{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:20:55Z","timestamp":1791555655859,"version":"4.3.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004100","name":"Labex","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004100","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004100","name":"Labex","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004100","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Shigella<\/jats:italic>, the causative agent of bacillary dysentery, subvert cytoskeletal and trafficking processes to invade and replicate in epithelial cells using an arsenal of bacterial effectors translocated through a type III secretion system. Here, we review the various roles of the type III effector IpgD, initially characterized as phosphatidylinositol 4,5 bisphosphate (PI4,5P<jats:sub>2<\/jats:sub>) 4-phosphatase. By decreasing PI4,5P<jats:sub>2<\/jats:sub> levels, IpgD triggers the disassembly of cortical actin filaments required for bacterial invasion and cell migration. PI5P produced by IpgD further stimulates signaling pathways regulating cell survival, macropinosome formation, endosomal trafficking and dampening of immune responses. Recently, IpgD was also found to exhibit phosphotransferase activity leading to PI3,4P<jats:sub>2<\/jats:sub> synthesis adding a new flavor to this multipotent bacterial enzyme. The substrate of IpgD, PI4,5P<jats:sub>2<\/jats:sub> is also the main substrate hydrolyzed by endogenous phospholipases C to produce inositoltriphosphate (InsP<jats:sub>3<\/jats:sub>), a major Ca<jats:sup>2+<\/jats:sup> second messenger. Hence, beyond the repertoire of effects associated with the direct diversion of phoshoinositides, IpgD indirectly down-regulates InsP<jats:sub>3<\/jats:sub>-mediated Ca<jats:sup>2+<\/jats:sup> release by limiting InsP<jats:sub>3<\/jats:sub> production. Furthermore, IpgD controls the intracellular lifestyle of <jats:italic>Shigella<\/jats:italic> promoting Rab8\/11 -dependent recruitment of the exocyst at macropinosomes to remove damaged vacuolar membrane remnants and promote bacterial cytosolic escape. IpgD thus emerges as a key bacterial effector for the remodeling of host cell membranes.<\/jats:p>","DOI":"10.3389\/fcimb.2022.1012533","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T06:30:12Z","timestamp":1666852212000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Modification of phosphoinositides by the Shigella effector IpgD during host cell infection"],"prefix":"10.3389","volume":"12","author":[{"given":"Guy","family":"Tran Van Nhieu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Latour-Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jost","family":"Enninga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1242\/jcs.166314","article-title":"TOM1 is a PI5P effector involved in the regulation of endosomal maturation","volume":"128","author":"Boal","year":"2015","journal-title":"J. Cell Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.celrep.2015.12.079","article-title":"PI5P triggers ICAM-1 degradation in shigella infected cells, thus dampening immune cell recruitment","volume":"14","author":"Boal","year":"2016","journal-title":"Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1111\/j.1462-5822.2010.01476.x","article-title":"Sorting nexin 3 (SNX3) is a component of a tubular endosomal network induced by salmonella and involved in maturation of the salmonella-containing vacuole","volume":"12","author":"Braun","year":"2010","journal-title":"Cell Microbiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3915","DOI":"10.1073\/pnas.1616418114","article-title":"MYO6 is targeted by salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells","volume":"114","author":"Brooks","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2027","DOI":"10.1242\/jcs.018432","article-title":"Sorting nexin-1 defines an early phase of salmonella-containing vacuole-remodeling during salmonella infection","volume":"121","author":"Bujny","year":"2008","journal-title":"J. Cell Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nature12004","article-title":"Proteolytic elimination of n-myristoyl modifications by the shigella virulence factor IpaJ","volume":"496","author":"Burnaevskiy","year":"2013","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.13342","article-title":"New methods to decrypt emerging macropinosome functions during the host-pathogen crosstalk","volume":"23","author":"Chang","year":"2021","journal-title":"Cell Microbiol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008822","article-title":"Shigella hijacks the exocyst to cluster macropinosomes for efficient vacuolar escape","volume":"16","author":"Chang","year":"2020","journal-title":"PloS Pathog."