{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:38:48Z","timestamp":1791049128388,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T00:00:00Z","timestamp":1752883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI","award":["U19AI131135"],"award-info":[{"award-number":["U19AI131135"]}]},{"name":"NCI","award":["1R01AI150181-01A1"],"award-info":[{"award-number":["1R01AI150181-01A1"]}]},{"name":"NCI","award":["5R21AI109303-02"],"award-info":[{"award-number":["5R21AI109303-02"]}]},{"name":"NCI","award":["MIT P30-CA14051"],"award-info":[{"award-number":["MIT P30-CA14051"]}]},{"DOI":"10.13039\/100000060","name":"NIH","doi-asserted-by":"publisher","award":["U19AI131135"],"award-info":[{"award-number":["U19AI131135"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIH","doi-asserted-by":"publisher","award":["1R01AI150181-01A1"],"award-info":[{"award-number":["1R01AI150181-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIH","doi-asserted-by":"publisher","award":["5R21AI109303-02"],"award-info":[{"award-number":["5R21AI109303-02"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIH","doi-asserted-by":"publisher","award":["MIT P30-CA14051"],"award-info":[{"award-number":["MIT P30-CA14051"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BroadIgnite Fellowship","award":["U19AI131135"],"award-info":[{"award-number":["U19AI131135"]}]},{"name":"BroadIgnite Fellowship","award":["1R01AI150181-01A1"],"award-info":[{"award-number":["1R01AI150181-01A1"]}]},{"name":"BroadIgnite Fellowship","award":["5R21AI109303-02"],"award-info":[{"award-number":["5R21AI109303-02"]}]},{"name":"BroadIgnite Fellowship","award":["MIT P30-CA14051"],"award-info":[{"award-number":["MIT P30-CA14051"]}]},{"name":"Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility of the Swanson Biotechnology Center","award":["U19AI131135"],"award-info":[{"award-number":["U19AI131135"]}]},{"name":"Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility of the Swanson Biotechnology Center","award":["1R01AI150181-01A1"],"award-info":[{"award-number":["1R01AI150181-01A1"]}]},{"name":"Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility of the Swanson Biotechnology Center","award":["5R21AI109303-02"],"award-info":[{"award-number":["5R21AI109303-02"]}]},{"name":"Barbara K. Ostrom (1978) Bioinformatics and Computing Core Facility of the Swanson Biotechnology Center","award":["MIT P30-CA14051"],"award-info":[{"award-number":["MIT P30-CA14051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood\u2013brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.<\/jats:p>","DOI":"10.3390\/jof11070539","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Human Brain Organoids: A New Model to Study Cryptococcus neoformans Neurotropism"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1446-2359","authenticated-orcid":false,"given":"Alfred T.","family":"Harding","sequence":"first","affiliation":[{"name":"Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9387-8212","authenticated-orcid":false,"given":"Lee","family":"Gehrke","sequence":"additional","affiliation":[{"name":"Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-9565","authenticated-orcid":false,"given":"Jatin M.","family":"Vyas","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Division of Infectious Disease, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9175-8209","authenticated-orcid":false,"given":"Hannah Brown","family":"Harding","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: An updated analysis","volume":"17","author":"Rajasingham","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bratton, E.W., El Husseini, N., Chastain, C.A., Lee, M.S., Poole, C., St\u00fcrmer, T., Juliano, J.J., Weber, D.J., Perfect, J.R., and Scheurer, M. (2012). Comparison and Temporal Trends of Three Groups with Cryptococcosis: HIV-Infected, Solid Organ Transplant, and HIV-Negative\/Non-Transplant. PLoS ONE, 7.","DOI":"10.1371\/annotation\/a94bc542-6682-4579-a315-57019cef7e0e"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.2217\/fmb.12.102","article-title":"Mechanisms of Infection by the Human Fungal Pathogen Cryptococcus neoformans","volume":"7","author":"Sabiiti","year":"2012","journal-title":"Future Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1172\/JCI42949","article-title":"Cryptococci at the brain gate: Break and enter or use a Trojan horse?","volume":"120","author":"Casadevall","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1128\/IAI.72.9.4985-4995.2004","article-title":"Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier","volume":"72","author":"Chang","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Santiago-Tirado, F.H., Klein, R.S., and Doering, T.L. (2019). An In Vitro Brain Endothelial Model for Studies of Cryptococcal Transmigration into the Central Nervous System. Curr. Protoc. Microbiol., 53.","DOI":"10.1002\/cpmc.78"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Normile, T.G., Bryan, A.M., and Del Poeta, M. (2020). Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.581750"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0046-8177(96)90459-1","article-title":"Pathology of cryptococcal meningoencephalitis: Analysis of 27 patients with pathogenetic implications","volume":"27","author":"Lee","year":"1996","journal-title":"Hum. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41698-021-00168-1","article-title":"Patient-derived organoids as a predictive biomarker for treatment response in cancer patients","volume":"5","author":"Wensink","year":"2021","journal-title":"NPJ Precis. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.stem.2016.04.014","article-title":"Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3","volume":"19","author":"Dang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Halioti, A., Vrettou, C.S., Neromyliotis, E., Gavrielatou, E., Sarri, A., Psaroudaki, Z., and Magira, E.E. (2024). Cerebrospinal Drain Infection by Candida auris: A Case Report and Review of the Literature. J. Fungi, 10.","DOI":"10.3390\/jof10120859"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12974-024-03237-x","article-title":"IL-6 deficiency accelerates cerebral cryptococcosis and alters glial cell responses","volume":"21","author":"Munzen","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12038-014-9496-y","article-title":"Lack of IL-6 increases blood\u2013brain barrier permeability in fungal meningitis","volume":"40","author":"Li","year":"2015","journal-title":"J. Biosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jarvis, J.N., Meintjes, G., Bicanic, T., Buffa, V., Hogan, L., Mo, S., Tomlinson, G., Kropf, P., Noursadeghi, M., and Harrison, T.S. (2015). Cerebrospinal Fluid Cytokine Profiles Predict Risk of Early Mortality and Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004754"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3109\/13550289909029748","article-title":"Dissemination of C. neoformans to the central nervous system: Role of chemokines, Th1 immunity and leukocyte recruitment","volume":"5","author":"Huffnagle","year":"1999","journal-title":"J. Neurovirol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"674","DOI":"10.4049\/jimmunol.2000073","article-title":"IL-25 Receptor Signaling Modulates Host Defense against Cryptococcus neoformans Infection","volume":"205","author":"Hansakon","year":"2020","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5753","DOI":"10.4049\/jimmunol.178.9.5753","article-title":"Protection from Direct Cerebral Cryptococcus Infection by Interferon-\u03b3-Dependent Activation of Microglial Cells","volume":"178","author":"Zhou","year":"2007","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1084\/jem.180.1.365","article-title":"Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism","volume":"180","author":"Lee","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/13693780410001731510","article-title":"Cytokine and chemokine expression in the central nervous system associated with protective cell-mediated immunity against Cryptococcus neoformans","volume":"43","author":"Uicker","year":"2005","journal-title":"Med. Mycol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01415-17","DOI":"10.1128\/mBio.01415-17","article-title":"Cd4+ T cells orchestrate lethal immune pathology despite fungal clearance during Cryptococcus neoformans meningoencephalitis","volume":"8","author":"Neal","year":"2017","journal-title":"mBio"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eaba2502","DOI":"10.1126\/sciadv.aba2502","article-title":"Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis","volume":"6","author":"Xu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nature22047","article-title":"Cell diversity and network dynamics in photosensitive human brain organoids","volume":"545","author":"Quadrato","year":"2017","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1074\/jbc.M116.748335","article-title":"Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival","volume":"292","author":"Rech","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0169-328X(00)00062-0","article-title":"N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease","volume":"77","author":"Ferrer","year":"2000","journal-title":"Mol. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"891","DOI":"10.2353\/ajpath.2009.080583","article-title":"The Neuronal Expression of MYC Causes a Neurodegenerative Phenotype in a Novel Transgenic Mouse","volume":"174","author":"Lee","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.neulet.2011.10.004","article-title":"Early induction of c-Myc is associated with neuronal cell death","volume":"505","author":"Lee","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.micinf.2015.08.017","article-title":"Cryptococcal transmigration across a model brain blood-barrier: Evidence of the Trojan horse mechanism and differences between Cryptococcus neoformans var. grubii strain H99 and Cryptococcus gattii strain R265","volume":"18","author":"Sorrell","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1128\/EC.00240-09","article-title":"Immortalized human brain endothelial cell line HCMEC\/D3 as a model of the blood-brain barrier facilitates in vitro studies of central nervous system infection by Cryptococcus neoformans","volume":"8","author":"Vu","year":"2009","journal-title":"Eukaryot. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Erta, M., Quintana, A., and Hidalgo, J. (2012). Interleukin-6, a Major Cytokine in the Central Nervous System. Int. J. Biol. Sci., 8.","DOI":"10.7150\/ijbs.4679"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Metcalfe, R.D., Putoczki, T.L., and Griffin, M.D.W. (2020). Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01424"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/art.1780330506","article-title":"Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system invol vement","volume":"33","author":"Hirohata","year":"1990","journal-title":"Arthritis Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0090-1229(90)90037-Q","article-title":"Cerebrospinal fluid interleukin-6 activity in HIV infection and inflammatory and noninflammatory diseases of the nervous system","volume":"57","author":"Laurenzi","year":"1990","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11457","DOI":"10.1128\/JVI.79.17.11457-11466.2005","article-title":"Neuronal CXCL10 Directs CD8+ T-Cell Recruitment and Control of West Nile Virus Encephalitis","volume":"79","author":"Klein","year":"2005","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Petrisko, T.J., Bloemer, J., Pinky, P.D., Srinivas, S., Heslin, R.T., Du, Y., Setti, S.E., Hong, H., Suppiramaniam, V., and Konat, G.W. (2020). Neuronal CXCL10\/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00220"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"231.2","DOI":"10.4049\/jimmunol.204.Supp.231.2","article-title":"IFN-\u03b3 signaling is essential for the clearance of C. neoformans in the brain and survival of the infected mice","volume":"204","author":"Chen","year":"2020","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.4049\/jimmunol.174.3.1746","article-title":"IFN-\u03b3 at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis","volume":"174","author":"Siddiqui","year":"2005","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s12967-023-04044-3","article-title":"CCL5\/CCR5-mediated peripheral inflammation exacerbates blood\u2013brain barrier disruption after intracerebral hemorrhage in mice","volume":"21","author":"Lin","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pittaluga, A. (2017). CCL5-glutamate cross-talk in astrocyte-neuron communication in multiple sclerosis. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01079"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00365-18","DOI":"10.1128\/mBio.00365-18","article-title":"Pathogenic effects of IFIT2 and interferon-\u03b2 during fatal systemic Candida albicans infection","volume":"9","author":"Stawowczyk","year":"2018","journal-title":"mBio"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.immuni.2013.05.010","article-title":"Interferon-\u03b2 Production via Dectin-1-Syk-IRF5 Signaling in Dendritic Cells Is Crucial for Immunity to C. albicans","volume":"38","author":"Soulat","year":"2013","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Majer, O., Bourgeois, C., Zwolanek, F., Lassnig, C., Kerjaschki, D., Mack, M., M\u00fcller, M., Kuchler, K., and Klein, B.S. (2012). Type I Interferons Promote Fatal Immunopathology by Regulating Inflammatory Monocytes and Neutrophils during Candida Infections. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002811"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eaan5357","DOI":"10.1126\/sciimmunol.aan5357","article-title":"Type III interferon is a critical regulator of innate antifungal immunity","volume":"2","author":"Espinosa","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1038\/ncomms2343","article-title":"Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans","volume":"4","author":"Smeekens","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/s41564-021-00875-2","article-title":"Candida pathogens induce protective mitochondria-associated type I interferon signalling and a damage-driven response in vaginal epithelial cells","volume":"6","author":"Pekmezovic","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41564-023-01546-0","article-title":"Candida albicans Extracellular Vesicles Trigger Type I IFN Signaling via cGAS and STING","volume":"9","author":"Harding","year":"2024","journal-title":"Nat. Microbiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108366","DOI":"10.1016\/j.exer.2020.108366","article-title":"The cGAS-STING signaling pathway contributes to the inflammatory response and autophagy in Aspergillus fumigatus keratitis","volume":"202","author":"Han","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kwaku, G.N., Jensen, K.N., Simaku, P., Floyd, D.J., Saelens, J.W., Reardon, C.M., Ward, R.A., Basham, K.J., Hepworth, O.W., and Vyas, T.D. (2025). Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation. PLoS Pathog., 21.","DOI":"10.1101\/2025.01.03.631181"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.stem.2016.11.017","article-title":"Induction of expansion and folding in human cerebral organoids","volume":"20","author":"Li","year":"2016","journal-title":"Cell Stem Cell"}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/7\/539\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:12:35Z","timestamp":1760033555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/7\/539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,19]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["jof11070539"],"URL":"https:\/\/doi.org\/10.3390\/jof11070539","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,19]]}}}