{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:55:28Z","timestamp":1775580928118,"version":"3.50.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["MOST 107-2320-B-040-010-MY3, CSH-2019-D-005, CSH-2020-D-002"],"award-info":[{"award-number":["MOST 107-2320-B-040-010-MY3, CSH-2019-D-005, CSH-2020-D-002"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]}],"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>Allergic asthma, a chronic airway inflammatory disease, is a critical public health problem. Indoor house dust mites (HDMs) could cause allergic asthma. The prevalence of sensitization to <jats:italic>Dermatophagoides microceras<\/jats:italic> (<jats:italic>Der m<\/jats:italic>) was approximately 80% and is related to the immunoglobulin E crossing-reactivity of mites belonging to the same genus, <jats:italic>Dermatophagoides pteronyssinus<\/jats:italic> (<jats:italic>Der p<\/jats:italic>) and <jats:italic>Dermatophagoides farina<\/jats:italic> (<jats:italic>Der f<\/jats:italic>). However, studies on <jats:italic>Der m<\/jats:italic> are scant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used integrated OMICs approaches to identify and characterize the group 2 mite allergen-like protein in <jats:italic>Der m<\/jats:italic> (<jats:italic>Der m 2<\/jats:italic>). We established a <jats:italic>Der m 2<\/jats:italic>-induced allergic asthma mouse model and treated the mice with a fungal immunomodulatory protein (FIP-<jats:italic>fve<\/jats:italic>) isolated from <jats:italic>Flammulina veluptipes<\/jats:italic> to evaluate the allergenicity of <jats:italic>Der m 2<\/jats:italic> and the immunomodulatory effects of FIP-<jats:italic>fve<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By performing <jats:italic>de novo<\/jats:italic> draft genome assembly and comparative genome analysis, we identified the putative 144-amino acid <jats:italic>Der m 2 in silico<\/jats:italic> and further confirmed its existence through liquid chromatography\u2013tandem mass spectrometry. <jats:italic>Der m 2<\/jats:italic> is a lipopolysaccharides (LPS)-binding protein. Thus, we examined the LPS-binding activity of recombinant <jats:italic>Der m 2<\/jats:italic> by performing molecular docking analysis, co-immunoprecipitation (Co-IP), and a pull-down assay. <jats:italic>Der m 2<\/jats:italic> elicited the production of pro-inflammatory cytokines, interleukin (IL)-6, and IL-8 in BEAS-2B cells, a human bronchial epithelial cell line, and induced airway hyperresponsiveness in mice. Furthermore, in mice sensitized with <jats:italic>Der m 2<\/jats:italic>, the administration of FIP-<jats:italic>fve<\/jats:italic> in either the earlier stage or the late stage, FIP-<jats:italic>fve<\/jats:italic> alleviated allergic asthma by moderating airway inflammation and remodeling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>Der m 2<\/jats:italic> induced inflammatory responses in cell and mouse models. FIP-<jats:italic>fve<\/jats:italic> alleviated inflammation in <jats:italic>Der m 2<\/jats:italic>-induced asthma in mice by exerting an immunomodulatory effect.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2021.793559","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T06:16:05Z","timestamp":1642400165000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Systematic Characterization of the Group 2 House Dust Mite Allergen in Dermatophagoides microceras"],"prefix":"10.3389","volume":"11","author":[{"given":"Rei-Hsing","family":"Hu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Ta","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-Shuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng-Yih","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiunn-Liang","family":"Ko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ko-Huang","family":"Lue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1111\/all.12364","article-title":"Allergic Airway Diseases in a Tropical Urban Environment Are Driven by Dominant Mono-Specific Sensitization Against House Dust Mites","volume":"69","author":"Andiappan","year":"2014","journal-title":"Allergy"},{"key":"B2","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1101\/gr.1865504","article-title":"GeneWise and Genomewise","volume":"14","author":"Birney","year":"2004","journal-title":"Genome Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A Flexible Trimmer for Illumina Sequence Data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.antiviral.2014.08.006","article-title":"Alleviation of Respiratory Syncytial Virus Replication and Inflammation by Fungal Immunomodulatory