{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T12:44:33Z","timestamp":1767962673683,"version":"3.49.0"},"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 Syst Biol"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>The octapeptide Angiotensin II is a key hormone that acts via its receptor AT1R in the brainstem to modulate the blood pressure control circuits and thus plays a central role in the cardiac and respiratory homeostasis. This modulation occurs via activation of a complex network of signaling proteins and transcription factors, leading to changes in levels of key genes and proteins. AT1R initiated activity in the nucleus tractus solitarius (NTS), which regulates blood pressure, has been the subject of extensive molecular analysis. But the adaptive network interactions in the NTS response to AT1R, plausibly related to the development of hypertension, are not understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We developed and analyzed a mathematical model of AT1R-activated signaling kinases and a downstream gene regulatory network, with structural basis in our transcriptomic data analysis and literature. To our knowledge, our report presents the first computational model of this key regulatory network. Our simulations and analysis reveal a dynamic balance among distinct dimers of the AP-1 family of transcription factors. We investigated the robustness of this behavior to simultaneous perturbations in the network parameters using a novel multivariate approach that integrates global sensitivity analysis with decision-tree methods. Our analysis implicates a subset of Fos and Jun dependent mechanisms, with dynamic sensitivities shifting from Fos-regulating kinase (FRK)-mediated processes to those downstream of c-Jun N-terminal kinase (JNK). Decision-tree analysis indicated that while there may be a large combinatorial functional space feasible for neuronal states and parameters, the network behavior is constrained to a small set of AP-1 response profiles. Many of the paths through the combinatorial parameter space lead to a dynamic balance of AP-1 dimer forms, yielding a robust AP-1 response counteracting the biological variability.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Based on the simulation and analysis results, we demonstrate that a dynamic balance among distinct dimers of the AP-1 family of transcription factors underlies the robust activation of neuronal gene expression in the NTS response to AT1R activation. Such a differential sensitivity to limited set of mechanisms is likely to underlie the stable homeostatic physiological response.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-4-171","type":"journal-article","created":{"date-parts":[[2011,1,5]],"date-time":"2011-01-05T19:27:47Z","timestamp":1294255667000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Robust dynamic balance of AP-1 transcription factors in a neuronal gene regulatory network"],"prefix":"10.1186","volume":"4","author":[{"given":"Gregory M","family":"Miller","sequence":"first","affiliation":[]},{"given":"Babatunde A","family":"Ogunnaike","sequence":"additional","affiliation":[]},{"given":"James S","family":"Schwaber","sequence":"additional","affiliation":[]},{"given":"Rajanikanth","family":"Vadigepalli","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2010,12,17]]},"reference":[{"key":"582_CR1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/0033-0620(74)90038-3","volume":"17","author":"DJ Reis","year":"1974","unstructured":"Reis DJ, Doba N: The central nervous system and neurogenic hypertension. Prog Cardiovasc Dis. 1974, 17: 51-71. 10.1016\/0033-0620(74)90038-3","journal-title":"Prog Cardiovasc Dis"},{"key":"582_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0006-8993(89)90343-0","volume":"484","author":"DP Healy","year":"1989","unstructured":"Healy DP, Rettig R, Nguyen T, Printz MP: Quantitative autoradiography of angiotensin II receptors in the rat solitary-vagal area: Effects of nodose ganglionectomy or sinoaortic denervation. Brain Res. 1989, 484: 1-12. 