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022260","article-title":"Activation of akt by the bacterial inositol phosphatase, SopB, is wortmannin insensitive","volume":"6","author":"Cooper","year":"2011","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1093\/protein\/10.6.673","article-title":"Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: The dense alignment surface method","volume":"10","author":"Cserz\u00f6","year":"1997","journal-title":"Protein Eng."},{"key":"B11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1242\/jcs.113.1.71","article-title":"Src tyrosine kinase activity down-regulates rho-dependent responses during shigella entry into epithelial cells and stress fibre formation","volume":"113","author":"Dum\u00e9nil","year":"2000","journal-title":"J. Cell Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1038\/nmeth804","article-title":"Secretion of type III effectors into host cells in real time","volume":"2","author":"Enninga","year":"2005","journal-title":"Nat. Methods"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02584-14","article-title":"Shigella flexneri regulation of ARF6 activation during bacterial entry via an IpgD-mediated positive feedback loop","volume":"6","author":"Garza-Mayers","year":"2015","journal-title":"mBio"},{"key":"B14","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.chom.2019.08.007","article-title":"Bioengineered human organ-on-Chip reveals intestinal microenvironment and mechanical forces impacting shigella infection","volume":"26","author":"Grassart","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B15","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.micinf.2007.11.011","article-title":"IpgB1 and IpgB2, two homologous effectors secreted via the mxi-spa type III secretion apparatus, cooperate to mediate polarized cell invasion and inflammatory potential of shigella flexenri","volume":"10","author":"Hachani","year":"2008","journal-title":"Microbes Infect."},{"key":"B16","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/ncb1526","article-title":"Shigella IpgB1 promotes bacterial entry through the ELMO-Dock180 machinery","volume":"9","author":"Handa","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1128\/IAI.00252-09","article-title":"Requirement for formin-induced actin polymerization during spread of shigella flexneri","volume":"78","author":"Heindl","year":"2010","journal-title":"Infect. Immun."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1126\/science.1098188","article-title":"Salmonella modulates vesicular traffic by altering phosphoinositide metabolism","volume":"304","author":"Hernandez","year":"2004","journal-title":"Science"},{"key":"B19","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/j.bbalip.2014.09.015","article-title":"The structure of phosphoinositide phosphatases: Insights into substrate specificity and catalysis","volume":"1851","author":"Hsu","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"B20","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.chom.2012.01.006","article-title":"Salmonella virulence effector SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion","volume":"11","author":"Humphreys","year":"2012","journal-title":"Cell Host Microbe"},{"key":"B21","doi-asserted-by":"publisher","first-page":"16880","DOI":"10.1073\/pnas.1311680110","article-title":"Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by salmonella to invade host cells","volume":"110","author":"Humphreys","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B22","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.chom.2017.07.009","article-title":"Salmonella SPI-2 type III secretion system effectors: Molecular mechanisms and physiological consequences","volume":"22","author":"Jennings","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B23","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"9058","DOI":"10.1074\/jbc.M412588200","article-title":"The salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of akt","volume":"280","author":"Knodler","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.chom.2011.03.010","article-title":"The shigella flexneri type three secretion system effector IpgD inhibits T cell migration by manipulating host phosphoinositide metabolism","volume":"9","author":"Konradt","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010324","article-title":"The type 3 secretion effector IpgD promotes s. flexneri dissemination","volume":"18","author":"K\u00f6seo\u011flu","year":"2022","journal-title":"PloS Pathog."