{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:00:16Z","timestamp":1762430416012},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diagn Pathol"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Primary open-angle glaucoma (POAG) is the most common form of glaucoma which is an irreversible blind leading disease and lacks effective remedies. In recent years, POAG has been linked to the gene <jats:italic>MYOC<\/jats:italic> encoding myocilin that has been identified to harbor causal mutations. A variety of studies show that the mutant myocilin acts by gain of function. The mutant <jats:italic>MYOC<\/jats:italic> protein induces endoplasmic reticulum (ER) stress and the resultant unfolded protein response (UPR) induces apoptosis in the trabecular meshwork cells, which then leads to an increase in resistance to aqueous humor outflow, elevated intraocular pressure (IOP), and, ultimately, glaucoma. Culturing human trabecular meshwork (HTM) cells at a condition facilitating protein folding promotes secretion of mutant myocilin, normalizes cell morphology and reverses cell lethality.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Presentation of the Hypothesis<\/jats:title>\n            <jats:p>We speculate that a complete elimination of mutant myocilin expression in trabecular meshwork cells is safe and that gives the possibility of avoiding the POAG phenotype.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Testing the Hypothesis<\/jats:title>\n            <jats:p>We propose RNA interference (RNAi) as a gene silencing therapy to eliminate the mutant myocilin proteins in the trabecular meshwork cells, either in a mutation-dependent or mutation-independent way due to the different engineering of the small interfering (si) RNA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Implications of the Hypothesis<\/jats:title>\n            <jats:p>The RNAi strategy can reverse the pathological process of trabecular meshwork cells and thus treat the POAG caused by myocilin gene mutation. This strategy can also be applicable to many protein-misfolding diseases caused by gain-of-function mutant proteins.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1746-1596-4-46","type":"journal-article","created":{"date-parts":[[2009,12,16]],"date-time":"2009-12-16T19:15:52Z","timestamp":1260990952000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RNA interference as a gene silencing therapy for mutant MYOC protein in primary open angle glaucoma"],"prefix":"10.1186","volume":"4","author":[{"given":"Mao","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueli","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinghuai","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2009,12,16]]},"reference":[{"key":"244_CR1","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1016\/S0140-6736(04)16257-0","volume":"363","author":"RN Weinreb","year":"2004","unstructured":"Weinreb RN, Khaw PT: Primary open-angle glaucoma. Lancet. 2004, 363: 1711-1720. 10.1016\/S0140-6736(04)16257-0.","journal-title":"Lancet"},{"key":"244_CR2","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1016\/S0161-6420(96)30435-1","volume":"103","author":"B Rahmani","year":"1996","unstructured":"Rahmani B, Tielsch JM, Katz J, Gottsch J, Quigley H, Javitt J, Sommer A: The cause-specific prevalence of visual impairment in an urban population. The Baltimore Eye Survey. Ophthalmology. 1996, 103: 1721-1726.","journal-title":"Ophthalmology"},{"key":"244_CR3","first-page":"83","volume":"38","author":"HA Quigley","year":"1997","unstructured":"Quigley HA, Vitale S: Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci. 1997, 38: 83-91.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR4","doi-asserted-by":"publisher","first-page":"4254","DOI":"10.1167\/iovs.06-0299","volume":"47","author":"AR Rudnicka","year":"2006","unstructured":"Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D: Variations in primary open-angle glaucoma prevalence by age, gender, and race: a Bayesian meta-analysis. Invest Ophthalmol Vis Sci. 2006, 47: 4254-4261. 10.1167\/iovs.06-0299.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR5","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1093\/hmg\/ddh128","volume":"13","author":"Y Liu","year":"2004","unstructured":"Liu Y, Vollrath D: Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma. Hum Mol Genet. 2004, 13: 1193-1204. 10.1093\/hmg\/ddh128.","journal-title":"Hum Mol Genet"},{"key":"244_CR6","volume-title":"Preferred practice pattern: primary open-angle glaucoma","author":"American Academy of Ophthalmology PPPC, Glaucoma Panel","year":"2000","unstructured":"American Academy of Ophthalmology PPPC, Glaucoma Panel: Preferred practice pattern: primary open-angle glaucoma. 