{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T02:18:12Z","timestamp":1767665892286},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2006,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Recently there has been a lot of interest in identifying modules at the level of genetic and metabolic networks of organisms, as well as in identifying single genes and reactions that are essential for the organism. A goal of computational and systems biology is to go beyond identification towards an explanation of specific modules and essential genes and reactions in terms of specific structural or evolutionary constraints.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In the metabolic networks of <jats:italic>Escherichia coli, Saccharomyces cerevisiae<\/jats:italic> and <jats:italic>Staphylococcus aureus<\/jats:italic>, we identified metabolites with a low degree of connectivity, particularly those that are produced and\/or consumed in just a single reaction. Using flux balance analysis (FBA) we also determined reactions essential for growth in these metabolic networks. We find that most reactions identified as essential in these networks turn out to be those involving the production or consumption of low degree metabolites. Applying graph theoretic methods to these metabolic networks, we identified connected clusters of these low degree metabolites. The genes involved in several operons in <jats:italic>E. coli<\/jats:italic> are correctly predicted as those of enzymes catalyzing the reactions of these clusters. Furthermore, we find that larger sized clusters are over-represented in the real network and are analogous to a 'network motif. Using FBA for the above mentioned three organisms we independently identified clusters of reactions whose fluxes are perfectly correlated. We find that the composition of the latter 'functional clusters' is also largely explained in terms of clusters of low degree metabolites in each of these organisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our findings mean that most metabolic reactions that are essential can be tagged by one or more low degree metabolites. Those reactions are essential because they are the only ways of producing or consuming their respective tagged metabolites. Furthermore, reactions whose fluxes are strongly correlated can be thought of as 'glued together' by these low degree metabolites. The methods developed here could be used in predicting essential reactions and metabolic modules in other organisms from the list of metabolic reactions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-7-118","type":"journal-article","created":{"date-parts":[[2006,3,10]],"date-time":"2006-03-10T19:19:59Z","timestamp":1142018399000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Low degree metabolites explain essential reactions and enhance modularity in biological networks"],"prefix":"10.1186","volume":"7","author":[{"given":"Areejit","family":"Samal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shalini","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varun","family":"Giri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep","family":"Krishna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nandula","family":"Raghuram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2006,3,8]]},"reference":[{"key":"857_CR1","doi-asserted-by":"publisher","first-page":"5528","DOI":"10.1073\/pnas.97.10.5528","volume":"97","author":"JS Edwards","year":"2000","unstructured":"Edwards JS, Palsson BO: The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. Proc Natl Acad Sci USA 2000, 97: 5528\u20135533. 10.1073\/pnas.97.10.5528","journal-title":"Proc Natl Acad Sci USA"},{"key":"857_CR2","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1101\/gr.2250904","volume":"14","author":"NC Duarte","year":"2004","unstructured":"Duarte NC, Herrgard MJ, Palsson BO: Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. Genome Res 2004, 14: 1298\u20131309. 10.1101\/gr.2250904","journal-title":"Genome Res"},{"key":"857_CR3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/nature02456","volume":"429","author":"MW Covert","year":"2004","unstructured":"Covert MW, Knight EM, Reed JL, Herrgard MJ, Palsson BO: Integrating high-throughput and computational data elcidates bacterial networks. Nature 2004, 429: 92\u201396. 10.1038\/nature02456","journal-title":"Nature"},{"key":"857_CR4","doi-asserted-by":"publisher","first-page":"R54","DOI":"10.1186\/gb-2003-4-9-r54","volume":"4","author":"JL Reed","year":"2003","unstructured":"Reed JL, Vo TD, Schilling CH, Palsson BO: An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM\/GPR). Genome Biol 2003, 4: R54-. 10.1186\/gb-2003-4-9-r54","journal-title":"Genome Biol"},{"key":"857_CR5","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1471-2180-5-8","volume":"5","author":"SA Becker","year":"2005","unstructured":"Becker SA, Palsson BO: Genome-scale reconstruction Staphylococcus aureus N315: an initial draft to the two-dimensional annotation. BMC Microbiology 2005, 5: 8. 