{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T21:08:58Z","timestamp":1782594538564,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005924","name":"International Association for the Study of Pain","doi-asserted-by":"publisher","award":["2014"],"award-info":[{"award-number":["2014"]}],"id":[{"id":"10.13039\/100005924","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Botulinum neurotoxin type A (BoNT\/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT\/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT\/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT\/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT\/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT\/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT\/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation.<\/jats:p>","DOI":"10.3390\/toxins12080491","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T07:45:57Z","timestamp":1596440757000},"page":"491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice"],"prefix":"10.3390","volume":"12","author":[{"given":"Valentina","family":"Vacca","sequence":"first","affiliation":[{"name":"CNR\u2014National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy"},{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0839-5724","authenticated-orcid":false,"given":"Luca","family":"Madaro","sequence":"additional","affiliation":[{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"},{"name":"DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-3414","authenticated-orcid":false,"given":"Federica","family":"De Angelis","sequence":"additional","affiliation":[{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Proietti","sequence":"additional","affiliation":[{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"},{"name":"DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4588-8982","authenticated-orcid":false,"given":"Stefano","family":"Cobianchi","sequence":"additional","affiliation":[{"name":"Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, E-08193 Bellaterra, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0023-7916","authenticated-orcid":false,"given":"Tiziana","family":"Orsini","sequence":"additional","affiliation":[{"name":"CNR\u2014National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Lorenzo","family":"Puri","sequence":"additional","affiliation":[{"name":"Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-2152","authenticated-orcid":false,"given":"Siro","family":"Luvisetto","sequence":"additional","affiliation":[{"name":"CNR\u2014National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5189-2748","authenticated-orcid":false,"given":"Flaminia","family":"Pavone","sequence":"additional","affiliation":[{"name":"CNR\u2014National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy"},{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5393-4796","authenticated-orcid":false,"given":"Sara","family":"Marinelli","sequence":"additional","affiliation":[{"name":"CNR\u2014National Research Council, Institute of Biochemistry and Cell Biology, 00015 Monterotondo Scalo (RM), Italy"},{"name":"IRCCS Santa Lucia Foundation, 00143 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Consortium for Spinal Cord Medicine (2008). Early acute management in adults with spinal cord injury. J. Spinal Cord Med., 31, 403\u2013479.","DOI":"10.1080\/10790268.2008.11760744"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e345","DOI":"10.1016\/j.wneu.2018.02.033","article-title":"Traumatic spinal injury: Global epidemiology and worldwide volume","volume":"113","author":"Kumar","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/sc.2012.158","article-title":"The global map for traumatic spinal cord injury epidemiology: Update 2011, global incidence rate","volume":"52","author":"Lee","year":"2013","journal-title":"Spinal Cord"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4055\/cios.2017.9.1.1","article-title":"Spinal cord injury and related clinical trials","volume":"9","author":"Kim","year":"2017","journal-title":"CIOS Clin. Orthop. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fnmol.2015.00035","article-title":"Myelin damage and repair in pathologic CNS: Challenges and prospects","volume":"8","author":"Alizadeh","year":"2015","journal-title":"Front. Mol. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41582-019-0280-3","article-title":"The translational landscape in spinal cord injury: Focus on neuroplasticity and regeneration","volume":"15","author":"Hutson","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Boccella, S., Vacca, V., Errico, F., Marinelli, S., Squillace, M., Guida, F., Di Maio, A., Vitucci, D., Palazzo, E., and De Novellis, V. (2015). D-aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/905906"},{"key":"ref_8","first-page":"1","article-title":"Innovative mouse model mimicking human-like features of spinal cord injury: Efficacy of Docosahexaenoic acid on acute and chronic phases","volume":"9","author":"Marinelli","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fonfria, E., Maignel, J., Lezmi, S., Martin, V., Splevins, A., Shubber, S., Kalinichev, M., Foster, K., Picaut, P., and Krupp, J. (2018). The expanding therapeutic utility of botulinum neurotoxins. Toxins, 10.","DOI":"10.3390\/toxins10050208"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1523\/JNEUROSCI.0375-08.2008","article-title":"Long-distance retrograde effects of botulinum neurotoxin