2000, San Francisco, Calif: American Academy of Ophthalmology"},{"key":"244_CR7","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1001\/archopht.120.6.701","volume":"120","author":"MA Kass","year":"2002","unstructured":"Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK, Wilson MR, Gordon MO: The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002, 120: 701-713.","journal-title":"Arch Ophthalmol"},{"key":"244_CR8","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1001\/archopht.120.10.1268","volume":"120","author":"A Heijl","year":"2002","unstructured":"Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M: Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002, 120: 1268-1279.","journal-title":"Arch Ophthalmol"},{"key":"244_CR9","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1016\/S0161-6420(01)00873-9","volume":"108","author":"PR Lichter","year":"2001","unstructured":"Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, Mills RP: Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001, 108: 1943-1953. 10.1016\/S0161-6420(01)00873-9.","journal-title":"Ophthalmology"},{"key":"244_CR10","doi-asserted-by":"crossref","unstructured":"The Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of treatment outcomes within race. Seven-year results. Ophthalmology. 1998, 105: 1146-1164. 10.1016\/S0161-6420(98)97013-0.","DOI":"10.1016\/S0161-6420(98)97013-0"},{"key":"244_CR11","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1093\/hmg\/8.5.899","volume":"8","author":"JH Fingert","year":"1999","unstructured":"Fingert JH, H\u00e9on E, Liebmann JM, Yamamoto T, Craig JE, Rait J, Kawase K, Hoh ST, Buys YM, Dickinson J, Hockey RR, Williams-Lyn D, Trope G, Kitazawa Y, Ritch R, Mackey DA, Alward WL, Sheffield VC, Stone EM: Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet. 1999, 8: 899-905. 10.1093\/hmg\/8.5.899.","journal-title":"Hum Mol Genet"},{"key":"244_CR12","first-page":"2513","volume":"43","author":"T Borras","year":"2002","unstructured":"Borras T, Brandt CR, Nickells R, Ritch R: Gene therapy for glaucoma: treating a multifaceted, chronic disease. Invest Ophthalmol Vis Sci. 2002, 43: 2513-2518.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR13","first-page":"729","volume":"41","author":"A Karali","year":"2000","unstructured":"Karali A, Russell P, Stefani FH, Tamm ER: Localization of myocilin\/trabecular meshwork--inducible glucocorticoid response protein in the human eye. Invest Ophthalmol Vis Sci. 2000, 41: 729-740.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR14","first-page":"3420","volume":"41","author":"RE Swiderski","year":"2000","unstructured":"Swiderski RE, Ross JL, Fingert JH, Clark AF, Alward WL, Stone EM, Sheffield VC: Localization of MYOC transcripts in human eye and optic nerve by in situ hybridization. Invest Ophthalmol Vis Sci. 2000, 41: 3420-3428.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR15","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1093\/hmg\/6.12.2091","volume":"6","author":"MF Adam","year":"1997","unstructured":"Adam MF, Belmouden A, Binisti P, Br\u00e9zin AP, Valtot F, B\u00e9chetoille A, Dascotte JC, Copin B, Gomez L, Chaventr\u00e9 A, Bach JF, Garchon HJ: Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Hum Mol Genet. 1997, 6: 2091-2097. 10.1093\/hmg\/6.12.2091.","journal-title":"Hum Mol Genet"},{"key":"244_CR16","doi-asserted-by":"publisher","first-page":"7707","DOI":"10.1128\/MCB.21.22.7707-7713.2001","volume":"21","author":"BS Kim","year":"2001","unstructured":"Kim BS, Savinova OV, Reedy MV, Martin J, Lun Y, Gan L, Smith RS, Tomarev SI, John SW, Johnson RL: Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function. Mol Cell Biol. 2001, 21: 7707-7713. 10.1128\/MCB.21.22.7707-7713.2001.","journal-title":"Mol Cell Biol"},{"key":"244_CR17","first-page":"3231","volume":"43","author":"CP Pang","year":"2002","unstructured":"Pang CP, Leung YF, Fan B, Baum L, Tong WC, Lee WS, Chua JK, Fan DS, Liu Y, Lam DS: TIGR\/MYOC gene sequence alterations in individuals with and without primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2002, 43: 3231-3235.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR18","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1001\/archopht.119.11.1674","volume":"119","author":"JL Wiggs","year":"2001","unstructured":"Wiggs JL, Vollrath D: Molecular and clinical evaluation of a patient hemizygous for TIGR\/MYOC. Arch Ophthalmol. 2001, 119: 1674-1678.","journal-title":"Arch Ophthalmol"},{"key":"244_CR19","doi-asserted-by":"publisher","first-page":"9019","DOI":"10.1128\/MCB.24.20.9019-9025.2004","volume":"24","author":"DB Gould","year":"2004","unstructured":"Gould DB, Miceli-Libby L, Savinova OV, Torrado M, Tomarev SI, Smith RS, John SW: Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol. 2004, 24: 9019-9025. 