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107638","article-title":"Actin assembly around the shigella-containing vacuole promotes successful infection","volume":"31","author":"K\u00fchn","year":"2020","journal-title":"Cell Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2554","DOI":"10.1128\/IAI.01235-10","article-title":"Protective role of Akt2 in salmonella enterica serovar typhimurium-induced gastroenterocolitis","volume":"79","author":"Kum","year":"2011","journal-title":"Infect. Immun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/s41564-018-0215-6","article-title":"N\u03f5-fatty acylation of multiple membrane-associated proteins by shigella IcsB effector to modulate host function","volume":"3","author":"Liu","year":"2018","journal-title":"Nat. Microbiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1080\/21541248.2016.1240494","article-title":"Diverted recycling-shigella subversion of rabs","volume":"9","author":"L\u00f3pez-Montero","year":"2018","journal-title":"Small GTPases"},{"key":"B31","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.chom.2014.09.005","article-title":"Shigella subverts the host recycling compartment to rupture its vacuole","volume":"16","author":"Mellouk","year":"2014","journal-title":"Cell Host Microbe"},{"key":"B32","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1099\/mic.0.000637","article-title":"Identification of interactions among host and bacterial proteins and evaluation of their role early during shigella flexneri infection","volume":"164","author":"Miller","year":"2018","journal-title":"Microbiol. (Reading)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.59022","article-title":"NAIP-NLRC4-deficient mice are susceptible to shigellosis","volume":"9","author":"Mitchell","year":"2020","journal-title":"Elife"},{"key":"B34","doi-asserted-by":"publisher","first-page":"jcs213272","DOI":"10.1242\/jcs.213272","article-title":"TMEM55a localizes to macrophage phagosomes to downregulate phagocytosis","volume":"131","author":"Morioka","year":"2018","journal-title":"J. Cell Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1242\/jcs.112.13.2069","article-title":"Rho family GTPases control entry of shigella flexneri into epithelial cells but not intracellular motility","volume":"112","author":"Mounier","year":"1999","journal-title":"J. Cell Sci."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms9020451","article-title":"The shigella type III secretion system: An overview from top to bottom","volume":"9","author":"Muthuramalingam","year":"2021","journal-title":"Microorganisms"},{"key":"B37","doi-asserted-by":"publisher","first-page":"5069","DOI":"10.1093\/emboj\/cdf522","article-title":"Conversion of PtdIns(4,5)P(2) into PtdIns(5)P by the s.flexneri effector IpgD reorganizes host cell morphology","volume":"21","author":"Niebuhr","year":"2002","journal-title":"EMBO J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"14057","DOI":"10.1073\/pnas.95.24.14057","article-title":"SopB, a protein required for virulence of salmonella dublin, is an inositol phosphate phosphatase","volume":"95","author":"Norris","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.cell.2009.01.056","article-title":"Diversification of a salmonella virulence protein function by ubiquitin-dependent differential localization","volume":"137","author":"Patel","year":"2009","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/978-94-007-3015-1_12","article-title":"Phosphoinositides and cellular pathogens","volume":"59","author":"Payrastre","year":"2012","journal-title":"Subcell Biochem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1038\/sj.emboj.7601001","article-title":"PtdIns5P activates the host cell PI3-kinase\/Akt pathway during shigella flexneri infection","volume":"25","author":"Pendaries","year":"2006","journal-title":"EMBO J."},{"key":"B42","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1111\/cmi.12542","article-title":"Dual 4- and 5-phosphatase activities regulate SopB-dependent phosphoinositide dynamics to promote bacterial entry","volume":"18","author":"Piscatelli","year":"2016","journal-title":"Cell Microbiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/j.bbalip.2014.09.011","article-title":"Phosphoinositides and host-pathogen interactions","volume":"1851","author":"Pizarro-Cerd\u00e1","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2016.00073","article-title":"Modification of bacterial effector proteins inside eukaryotic host cells","volume":"6","author":"Popa","year":"2016","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/j.immuni.2013.11.013","article-title":"A shigella effector dampens inflammation by regulating epithelial release of danger signal ATP through production of the lipid mediator PtdIns5P","volume":"39","author":"Puhar","year":"2013","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"publisher","first-page":"ra61","DOI":"10.1126\/scisignal.2001619","article-title":"Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling","volume":"4","author":"Ramel","year":"2011","journal-title":"Sci. Signal"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008446","article-title":"Transcytosis subversion by m cell-to-enterocyte spread promotes shigella flexneri and listeria monocytogenes intracellular bacterial dissemination","volume":"16","author":"Rey","year":"2020","journal-title":"PloS Pathog."