10.1186\/1471-2180-5-8","journal-title":"BMC Microbiology"},{"key":"857_CR6","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/35036627","volume":"407","author":"H Jeong","year":"2000","unstructured":"Jeong H, Tombor B, Albert R, Oltvai ZN, Barabasi AL: The large-scale organization of metabolic networks. Nature 2000, 407: 651\u2013654. 10.1038\/35036627","journal-title":"Nature"},{"key":"857_CR7","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1098\/rspb.2001.1711","volume":"268","author":"A Wagner","year":"2001","unstructured":"Wagner A, Fell DA: The small world inside large metabolic networks. Proc Biol Sci 2001, 268: 1803\u20131810. 10.1098\/rspb.2001.1711","journal-title":"Proc Biol Sci"},{"key":"857_CR8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/35075138","volume":"411","author":"H Jeong","year":"2001","unstructured":"Jeong H, Mason SP, Barabasi AL, Oltvai ZN: Lethality and centrality in protein networks. Nature 2001, 411: 41\u201342. 10.1038\/35075138","journal-title":"Nature"},{"key":"857_CR9","doi-asserted-by":"publisher","first-page":"L7","DOI":"10.1529\/biophysj.104.055723","volume":"88","author":"R Mahadevan","year":"2005","unstructured":"Mahadevan R, Palsson BO: Properties of Metabolic Networks: Structure vs. Function. Biophysical Journal 2005, 88: L7-L9. 10.1529\/biophysj.104.055723","journal-title":"Biophysical Journal"},{"key":"857_CR10","doi-asserted-by":"publisher","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","volume":"95","author":"MB Eisen","year":"1998","unstructured":"Eisen MB, Spellman PT, Brown PO, Bostein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998, 95: 14863\u201314868. 10.1073\/pnas.95.25.14863","journal-title":"Proc Natl Acad Sci USA"},{"key":"857_CR11","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/ng941","volume":"31","author":"J Ihmels","year":"2002","unstructured":"Ihmels J, Friedlander G, Bergmann S, Sarig O, Ziv Y, Barkai N: Revealing modular organization in yeast transcriptional network. Nat Genet 2002, 31: 370\u2013377.","journal-title":"Nat Genet"},{"key":"857_CR12","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/ng1165","volume":"34","author":"E Segal","year":"2003","unstructured":"Segal E, Shapira M, Regev A, Peer D, Botstein D, Koller D, Friedman N: Module networks: Identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet 2003, 34: 166\u2013176.","journal-title":"Nat Genet"},{"key":"857_CR13","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1093\/bioinformatics\/15.3.251","volume":"15","author":"T Pfeiffer","year":"1999","unstructured":"Pfeiffer T, Sanchez-Valdenebro I, Nuno JC, Montero F, Schuster S: METATOOL: for studying metabolic networks. Bioinformatics 1999, 15: 251\u2013257. 10.1093\/bioinformatics\/15.3.251","journal-title":"Bioinformatics"},{"key":"857_CR14","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s004490100253","volume":"24","author":"S Schuster","year":"2002","unstructured":"Schuster S, Klarnt S, Weckwerth W, Moldenhauer F, Pfeiffer T: Use of network analysis of metabolic systems in bioengineering. Bioprocess Biosyst Eng 2002, 24: 363\u2013372. 10.1007\/s004490100253","journal-title":"Bioprocess Biosyst Eng"},{"key":"857_CR15","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/nature01166","volume":"420","author":"J Stelling","year":"2002","unstructured":"Stelling J, Klamt S, Bettenbrock K, Schuster S, Gilles ED: Metabolic network structure determines key aspects of functionality and regulation. Nature 2002, 420: 190\u2013193. 10.1038\/nature01166","journal-title":"Nature"},{"key":"857_CR16","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1101\/gr.327702","volume":"12","author":"JA Papin","year":"2002","unstructured":"Papin JA, Price ND, Palsson BO: Extreme pathway lengths and reaction participation in genome-scale metabolic networks. Genome Res 2002, 12: 1889\u20131900. 10.1101\/gr.327702","journal-title":"Genome Res"},{"key":"857_CR17","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1101\/gr.1926504","volume":"14","author":"AP Burgard","year":"2004","unstructured":"Burgard AP, Nikolaev EV, Schilling CH, Maranas CD: Flux coupling analysis of genome-scale metabolic network reconstructions. Genome Res 2004, 14: 301\u2013312. 10.1101\/gr.1926504","journal-title":"Genome Res"},{"key":"857_CR18","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1101\/gr.2546004","volume":"14","author":"JL Reed","year":"2004","unstructured":"Reed JL, Palsson BO: Genome-scale in silico models of E. coli have multiple equivalent phenotypic states: assessment of correlated reaction subsets that comprise network states. Genome Res 2004, 14: 1797\u20131805. 10.1101\/gr.2546004","journal-title":"Genome Res"},{"key":"857_CR19","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1093\/bioinformatics\/btg115","volume":"19","author":"J Gagneur","year":"2003","unstructured":"Gagneur J, Jackson DB, Casari G: Hierarchical analysis of dependency in metabolic networks. Bioinformatics 2003, 19: 1027\u20131034. 