10.1128\/MCB.24.20.9019-9025.2004.","journal-title":"Mol Cell Biol"},{"key":"244_CR20","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1167\/iovs.04-0988","volume":"46","author":"M Zillig","year":"2005","unstructured":"Zillig M, Wurm A, Grehn FJ, Russell P, Tamm ER: Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice. Invest Ophthalmol Vis Sci. 2005, 46: 223-234. 10.1167\/iovs.04-0988.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR21","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/S0925-4439(00)00068-5","volume":"1502","author":"M Caballero","year":"2000","unstructured":"Caballero M, Rowlette LL, Borras T: Altered secretion of a TIGR\/MYOC mutant lacking the olfactomedin domain. Biochim Biophys Acta. 2000, 1502: 447-460.","journal-title":"Biochim Biophys Acta"},{"key":"244_CR22","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1006\/bbrc.2001.4624","volume":"282","author":"M Caballero","year":"2001","unstructured":"Caballero M, Borras T: Inefficient processing of an olfactomedin-deficient myocilin mutant: potential physiological relevance to glaucoma. Biochem Biophys Res Commun. 2001, 282: 662-670. 10.1006\/bbrc.2001.4624.","journal-title":"Biochem Biophys Res Commun"},{"key":"244_CR23","first-page":"3680","volume":"43","author":"S Sohn","year":"2002","unstructured":"Sohn S, Hur W, Joe MK, Kim JH, Lee ZW, Ha KS, Kee C: Expression of wild-type and truncated myocilins in trabecular meshwork cells: their subcellular localizations and cytotoxicities. Invest Ophthalmol Vis Sci. 2002, 43: 3680-3685.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR24","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.bbrc.2003.10.162","volume":"312","author":"MK Joe","year":"2003","unstructured":"Joe MK, Sohn S, Hur W, Moon Y, Choi YR, Kee C: Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem Biophys Res Commun. 2003, 312: 592-600. 10.1016\/j.bbrc.2003.10.162.","journal-title":"Biochem Biophys Res Commun"},{"key":"244_CR25","doi-asserted-by":"publisher","first-page":"3560","DOI":"10.1167\/iovs.04-0300","volume":"45","author":"S Gobeil","year":"2004","unstructured":"Gobeil S, Rodrigue MA, Moisan S, Nguyen TD, Polansky JR, Morissette J, Raymond V: Intracellular sequestration of hetero-oligomers formed by wild-type and glaucoma-causing myocilin mutants. Invest Ophthalmol Vis Sci. 2004, 45: 3560-3567. 10.1167\/iovs.04-0300.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"244_CR26","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1093\/hmg\/10.2.117","volume":"10","author":"N Jacobson","year":"2001","unstructured":"Jacobson N, Andrews M, Shepard AR, Nishimura D, Searby C, Fingert JH, Hageman G, Mullins R, Davidson BL, Kwon YH, Alward WL, Stone EM, Clark AF, Sheffield VC: Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Hum Mol Genet. 2001, 10: 117-125. 10.1093\/hmg\/10.2.117.","journal-title":"Hum Mol Genet"},{"key":"244_CR27","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.exer.2005.11.002","volume":"82","author":"S Gobeil","year":"2006","unstructured":"Gobeil S, Letartre L, Raymond V: Functional analysis of the glaucoma-causing TIGR\/myocilin protein: integrity of amino-terminal coiled-coil regions and olfactomedin homology domain is essential for extracellular adhesion and secretion. Exp Eye Res. 2006, 82: 1017-1029. 10.1016\/j.exer.2005.11.002.","journal-title":"Exp Eye Res"},{"key":"244_CR28","doi-asserted-by":"publisher","first-page":"100","DOI":"10.2353\/ajpath.2007.060806","volume":"170","author":"GH Yam","year":"2007","unstructured":"Yam GH, Gaplovska-Kysela K, Zuber C, Roth J: Aggregated myocilin induces russell bodies and causes apoptosis: implications for the pathogenesis of myocilin-caused primary open-angle glaucoma. Am J Pathol. 2007, 170: 100-109. 10.2353\/ajpath.2007.060806.","journal-title":"Am J Pathol"},{"key":"244_CR29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.mrfmmm.2004.06.056","volume":"569","author":"M Schroder","year":"2005","unstructured":"Schroder M, Kaufman RJ: ER stress and the unfolded protein response. Mutat Res. 2005, 569: 29-63.","journal-title":"Mutat Res"},{"key":"244_CR30","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/S0161-6420(84)34248-8","volume":"91","author":"J Alvarado","year":"1984","unstructured":"Alvarado J, Murphy C, Juster R: Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals. Ophthalmology. 