{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T05:44:00Z","timestamp":1767851040678,"version":"3.49.0"},"reference-count":63,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,30]],"date-time":"2019-11-30T00:00:00Z","timestamp":1575072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Padova","award":["BIRD 2017"],"award-info":[{"award-number":["BIRD 2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca2+ concentration) of the channels, and local coupling in ion channel complexes (e.g., via local Ca2+ concentration surrounding Ca2+ channels (CaVs), the so-called Ca2+ nanodomains). We recently devised a model of large-conductance BKCa potassium currents, and hence BKCa\u2013CaV complexes controlled locally by CaVs via Ca2+ nanodomains. We showed how different CaV types and BKCa\u2013CaV stoichiometries affect whole-cell electrical behavior. Ca2+ nanodomains are also important for triggering exocytosis of hormone-containing granules, and in this regard, we implemented a strategy to characterize the local interactions between granules and CaVs. In this study, we coupled electrical and exocytosis models respecting the local effects via Ca2+ nanodomains. By simulating scenarios with BKCa\u2013CaV complexes with different stoichiometries in pituitary cells, we achieved two main electrophysiological responses (continuous spiking or bursting) and investigated their effects on the downstream exocytosis process. By varying the number and distance of CaVs coupled with the granules, we found that bursting promotes exocytosis with faster rates than spiking. However, by normalizing to Ca2+ influx, we found that bursting is only slightly more efficient than spiking when CaVs are far away from granules, whereas no difference in efficiency between bursting and spiking is observed with close granule-CaV coupling.<\/jats:p>","DOI":"10.3390\/ijms20236057","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T10:50:45Z","timestamp":1575283845000},"page":"6057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["From Local to Global Modeling for Characterizing Calcium Dynamics and Their Effects on Electrical Activity and Exocytosis in Excitable Cells"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3264-9686","authenticated-orcid":false,"given":"Francesco","family":"Montefusco","sequence":"first","affiliation":[{"name":"Department of Information Engineering, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2639-2394","authenticated-orcid":false,"given":"Morten","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Padova, 35131 Padova, Italy"},{"name":"Department of Mathematics \u201cTullio Levi-Civita\u201d, University of Padova, 35131 Padova, Italy"},{"name":"Padova Neuroscience Center, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A quantitative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"Hodgkin","year":"1952","journal-title":"J. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nn.2493","article-title":"Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes","volume":"13","author":"Anderson","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1152\/physrev.00049.2009","article-title":"Ca2+-Activated K+ Channels: From Protein Complexes to Function","volume":"90","author":"Berkefeld","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36750","DOI":"10.1074\/jbc.M113.511485","article-title":"Caveolin-1 Facilitates the Direct Coupling between Large Conductance Ca2+-activated K+(BKCa) and Cav1.2 Ca2+ Channels and Their Clustering to Regulate Membrane Excitability in Vascular Myocytes","volume":"288","author":"Suzuki","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/S0006-3495(84)84244-7","article-title":"Calcium domains associated with individual channels can account for anomalous voltage relations of CA-dependent responses","volume":"45","author":"Chad","year":"1984","journal-title":"Biophys. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0006-3495(85)83804-2","article-title":"Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release","volume":"48","author":"Simon","year":"1985","journal-title":"Biophys. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S0896-6273(00)80983-6","article-title":"Vesicle Pools and Ca2+ Microdomains: New Tools for Understanding Their Roles in Neurotransmitter Release","volume":"20","author":"Neher","year":"1998","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.neuron.2008.09.001","article-title":"Control of KCa Channels by Calcium Nano\/Microdomains","volume":"59","author":"Fakler","year":"2008","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7358","DOI":"10.1523\/JNEUROSCI.5443-12.2013","article-title":"Ligand-Gating by Ca2+ Is Rate Limiting for Physiological Operation of BKCa Channels","volume":"33","author":"Berkefeld","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1016\/j.bpj.2014.10.069","article-title":"Modeling a Ca2+ Channel\/BKCa Channel Complex at the Single-Complex Level","volume":"107","author":"Cox","year":"2014","journal-title":"Biophys. J."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Buchholz, P., Kriege, J., and Felko, I. (2014). Phase-Type Distributions. Input Modeling with Phase-Type Distributions and Markov Models, Springer International Publishing.","DOI":"10.1007\/978-3-319-06674-5"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1137\/1031091","article-title":"The Quasi-Steady-State Assumption: A Case Study in Perturbation","volume":"31","author":"Segel","year":"1989","journal-title":"SIAM Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1016\/j.bpj.2017.04.035","article-title":"Concise Whole-Cell Modeling of BKCa-CaV Activity Controlled by Local Coupling and Stoichiometry","volume":"112","author":"Montefusco","year":"2017","journal-title":"Biophys. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1529\/biophysj.106.099861","article-title":"A Probability Density Approach to Modeling Local Control of Calcium-Induced Calcium Release in Cardiac Myocytes","volume":"92","author":"Williams","year":"2007","journal-title":"Biophys. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1152\/physrev.00031.2002","article-title":"Secretory Granule Exocytosis","volume":"83","author":"Burgoyne","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1034\/j.1600-0773.2003.920102.x","article-title":"Mechanisms of Exocytosis in Insulin-Secreting Beta-Cells and Glucagon-Secreting Alpha-Cells","volume":"92","author":"Barg","year":"2003","journal-title":"Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/29871","article-title":"SNAREs line up in new environment","volume":"393","author":"Jahn","year":"1998","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/jnc.13602","article-title":"Exocytosis in non-neuronal cells","volume":"137","author":"Thorn","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.mbs.2016.11.010","article-title":"Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells","volume":"283","author":"Pedersen","year":"2017","journal-title":"Math. Biosci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bornschein, G., and Schmidt, H. (2019). Synaptotagmin Ca2+ Sensors and Their Spatial Coupling to Presynaptic Cav Channels in Central Cortical Synapses. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00494"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1172\/JCI88491","article-title":"Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes","volume":"127","author":"Gandasi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/5721097","article-title":"Explicit Theoretical Analysis of How the Rate of Exocytosis Depends on Local Control by Ca2+ Channels","volume":"2018","author":"Montefusco","year":"2018","journal-title":"Comput. Math. Methods Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vivas, O., Moreno, C.M., Santana, L.F., and Hille, B. (2017). Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage. eLife, 6.","DOI":"10.7554\/eLife.28029"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tem.2005.02.002","article-title":"Ca2+-regulated exocytosis and SNARE function","volume":"16","author":"Stojilkovic","year":"2005","journal-title":"Trends Endocrinol. Metab. TEM"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E515","DOI":"10.1152\/ajpendo.00500.2015","article-title":"Is bursting more effective than spiking in evoking pituitary hormone secretion? A spatiotemporal simulation study of calcium and granule dynamics","volume":"310","author":"Tagliavini","year":"2016","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10827-006-0008-4","article-title":"Low dose of dopamine may stimulate prolactin secretion by increasing fast potassium currents","volume":"22","author":"Tabak","year":"2006","journal-title":"J. Comput. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1126\/science.1132915","article-title":"BKCa-Cav Channel Complexes Mediate Rapid and Localized Ca2-Activated K+ Signaling","volume":"314","author":"Berkefeld","year":"2006","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1023\/A:1027424128972","article-title":"AHP\u2019s, HAP\u2019s and DAP\u2019s: How Potassium Currents Regulate the Excitability of Rat Supraoptic Neurones","volume":"15","author":"Roper","year":"2003","journal-title":"J. Comput. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1016\/j.bpj.2010.09.004","article-title":"A Biophysical Model of Electrical Activity in Human Beta-Cells","volume":"99","author":"Pedersen","year":"2010","journal-title":"Biophys. J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Riz, M., Braun, M., and Pedersen, M.G. (2014). Mathematical Modeling of Heterogeneous Electrophysiological Responses in Human Beta-Cells. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003389"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/293471a0","article-title":"Single channel recordings of Ca2+-activated K+ currents in rat muscle cell culture","volume":"293","author":"Pallotta","year":"1981","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1152\/jn.00127.2012","article-title":"Iberiotoxin-sensitive and -insensitive BK currents in Purkinje neuron somata","volume":"109","author":"Benton","year":"2013","journal-title":"J. Neurophysiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1113\/jphysiol.1987.sp016517","article-title":"Action potential repolarization and a fast after-hyperpolarization in rat hippocampal pyramidal cells","volume":"385","author":"Storm","year":"1987","journal-title":"J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.2337\/db07-0991","article-title":"Voltage-Gated Ion Channels in Human Pancreatic Beta-Cells: Electrophysiological Characterization and Role in Insulin Secretion","volume":"57","author":"Braun","year":"2008","journal-title":"Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1113\/jphysiol.2009.184341","article-title":"BK channels mediate a novel ionic mechanism that regulates glucose-dependent electrical activity and insulin secretion in mouse pancreatic beta-cells","volume":"588","author":"Houamed","year":"2010","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1016\/S0006-3495(01)75964-4","article-title":"Fast exocytosis with few Ca2+ channels in insulin-secreting mouse pancreatic beta-cells","volume":"81","author":"Barg","year":"2001","journal-title":"Biophys. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.2337\/diabetes.49.9.1500","article-title":"Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells","volume":"49","author":"Barg","year":"2000","journal-title":"Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S0896-6273(00)80812-0","article-title":"Mechanisms Underlying Phasic and Sustained Secretion in Chromaffin Cells from Mouse Adrenal Slices","volume":"23","author":"Voets","year":"1999","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1529\/biophysj.107.118190","article-title":"Real-Time Kinetic Modeling of Voltage-Gated Ion Channels Using Dynamic Clamp","volume":"95","author":"Milescu","year":"2008","journal-title":"Biophys. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.1113\/JP270777","article-title":"Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha-cells","volume":"593","author":"Montefusco","year":"2015","journal-title":"J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"385","DOI":"10.4067\/S0716-97602006000300003","article-title":"Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage","volume":"39","author":"Latorre","year":"2006","journal-title":"Biol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1085\/jgp.110.3.257","article-title":"Allosteric Gating of a Large Conductance Ca-activated K+ Channel","volume":"110","author":"Cox","year":"1997","journal-title":"J. Gen. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1085\/jgp.20028627","article-title":"Elimination of the BKCa Channel\u2019s High-Affinity Ca2+ Sensitivity","volume":"120","author":"Bao","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nature00956","article-title":"Multiple regulatory sites in large-conductance calcium-activated potassium channels","volume":"418","author":"Xia","year":"2002","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1073\/pnas.0705261105","article-title":"The RCK2 domain of the human BKCa channel is a calcium sensor","volume":"105","author":"Yusifov","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1085\/jgp.114.2.305","article-title":"Allosteric Voltage Gating of Potassium Channels II","volume":"114","author":"Horrigan","year":"1999","journal-title":"J. Gen. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S0006-3495(90)82443-7","article-title":"Domain model for Ca2+-inactivation of Ca2+ channels at low channel density","volume":"58","author":"Sherman","year":"1990","journal-title":"Biophys. J."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Neher, E. (1986). Concentration profiles of intracellular Ca2+ in the presence of diffusible chelator. Calcium Electrogenesis and Neuronal Functioning, Exp. Brain Res. 14, Springer-Verlag.","DOI":"10.1007\/978-3-642-70744-5_8"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6961","DOI":"10.1523\/JNEUROSCI.17-18-06961.1997","article-title":"Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel","volume":"17","author":"Naraghi","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1137\/S0036139900368996","article-title":"Asymptotic Analysis of Buffered Calcium Diffusion near a Point Source","volume":"61","author":"Sherman","year":"2001","journal-title":"SIAM J. Appl. Math."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1016\/S0006-3495(04)74324-6","article-title":"Facilitation through Buffer Saturation: Constraints on Endogenous Buffering Properties","volume":"86","author":"Matveev","year":"2004","journal-title":"Biophys. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1523\/JNEUROSCI.13-02-00516.1993","article-title":"Modulation of N-type calcium channels in bullfrog sympathetic neurons by luteinizing hormone-releasing hormone: Kinetics and voltage dependence","volume":"13","author":"Boland","year":"1993","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/nn.2657","article-title":"N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release","volume":"13","author":"Weber","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1523\/JNEUROSCI.4961-09.2010","article-title":"Loss of Cav1.3 Channels Reveals the Critical Role of L-Type and BK Channel Coupling in Pacemaking Mouse Adrenal Chromaffin Cells","volume":"30","author":"Marcantoni","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8238","DOI":"10.1523\/JNEUROSCI.2274-08.2008","article-title":"Repolarizing Responses of BKCa-Cav Complexes Are Distinctly Shaped by Their Cav Subunits","volume":"28","author":"Berkefeld","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Rehak, R., Bartoletti, T.M., Engbers, J.D.T., Berecki, G., Turner, R.W., and Zamponi, G.W. (2013). Low Voltage Activation of KCa1.1 Current by Cav3-KCa1.1 Complexes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061844"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1523\/JNEUROSCI.3816-06.2007","article-title":"Nanodomains of Single Ca2+ Channels Contribute to Action Potential Repolarization in Cortical Neurons","volume":"27","author":"Muller","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/jnc.13865","article-title":"C2-domain containing calcium sensors in neuroendocrine secretion","volume":"139","author":"Pinheiro","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0896-6273(00)00131-8","article-title":"Dissection of Three Ca2+-Dependent Steps Leading to Secretion in Chromaffin Cells from Mouse Adrenal Slices","volume":"28","author":"Voets","year":"2000","journal-title":"Neuron"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1152\/jn.00316.2005","article-title":"Mouse Chromaffin Cells Have Two Populations of Dense Core Vesicles","volume":"94","author":"Grabner","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00424-011-0979-5","article-title":"Glucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell","volume":"462","author":"Andersson","year":"2011","journal-title":"Pfl\u00fcgers Arch. Eur. J. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00424-002-0781-5","article-title":"Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic beta-cells","volume":"444","author":"Olofsson","year":"2002","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/BF01230690","article-title":"Ultrastructural morphometry of the pancreatic beta-cell","volume":"9","author":"Dean","year":"1973","journal-title":"Diabetologia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6057\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:39:01Z","timestamp":1760189941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,30]]},"references-count":63,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20236057"],"URL":"https:\/\/doi.org\/10.3390\/ijms20236057","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,30]]}}}