10.1016\/0006-8993(89)90343-0","journal-title":"Brain Res"},{"key":"582_CR3","first-page":"R193","volume":"250","author":"R Casto","year":"1986","unstructured":"Casto R, Phillips MI: Angiotensin II attenuates baroreflexes at nucleus tractus solitarius of rats. Am J Physiol. 1986, 250: R193-8.","journal-title":"Am J Physiol"},{"key":"582_CR4","doi-asserted-by":"publisher","first-page":"I45","DOI":"10.1161\/01.HYP.15.2_Suppl.I45","volume":"15","author":"LC Michelini","year":"1990","unstructured":"Michelini LC, Bonagamba LG: Angiotensin II as a modulator of baroreceptor reflexes in the brainstem of conscious rats. Hypertension. 1990, 15: I45-50.","journal-title":"Hypertension"},{"key":"582_CR5","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0006-8993(97)01198-0","volume":"782","author":"HF Luoh","year":"1998","unstructured":"Luoh HF, Chan SH: Participation of AT1 and AT2 receptor subtypes in the tonic inhibitory modulation of baroreceptor reflex response by endogenous angiotensins at the nucleus tractus solitarii in the rat. Brain Res. 1998, 782: 73-82. 10.1016\/S0006-8993(97)01198-0","journal-title":"Brain Res"},{"key":"582_CR6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0306-4522(03)00606-7","volume":"122","author":"J Huang","year":"2003","unstructured":"Huang J, Hara Y, Anrather J, Speth RC, Iadecola C, Pickel VM: Angiotensin II subtype 1A (AT1A) receptors in the rat sensory vagal complex: subcellular localization and association with endogenous angiotensin. Neuroscience. 2003, 122: 21-36. 10.1016\/S0306-4522(03)00606-7","journal-title":"Neuroscience"},{"key":"582_CR7","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1152\/ajpregu.00041.2007","volume":"293","author":"JW Polson","year":"2007","unstructured":"Polson JW, Dampney RA, Boscan P, Pickering AE, Paton JF: Differential baroreflex control of sympathetic drive by angiotensin II in the nucleus tractus solitarii. Am J Physiol Regul Integr Comp Physiol. 2007, 293: 1954-1960.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"582_CR8","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1113\/expphysiol.2008.042861","volume":"93","author":"MK Raizada","year":"2008","unstructured":"Raizada MK, Paton JR: Recent advances in the renin-angiotensin system: angiotensin-converting enzyme 2 and (pro)renin receptor. Exp Phys. 2008, 93: 517-8. 10.1113\/expphysiol.2008.042861.","journal-title":"Exp Phys"},{"key":"582_CR9","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1161\/01.RES.46.6.842","volume":"46","author":"W Talman","year":"1980","unstructured":"Talman W, Snyder D, Reis D: Chronic lability of arterial pressure produced by destruction of A2 catecholaminergic neurons in rat brainstem. Circulation Research. 1980, 46: 842-53.","journal-title":"Circulation Research"},{"key":"582_CR10","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1007\/s11906-007-0043-1","volume":"9","author":"J Paton","year":"2007","unstructured":"Paton J, Waki H, Abdala A, Dickinson J, Kasparov S: Vascular-brain signaling in hypertension: role of angiotensin II and nitric oxide. Curr Hypertens Rep. 2007, 9: 242-7. 10.1007\/s11906-007-0043-1","journal-title":"Curr Hypertens Rep"},{"key":"582_CR11","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1113\/expphysiol.2007.041814","volume":"93","author":"S Kasparov","year":"2008","unstructured":"Kasparov S, Teschemacher AG: Altered central catecholaminergic transmission and cardiovascular disease. Exp Phys. 2008, 93: 725-40. 10.1113\/expphysiol.2007.041814.","journal-title":"Exp Phys"},{"key":"582_CR12","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1152\/ajpcell.1987.252.6.C650","volume":"252","author":"C Sumners","year":"1987","unstructured":"Sumners C, Shalit S, Kalberg C, Raizada M: Norepinephrine metabolism in neuronal cultures is increased by angiotensin II. Am J Physiol. 1987, 252: 650-6.","journal-title":"Am J Physiol"},{"key":"582_CR13","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1196\/annals.1296.036","volume":"1018","author":"I Armando","year":"2004","unstructured":"Armando I, Jezova M, Bregonzio C, Baiardi G, Saavedra JM: Angiotensin II AT1 and AT2 receptor types regulate basal and stress-induced adrenomedullary catecholamine production through transcriptional regulation of tyrosine hydroxylase. Ann N Y Acad Sci. 2004, 1018: 302-9. 