{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:47Z","timestamp":1792790447798,"version":"4.5.0"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,20]],"date-time":"2022-02-20T00:00:00Z","timestamp":1645315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004054","name":"King Abdulaziz University","doi-asserted-by":"publisher","award":["IFPHI-085-130-2020"],"award-info":[{"award-number":["IFPHI-085-130-2020"]}],"id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Candida auris, an evolving multidrug-resistant pathogenic yeast, is known for causing severe invasive infections associated with high mortality rates in hospitalized individuals. Distinct from other Candida species, C. auris can persist for longer periods on different surfaces and is resistant to all of the major classes of antifungal drugs. Therefore, there is an urgent need for new antimycotic drugs with improved efficacy and reduced toxicity. The development of new antifungals based on antimicrobial peptides from various sources is considered a promising alternative. In this study, we examined the in vitro anti-yeast activity of the human cathelicidin peptides LL-37 against clinical strains of C. auris alone and in combination with different antifungal drugs by broth microdilution assay. To understand the antifungal mechanism of action, cell envelopes, cell cycle arrest, and effect on oxidative stress enzymes were studied using standard protocols. The minimum inhibitory and fungicidal concentrations of cathelicidin LL-37 ranged from 25\u2013100 and 50\u2013200 \u00b5g\/mL, respectively. A combination interaction in a 1:1 ratio (cathelicidin LL-37: antifungal drug) resulted in 70% synergy with fluconazole and 100% synergy with amphotericin B and caspofungin. Assessment of the C. auris membrane by using propidium iodide assay after exposure to cathelicidin LL-37 linked membrane permeabilization with inhibition of C. auris cell growth and viability. These results were backed up by scanning electron microscopy studies demonstrating that exposure with cathelicidin LL-37 caused C. auris cells to undergo extensive surface changes. Spectrophotometric analysis revealed that cathelicidin LL-37 caused oxidative stress in C. auris, as is evident from the significant increase in the activity of primary antioxidant enzymes. In addition, cathelicidin LL-37 inhibited the cell cycle and accumulated cells in the S phase. Therefore, these results specify the potential of cathelicidin LL-37 for developing a new and effective anti-Candida agent.<\/jats:p>","DOI":"10.3390\/jof8020204","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:22:19Z","timestamp":1645431739000},"page":"204","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Antifungal Activity of Human Cathelicidin LL-37, a Membrane Disrupting Peptide, by Triggering Oxidative Stress and Cell Cycle Arrest in Candida auris"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-0519","authenticated-orcid":false,"given":"Irfan A.","family":"Rather","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia"},{"name":"Centre of Excellence in Bionanoscience Research, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal S. M.","family":"Sabir","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia"},{"name":"Centre of Excellence in Bionanoscience Research, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amer H.","family":"Asseri","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajad","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Yeungnam University, Gyeongsan 385541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e01588-17","DOI":"10.1128\/JCM.01588-17","article-title":"Candida auris: An Emerging Fungal Pathogen","volume":"56","author":"Spivak","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.3201\/eid2410.180649","article-title":"Candida auris in Healthcare Facilities, New York, USA, 2013\u20132017","volume":"24","author":"Adams","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00134-014-3603-2","article-title":"Incidence, Characteristics, and Outcome of ICU-Acquired Candidemia in India","volume":"41","author":"Chakrabarti","year":"2015","journal-title":"Intensive Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jinf.2016.07.008","article-title":"First report of Candida auris in America: Clinical and Microbiological Aspects of 18 Episodes of Candidemia","volume":"73","author":"Calvo","year":"2016","journal-title":"J. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1093\/cid\/ciw691","article-title":"Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses","volume":"64","author":"Lockhart","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s12257-018-0477-0","article-title":"Invasive Fungal Infections and Their Epidemiology: Measures in the Clinical Scenario","volume":"24","author":"Bajpai","year":"2019","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jphs.2020.06.003","article-title":"Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections","volume":"144","author":"Campione","year":"2020","journal-title":"J. Pharmacol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cosio, T., Gaziano, R., Zuccari, G., Costanza, G., Grelli, S., Di Francesco, P., Bianchi, L., and Campione, E. (2021). Retinoids in fungal infections: From bench to bedside. Pharmaceuticals, 14.","DOI":"10.3390\/ph14100962"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fcimb.2016.00194","article-title":"Antimicrobial Peptides: An Emerging Category of Therapeutic Agents","volume":"6","author":"Mahlapuu","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/201456a0","article-title":"Antimicrobial Agents and Chemotherapy","volume":"201","author":"Perlman","year":"1964","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20172687","DOI":"10.1098\/rspb.2017.2687","article-title":"Predicting Drug Resistance Evolution: Insights from Antimicrobial Peptides and