Protein FIP-Fve From Flammulina Velutipes","volume":"110","author":"Chang","year":"2014","journal-title":"Antiviral Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1080\/09168451.2014.956682","article-title":"Alleviation of Dermatophagoides Microceras-Induced Allergy by an Immunomodulatory Protein, FIP-Fve, From Flammulina Velutipes in Mice","volume":"79","author":"Chang","year":"2015","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.jaci.2012.05.035","article-title":"Hypoallergenic Der P 1\/Der P 2 Combination Vaccines for Immunotherapy of House Dust Mite Allergy","volume":"130","author":"Chen","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.drudis.2018.01.015","article-title":"Recent Progress in the Discovery of Myeloid Differentiation 2 (MD2) Modulators for Inflammatory Diseases","volume":"23","author":"Chen","year":"2018","journal-title":"Drug Discov. Today"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1111\/all.12764","article-title":"The TLR4-Associated Phospholipase D1 Activation Is Crucial for Der F 2-Induced IL-13 Production","volume":"70","author":"Choi","year":"2015","journal-title":"Allergy"},{"key":"B9","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.jmii.2015.07.013","article-title":"Oral Fungal Immunomodulatory Protein-Flammulina Velutipes has Influence on Pulmonary Inflammatory Process and Potential Treatment for Allergic Airway Disease: A Mouse Model","volume":"50","author":"Chu","year":"2017","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B10","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1165\/rcmb.2012-0331OC","article-title":"Lipopolysaccharide Inhibits Th2 Lung Inflammation Induced by House Dust Mite Allergens in Mice","volume":"48","author":"Daan de Boer","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S0022-2836(02)00027-X","article-title":"The Crystal Structure of a Major Dust Mite Allergen Der P 2, and Its Biological Implications","volume":"318","author":"Derewenda","year":"2002","journal-title":"J. Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1016\/S0140-6736(17)32154-2","article-title":"Global, Regional, and National Incidence, Prevalence, and Years Lived With Disability for 328 Diseases and Injuries for 195 Countrie-2016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"390","author":"Disease","year":"2017","journal-title":"Lancet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/S0929-6646(09)60214-X","article-title":"Eosinophil Apoptosis Induced by Fungal Immunomodulatory Peptide-Fve via Reducing IL-5alpha Receptor","volume":"106","author":"Hsieh","year":"2007","journal-title":"J. Formos Med. Assoc."},{"key":"B14","first-page":"127","article-title":"Distribution of Allergens in Children With Different Atopic Disorders in Central Taiwan","volume":"47","author":"Huang","year":"2006","journal-title":"Acta Paediatr. Taiwan"},{"key":"B15","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1159\/000504320","article-title":"Identifying Potential Co-Sensitization and Cross-Reactivity Patterns Based on Component-Resolved Diagnosis","volume":"181","author":"Huang","year":"2020","journal-title":"Int. Arch. Allergy Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1111\/j.1365-2443.2009.01334.x","article-title":"Lipopolysaccharide Binding of the Mite Allergen Der F 2","volume":"14","author":"Ichikawa","year":"2009","journal-title":"Genes Cells"},{"key":"B17","doi-asserted-by":"publisher","first-page":"294","DOI":"10.5114\/ceji.2014.45938","article-title":"Effects of the Recombinant Allergen Rder F 2 on Neuro-Endocrino-Immune Network in Asthmatic Mice","volume":"39","author":"Jiang","year":"2014","journal-title":"Cent Eur. J. Immunol."},{"key":"B18","first-page":"36","article-title":"Immune Reactivity of Recombinant Group 2 Allergens of House Dust Mite, Dermatophagoides Pteronyssinus, and Dermatophagoides Farinae","volume":"13","author":"Jin","year":"2003","journal-title":"J. Investig. Allergol Clin. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"5375","DOI":"10.4049\/jimmunol.178.8.5375","article-title":"Airway Exposure Levels of Lipopolysaccharide Determine Type 1 Versus Type 2 Experimental Asthma","volume":"178","author":"Kim","year":"2007","journal-title":"J. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1111\/j.1432-1033.1995.tb20256.x","article-title":"A New Fungal Immunomodulatory Protein, FIP-Fve Isolated From the Edible Mushroom, Flammulina Velutipes and its Complete Amino Acid Sequence","volume":"228","author":"Ko","year":"1995","journal-title":"Eur. J. Biochem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf Model"},{"key":"B22","doi-asserted-by":"publisher","first-page":"12022","DOI":"10.1128\/JVI.05595-11","article-title":"The Interaction Between Bamboo Mosaic Virus Replication Protein and Coat Protein Is Critical for Virus Movement in Plant Hosts","volume":"85","author":"Lee","year":"2011","journal-title":"J. Virol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0083-4","article-title":"Therapeutic Potential of a Phospholipase D1 Inhibitory Peptide Fused With a Cell-Penetrating Peptide as a Novel Anti-Asthmatic Drug in a Der F 2-Induced Airway Inflammation Model","volume":"50","author":"Lee","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.cyto.2012.09.024","article-title":"Effect of the Fungal Immunomodulatory Protein FIP-Fve on Airway Inflammation and Cytokine Production in Mouse Asthma Model","volume":"61","author":"Lee","year":"2013","journal-title":"Cytokine"},{"key":"B25","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.jmii.2017.06.008","article-title":"Fungal Immunomodulatory Protein-Fve Could Modulate Airway Remodel Through by Affect IL17 Cytokine","volume":"51","author":"Lee","year":"2018","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B26","doi-asserted-by":"publisher","first-page":"497","DOI":"10.4168\/aair.2015.7.5.497","article-title":"Enhanced Allergic Inflammation of Der P 2 Affected by Polymorphisms of MD-2 Promoter","volume":"7","author":"Liao","year":"2015","journal-title":"Allergy Asthma Immunol. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1007\/s12026-012-8339-x","article-title":"Prevention and Treatment of Allergic Inflammation by an Fcgamma-Der F2 Fusion Protein in a Murine Model of Dust Mite-Induced Asthma","volume":"52","author":"Lin","year":"2012","journal-title":"Immunol. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4914","DOI":"10.1021\/jf300957k","article-title":"IFN-Gamma Induction on Carbohydrate Binding Module of Fungal Immunomodulatory Protein in Human Peripheral Mononuclear Cells","volume":"60","author":"Liu","year":"2012","journal-title":"J.\u00a0Agric. Food Chem."},{"key":"B29","first-page":"388","article-title":"Methods of Endotoxin Removal From Biological Preparations: A Review","volume":"10","author":"Magalhaes","year":"2007","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1111\/j.1365-2222.1994.tb02741.x","article-title":"Comparison of the Levels of the Major Allergens Der P I and Der P II in Standardized Extracts of the House Dust Mite, Dermatophagoides Pteronyssinus","volume":"24","author":"Meyer","year":"1994","journal-title":"Clin. Exp. Allergy"},{"key":"B31","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1513\/AnnalsATS.201703-259OC","article-title":"The Economic Burden of Asthma in the United State-2013","volume":"15","author":"Nurmagambetov","year":"2018","journal-title":"Ann. Am. Thorac. Soc."},{"key":"B32","doi-asserted-by":"publisher","first-page":"11008","DOI":"10.1021\/jf902725s","article-title":"FIP-Fve Stimulates Interferon-Gamma Production via Modulation of Calcium Release and PKC-Alpha Activation","volume":"57","author":"Ou","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1002\/tox.22701","article-title":"Epithelial Growth Factor Receptor Tyrosine Kinase Inhibitors Alleviate House Dust Mite Allergen Der P2-Induced IL-6 and IL-8","volume":"34","author":"Pan","year":"2019","journal-title":"Environ. Toxicol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"L1229","DOI":"10.1152\/ajplung.00103.2020","article-title":"The Importance of Reporting House Dust Mite Endotoxin Abundance: Impact on the Lung Transcriptome","volume":"318","author":"Pascoe","year":"2020","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/j.1365-2222.2004.1930.x","article-title":"Component-Resolved Diagnosis of House-Dust Mite Allergy With Purified Natural and Recombinant Mite Allergens","volume":"34","author":"Pittner","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0207311","DOI":"10.1371\/journal.pone.0207311","article-title":"Synergistic Effect of Dermatophagoides Pteronyssinus Allergen and Escherichia Coli Lipopolysaccharide on Human Blood Cells","volume":"13","author":"Radzyukevich","year":"2018","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"143","DOI":"10.2460\/ajvr.2005.66.143","article-title":"Quantitation of House Dust Mite Allergens (Der F 1 and Group 2) on the Skin and Hair of Dogs","volume":"66","author":"Randall","year":"2005","journal-title":"Am. J. Vet. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"51","DOI":"10.12932\/AP0670.34.1.2016","article-title":"Allergenicity of Native and Recombinant Major Allergen Groups 1 and 2 of Dermatophagoides Mites in Mite Sensitive Thai Patients","volume":"34","author":"Sookrung","year":"2016","journal-title":"Asian Pac J. Allergy Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1111\/all.12399","article-title":"Epicutaneously Applied Der P 2 Induces a Strong TH 2-Biased Antibody Response in C57BL\/6 Mice, Independent of Functional TLR4","volume":"69","author":"Stremnitzer","year":"2014","journal-title":"Allergy"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e02864","DOI":"10.1016\/j.heliyon.2019.e02864","article-title":"An Experimental Model of Asthma in Rats Using Ovalbumin and Lipopolysaccharide Allergens","volume":"5","author":"Thakur","year":"2019","journal-title":"Heliyon"},{"key":"B41","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nature07548","article-title":"Allergenicity Resulting From Functional Mimicry of a Toll-Like Receptor Complex Protein","volume":"457","author":"Trompette","year":"2009","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e23249","DOI":"10.1371\/journal.pone.0023249","article-title":"Mite Allergen Der-P2 Triggers Human B Lymphocyte Activation and Toll-Like Receptor-4 Induction","volume":"6","author":"Tsai","year":"2011","journal-title":"PloS One"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00190","article-title":"Measurement of Airway Function Using Invasive and Non-Invasive Methods in Mild and Severe Models for Allergic Airway Inflammation in Mice","volume":"5","author":"Verheijden","year":"2014","journal-title":"Front. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1021\/jf034556s","article-title":"Fungal Immunomodulatory Protein From Flammulina Velutipes Induces Interferon-Gamma Production Through P38 Mitogen-Activated Protein Kinase Signaling Pathway","volume":"52","author":"Wang","year":"2004","journal-title":"J. Agric. Food Chem."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005590118","article-title":"Single-Cell Transcriptomic Analysis Reveals the Immune Landscape of Lung in Steroid-Resistant Asthma Exacerbation","volume":"118","author":"Wang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B47","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1016\/j.jmii.2020.07.006","article-title":"Role of Biomarkers and Effect of FIP-Fve in Acute and Chronic Animal Asthma Models","volume":"53","author":"Wu","year":"2020","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2017.12.012","article-title":"Disruption of Liver Development and Coagulation Pathway by Ochratoxin A in Embryonic Zebrafish","volume":"340","author":"Wu","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"L216","DOI":"10.1152\/ajplung.00165.2010","article-title":"Dermatophagoides Pteronyssinus 2 Regulates Nerve Growth Factor Release to Induce Airway Inflammation via a Reactive Oxygen Species-Dependent Pathway","volume":"300","author":"Ye","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"393","DOI":"10.4168\/aair.2015.7.4.393","article-title":"Der P2 Internalization by Epithelium Synergistically Augments Toll-Like Receptor-Mediated Proinflammatory Signaling","volume":"7","author":"Yin","year":"2015","journal-title":"Allergy Asthma Immunol. Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"5334","DOI":"10.1021\/jf049303t","article-title":"Development of a Sensitive Enzyme-Linked Immunosorbent Assay for the Determination of Domoic Acid in Shellfish","volume":"52","author":"Yu","year":"2004","journal-title":"J. Agric. Food Chem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1465-9921-10-61","article-title":"Does Unrestrained Single-Chamber Plethysmography Provide a Valid Assessment of Airway Responsiveness in Allergic BALB\/c Mice","volume":"10","author":"Zhang","year":"2009","journal-title":"Respir. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1080\/02770903.2016.1223687","article-title":"Lipopolysaccharides Promote a Shift From Th2-Derived Airway Eosinophilic Inflammation to Th17-Derived Neutrophilic Inflammation in an Ovalbumin-Sensitized Murine Asthma Model","volume":"54","author":"Zhao","year":"2017","journal-title":"J. Asthma"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.793559\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T06:16:10Z","timestamp":1642400170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.793559\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,17]]},"references-count":53,"alternative-id":["10.3389\/fcimb.2021.793559"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.793559","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,17]]},"article-number":"793559"}}