10.1093\/bioinformatics\/btg115","journal-title":"Bioinformatics"},{"key":"857_CR20","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/nature03288","volume":"433","author":"R Guimera","year":"2005","unstructured":"Guimera R, Amaral LAN: Functional cartography of complex metabolic networks. Nature 2005, 433: 895\u2013900. 10.1038\/nature03288","journal-title":"Nature"},{"key":"857_CR21","doi-asserted-by":"publisher","first-page":"C47","DOI":"10.1038\/35011540","volume":"402","author":"LH Hartwell","year":"1999","unstructured":"Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature 1999, 402: C47-C52. 10.1038\/35011540","journal-title":"Nature"},{"key":"857_CR22","doi-asserted-by":"publisher","first-page":"D303","DOI":"10.1093\/nar\/gkh140","volume":"32","author":"H Salgado","year":"2004","unstructured":"Salgado H, Gama-Castro S, Martinez-Antonio A, Diaz-Peredo E, Sanchez-Solano F, Peralta-Gil M, Garcia-Alonso D, Jimenez-Jacinto V, Santos-Zavaleta A, Bonavides-Martinez C, Collado-Vides J: RegulonDB (version 4.0): Transcriptional regulation, operon organization and growth conditions in Escherichia coli K-12. Nucleic Acid Res 2004, 32: D303-D306. 10.1093\/nar\/gkh140","journal-title":"Nucleic Acid Res"},{"key":"857_CR23","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1093\/nar\/30.1.56","volume":"30","author":"PD Karp","year":"2002","unstructured":"Karp PD, Riley M, Saier M, Paulsen IT, Collado-Vides J, Paley SM, Pellegrini-Toole A, Bonavides C, Gama-Castro S: The Ecocyc Database. Nucleic Acid Res 2002, 30: 56\u201358. 10.1093\/nar\/30.1.56","journal-title":"Nucleic Acid Res"},{"key":"857_CR24","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/S0097-8485(01)00119-X","volume":"26","author":"LT Fan","year":"2002","unstructured":"Fan LT, Bertok B, Friedler F: A graph-theoretic method to identify candidate mechanisms for deriving the rate law of a catalytic reaction. Comput Chem 2002, 26: 265\u2013292. 10.1016\/S0097-8485(01)00119-X","journal-title":"Comput Chem"},{"key":"857_CR25","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1023\/A:1011913225764","volume":"23","author":"H Seo","year":"2001","unstructured":"Seo H, Lee DY, Fan LT, Shafie S, Bertok B, Friedler F: Graph-theoretic identification of pathways for biochemical reactions. Biotechnology Letters 2001, 23: 1551\u20131557. 10.1023\/A:1011913225764","journal-title":"Biotechnology Letters"},{"key":"857_CR26","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.ymben.2005.02.002","volume":"7","author":"DY Lee","year":"2005","unstructured":"Lee DY, Fan LT, Park S, Lee SY, Shafie S, Bertok B, Friedler F: Complementary identification of multiple flux distributions and multiple metabolic pathways. Metabolic Engineering 2005, 7: 182\u2013200. 10.1016\/j.ymben.2005.02.002","journal-title":"Metabolic Engineering"},{"key":"857_CR27","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/nbt1094-994","volume":"12","author":"A Varma","year":"1994","unstructured":"Varma A, Palsson BO: Metabolic flux balancing: Basic concepts, scientific and practical use. Bio\/Technology 1994, 12: 994\u2013998. 10.1038\/nbt1094-994","journal-title":"Bio\/Technology"},{"key":"857_CR28","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/84379","volume":"19","author":"JS Edwards","year":"2001","unstructured":"Edwards JS, Ibarra RU, Palsson BO: In silico predictions of Escherichi coli metabolic capabilities are consistent with experimental data. Nat Biotechnol 2001, 19: 125\u2013130. 10.1038\/84379","journal-title":"Nat Biotechnol"},{"key":"857_CR29","doi-asserted-by":"publisher","first-page":"15112","DOI":"10.1073\/pnas.232349399","volume":"99","author":"D Segre","year":"2002","unstructured":"Segre D, Vitkup D, Church GM: Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci U S A 2002, 99: 15112\u201315117. 10.1073\/pnas.232349399","journal-title":"Proc Natl Acad Sci U S A"},{"key":"857_CR30","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/BF01192571","volume":"6","author":"S Schuster","year":"1991","unstructured":"Schuster S, Schuster R: Detecting strictly detailed balanced subnetworks in open chemical reaction networks. J Math Chem 1991, 6: 17\u201340. 10.1007\/BF01192571","journal-title":"J Math Chem"},{"key":"857_CR31","doi-asserted-by":"publisher","first-page":"026103","DOI":"10.1103\/PhysRevE.65.026103","volume":"65","author":"S Jain","year":"2002","unstructured":"Jain S, Krishna S: Crashes, recoveries and core shifts in a model of evolving networks. Phys Rev E Stat Nonlin Soft Matter Phys 2002, 65: 026103. 