10.1196\/annals.1296.036","journal-title":"Ann N Y Acad Sci"},{"key":"582_CR14","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/0306-4522(94)00600-A","volume":"66","author":"RK Chan","year":"1995","unstructured":"Chan RK, Sawchenko PE: Hemodynamic regulation of tyrosine hydroxylase messenger RNA in medullary catecholamine neurons: a c-fos-guided hybridization histochemical study. Neuroscience. 1995, 66: 377-390. 10.1016\/0306-4522(94)00600-A","journal-title":"Neuroscience"},{"key":"582_CR15","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/0306-4522(94)00482-K","volume":"65","author":"CJ Lebrun","year":"1995","unstructured":"Lebrun CJ, Blume A, Herdegen T, Seifert K, Bravo R, Unger T: Angiotensin II induces a complex activation of transcription factors in the rat brain: expression of Fos, Jun and Krox proteins. Neuroscience. 1995, 65: 93-99. 10.1016\/0306-4522(94)00482-K","journal-title":"Neuroscience"},{"key":"582_CR16","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/0167-0115(96)00046-8","volume":"66","author":"CJ Lebrun","year":"1996","unstructured":"Lebrun CJ, Blume A, Herdegen T, Mollenhoff E, Unger T: Complex activation of inducible transcription factors in the brain of normotensive and spontaneously hypertensive rats following central angiotensin II administration. Regul Pept. 1996, 66: 19-23. 10.1016\/0167-0115(96)00046-8","journal-title":"Regul Pept"},{"key":"582_CR17","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/BF02741376","volume":"19","author":"EM Richards","year":"1999","unstructured":"Richards EM, Raizada MK, Gelband CH, Sumners C: Angiotensin II type 1 receptor-modulated signaling pathways in neurons. Mol Neurobiol. 1999, 19: 25-41. 10.1007\/BF02741376","journal-title":"Mol Neurobiol"},{"key":"582_CR18","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1590\/S0100-879X2002000900001","volume":"35","author":"RM Touyz","year":"2002","unstructured":"Touyz RM, Berry C: Recent advances in angiotensin II signaling. Braz J Med Biol Res. 2002, 35: 1001-1015. 10.1590\/S0100-879X2002000900001","journal-title":"Braz J Med Biol Res"},{"key":"582_CR19","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1046\/j.1440-1681.2002.03660.x","volume":"29","author":"C Sumners","year":"2002","unstructured":"Sumners C, Fleegal MA, Zhu M: Angiotensin AT1 receptor signalling pathways in neurons. Clin Exp Pharmacol Physiol. 2002, 29: 483-490. 10.1046\/j.1440-1681.2002.03660.x","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"582_CR20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1152\/ajpregu.00152.2008","volume":"295","author":"RL Khan","year":"2008","unstructured":"Khan RL, Vadigepalli R, McDonald MK, Rogers RF, Gao GR, Schwaber JS: Dynamic transcriptomic response to acute hypertension in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol. 2008, 295: 15-27.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"582_CR21","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1089\/153623103322452378","volume":"7","author":"R Vadigepalli","year":"2003","unstructured":"Vadigepalli R, Chakravarthula P, Zak DE, Schwaber JS, Gonye GE: PAINT: a promoter analysis and interaction network generation tool for gene regulatory network identification. OMICS. 2003, 7: 235-52. 10.1089\/153623103322452378","journal-title":"OMICS"},{"key":"582_CR22","volume-title":"Methods in Bioengineering: Systems Analysis of Biological Networks","author":"R Vadigepalli","year":"2009","unstructured":"Vadigepalli R: A workflow from time series gene expression to transcriptional regulatory networks. Methods in Bioengineering: Systems Analysis of Biological Networks. Edited by: Jayaraman A, Hahn J. 2009, Artech House"},{"key":"582_CR23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/978-1-59745-547-3_4","volume":"408","author":"GE Gonye","year":"2007","unstructured":"Gonye GE, Chakravarthula P, Schwaber JS, Vadigepalli R: From promoter analysis to transcriptional regulatory network prediction using PAINT. Methods Mol Biol. 2007, 408: 49-68. full_text","journal-title":"Methods Mol Biol"},{"key":"582_CR24","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/sj.bjp.0705262","volume":"139","author":"S Veerasingham","year":"2003","unstructured":"Veerasingham S, Raizada MK: Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharm. 2003, 139: 191-202. 