{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T12:42:08Z","timestamp":1765888928244,"version":"3.41.2"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Schistosomiasis is a severe parasitic disease that is primarily driven by the host\u2019s immune response to schistosome eggs trapped in tissue and by the granulomatous inflammatory and fibrotic reaction they cause. Despite significant progress in understanding the complex immunological processes involved in the relationship between schistosomes and their host, neither an effective vaccine against the infection nor anti-fibrotic drugs currently exists, making the search for new targets for schistosome drugs and vaccine candidates even more important. In order to identify new molecular targets for defense against or elimination of the parasite, we investigate herein the interplay between the host and male or female schistosomes, clearly separating this from the action of the parasite eggs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>For this purpose, we infected 6\u20138-week-old female NMRI mice with 100 male (M), female (F), or both (MF)<jats:italic>S. mansoni<\/jats:italic>cercariae and performed a comparative transcriptomic and flow cytometric analysis of their spleens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Principal component analysis of a total of 22,207 transcripts showed a clear clustering of the experimental groups. We identified a total of 1,293 genes in group M, 512 genes in group F, and 4,062 genes in group MF that were differentially expressed compared to naive controls. The highest percentage of regulated genes (2,972; 65.9%) was found in group MF alone, but there was a large overlap between groups M and MF (798; 17.7%) and a small overlap between groups F and MF (91; 2.0%). Only 4.5% of genes (201) were revealed to be regulated in all experimental groups (M\/F\/MF). In addition, we were able to show that both worm sexes trigger immune responses in an egg-independent manner (non-polarized Th1 and Th2 response), with female worms exerting less regulatory influence than males.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data show that adult schistosomes trigger sex-specific, egg-independent immune responses. The lists of genes regulated by adult female or male worms presented here may be useful in deciphering host\u2013parasite interactions to identify targets for schistosome elimination.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.893632","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T08:12:36Z","timestamp":1657008756000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Sex-Specific Modulation of the Host Transcriptome in the Spleen of Schistosoma mansoni-Infected Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Franziska","family":"Winkelmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Rabes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Reinholdt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Koslowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Koczan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil C.","family":"Reisinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Sombetzki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1074\/jbc.M411223200","article-title":"Double-Stranded RNAs From the Helminth Parasite Schistosoma Activate TLR3 in Dendritic Cells","volume":"280","author":"Aksoy","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01018","article-title":"Behind Enemy Lines: Immunomodulatory Armamentarium of the Schistosome Parasite","volume":"11","author":"Angeles","year":"2020","journal-title":"Front. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/j.1365-3024.1981.tb00383.x","article-title":"Proteolytic Cleavage of IgG Bound to the Fc Receptor of Schistosoma Mansoni Schistosomula","volume":"3","author":"Auriault","year":"1981","journal-title":"Parasite Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1111\/j.1420-9101.2010.02190.x","article-title":"Vertebrate Host Protective Immunity Drives Genetic Diversity and Antigenic Polymorphism in Schistosoma Mansoni","volume":"24","author":"Beltran","year":"2011","journal-title":"J. Evol. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/S1359-6101(02)00028-X","article-title":"Evolution of Interleukin-1\u03b2","volume":"13","author":"Bird","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/s00436-003-0943-1","article-title":"Preliminary Study on Sex-Related Inflammatory Reactions in Mice Infected With Schistosoma Mansoni","volume":"91","author":"Boissier","year":"2003","journal-title":"Parasitol. