133369.","journal-title":"Nucleic Acids Res"},{"key":"BFEMMM201303672_CR38","doi-asserted-by":"crossref","first-page":"5123","DOI":"10.1128\/MCB.00619-10","volume":"30","author":"Y Suzuki","year":"2010","unstructured":"Suzuki Y, Holmes JB, Cerritelli SM, Sakhuja K, Minczuk M, Holt IJ, Crouch RJ (2010) An upstream open reading frame and the context of the two AUG codons affect the abundance of mitochondrial and nuclear RNase H1. Mol Cell Biol 30: 5123\u20135134.","journal-title":"Mol Cell Biol"},{"key":"BFEMMM201303672_CR39","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nbt1317","volume":"25","author":"M Szczepek","year":"2007","unstructured":"Szczepek M, Brondani V, Buchel J, Serrano L, Segal DJ, Cathomen T (2007) Structure\u2010based redesign of the dimerization interface reduces the toxicity of zinc\u2010finger nucleases. Nat Biotechnol 25: 786\u2013793","journal-title":"Nat Biotechnol"},{"key":"BFEMMM201303672_CR40","first-page":"534","volume":"9","author":"M Tanaka","year":"2002","unstructured":"Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M, Maruyama W, Naoi M, Ibi T, Sahashi K et\u00a0al (2002) Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J Biomed Sci 9: 534\u2013541","journal-title":"J Biomed Sci"},{"key":"BFEMMM201303672_CR41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/ng0297-212","volume":"15","author":"RW Taylor","year":"1997","unstructured":"Taylor RW, Chinnery PF, Turnbull DM, Lightowlers RN (1997) Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet 15: 212\u2013215","journal-title":"Nat Genet"},{"key":"BFEMMM201303672_CR42","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/nature11707","volume":"491","author":"SB Vafai","year":"2012","unstructured":"Vafai SB, Mootha VK (2012) Mitochondrial disorders as windows into an ancient organelle. Nature 491: 374\u2013383","journal-title":"Nature"}],"container-title":["EMBO Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201303672.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/emmm.201303672","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1002\/emmm.201303672\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.1002\/emmm.201303672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201303672.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:09:05Z","timestamp":1779084545000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1002\/emmm.201303672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,24]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2014,4,1]]}},"alternative-id":["BFEMMM201303672"],"URL":"https:\/\/doi.org\/10.1002\/emmm.201303672","relation":{},"ISSN":["1757-4676","1757-4684"],"issn-type":[{"value":"1757-4676","type":"print"},{"value":"1757-4684","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,24]]},"assertion":[{"value":"14 November 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2014","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2014","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}