{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:20:12Z","timestamp":1783462812554,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T00:00:00Z","timestamp":1629158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004773","name":"Henan University","doi-asserted-by":"publisher","award":["Double First-Class Project Program"],"award-info":[{"award-number":["Double First-Class Project Program"]}],"id":[{"id":"10.13039\/501100004773","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["15\/SIRG\/3508T"],"award-info":[{"award-number":["15\/SIRG\/3508T"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1;\u00a0CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A;\u00a0NPY2R, neuropeptide Y receptor Y2;\u00a0GPR52, G protein-coupled receptor 52;\u00a0SCN9A, sodium voltage-gated channel alpha subunit 9;\u00a0TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.<\/jats:p>","DOI":"10.3390\/ijms22168826","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T21:27:40Z","timestamp":1629235660000},"page":"8826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release"],"prefix":"10.3390","volume":"22","author":[{"given":"Wanzhi","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Kong","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Dou","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanghai","family":"Xue","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghui","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"},{"name":"School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3654-4400","authenticated-orcid":false,"given":"Jiafu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Henan University, Kaifeng 475001, China"},{"name":"School of Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Goldberg, D.S., and McGee, S.J. (2011). Pain as a global public health priority. BMC Public Health, 11.","DOI":"10.1186\/1471-2458-11-770"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1056\/NEJMra1800222","article-title":"Opioid Tolerance in Critical Illness","volume":"380","author":"Martyn","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S1474-4422(18)30331-4","article-title":"Novel ways to manage chronic pain are needed","volume":"17","author":"Lancet","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40744-020-00219-2","article-title":"Understanding the Role of Interleukin-6 (IL-6) in the Joint and Beyond: A Comprehensive Review of IL-6 Inhibition for the Management of Rheumatoid Arthritis","volume":"7","author":"Favalli","year":"2020","journal-title":"Rheumatol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1093\/rheumatology\/kex315","article-title":"Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: Is dose tapering practical in good responders?","volume":"56","author":"Ibrahim","year":"2017","journal-title":"Rheumatology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ruscitti, P., Masedu, F., Alvaro, S., Air\u00f2, P., Battafarano, N., Cantarini, L., Cantatore, F.P., Carlino, G., D\u2019Abrosca, V., and Frassi, M. (2019). Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial. PLoS Med., 16.","DOI":"10.1371\/journal.pmed.1002901"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1136\/annrheumdis-2019-216296","article-title":"Subcutaneous tanezumab for osteoarthritis of the hip or knee: Efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period","volume":"79","author":"Berenbaum","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.semarthrit.2020.03.004","article-title":"Onset and maintenance of efficacy of subcutaneous tanezumab in patients with moderate to severe osteoarthritis of the knee or hip: A 16-week dose-titration study","volume":"50","author":"Schnitzer","year":"2020","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1001\/jama.2019.8044","article-title":"Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients with Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial","volume":"322","author":"Schnitzer","year":"2019","journal-title":"JAMA"},{"key":"ref_10","first-page":"321","article-title":"Nav1.7 withholds its pain potential","volume":"18","author":"Kingwell","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1111\/bph.14044","article-title":"Targeting nociceptive transient receptor potential channels to treat chronic pain: Current state of the field","volume":"175","author":"Moran","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E5511","DOI":"10.1073\/pnas.1605295113","article-title":"A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates","volume":"113","author":"Ding","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1016\/j.bja.2018.10.065","article-title":"BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates","volume":"122","author":"Kiguchi","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/BF03033937","article-title":"Long term effects of intra-articular botulinum toxin a for refractory joint pain","volume":"9","author":"Mahowald","year":"2006","journal-title":"Neurotox. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Blanshan, N., and Krug, H. (2020). The Use of Botulinum Toxin for the Treatment of Chronic Joint Pain: Clinical and Experimental Evidence. Toxins, 12.","DOI":"10.3390\/toxins12050314"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0378-1119(03)00792-3","article-title":"Complete DNA sequences of the botulinum neurotoxin complex of Clostridium botulinum type A-Hall (Allergan) strain","volume":"315","author":"Zhang","year":"2003","journal-title":"Gene"},{"key":"ref_17","first-page":"011616","article-title":"Botulinum toxins for the prevention of migraine in adults","volume":"6","author":"Herd","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Becker, W.J. (2020). Botulinum Toxin in the Treatment of Headache. Toxins, 12.","DOI":"10.3390\/toxins12120803"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.tins.2005.06.001","article-title":"Beyond BOTOX: Advantages and limitations of individual botulinum neurotoxins","volume":"28","author":"Davletov","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1146\/annurev-biochem-013118-111654","article-title":"Botulinum and Tetanus Neurotoxins","volume":"88","author":"Dong","year":"2019","journal-title":"Annu. Rev. Biochem."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nrmicro3295","article-title":"Botulinum neurotoxins: Genetic, structural and mechanistic insights","volume":"12","author":"Rossetto","year":"2014","journal-title":"Nat. Rev. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1002\/1873-3468.13508","article-title":"Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations","volume":"593","author":"Pellett","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.3390\/toxins7114519","article-title":"Current Status and Future Directions of Botulinum Neurotoxins for Targeting Pain Processing","volume":"7","author":"Pellett","year":"2015","journal-title":"Toxins"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14130","DOI":"10.1038\/ncomms14130","article-title":"Identification and characterization of a novel botulinum neurotoxin","volume":"8","author":"Zhang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tehran, D.A., and Pirazzini, M. (2018). Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip. Toxins, 10.","DOI":"10.3390\/toxins10050190"},{"key":"ref_27","first-page":"1","article-title":"Two Feet on the Membrane: Uptake of Clostridial Neurotoxins","volume":"406","author":"Rummel","year":"2016","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sikorra, S., Donald, S., Elliott, M., Schwede, S., Coker, S.-F., Kupinski, A.P., Tripathi, V., Foster, K., Beard, M., and Binz, T. (2020). Engineering an Effective Human SNAP-23 Cleaving Botulinum Neurotoxin A Variant. Toxins, 12.","DOI":"10.3390\/toxins12120804"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.toxicon.2020.02.006","article-title":"Neuronal selectivity of botulinum neurotoxins","volume":"178","author":"Poulain","year":"2020","journal-title":"Toxicon"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1242\/jcs.012211","article-title":"Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential","volume":"120","author":"Meng","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0041-0101(99)00153-1","article-title":"Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins","volume":"38","author":"Welch","year":"2000","journal-title":"Toxicon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"21226","DOI":"10.1038\/srep21226","article-title":"TNFalpha induces co-trafficking of TRPV1\/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1\/syntaxin1\/SNAP-25 mediated fusion","volume":"6","author":"Meng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1177\/0022034516659278","article-title":"Antinociceptive Effects of Botulinum Toxin Type A on Trigeminal Neuropathic Pain","volume":"95","author":"Yang","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","unstructured":"Weise, D., Weise, C.M., and Naumann, M. (2019). Central Effects of Botulinum Neurotoxin\u2014Evidence from Human Studies. Toxins, 11.","DOI":"10.3390\/toxins11010021"},{"key":"ref_36","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_37","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.cell.2008.02.053","article-title":"Pirt, a Phosphoinositide-Binding Protein, Functions as a Regulatory Subunit of TRPV1","volume":"133","author":"Kim","year":"2008","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.jneumeth.2007.09.023","article-title":"Dual-promoter lentiviral vectors for constitutive and regulated gene expression in neurons","volume":"168","author":"Scheiffele","year":"2008","journal-title":"J. Neurosci. Methods"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13075-015-0858-0","article-title":"Interleukin-6-dependent influence of nociceptive sensory neurons on antigen-induced arthritis","volume":"17","author":"Ebbinghaus","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1471-4159.2005.03524.x","article-title":"Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons","volume":"96","author":"Bowen","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Joussain, C., Le Coz, O., Pichugin, A., Marconi, P., Lim, F., Sicurella, M., Salonia, A., Montorsi, F., Wandosell, F., and Foster, K. (2019). Botulinum Neurotoxin Light Chains Expressed by Defective Herpes Simplex Virus Type-1 Vectors Cleave SNARE Proteins and Inhibit CGRP Release in Rat Sensory Neurons. Toxins, 11.","DOI":"10.3390\/toxins11020123"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1128\/iai.42.1.409-413.1983","article-title":"Herpes simplex virus infection of motor neurons: Hypoglossal model","volume":"42","author":"Openshaw","year":"1983","journal-title":"Infect Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/sj.gt.3302400","article-title":"Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination","volume":"12","author":"Teng","year":"2005","journal-title":"Gene Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/sj.mt.6300069","article-title":"Viral Clostridial Light Chain Gene-based Control of Penicillin-induced Neocortical Seizures","volume":"15","author":"Yang","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1212\/WNL.0000000000001382","article-title":"Ion channels in nociceptors: Recent developments","volume":"84","author":"Benarroch","year":"2015","journal-title":"Neurology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-cellbio-101011-155833","article-title":"TRP Channels and Pain","volume":"29","author":"Julius","year":"2013","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"696784","DOI":"10.3389\/fimmu.2021.696784","article-title":"Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis","volume":"12","author":"Meng","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1172\/JCI43158","article-title":"Pain as a channelopathy","volume":"120","author":"Raouf","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0014-5793(99)00948-5","article-title":"Persistence of botulinum neurotoxin action in cultured spinal cord cells1,2","volume":"456","author":"Keller","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6375","DOI":"10.1074\/jbc.M110.181784","article-title":"A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: Transfer of longevity to a novel potential therapeutic","volume":"286","author":"Wang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neuron.2012.09.014","article-title":"Neuropeptide Transmission in Brain Circuits","volume":"76","year":"2012","journal-title":"Neuron"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15067","DOI":"10.1074\/jbc.M111.224493","article-title":"Association of Botulinum Neurotoxin Serotype a Light Chain with Plasma Membrane-bound SNAP-25","volume":"286","author":"Chen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Tang, M., Meng, J., and Wang, J. (2019). New Engineered-Botulinum Toxins Inhibit the Release of Pain-Related Mediators. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010262"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.jaci.2020.09.028","article-title":"Novel insights into the TRPV3-mediated itch in atopic dermatitis","volume":"147","author":"Larkin","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1007\/s12035-014-8665-1","article-title":"Selective Cleavage of SNAREs in Sensory Neurons Unveils Protein Complexes Mediating Peptide Exocytosis Triggered by Different Stimuli","volume":"50","author":"Meng","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Eldeiry, M., Yamanaka, K., Reece, T.B., and Aftab, M. (2017). Spinal Cord Neurons Isolation and Culture from Neonatal Mice. J. Vis. Exp., e55856.","DOI":"10.3791\/55856-v"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8826\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:30Z","timestamp":1760165130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,17]]},"references-count":56,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168826"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168826","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,17]]}}}