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1017\/S0031182099005004","article-title":"A Review of Performance and Pathogenicity of Male and Female Schistosoma Mansoni During the Life-Cycle","volume":"119","author":"Boissier","year":"1999","journal-title":"Parasitology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.4049\/jimmunol.174.9.5789","article-title":"Resistin, an Adipokine With Potent Proinflammatory Properties","volume":"174","author":"Bokarewa","year":"2005","journal-title":"J. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1111\/j.1365-3024.2009.01098.x","article-title":"Immunopathogenesis of Human Schistosomiasis","volume":"31","author":"Burke","year":"2009","journal-title":"Parasite Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"3669","DOI":"10.1182\/blood-2010-04-282350","article-title":"Sox6 Enhances Erythroid Differentiation in Human Erythroid Progenitors","volume":"117","author":"Cant\u00f9","year":"2011","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1084\/jem.180.5.1841","article-title":"B70\/B7-2 is Identical to CD86 and is the Major Functional Ligand for CD28 Expressed on Human Dendritic Cells","volume":"180","author":"Caux","year":"1994","journal-title":"J. Exp. Med."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03137","article-title":"The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry","volume":"9","author":"Cosenza-Contreras","year":"2018","journal-title":"Front. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s00436-007-0476-0","article-title":"Influence of Pattern of Exposure, Parasite Genetic Diversity and Sex on the Degree of Protection Against Reinfection With Schistosoma Mansoni","volume":"101","author":"Dumont","year":"2007","journal-title":"Parasitol. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"83","DOI":"10.4269\/ajtmh.1994.51.83","article-title":"Drug-Resistant Schistosomiasis: Resistance to Praziquantel and Oxamniquine Induced in Schistosoma Mansoni in Mice is Drug Specific","volume":"51","author":"Fallon","year":"1994","journal-title":"Am. J. Trop. Med. Hyg"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/j.ijpara.2006.06.007","article-title":"Dioecious Schistosoma Mansoni Express Divergent Gene Repertoires Regulated by Pairing","volume":"36","author":"Fitzpatrick","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"B16","doi-asserted-by":"crossref","first-page":"5190","DOI":"10.4049\/jimmunol.153.11.5190","article-title":"Regulation of T Helper Cell Responses in Experimental Murine Schistosomiasis by IL-10. Effect on Expression of B7 and B7-2 Costimulatory Molecules by Macrophages","volume":"153","author":"Flores Villanueva","year":"1994","journal-title":"J. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A Graphical Gene-Set Enrichment Tool for Animals and Plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.aca.2017.11.058","article-title":"The Schistosoma Mansoni Lipidome: Leads for Immunomodulation","volume":"1037","author":"Giera","year":"2018","journal-title":"Anal. Chim. Acta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1016\/S0140-6736(06)69440-3","article-title":"Human Schistosomiasis","volume":"368","author":"Gryseels","year":"2006","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.4049\/jimmunol.146.4.1322","article-title":"Egg Deposition is the Major Stimulus for the Production of Th2 Cytokines in Murine Schistosomiasis Mansoni","volume":"146","author":"Grzych","year":"1991","journal-title":"J. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/j.1348-0421.2009.00203.x","article-title":"Plasma Lipoproteins are Important Components of the Immune System","volume":"54","author":"Han","year":"2010","journal-title":"Microbiol. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1016\/S0140-6736(17)32130-X","article-title":"Global, Regional, and National Disability-Adjusted Life-Years (DALYs) for 333 Diseases and Injuries and Healthy Life Expectancy (HALE) for 195 Countries and Territories 1990\u20132016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"390","author":"Hay","year":"2017","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/0014-4894(69)90066-6","article-title":"Sex of Schistosome Cercariae as a Factor in the Immunization of Rhesus Monkeys","volume":"25","author":"Hs\u00fc","year":"1969","journal-title":"Exp. Parasitol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e0008145","DOI":"10.1371\/journal.pntd.0008145","article-title":"Tissue- and Sex-Specific Lipidomic Analysis of Schistosoma Mansoni Using High-Resolution Atmospheric Pressure Scanning Microprobe Matrix-Assisted Laser Desorption\/Ionization Mass Spectrometry Imaging","volume":"14","author":"Kadesch","year":"2020","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.tibs.2016.12.001","article-title":"Cdc20: At the Crossroads Between Chromosome Segregation and Mitotic Exit","volume":"42","author":"Kapanidou","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005595","article-title":"Single-Sex Infection With Female Schistosoma Mansoni Cercariae Mitigates Hepatic Fibrosis After Secondary Infection","volume":"11","author":"Koslowski","year":"2017","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"732","DOI":"10.7326\/L18-0438","article-title":"Katayama Syndrome Without Schistosoma Mansoni Eggs","volume":"170","author":"Langenberg","year":"2019","journal-title":"Ann. Intern. Med."