A","volume":"28","author":"Antonucci","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Marinelli, S., Vacca, V., Ricordy, R., Uggenti, C., Tata, A.M., Luvisetto, S., and Pavone, F. (2012). The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and Astrocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047977"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.toxicon.2017.10.027","article-title":"Direct central nervous system effects of botulinum neurotoxin","volume":"147","author":"Caleo","year":"2018","journal-title":"Toxicon"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.neuroscience.2010.08.067","article-title":"Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models","volume":"171","author":"Marinelli","year":"2010","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.3390\/toxins2122890","article-title":"Botulinum neurotoxin for pain management: Insights from animal models","volume":"2","author":"Pavone","year":"2010","journal-title":"Toxins"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neuroscience.2017.07.011","article-title":"Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers","volume":"359","author":"Cobianchi","year":"2017","journal-title":"Neuroscience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum neurotoxins: Biology, pharmacology, and toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_17","unstructured":"Marinelli, S., Pavone, F., Luvisetto, S., and Vacca, V. (2015). A New Therapeutic Use of the Botulinum Neurotoxin Serotype A. (Application No. PCT\/IB2016\/052280), International Patent."},{"key":"ref_18","first-page":"1","article-title":"Spinal cord injury: Current mammalian models","volume":"4","author":"Kundi","year":"2013","journal-title":"Am. J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/sc.2014.91","article-title":"Spinal cord injury models: A review","volume":"52","author":"Cheriyan","year":"2014","journal-title":"Spinal Cord"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1089\/neu.2006.23.635","article-title":"Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains","volume":"23","author":"Basso","year":"2006","journal-title":"J. Neurotrauma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fncel.2020.00078","article-title":"Dissecting the dual role of the glial scar and scar-forming astrocytes in spinal cord injury","volume":"14","author":"Yang","year":"2020","journal-title":"Front. Cell Neurosci."},{"key":"ref_22","first-page":"21","article-title":"Intensity of pain and biochemical changes in blood plasma in spinal cord trauma","volume":"48","author":"Sramkova","year":"2009","journal-title":"Spinal Cord"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"256ra137","DOI":"10.1126\/scitranslmed.3009430","article-title":"Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans","volume":"6","author":"Kobayakawa","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Laclaustra, M., van den Berg, E.L.M., Hurtado-Roca, Y., and Castellote, J.M. (2015). Serum lipid profile in subjects with traumatic spinal cord injury. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0115522"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1006\/exnr.2001.7721","article-title":"Changes in Metabotropic Glutamate receptor expression following spinal cord injury","volume":"170","author":"Mills","year":"2001","journal-title":"Exp. Neurol."},{"key":"ref_26","first-page":"20","article-title":"Oligodendrocyte precursor cells in spinal cord injury: A review and update","volume":"2015","author":"Li","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/(SICI)1098-1136(199807)23:3<278::AID-GLIA10>3.0.CO;2-Q","article-title":"Oligodendroglial reaction following spinal cord injury in rat: Transient upregulation of MBP mRNA","volume":"23","author":"Bartholdi","year":"1998","journal-title":"Glia"},{"key":"ref_28","first-page":"55","article-title":"Spinal Cord Stem Cells in Their Microenvironment: The Ependyma as a Stem Cell Niche","volume":"Volume 1041","author":"Marichal","year":"2017","journal-title":"Retinal Degenerative Diseases"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1016\/j.biocel.2013.04.023","article-title":"Protein breakdown in muscle wasting: Role of autophagy-lysosome and ubiquitin-proteasome","volume":"45","author":"Sandri","year":"2013","journal-title":"Int. J. Biochem. Cell Boil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cell.2010.09.004","article-title":"Myogenin and class II HDACs control neurogenic muscle atrophy by inducing E3 Ubiquitin Ligases","volume":"143","author":"Moresi","year":"2010","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.3390\/toxins7072354","article-title":"A highly specific Monoclonal antibody for botulinum neurotoxin Type A-Cleaved SNAP25","volume":"7","author":"Cai","year":"2015","journal-title":"Toxins"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"572","DOI":"10.4103\/1673-5374.180740","article-title":"Extrinsic and intrinsic mechanisms of axon regeneration: The need for spinal cord injury treatment strategies to address both","volume":"11","author":"Vogelaar","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrn1956","article-title":"Glial inhibition of CNS axon regeneration","volume":"7","author":"Yiu","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s12035-012-8287-4","article-title":"Reactive Astrogliosis after spinal cord injury\u2014Beneficial and detrimental effects","volume":"46","author":"Billakanti","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/sj.sc.3101483","article-title":"Post-traumatic inflammation following spinal cord injury","volume":"41","author":"Hausmann","year":"2003","journal-title":"Spinal Cord"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"789","DOI":"10.4103\/1673-5374.131591","article-title":"Spinal cord contusion","volume":"9","author":"Ju","year":"2014","journal-title":"Neural Regen. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.expneurol.2014.02.001","article-title":"Neuroinflammatory contributions to pain after SCI: Roles for central glial mechanisms and nociceptor-mediated host defense","volume":"258","author":"Walters","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71052","DOI":"10.18632\/oncotarget.11958","article-title":"Review: Traumatic brain injury and hyperglycemia, a potentially modifiable risk factor","volume":"7","author":"Shi","year":"2016","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.neuron.2011.05.001","article-title":"Adult neurogenesis in the mammalian brain: Significant answers and significant questions","volume":"70","author":"Ming","year":"2011","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1634\/stemcells.2005-0249","article-title":"Early response of endogenous adult neural progenitor cells to acute spinal cord injury in mice","volume":"24","author":"Ke","year":"2005","journal-title":"Stem Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.ijdevneu.2008.06.002","article-title":"Nestin-positive cells in the spinal cord: A potential source of neural stem cells","volume":"26","author":"Xu","year":"2008","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/jnr.23480","article-title":"Current states of endogenous stem cells in adult spinal cord","volume":"93","author":"Qin","year":"2014","journal-title":"J. Neurosci. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nrn1908","article-title":"The therapeutic potential of neural stem cells","volume":"7","author":"Martino","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pharmthera.2013.08.001","article-title":"Immunopharmacological intervention for successful neural stem cell therapy: New perspectives in CNS neurogenesis and repair","volume":"141","author":"Dooley","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/sc.2017.70","article-title":"Neuropathic pain and spasticity: Iintricate consequences of spinal cord injury","volume":"55","author":"Finnerup","year":"2017","journal-title":"Spinal Cord"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/10790268.2006.11753898","article-title":"Bone loss and muscle atrophy in spinal cord injury: Epidemiology, fracture prediction, and rehabilitation strategies","volume":"29","author":"Giangregorio","year":"2006","journal-title":"J. Spinal Cord Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/cne.10964","article-title":"Neural stem and progenitor cells in nestin-GFP transgenic mice","volume":"469","author":"Mignone","year":"2004","journal-title":"J. Comp. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals","volume":"16","author":"Zimmermann","year":"1983","journal-title":"Pain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00335-017-9723-6","article-title":"Three-dimensional microCT imaging of murine embryonic development from immediate post-implantation to organogenesis: Application for phenotyping analysis of early embryonic lethality in mutant animals","volume":"29","author":"Ermakova","year":"2017","journal-title":"Mamm. Genome"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/0076-6879(95)48041-2","article-title":"Tetanus and botulism neurotoxins: Isolation and assay","volume":"248","author":"Schiavo","year":"1995","journal-title":"Methods Enzymol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0041-0101(02)00370-7","article-title":"Toxicity of botulinum neurotoxins in central nervous system of mice","volume":"41","author":"Luvisetto","year":"2003","journal-title":"Toxicon"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.brainres.2006.01.117","article-title":"Botulinum neurotoxins and formalin-induced pain: Central vs. peripheral effects in mice","volume":"1082","author":"Luvisetto","year":"2006","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2006.12.004","article-title":"Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain","volume":"145","author":"Luvisetto","year":"2007","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1038\/cdd.2016.70","article-title":"Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles","volume":"23","author":"Fiacco","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1096\/fj.12-215475","article-title":"Intracellular signaling in ER stress-induced autophagy in skeletal muscle cells","volume":"27","author":"Madaro","year":"2013","journal-title":"FASEB J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1242\/jcs.103.3.857","article-title":"Dynamics of three-dimensional replication patterns during the S-phase, analysed by double labelling of DNA and confocal microscopy","volume":"103","author":"Manders","year":"1992","journal-title":"J. Cell Sci."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/8\/491\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:53:20Z","timestamp":1760176400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/8\/491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,31]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["toxins12080491"],"URL":"https:\/\/doi.org\/10.3390\/toxins12080491","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,31]]}}}