10.1038\/sj.bjp.0705262.","journal-title":"Br J Pharm"},{"key":"582_CR25","doi-asserted-by":"publisher","first-page":"15635","DOI":"10.1074\/jbc.271.26.15635","volume":"271","author":"XC Huang","year":"1996","unstructured":"Huang XC, Richards EM, Sumners C: Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors. J Biol Chem. 1996, 271: 15635-15641. 10.1074\/jbc.271.26.15635","journal-title":"J Biol Chem"},{"key":"582_CR26","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1210\/en.139.1.245","volume":"139","author":"XC Huang","year":"1998","unstructured":"Huang XC, Deng T, Sumners C: Angiotensin II stimulates activation of Fos-regulating kinase and c-Jun NH2-terminal kinase in neuronal cultures from rat brain. Endocrinology. 1998, 139: 245-251. 10.1210\/en.139.1.245","journal-title":"Endocrinology"},{"key":"582_CR27","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/S0955-0674(97)80068-3","volume":"9","author":"M Karin","year":"1997","unstructured":"Karin M, Liu Z, Zandi E: AP-1 function and regulation. Curr Opin Cell Biol. 1997, 9: 240-246. 10.1016\/S0955-0674(97)80068-3","journal-title":"Curr Opin Cell Biol"},{"key":"582_CR28","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1523\/JNEUROSCI.16-13-04047.1996","volume":"16","author":"H Yang","year":"1996","unstructured":"Yang H, Lu D, Yu K, Raizada MK: Regulation of neuromodulatory actions of angiotensin II in the brain neurons by the Ras-dependent mitogen-activated protein kinase pathway. J Neurosci. 1996, 16: 4047-58.","journal-title":"J Neurosci"},{"key":"582_CR29","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1101\/gr.1198103","volume":"13","author":"DE Zak","year":"2003","unstructured":"Zak DE, Gonye GE, Schwaber JS, Doyle FJ: Importance of input perturbations and stochastic gene expression in the reverse engineering of genetic regulatory networks: insights from an identifiability analysis of an in silico network. Genome Res. 2003, 13: 2396-405. 10.1101\/gr.1198103","journal-title":"Genome Res"},{"key":"582_CR30","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1046\/j.1432-1327.2000.01197.x","volume":"267","author":"BN Kholodenko","year":"2000","unstructured":"Kholodenko BN: Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur J Biochem. 2000, 267: 1583-8. 10.1046\/j.1432-1327.2000.01197.x","journal-title":"Eur J Biochem"},{"key":"582_CR31","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/msb4100188","volume":"3","author":"MR Birtwistle","year":"2007","unstructured":"Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN: Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol. 2007, 3: 144- 10.1038\/msb4100188","journal-title":"Mol Syst Biol"},{"key":"582_CR32","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.febslet.2004.11.104","volume":"579","author":"I Oney","year":"2005","unstructured":"Oney I, Kurnaz I, Kurnaz M: Cytoplasmic-to-nuclear volume ratio affects AP-1 complex formation as an indicator of cell cycle responsiveness. FEBS Lett. 2005, 579: 433-40. 10.1016\/j.febslet.2004.11.104","journal-title":"FEBS Lett"},{"key":"582_CR33","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1083\/jcb.135.6.1609","volume":"135","author":"D Lu","year":"1996","unstructured":"Lu D, Yang H, Raizada MK: Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase. J Cell Biol. 1996, 135: 1609-17. 10.1083\/jcb.135.6.1609","journal-title":"J Cell Biol"},{"key":"582_CR34","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1210\/en.137.2.763","volume":"137","author":"D Lu","year":"2003","unstructured":"Lu D, Yu K, Paddy M, Rowland N, Raizada MK: Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. Endocrinology. 