{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:51:27Z","timestamp":1791219087618,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSERC Postdoctoral Fellowship","award":["FDN-154288"],"award-info":[{"award-number":["FDN-154288"]}]},{"name":"Mitacs Accelerate Postdoctoral Fellowship","award":["FDN-154288"],"award-info":[{"award-number":["FDN-154288"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research Foundation Grant","doi-asserted-by":"publisher","award":["FDN-154288"],"award-info":[{"award-number":["FDN-154288"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Invasive fungal infections have mortality rates of 30\u201390%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1\u21923)-\u03b2-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans.<\/jats:p>","DOI":"10.3390\/jof8101102","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T22:19:53Z","timestamp":1666217993000},"page":"1102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6218-2247","authenticated-orcid":false,"given":"Sean D.","family":"Liston","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Whitesell","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mili","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Pfizer Inc., San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen J.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Hearts Consulting Group, LLC, Poway, CA 92064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah E.","family":"Cowen","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: Human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. (2017). Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J. Fungi, 3.","DOI":"10.3390\/jof3040057"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3410\/M3-14","article-title":"Emerging fungal infections in immunocompromised patients","volume":"3","author":"Low","year":"2011","journal-title":"F1000 Med. Rep."},{"key":"ref_4","first-page":"1","article-title":"Epidemiology of invasive mycoses in North America","volume":"36","author":"Pfaller","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1099\/jmm.0.46548-0","article-title":"Invasive fungal infections: A review of epidemiology and management options","volume":"55","author":"Enoch","year":"2006","journal-title":"J. Med. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1046\/j.1524-4733.2002.51108.x","article-title":"The direct cost and incidence of systemic fungal infections","volume":"5","author":"Wilson","year":"2002","journal-title":"Value Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1128\/microbiolspec.FUNK-0002-2016","article-title":"Antifungal Drugs: The Current Armamentarium and Development of New Agents","volume":"4","author":"Robbins","year":"2016","journal-title":"Microbiol. Spectr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S474","DOI":"10.1093\/infdis\/jix130","article-title":"Novel Agents and Drug Targets to Meet the Challenges of Resistant Fungi","volume":"216","author":"McCarthy","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1080\/13543784.2022.2086120","article-title":"Invasive candidiasis: Investigational drugs in the clinical development pipeline and mechanisms of action","volume":"31","author":"Hoenigl","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.idc.2020.05.003","article-title":"Emerging Issues in Antifungal Resistance","volume":"34","author":"Perfect","year":"2020","journal-title":"Infect. Dis. Clin. North Am."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal pipeline: A reality check","volume":"16","author":"Perfect","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.4155\/fmc-2016-0110","article-title":"The GPI anchor pathway: A promising antifungal target?","volume":"8","author":"Mutz","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/20477724.2018.1442764","article-title":"Targeting the GPI biosynthetic pathway","volume":"112","author":"Yadav","year":"2018","journal-title":"Pathog. Glob. Health"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Shaw, K.J., and Ibrahim, A.S. (2020). Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections. J. Fungi, 6.","DOI":"10.3390\/jof6040239"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"911322","DOI":"10.3389\/fmicb.2022.911322","article-title":"Novel Promising Antifungal Target Proteins for Conquering Invasive Fungal Infections","volume":"13","author":"Zhen","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.bbalip.2006.05.015","article-title":"Biosynthesis and function of GPI proteins in the yeast Saccharomyces cerevisiae","volume":"1771","author":"Pittet","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nrd3074","article-title":"An insight into the antifungal pipeline: Selected new molecules and beyond","volume":"9","author":"Casadevall","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00899-20","DOI":"10.1128\/AAC.00899-20","article-title":"Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability","volume":"64","author":"Liston","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1021\/cb300235m","article-title":"Inhibiting GPI anchor biosynthesis in fungi stresses the endoplasmic reticulum and enhances