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045185","article-title":"CD80 and CD86 Differentially Regulate Mechanical Interactions of T-Cells With Antigen-Presenting Dendritic Cells and B-Cells","volume":"7","author":"Lim","year":"2012","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1139\/z03-217","article-title":"Schistosoma Mansoni Male\u2013Female Interactions","volume":"82","author":"LoVerde","year":"2004","journal-title":"Can. J. Zool."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006817","article-title":"Single-Sex Schistosome Infections of Definitive Hosts: Implications for Epidemiology and Disease Control in a Changing World","volume":"14","author":"Lu","year":"2018","journal-title":"PLoS Pathog."},{"key":"B31","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.ijpara.2021.03.005","article-title":"Extended Survival and Reproductive Potential of Single-Sex Male and Female Schistosoma Japonicum Within Definitive Hosts","volume":"51","author":"Lu","year":"2021","journal-title":"Int. J. Parasitol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"11315","DOI":"10.1038\/s41598-017-11803-y","article-title":"IL-4 Enhances IL-10 Production in Th1 Cells: Implications for Th1 and Th2 Regulation","volume":"7","author":"Mitchell","year":"2017","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"831","DOI":"10.4269\/ajtmh.1956.5.831","article-title":"The Relative Egg Producing Capacity of Schistosoma Mansoni and Schistosoma Japonicum","volume":"5","author":"Moore","year":"1956","journal-title":"Am. J. Trop. Med. Hyg"},{"key":"B34","first-page":"1","article-title":"Properties and Functions of Interleukin-10","volume-title":"Advances in Immunology Volume","author":"Mosman","year":"1994"},{"key":"B35","doi-asserted-by":"publisher","first-page":"727","DOI":"10.4269\/ajtmh.1977.26.727","article-title":"Immunosuppression Mediated by Adult Worms in Chronic Schistosomiasis Mansoni","volume":"26","author":"Mota-Santos","year":"1977","journal-title":"Am. J. Trop. Med. Hyg"},{"key":"B36","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","article-title":"Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme","volume":"102","author":"Muramatsu","year":"2000","journal-title":"Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1084\/jem.185.7.1163","article-title":"Molecular and Functional Characterization of Two Novel Human C-C Chemokines as Inhibitors of Two Distinct Classes of Myeloid Progenitors","volume":"185","author":"Patel","year":"1997","journal-title":"J. Exp. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/375318a0","article-title":"Lethal Beta-Thalassaemia in Mice Lacking the Erythroid CACCC-Transcription Factor EKLF","volume":"375","author":"Perkins","year":"1995","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000393","article-title":"Retnla (Relmalpha\/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity","volume":"5","author":"Pesce","year":"2009","journal-title":"PLoS Pathog."},{"key":"B40","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1159\/000024317","article-title":"Cleavage of Human IgE Mediated by Schistosoma Mansoni","volume":"121","author":"Pleass","year":"2000","journal-title":"Int. Arch. Allergy Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e12642","DOI":"10.1111\/sji.12642","article-title":"Plasma Levels of Innate Immune Mediators are Associated With Liver Fibrosis in Low Parasite Burden Schistosoma Mansoni-Infected Individuals","volume":"87","author":"Rodrigues Oliveira","year":"2018","journal-title":"Scand. J. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.bcmd.2009.01.005","article-title":"Protein 4.2: A Complex Linker","volume":"42","author":"Satchwell","year":"2009","journal-title":"Blood Cells Mol. Dis."},{"key":"B43","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.micinf.2010.06.001","article-title":"Th2 Immune Response Against Schistosoma Mansoni Infection","volume":"12","author":"Schramm","year":"2010","journal-title":"Microbes Infect."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02492","article-title":"Schistosoma \"Eggs-Iting\" the Host: Granuloma Formation and Egg Excretion","volume":"9","author":"Schwartz","year":"2018","journal-title":"Front. Immunol."