{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:27:33Z","timestamp":1790832453376,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T00:00:00Z","timestamp":1635984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Million Dollar Bike Ride Pilot Grant Award","award":["MDBR-2019"],"award-info":[{"award-number":["MDBR-2019"]}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["TMLGCBX16TT"],"award-info":[{"award-number":["TMLGCBX16TT"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione Italiana per la Ricerca sulla Fibrosi Cistica","award":["FFC#6\/2019"],"award-info":[{"award-number":["FFC#6\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation.<\/jats:p>","DOI":"10.3390\/ijms222111972","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T22:25:54Z","timestamp":1636064754000},"page":"11972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-1517","authenticated-orcid":false,"given":"Arianna","family":"Venturini","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Musante","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Universit\u00e0 degli Studi di Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8112-4800","authenticated-orcid":false,"given":"Paolo","family":"Scudieri","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Universit\u00e0 degli Studi di Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-1171","authenticated-orcid":false,"given":"Valeria","family":"Capurro","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Renda","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-1720","authenticated-orcid":false,"given":"Nicoletta","family":"Pedemonte","sequence":"additional","affiliation":[{"name":"U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J. V.","family":"Galietta","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"},{"name":"Department of Translational Medical Sciences (DISMET), Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.3389\/fphar.2019.01662","article-title":"CFTR modulators: The changing face of cystic fibrosis in the era of precision medicine","volume":"10","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1164\/rccm.201910-1943SO","article-title":"Cystic fibrosis: Emergence of highly effective targeted therapeutics and potential clinical implications","volume":"201","author":"Mall","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/S2213-2600(16)00023-0","article-title":"Progress in therapies for cystic fibrosis","volume":"4","author":"Amaral","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18825","DOI":"10.1073\/pnas.0904709106","article-title":"Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770","volume":"106","author":"Hadida","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1073\/pnas.1105787108","article-title":"Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809","volume":"108","author":"Hadida","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1056\/NEJMoa1807120","article-title":"VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles","volume":"379","author":"Keating","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1091\/mbc.e13-05-0240","article-title":"VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1","volume":"24","author":"Ren","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1038\/s41591-018-0200-x","article-title":"Structure-guided combination therapy to potently improve the function of mutant CFTRs","volume":"24","author":"Veit","year":"2018","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.chembiol.2013.06.004","article-title":"Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction","volume":"20","author":"Farinha","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nchembio.1253","article-title":"Mechanism-based corrector combination restores \u0394F508-CFTR folding and function","volume":"9","author":"Okiyoneda","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1124\/mol.117.108373","article-title":"Direct binding of the corrector VX-809 to human CFTR NBD1: Evidence of an allosteric coupling between the binding site and the NBD1:CL4 interface","volume":"92","author":"Hudson","year":"2017","journal-title":"Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Capurro, V., Tomati, V., Sondo, E., Renda, M., Borrelli, A., Pastorino, C., Guidone, D., Venturini, A., Giraudo, A., and Mandrup Bertozzi, S. (2021). Partial rescue of F508del-CFTR stability and trafficking defects by double corrector treatment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105262"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e139983","DOI":"10.1172\/jci.insight.139983","article-title":"Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination","volume":"5","author":"Veit","year":"2020","journal-title":"JCI Insight"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jcf.2021.03.011","article-title":"Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR","volume":"20","author":"Veit","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2002774","DOI":"10.1183\/13993003.02774-2020","article-title":"Rescue of multiple class II CFTR mutations by elexacaftor + tezacaftor + ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator","volume":"57","author":"Laselva","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1091\/mbc.e14-04-0935","article-title":"From CFTR biology toward combinatorial pharmacotherapy: Expanded classification of cystic fibrosis mutations","volume":"27","author":"Veit","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/nm1197-1280","article-title":"Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line","volume":"3","author":"Bedwell","year":"1997","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s10020-018-0024-7","article-title":"Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons","volume":"24","author":"Dabrowski","year":"2018","journal-title":"Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1016\/j.bmc.2010.03.060","article-title":"Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations","volume":"18","author":"Nudelman","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1021\/acsmedchemlett.6b00006","article-title":"Design of novel aminoglycoside derivatives with enhanced suppression of diseases-causing nonsense mutations","volume":"7","author":"Sabbavarapu","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1165\/rcmb.2013-0282OC","article-title":"Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor","volume":"50","author":"Xue","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1080\/13543784.2020.1828862","article-title":"ELX-02: An investigational read-through agent for the treatment of nonsense mutation-related genetic disease","volume":"29","author":"Kerem","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"175","DOI":"10.5483\/BMBRep.2017.50.4.015","article-title":"Nonsense-mediated mRNA decay at the crossroads of many cellular pathways","volume":"50","author":"Lejeune","year":"2017","journal-title":"BMB Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/nar\/gkw010","article-title":"Mechanism and regulation of the nonsense-mediated decay pathway","volume":"44","author":"Hug","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1083\/jcb.200611086","article-title":"Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies","volume":"178","author":"Durand","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Keeling, K.M., Wang, D., Dai, Y., Murugesan, S., Chenna, B., Clark, J., Belakhov, V., Kandasamy, J., Velu, S.E., and Baasov, T. (2013). Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060478"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1750-1172-7-58","article-title":"Rescue of nonsense mutations by amlexanox in human cells","volume":"7","author":"Beghyn","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1164\/rccm.201601-0154OC","article-title":"Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations","volume":"194","author":"Mutyam","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6636","DOI":"10.1016\/j.bmcl.2012.08.107","article-title":"Identification of pyrimidine derivatives as hSMG-1 inhibitors","volume":"22","author":"Gopalsamy","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1177\/2472555217729790","article-title":"Use of a high-throughput phenotypic screening strategy to identify amplifiers, a novel pharmacological class of small molecules that exhibit functional synergy with potentiators and correctors","volume":"23","author":"Giuliano","year":"2018","journal-title":"SLAS Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.jcf.2020.02.006","article-title":"Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA","volume":"19","author":"Dukovski","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1093\/hmg\/ddx196","article-title":"Identification of the amino acids inserted during suppression of CFTR nonsense mutations and determination of their functional consequences","volume":"26","author":"Xue","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.jcf.2018.12.001","article-title":"Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells","volume":"18","author":"Valley","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_35","unstructured":"Cystic Fibrosis Foundation (2018). Cystic Fibrosis Foundation Patient Registry, Cystic Fibrosis Foundation. [2018 ed.]."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1042\/BJ20080029","article-title":"Evidence for direct CFTR inhibition by CFTR(inh)-172 based on Arg347 mutagenesis","volume":"413","author":"Caci","year":"2018","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"C872","DOI":"10.1152\/ajpcell.00507.2010","article-title":"Rescue of the mutant CFTR chloride channel by pharmacological correctors and low temperature analyzed by gene expression profiling","volume":"301","author":"Sondo","year":"2011","journal-title":"Am. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eaay9669","DOI":"10.1126\/sciadv.aay9669","article-title":"Discovery of a picomolar potency pharmacological corrector of the mutant CFTR chloride channel","volume":"6","author":"Pedemonte","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1007\/BF02428306","article-title":"A 3\u2032 splice site consensus sequence mutation in the cystic fibrosis gene","volume":"85","author":"Guillermit","year":"1990","journal-title":"Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1016\/S2213-2600(16)30188-6","article-title":"Classification of CFTR mutation classes","volume":"4","author":"Marson","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sharma, N., Evans, T.A., Pellicore, M.J., Davis, E., Aksit, M.A., McCague, A.F., Joynt, A.T., Lu, Z., Han, S.T., and Anzmann, A.F. (2018). Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007723"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.jcf.2019.12.001","article-title":"Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action","volume":"19","author":"Laselva","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1165\/rcmb.2018-0316OC","article-title":"Nonsense-mediated RNA decay pathway inhibition restores expression and function of W1282X CFTR","volume":"61","author":"Keenan","year":"2019","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"McHugh, D.R., Cotton, C.U., and Hodges, C.A. (2020). Synergy between readthrough and nonsense mediated decay inhibition in a murine model of cystic fibrosis nonsense mutations. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010344"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Moreno, J.F., and Rom\u00e3o, L. (2020). Perspective in alternative splicing coupled to nonsense-mediated mRNA decay. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249424"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jcf.2021.01.009","article-title":"Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids","volume":"20","author":"Crawford","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1242\/jcs.198176","article-title":"Premature termination codon readthrough in human cells occurs in novel cytoplasmic foci and requires UPF proteins","volume":"130","author":"Jia","year":"2017","journal-title":"J. Cell. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1074\/jbc.M116.764720","article-title":"Correctors and potentiators rescue function of the truncated W1282X-cystic fibrosis transmembrane regulator (CFTR) translation product","volume":"292","author":"Haggie","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1093\/nar\/gkx1272","article-title":"Nonsense-mediated mRNA decay: A \u2018nonsense\u2019 pathway makes sense in stem cell biology","volume":"46","author":"Han","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1172\/JCI28523","article-title":"Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin","volume":"117","author":"Linde","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1113\/jphysiol.2012.240838","article-title":"Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia","volume":"590","author":"Scudieri","year":"2012","journal-title":"J. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"36016","DOI":"10.1038\/srep36016","article-title":"Goblet cell hyperplasia requires high bicarbonate transport to support mucin release","volume":"6","author":"Gorrieri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e123616","DOI":"10.1172\/jci.insight.123616","article-title":"Increased expression of ATP12A proton pump in cystic fibrosis airways","volume":"3","author":"Scudieri","year":"2018","journal-title":"JCI Insight"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.stem.2016.05.012","article-title":"Dual SMAD signaling inhibition enables long-term expansion of diverse epithelial basal cells","volume":"19","author":"Mou","year":"2016","journal-title":"Cell Stem Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11972\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:26:05Z","timestamp":1760167565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,4]]},"references-count":54,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111972"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111972","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,4]]}}}