10.1103\/PhysRevE.65.026103","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"key":"857_CR32","doi-asserted-by":"publisher","first-page":"5673","DOI":"10.1128\/JB.185.19.5673-5684.2003","volume":"185","author":"SY Gerdes","year":"2003","unstructured":"Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL: Experimental determination and system level analysis of essential genes in Escherichia coli MG1655. J Bacteriol 2003, 185: 5673\u201384. 10.1128\/JB.185.19.5673-5684.2003","journal-title":"J Bacteriol"},{"key":"857_CR33","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nature02289","volume":"427","author":"E Almaas","year":"2004","unstructured":"Almaas E, Kovacs B, Vicsek T, Oltvai ZN, Barabasi AL: Global organization of metabolic fluxes in the bacterium Escherichia coli . Nature 2004, 427: 839\u2013843. 10.1038\/nature02289","journal-title":"Nature"},{"key":"857_CR34","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/ng881","volume":"31","author":"S Shen-Orr","year":"2002","unstructured":"Shen-Orr S, Milo R, Mangan S, Alon U: Network motifs in the transcriptional regulation network of Escherichia coli . Nat Genet 2002, 31: 64\u201368. 10.1038\/ng881","journal-title":"Nat Genet"},{"key":"857_CR35","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1126\/science.298.5594.824","volume":"298","author":"R Milo","year":"2002","unstructured":"Milo R, Shen-Orr S, Itzkovitz S, Kashtan N, Chklovskii D, Alon U: Network Motifs: Simple Building Blocks of Complex Networks. Science 2002, 298: 824\u2013827. 10.1126\/science.298.5594.824","journal-title":"Science"},{"key":"857_CR36","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1126\/science.1089167","volume":"303","author":"R Milo","year":"2004","unstructured":"Milo R, Itzkovitz S, Kashtan N, Levitt R, Shen-Orr S, Ayzenshtat I, Sheffer M, Alon U: Superfamilies of Evolved and Designed Networks. Science 2004, 303: 1538\u20131542. 10.1126\/science.1089167","journal-title":"Science"},{"key":"857_CR37","unstructured":"These clusters are mentioned in a talk presented by one of the authors at the 22\n                    nd\n                  International Conference on Statistical Physics STATPHYS22 in July 2004 (this talk is not part of any published conference proceedings but its material can be viewed on the conference website[http:\/\/statphys.physics.iisc.ernet.in\/UPLOADS\/thursday\/HallJ\/SanjayJain.ppt]"},{"issue":"7","key":"857_CR38","doi-asserted-by":"publisher","first-page":"e68","DOI":"10.1371\/journal.pcbi.0010068","volume":"1","author":"E Almaas","year":"2005","unstructured":"Almaas E, Oltvai ZN, Barabasi AL: The activity reaction core and plasticity of metabolic networks. PLoS Comput Biol 2005, 1(7):e68. 10.1371\/journal.pcbi.0010068","journal-title":"PLoS Comput Biol"},{"key":"857_CR39","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nature02636","volume":"429","author":"B Papp","year":"2004","unstructured":"Papp B, Pal C, Hurst LD: Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast. Nature 2004, 429: 661\u2013664. 10.1038\/nature02636","journal-title":"Nature"},{"key":"857_CR40","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/(SICI)1099-0526(199907\/08)4:6<39::AID-CPLX8>3.0.CO;2-2","volume":"4","author":"HJ Morowitz","year":"1999","unstructured":"Morowitz HJ: A theory of biochemical organization, metabolic pathways, and evolution. Complexity 1999, 4: 39\u201353. Publisher Full Text 10.1002\/(SICI)1099-0526(199907\/08)4:6<39::AID-CPLX8>3.0.CO;2-2","journal-title":"Complexity"},{"key":"857_CR41","unstructured":"UCSD Systems Biology Research Group[http:\/\/gcrg.ucsd.edu\/organisms\/index.html]"},{"key":"857_CR42","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1002\/(SICI)1098-2418(199907)14:4<293::AID-RSA1>3.0.CO;2-G","volume":"14","author":"R Kannan","year":"1999","unstructured":"Kannan R, Tetali P, Vempala S: Simple Markov-chain algorithms for generating bipartite graphs and tournaments. Random Structures and Algorithms 1999, 14: 293\u2013308. Publisher Full Text 10.1002\/(SICI)1098-2418(199907)14:4<293::AID-RSA1>3.0.CO;2-G","journal-title":"Random Structures and Algorithms"},{"key":"857_CR43","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1126\/science.1065103","volume":"296","author":"S Maslov","year":"2002","unstructured":"Maslov S, Sneppen K: Specificity and stability in topology of protein networks. Science 2002, 296: 910\u2013913. 10.1126\/science.1065103","journal-title":"Science"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-7-118.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T03:21:20Z","timestamp":1630466480000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-7-118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,3,8]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2006,12]]}},"alternative-id":["857"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-7-118","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,3,8]]},"assertion":[{"value":"23 November 2005","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2006","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2006","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"118"}}