},{"key":"B48","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.chom.2015.05.002","article-title":"Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma","volume":"17","author":"Scanu","year":"2015","journal-title":"Cell Host Microbe"},{"key":"B49","author":"Schr\u00f6dinger","year":"2020","journal-title":"PyMOL"},{"key":"B50","doi-asserted-by":"publisher","first-page":"37718","DOI":"10.1074\/jbc.M008187200","article-title":"Activation of akt\/protein kinase b in epithelial cells by the salmonella typhimurium effector sigD","volume":"275","author":"Steele-Mortimer","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"3958","DOI":"10.1016\/j.celrep.2019.11.049","article-title":"Dynamic growth and shrinkage of the salmonella-containing vacuole determines the intracellular pathogen niche","volume":"29","author":"St\u00e9venin","year":"2019","journal-title":"Cell Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"5220","DOI":"10.1038\/s41596-021-00610-5","article-title":"Purification of infection-associated macropinosomes by magnetic isolation for proteomic characterization","volume":"16","author":"St\u00e9venin","year":"2021","journal-title":"Nat. Protoc."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.15252\/embj.201696272","article-title":"The shigella type III effector IpgD recodes Ca2+ signals during invasion of epithelial cells","volume":"36","author":"Sun","year":"2017","journal-title":"EMBO J."},{"key":"B54","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.chom.2012.10.009","article-title":"Salmonella transforms follicle-associated epithelial cells into m cells to promote intestinal invasion","volume":"12","author":"Tahoun","year":"2012","journal-title":"Cell Host Microbe"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2561","article-title":"Actin-based confinement of calcium responses during shigella invasion","volume":"4","author":"Tran Van Nhieu","year":"2013","journal-title":"Nat. Commun."},{"key":"B56","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1111\/cmi.12400","article-title":"Cytoskeletal mechanics during shigella invasion and dissemination in epithelial cells","volume":"17","author":"Valencia-Gallardo","year":"2015","journal-title":"Cell Microbiol."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5080","article-title":"Phosphatidylinositol 5-phosphate regulates invasion through binding and activation of Tiam1","volume":"5","author":"Viaud","year":"2014","journal-title":"Nat. Commun."},{"key":"B58","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/s41556-022-00895-y","article-title":"Kinase-independent synthesis of 3-phosphorylated phosphoinositides by a phosphotransferase","volume":"24","author":"Walpole","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1016\/j.csbj.2022.04.024","article-title":"Improving the topology prediction of \u03b1-helical transmembrane proteins with deep transfer learning","volume":"20","author":"Wang","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"B60","doi-asserted-by":"publisher","first-page":"e1007380","DOI":"10.1371\/journal.ppat.1007380","article-title":"Principles of intracellular bacterial pathogen spread from cell to cell","volume":"14","author":"Weddle","year":"2018","journal-title":"PloS Pathog."},{"key":"B61","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/s41467-017-00700-7","article-title":"A systematic exploration of the interactions between bacterial effector proteins and host cell membranes","volume":"8","author":"Weigele","year":"2017","journal-title":"Nat. Commun."},{"key":"B62","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.tim.2018.11.011","article-title":"The pathogen-host interface in three dimensions: Correlative FIB\/SEM applications","volume":"27","author":"Weiner","year":"2019","journal-title":"Trends Microbiol."},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005602","article-title":"Macropinosomes are key players in early shigella invasion and vacuolar escape in epithelial cells","volume":"12","author":"Weiner","year":"2016","journal-title":"PloS Pathog."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1012533\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T06:30:15Z","timestamp":1666852215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1012533\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,27]]},"references-count":63,"alternative-id":["10.3389\/fcimb.2022.1012533"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1012533","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,27]]},"article-number":"1012533"}}