immunogenicity","volume":"7","author":"McLellan","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1128\/AAC.00731-11","article-title":"E1210, a new broad-spectrum antifungal, suppresses Candida albicans hyphal growth through inhibition of glycosylphosphatidylinositol biosynthesis","volume":"56","author":"Watanabe","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23639","DOI":"10.1074\/jbc.M301044200","article-title":"GWT1 gene is required for inositol acylation of glycosylphosphatidylinositol anchors in yeast","volume":"278","author":"Umemura","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1046\/j.1365-2958.2003.03481.x","article-title":"Medicinal genetics approach towards identifying the molecular target of a novel inhibitor of fungal cell wall assembly","volume":"48","author":"Tsukahara","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"126713","DOI":"10.1016\/j.bmcl.2019.126713","article-title":"Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in vitro evaluation against Cryptococcus spp.","volume":"29","author":"Trzoss","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0092-8674(00)80358-X","article-title":"Nonfilamentous C. albicans mutants are avirulent","volume":"90","author":"Lo","year":"1997","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/ng.605","article-title":"Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity","volume":"42","author":"Noble","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15775","DOI":"10.1073\/pnas.1103496108","article-title":"Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans","volume":"108","author":"Salgado","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wheeler, R.T., and Fink, G.R. (2006). A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog., 2.","DOI":"10.1371\/journal.ppat.0020035"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1093\/emboj\/21.10.2343","article-title":"Essential role of calcineurin in response to endoplasmic reticulum stress","volume":"21","author":"Bonilla","year":"2002","journal-title":"EMBO J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103953","DOI":"10.1016\/j.isci.2022.103953","article-title":"The role of Candida albicans stress response pathways in antifungal tolerance and resistance","volume":"25","author":"Iyer","year":"2022","journal-title":"iScience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1021\/id5000212","article-title":"Chemical Genomics-Based Antifungal Drug Discovery: Targeting Glycosylphosphatidylinositol (GPI) Precursor Biosynthesis","volume":"1","author":"Mann","year":"2015","journal-title":"ACS Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1128\/jcm.32.7.1650-1653.1994","article-title":"Selection of candidate quality control isolates and tentative quality control ranges for in vitro susceptibility testing of yeast isolates by National Committee for Clinical Laboratory Standards proposed standard methods","volume":"32","author":"Pfaller","year":"1994","journal-title":"J. Clin. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1128\/EC.4.2.298-309.2005","article-title":"Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans","volume":"4","author":"Noble","year":"2005","journal-title":"Eukaryot. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Singh, S.D., Robbins, N., Zaas, A.K., Schell, W.A., Perfect, J.R., and Cowen, L.E. (2009). Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000532"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1046\/j.1365-2958.2003.03697.x","article-title":"Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery","volume":"50","author":"Roemer","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.1128\/IAI.71.9.4831-4841.2003","article-title":"Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates","volume":"71","author":"Nielsen","year":"2003","journal-title":"Infect. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/nature04332","article-title":"Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus","volume":"438","author":"Nierman","year":"2005","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D592","DOI":"10.1093\/nar\/gkw924","article-title":"The Candida Genome Database (CGD): Incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data","volume":"45","author":"Skrzypek","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/nmeth.1701","article-title":"SignalP 4.0: Discriminating signal peptides from transmembrane regions","volume":"8","author":"Petersen","year":"2011","journal-title":"Nature Methods"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pierleoni, A., Martelli, P.L., and Casadio, R. (2008). PredGPI: A GPI-anchor predictor. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-392"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/iub.1734","article-title":"Generating anchors only to lose them: The unusual story of glycosylphosphatidylinositol anchor biosynthesis and remodeling in yeast and fungi","volume":"70","author":"Komath","year":"2018","journal-title":"IUBMB Life"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6497","DOI":"10.1038\/s41467-021-26850-3","article-title":"Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets","volume":"12","author":"Fu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3389\/fgene.2013.00290","article-title":"Genetic interaction networks: Better understand to better predict","volume":"4","author":"Boucher","year":"2013","journal-title":"Front. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"W739","DOI":"10.1093\/nar\/gkac382","article-title":"SynergyFinder 3.0: An interactive analysis and consensus interpretation of multi-drug synergies across multiple samples","volume":"50","author":"Ianevski","year":"2022","journal-title":"Nucleic. Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Xu, D., Jiang, B., Ketela, T., Lemieux, S., Veillette, K., Martel, N., Davison, J., Sillaots, S., Trosok, S., and Bachewich, C. (2007). Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030092"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6741","DOI":"10.1038\/ncomms7741","article-title":"Global analysis of fungal morphology exposes mechanisms of host cell escape","volume":"6","author":"Veri","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.jmb.2004.01.025","article-title":"A sensitive predictor for potential GPI lipid modification sites in fungal protein sequences and its application to genome-wide studies for Aspergillus nidulans, Candida albicans, Neurospora crassa, Saccharomyces cerevisiae and Schizosaccharomyces pombe","volume":"337","author":"Eisenhaber","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1093\/glycob\/cwz045","article-title":"Updates to the Symbol Nomenclature for Glycans guidelines","volume":"29","author":"Neelamegham","year":"2019","journal-title":"Glycobiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"28513415","DOI":"10.1128\/microbiolspec.FUNK-0035-2016","article-title":"The Fungal Cell Wall: Structure, Biosynthesis, and Function","volume":"5","author":"Gow","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41579-018-0141-x","article-title":"Drug combinations: A strategy to extend the life of antibiotics in the 21st century","volume":"17","author":"Tyers","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/sj.bmt.1705687","article-title":"Combination antifungal therapy: What can and should we expect?","volume":"40","author":"Johnson","year":"2007","journal-title":"Bone Marrow Transpl."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nchembio.1205","article-title":"Systems-level antimicrobial drug and drug synergy discovery","volume":"9","author":"Roemer","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1080\/21505594.2016.1196300","article-title":"Combinatorial strategies for combating invasive fungal infections","volume":"8","author":"Spitzer","year":"2017","journal-title":"Virulence"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e01387-19","DOI":"10.1128\/AAC.01387-19","article-title":"Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species","volume":"64","author":"Kapoor","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6100","DOI":"10.1128\/AAC.00620-16","article-title":"Characterization of In Vitro Resistance Development to the Novel Echinocandin CD101 in Candida Species","volume":"60","author":"Locke","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e00261-20","DOI":"10.1128\/AAC.00261-20","article-title":"Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility","volume":"64","author":"Liston","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e0174821","DOI":"10.1128\/AAC.01748-21","article-title":"Inhibitor-Resistant Mutants Give Important Insights into Candida albicans ABC Transporter Cdr1 Substrate Specificity and Help Elucidate Efflux Pump Inhibition","volume":"66","author":"Niimi","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"21389","DOI":"10.1038\/s41598-021-00942-y","article-title":"CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients","volume":"11","author":"Fekete","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_58","first-page":"1002","article-title":"Dissecting the mechanism of T-cell anergy with immunophilin ligands","volume":"7","author":"Powell","year":"2006","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e0104922","DOI":"10.1128\/mbio.01049-22","article-title":"Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus","volume":"13","author":"Hoy","year":"2022","journal-title":"MBio"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e0300021","DOI":"10.1128\/mBio.03000-21","article-title":"Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs","volume":"12","author":"Gobeil","year":"2021","journal-title":"MBio"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1091\/mbc.10.3.627","article-title":"MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast","volume":"10","author":"Gaynor","year":"1999","journal-title":"Mol. Biol. Cell"}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/10\/1102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:07Z","timestamp":1760144227000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/10\/1102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":61,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jof8101102"],"URL":"https:\/\/doi.org\/10.3390\/jof8101102","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}