1984, 91: 564-579.","journal-title":"Ophthalmology"},{"key":"244_CR31","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1001\/archopht.1986.01050220111038","volume":"104","author":"JA Alvarado","year":"1986","unstructured":"Alvarado JA, Yun AJ, Murphy CG: Juxtacanalicular tissue in primary open angle glaucoma and in nonglaucomatous normals. Arch Ophthalmol. 1986, 104: 1517-1528.","journal-title":"Arch Ophthalmol"},{"key":"244_CR32","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/0014-4835(86)90004-7","volume":"42","author":"E Lutjen-Drecoll","year":"1986","unstructured":"Lutjen-Drecoll E, Shimizu T, Rohrbach M, Rohen JW: Quantitative analysis of 'plaque material' in the inner- and outer wall of Schlemm's canal in normal- and glaucomatous eyes. Exp Eye Res. 1986, 42: 443-455. 10.1016\/0014-4835(86)90004-7.","journal-title":"Exp Eye Res"},{"key":"244_CR33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1006\/exer.1993.1085","volume":"56","author":"JW Rohen","year":"1993","unstructured":"Rohen JW, Lutjen-Drecoll E, Flugel C, Meyer M, Grierson I: Ultrastructure of the trabecular meshwork in untreated cases of primary open-angle glaucoma (POAG). Exp Eye Res. 1993, 56: 683-692. 10.1006\/exer.1993.1085.","journal-title":"Exp Eye Res"},{"key":"244_CR34","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/430161a","volume":"430","author":"CD Novina","year":"2004","unstructured":"Novina CD, Sharp PA: The RNAi revolution. Nature. 2004, 430: 161-164. 10.1038\/430161a.","journal-title":"Nature"},{"key":"244_CR35","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1126\/science.1103076","volume":"305","author":"EJ Sontheimer","year":"2004","unstructured":"Sontheimer EJ, Carthew RW: Molecular biology. Argonaute journeys into the heart of RISC. Science. 2004, 305: 1409-1410. 10.1126\/science.1103076.","journal-title":"Science"},{"key":"244_CR36","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1038\/sj.gt.3302324","volume":"11","author":"NJ Caplen","year":"2004","unstructured":"Caplen NJ: Gene therapy progress and prospects. Downregulating gene expression: the impact of RNA interference. Gene Ther. 2004, 11: 1241-1248. 10.1038\/sj.gt.3302324.","journal-title":"Gene Ther"},{"key":"244_CR37","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/35078107","volume":"411","author":"SM Elbashir","year":"2001","unstructured":"Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T: Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001, 411: 494-498. 10.1038\/35078107.","journal-title":"Nature"},{"key":"244_CR38","doi-asserted-by":"publisher","first-page":"7195","DOI":"10.1073\/pnas.1231012100","volume":"100","author":"VM Miller","year":"2003","unstructured":"Miller VM, Xia H, Marrs GL, Gouvion CM, Lee G, Davidson BL, Paulson HL: Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci USA. 2003, 100: 7195-7200. 10.1073\/pnas.1231012100.","journal-title":"Proc Natl Acad Sci USA"},{"key":"244_CR39","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.ymthe.2005.03.028","volume":"12","author":"AS Kiang","year":"2005","unstructured":"Kiang AS, Palfi A, Ader M, Kenna PF, Millington-Ward S, Clark G, Kennan A, O'reilly M, Tam LC, Aherne A, McNally N, Humphries P, Farrar GJ: Toward a gene therapy for dominant disease: validation of an RNA interference-based mutation-independent approach. Mol Ther. 2005, 12: 555-561. 10.1016\/j.ymthe.2005.03.028.","journal-title":"Mol Ther"},{"key":"244_CR40","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/S0039-6257(02)00353-3","volume":"47","author":"JH Fingert","year":"2002","unstructured":"Fingert JH, Stone EM, Sheffield VC, Alward WL: Myocilin glaucoma. Surv Ophthalmol. 2002, 47: 547-561. 10.1016\/S0039-6257(02)00353-3.","journal-title":"Surv Ophthalmol"},{"key":"244_CR41","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.mehy.2007.04.041","volume":"70","author":"T Shinohara","year":"2008","unstructured":"Shinohara T, Mulhern ML, Madson CJ: Silencing gene therapy for mutant membrane, secretory, and lipid proteins in retinitis pigmentosa (RP). Med Hypotheses. 2008, 70: 378-380. 10.1016\/j.mehy.2007.04.041.","journal-title":"Med Hypotheses"}],"container-title":["Diagnostic Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1746-1596-4-46.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T23:43:55Z","timestamp":1630453435000},"score":1,"resource":{"primary":{"URL":"https:\/\/diagnosticpathology.biomedcentral.com\/articles\/10.1186\/1746-1596-4-46"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["244"],"URL":"https:\/\/doi.org\/10.1186\/1746-1596-4-46","relation":{},"ISSN":["1746-1596"],"issn-type":[{"value":"1746-1596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12]]},"assertion":[{"value":"9 December 2009","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"46"}}