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004246","article-title":"Schistosome Feeding and Regurgitation","volume":"10","author":"Skelly","year":"2014","journal-title":"PLoS Pathog."},{"key":"B46","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/0014-4894(62)90074-7","article-title":"Stimulation of Acquired Resistance to Schistosoma Mansoni in Monkeys: Role of Eggs and Worms","volume":"12","author":"Smithers","year":"1962","journal-title":"Exp. Parasitol."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1567254","article-title":"Biosensor for Hepatocellular Injury Corresponds to Experimental Scoring of Hepatosplenic Schistosomiasis in Mice","volume":"2016","author":"Sombetzki","year":"2016","journal-title":"BioMed. Res. Int."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00861","article-title":"Host Defense Versus Immunosuppression: Unisexual Infection With Male or Female Schistosoma Mansoni Differentially Impacts the Immune Response Against Invading Cercariae","volume":"9","author":"Sombetzki","year":"2018","journal-title":"Front. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/IAI.72.1.1-12.2004","article-title":"Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis","volume":"72","author":"Stavitsky","year":"2004","journal-title":"Infect. Immun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"5837","DOI":"10.4049\/jimmunol.171.11.5837","article-title":"Maturation of Dendritic Cell 2 Phenotype by a Helminth Glycan Uses a Toll-Like Receptor 4-Dependent Mechanism","volume":"171","author":"Thomas","year":"2003","journal-title":"J. Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/278447a0","article-title":"Receptor for IgG(Fc) and Human Beta2-Microglobulin on S. Mansoni Schistosomula","volume":"278","author":"Torpier","year":"1979","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","first-page":"557","DOI":"10.2307\/3283780","article-title":"Schistosoma Mansoni: In Vitro and In Vivo Excretion of CAA and CCA by Developing Schistosomula and Adult Worms","volume":"82","author":"Van Dam","year":"1996","journal-title":"J. Parasitol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"48122","DOI":"10.1074\/jbc.M206941200","article-title":"A Novel Host-Parasite Lipid Cross-Talk. Schistosomal Lyso-Phosphatidylserine Activates Toll-Like Receptor 2 and Affects Immune Polarization","volume":"277","author":"Van der Kleij","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.ijpara.2006.01.007","article-title":"Functions of the Tegument of Schistosomes: Clues From the Proteome and Lipidome","volume":"36","author":"Van Hellemond","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1016\/j.molimm.2006.12.012","article-title":"Schistosoma Mansoni Soluble Egg Antigens are Internalized by Human Dendritic Cells Through Multiple C-Type Lectins and Suppress TLR-Induced Dendritic Cell Activation","volume":"44","author":"Van Liempt","year":"2007","journal-title":"Mol. Immunol."},{"key":"B56","first-page":"418","article-title":"Uber Die Erworbene Resistenz Von Macacus Rhesus Gegen\u00fcber Schistosoma Japonicum","volume":"4","author":"Vogel","year":"1953","journal-title":"Z Tropenmed Parasitol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1128\/CMR.00137-14","article-title":"Advances in the Diagnosis of Human Schistosomiasis","volume":"28","author":"Weerakoon","year":"2015","journal-title":"Clin. Microbiol. Rev."},{"key":"B58","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1002\/jlb.62.5.667","article-title":"Cloning and Functional Characterization of a Novel Human CC Chemokine That Binds to the CCR3 Receptor and Activates Human Eosinophils","volume":"62","author":"White","year":"1997","journal-title":"J. Leukoc. Biol."},{"volume-title":"WHO Guideline on Control and Elimination of Human Schistosomiasis","year":"2022","key":"B59"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004272","article-title":"The Schistosome Esophagus Is a \u2018Hotspot\u2019 for Microexon and Lysosomal Hydrolase Gene Expression: Implications for Blood Processing","volume":"9","author":"Wilson","year":"2015","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"7569","DOI":"10.1038\/s41598-022-11645-3","article-title":"Comparative Proteome Analysis of the Tegument of Male and Female Adult Schistosoma Mansoni.","volume":"12","author":"Winkelmann","year":"2022","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.893632\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T21:21:01Z","timestamp":1676064061000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.893632\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,5]]},"references-count":61,"alternative-id":["10.3389\/fcimb.2022.893632"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.893632","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2022,7,5]]},"article-number":"893632"}}