Antibiotics","volume":"285","author":"Yu","year":"2018","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1111\/myc.13277","article-title":"New weapons to fight a new enemy: A systematic review of drug combinations against the drug-resistant fungus Candida auris","volume":"64","author":"Gharehbolagh","year":"2021","journal-title":"Mycoses"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1073\/pnas.92.1.195","article-title":"FALL-39, a Putative Human Peptide Antibiotic, Is Cysteine-Free and Expressed in Bone Marrow and Testis","volume":"92","author":"Agerberth","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3718","DOI":"10.1074\/jbc.273.6.3718","article-title":"Conformation-Dependent Antibacterial Activity of the Naturally Occurring Human Peptide LL-37","volume":"273","author":"Johansson","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1084\/jem.192.7.1069","article-title":"LL-37, the Neutrophil Granule- and Epithelial Cell-Derived Cathelicidin, Utilizes Formyl Peptide Receptor-like 1 (FPRL1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells","volume":"192","author":"Chen","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1128\/IAI.01218-07","article-title":"Expression of Cathelicidin LL-37 during Mycobacterium Tuberculosis Infection in Human Alveolar Macrophages, Monocytes, Neutrophils, and Epithelial Cells","volume":"76","author":"Carranza","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1189\/jlb.0609382","article-title":"Human Defensins and LL-37 in Mucosal Immunity","volume":"87","author":"Doss","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00005-009-0057-2","article-title":"Cathelicidin LL-37: A Multitask Antimicrobial Peptide","volume":"58","author":"Bucki","year":"2010","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"404","DOI":"10.4236\/abb.2011.26059","article-title":"Degradation of Naturally Occurring and Engineered Antimicrobial Peptides by Proteases","volume":"2","author":"Moncla","year":"2011","journal-title":"Adv. Biosci. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.3390\/ph6081055","article-title":"Characterization of Antimicrobial Peptides toward the Development of Novel Antibiotics","volume":"6","author":"Aoki","year":"2013","journal-title":"Pharmaceuticals"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ahmad, A., Wani, M.Y., Khan, A., Manzoor, N., and Molepo, J. (2015). Synergistic Interactions of Eugenol-Tosylate and Its Congeners with Fluconazole against Candida albicans. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145053"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.3389\/fmicb.2019.02853","article-title":"The Synergistic Antifungal Effect and Potential Mechanism of D-Penicillamine Combined With Fluconazole Against Candida albicans","volume":"10","author":"Li","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1128\/AAC.42.5.1207","article-title":"Influence of Test Conditions on Antifungal Time-Kill Curve Results: Proposal for Standardized Methods","volume":"42","author":"Klepser","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1139\/W10-066","article-title":"Effect of Diallyldisulphide on an Antioxidant Enzyme System in Candida Species","volume":"56","author":"Yousuf","year":"2010","journal-title":"Can. J. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Maras, B., Angiolella, L., Mignogna, G., Vavala, E., Macone, A., Colone, M., Pitari, G., Stringaro, A., Dupr\u00e9, S., and Palamara, A.T. (2014). Glutathione Metabolism in Candida albicans Resistant Strains to Fluconazole and Micafungin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098387"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"46035","DOI":"10.1038\/srep46035","article-title":"Antioxidant Efficacy and the Upregulation of Nrf2-Mediated HO-1 Expression by (+)-Lariciresinol, a Lignan Isolated from Rubia Philippinensis, through the Activation of P38","volume":"7","author":"Bajpai","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/jfbc.12230","article-title":"Partially Purified Exo-Polysaccharide from Lactobacillus Sakei Probio 65 with Antioxidant, \u03b1-Glucosidase and Tyrosinase Inhibitory Potential","volume":"40","author":"Bajpai","year":"2016","journal-title":"J. Food Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4183","DOI":"10.1007\/s00253-018-8906-8","article-title":"Cell Permeability and Nuclear DNA Staining by Propidium Iodide in Basidiomycetous Yeasts","volume":"102","author":"Zhang","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.micres.2016.12.008","article-title":"Antifungal Activity of Ionic Liquids Based on (\u2212)-Menthol: A Mechanism Study","volume":"197","author":"Suchodolski","year":"2017","journal-title":"Microbiol. Res."},{"key":"ref_30","unstructured":"CDC (2019). Candida auris: Information for Laboratorians and Health Professionals."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/978-981-13-3588-4_12","article-title":"Design of antimicrobial peptides: Progress made with human cathelicidin LL-37","volume":"1117","author":"Wang","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/wrr.12211","article-title":"Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: A randomized, placebo-controlled clinical trial","volume":"22","author":"Gronberg","year":"2014","journal-title":"Wound Repair Regen."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.1128\/JCM.01998-13","article-title":"Epidemiology, Species Distribution, Antifungal Susceptibility, and Outcome of Candidemia across Five Sites in Italy and Spain","volume":"51","author":"Bassetti","year":"2013","journal-title":"J. Clin. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/j.1365-2672.2010.04874.x","article-title":"Potential of Ceragenin CSA-13 and Its Mixture with Pluronic F-127 as Treatment of Topical Bacterial Infections","volume":"110","author":"Namiot","year":"2011","journal-title":"J. Appl. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2972","DOI":"10.1128\/AAC.02642-13","article-title":"Activity of Host Antimicrobials against Multidrug-Resistant Acinetobacter Baumannii Acquiring Colistin Resistance through Loss of Lipopolysaccharide","volume":"58","author":"Pulido","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1128\/AAC.02554-14","article-title":"LL-37-Derived Peptides Eradicate Multidrug-Resistant Staphylococcus Aureus from Thermally Wounded Human Skin Equivalents","volume":"58","author":"Haisma","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1042\/BJ20042099","article-title":"Candidacidal Effects of Two Antimicrobial Peptides: Histatin 5 Causes Small Membrane Defects, but LL-37 Causes Massive Disruption of the Cell Membrane","volume":"388","author":"Bolscher","year":"2005","journal-title":"Biochem. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s12275-014-3630-2","article-title":"Responses of Candida albicans to the Human Antimicrobial Peptide LL-37","volume":"52","author":"Tsai","year":"2014","journal-title":"J. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.peptides.2015.07.023","article-title":"Antifungal Activity of Cathelicidin Peptides against Planktonic and Biofilm Cultures of Candida Species Isolated from Vaginal Infections","volume":"71","author":"Scarsini","year":"2015","journal-title":"Peptides"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Spitzer, M., Robbins, N., and Wright, G.D. (2017). Combinatorial Strategies for Combating Invasive Fungal Infections. Virulence, 8.","DOI":"10.1080\/21505594.2016.1196300"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e01056-17","DOI":"10.1128\/AAC.01056-17","article-title":"In Vitro Interactions of Echinocandins with Triazoles against Multidrug-Resistant Candida auris","volume":"61","author":"Fakhim","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e314","DOI":"10.1016\/S2666-5247(20)30194-4","article-title":"Micafungin and Amphotericin B Synergy against Candida auris","volume":"1","author":"Jaggavarapu","year":"2020","journal-title":"Lancet Microbe"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.drudis.2006.11.008","article-title":"Multi-Target Therapeutics: When the Whole Is Greater than the Sum of the Parts","volume":"12","author":"Zimmermann","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bondaryk, M., Staniszewska, M., Zieli\u0144ska, P., and Urba\u0144czyk-Lipkowska, Z. (2017). Natural Antimicrobial Peptides as Inspiration for Design of a New Generation Antifungal Compounds. J. Fungi, 3.","DOI":"10.3390\/jof3030046"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s10096-013-1850-8","article-title":"Enhanced Efficacy of Synergistic Combinations of Antimicrobial Peptides with Caspofungin versus Candida albicans in Insect and Murine Models of Systemic Infection","volume":"32","author":"MacCallum","year":"2013","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"488","DOI":"10.24272\/j.issn.2095-8137.2019.062","article-title":"Antimicrobial peptides: New hope in the war against multidrug resistance","volume":"40","author":"Mwangi","year":"2019","journal-title":"Zool. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1016\/j.apsb.2021.07.014","article-title":"Membrane-disruptive peptides\/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era","volume":"11","author":"Lin","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.1567-1364.2010.00697.x","article-title":"Induction of oxidative stress as a possible mechanism of the antifungal action of three phenylpropanoids","volume":"11","author":"Khan","year":"2011","journal-title":"FEMS Yeast Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.micpath.2015.02.004","article-title":"Effect of two monoterpene phenols on antioxidant defence system in Candida albicans","volume":"20","author":"Khan","year":"2015","journal-title":"Microb. Pathog."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e01334-14","DOI":"10.1128\/mBio.01334-14","article-title":"Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes","volume":"5","author":"Kaloriti","year":"2014","journal-title":"Mbio"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"20911","DOI":"10.1074\/jbc.M116.748251","article-title":"The phylogeny and active site design of eukaryotic Cu-only superoxide dismutases","volume":"291","author":"Peterson","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3390\/biom5010142","article-title":"Oxidative stress responses in the human fungal pathogen, Candida albicans","volume":"5","author":"Dantas","year":"2015","journal-title":"Biomolecules"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.bbagen.2013.03.020","article-title":"Biomarkers of lipid peroxidation in clinical material","volume":"1840","author":"Niki","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25","DOI":"10.5941\/MYCO.2017.45.1.25","article-title":"In vitro antifungal activity of (1)-N-2-Methoxybenzyl-1,10-Phenanthrolinium bromide against Candida albicans and its effects on membrane Integrity","volume":"45","author":"Setiawati","year":"2017","journal-title":"Mycobiology"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Oren, Z., and Shai, Y. (1998). Mode of action of linear amphipathic \u03b1-Helical antimicrobial peptides. Biopolymers.","DOI":"10.1002\/(SICI)1097-0282(1998)47:6<451::AID-BIP4>3.0.CO;2-F"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0005-2736(99)00198-4","article-title":"Diversity of antimicrobial peptides and their mechanisms of action","volume":"1462","author":"Epand","year":"1999","journal-title":"Biochim. Biophys. Acta-Biomembr."}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/2\/204\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:23:32Z","timestamp":1760135012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/2\/204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,20]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jof8020204"],"URL":"https:\/\/doi.org\/10.3390\/jof8020204","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,20]]}}}