2003, 137: 763-72. 10.1210\/en.137.2.763.","journal-title":"Endocrinology"},{"key":"582_CR35","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.bbrc.2003.09.047","volume":"310","author":"M Fleegal","year":"2006","unstructured":"Fleegal M, Sumners C: Angiotensin II induction of AP-1 in neurons requires stimulation of PI3-K and JNK. Biochem Biophys Res Comm. 2006, 310: 470-7. 10.1016\/j.bbrc.2003.09.047.","journal-title":"Biochem Biophys Res Comm"},{"key":"582_CR36","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1529\/biophysj.105.065250","volume":"90","author":"H Hao","year":"2006","unstructured":"Hao H, Zak DE, Sauter T, Schwaber JS, Ogunnaike BA: Modeling the VPAC2-activated cAMP\/PKA signaling pathway: from receptor to circadian clock gene induction. Biophys J. 2006, 90: 1560-1571. 10.1529\/biophysj.105.065250","journal-title":"Biophys J"},{"key":"582_CR37","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1098\/rsif.2005.0109","volume":"3","author":"F Hua","year":"2006","unstructured":"Hua F, Hautaniemi S, Yokoo R, Lauffenburger DA: Integrated mechanistic and data-driven modelling for multivariate analysis of signalling pathways. J R Soc Interface. 2006, 3: 515-26. 10.1098\/rsif.2005.0109","journal-title":"J R Soc Interface"},{"key":"582_CR38","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S0378-4754(00)00270-6","volume":"55","author":"I Sobol","year":"2001","unstructured":"Sobol I: Global sensitivity indices for nonlinear mathematical models and their Monte Carlo estimates. Math and Comp in Sim. 2001, 55: 271-280. 10.1016\/S0378-4754(00)00270-6.","journal-title":"Math and Comp in Sim"},{"key":"582_CR39","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/S0010-4655(02)00280-1","volume":"145","author":"A Saltelli","year":"2002","unstructured":"Saltelli A: Making best use of model evaluations to compute sensitivity indices. Comp Phys Comm. 2002, 145: 280-97. 10.1016\/S0010-4655(02)00280-1.","journal-title":"Comp Phys Comm"},{"key":"582_CR40","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1523\/JNEUROSCI.17-05-01660.1997","volume":"17","author":"H Yang","year":"1997","unstructured":"Yang H, Lu D, Vinson GP, Raiazda MK: Involvement of MAP kinase in angiotensin II-induced phosphorylation and intracellular targeting of neuronal AT1 receptors. J Neurosci. 1997, 17: 1660-1669.","journal-title":"J Neurosci"},{"key":"582_CR41","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1006\/jcom.1998.0489","volume":"14","author":"J Matousek","year":"1998","unstructured":"Matousek J: On the L2-Discrepancy for Anchored Boxes. J Complex. 1998, 14: 527-56. 10.1006\/jcom.1998.0489.","journal-title":"J Complex"},{"key":"582_CR42","doi-asserted-by":"publisher","first-page":"research0042.1","DOI":"10.1186\/gb-2001-2-10-research0042","volume":"2","author":"P Pavlidis","year":"2001","unstructured":"Pavlidis P, Noble WS: Analysis of strain and regional variation in gene expression in mouse brain. Genome Biol. 2001, 2: research0042.1-0042.15. 10.1186\/gb-2001-2-10-research0042.","journal-title":"Genome Biol"},{"key":"582_CR43","doi-asserted-by":"publisher","first-page":"299","DOI":"10.2307\/1390807","volume":"5","author":"R Ihaka","year":"1996","unstructured":"Ihaka R, Gentlemen R: R: A language for data analysis and graphics. J Comp Graph Stat. 1996, 5: 299-314. 10.2307\/1390807.","journal-title":"J Comp Graph Stat"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-4-171.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T05:13:46Z","timestamp":1630473226000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-4-171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,12]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010,12]]}},"alternative-id":["582"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-4-171","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,12]]},"assertion":[{"value":"13 July 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2010","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2010","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"171"}}