{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T12:11:35Z","timestamp":1781957495818,"version":"3.54.5"},"reference-count":45,"publisher":"IMR Press","issue":"12","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Humanidades, Ciencias y Tecnolog\u00edas","doi-asserted-by":"crossref","award":["CY002261"],"award-info":[{"award-number":["CY002261"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Direcci\u00f3n General de Personal Acad\u00e9mico, UNAM: PAPIIT","award":["IN207720"],"award-info":[{"award-number":["IN207720"]}]},{"name":"Direcci\u00f3n General de Personal Acad\u00e9mico, UNAM: PAPIIT","award":["IN211823"],"award-info":[{"award-number":["IN211823"]}]},{"name":"Institutional Program \u201cPrograma de Investigaci\u00f3n para el Desarrollo y la Optimizaci\u00f3n de Vacunas, Inmunomoduladores y M\u00e9todos Diagn\u00f3sticos del IIBO''"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, progressive disease that severely affects human health of young adults. Neuroinflammation (NI) and demyelination, as well as their interactions, are key therapeutic targets to halt or slow disease progression. Potent steroidal anti-inflammatory drugs such as methylprednisolone (MP) and remyelinating neurosteroids such as allopregnanolone (ALLO) could be co-administered intranasally to enhance their efficacy by providing direct access to the central nervous system (CNS). Methods: The individual and combined effects of MP and ALLO to control the clinical score of murine experimental autoimmune encephalitis (EAE), to preserve spinal cord tissue integrity, modulate cellular infiltration and gliosis, promote remyelination, and modify the expression of Aryl hydrocarbon receptor (AhR) were evaluated. In silico studies, to deep insight into the mechanisms involved for the treatments, were also conducted. Results: MP was the only treatment that significantly reduced the EAE severity, infiltration of inflammatory cells and ionized calcium-binding adapter molecule 1 (Iba-1) expression respect to those EAE non-treated mice but with no-significant differences between the three treatments. MP, ALLO and MP+ALLO significantly reduced tissue damage, AhR expression, and promoted remyelination. Overall, these results suggest that MP, with or without the co-administration with ALLO is an effective and safe strategy to reduce the inflammatory status and the progression of EAE. Despite the expectations of the use of ALLO to reduce the inflammation in EAE, its effect in the dose-scheme used herein is limited only to improve myelination, an effect that supports its usefulness in demyelinating diseases. These results indicate the interest in exploring different doses of ALLO to recommend its use. Conclusions: ALLO treatment mainly maintain the integrity of the spinal cord tissue and the presence of myelin without affecting NI and the clinical outcome. AhR could be involved in the effect observed in both, MP and ALLO treatments. These results will help in the development of a more efficient therapy for MS patients.<\/jats:p>","DOI":"10.31083\/j.fbl2912420","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T11:37:01Z","timestamp":1735558621000},"source":"Crossref","is-referenced-by-count":1,"title":["Combined Use of Intranasal Methylprednisolone and Allopregnanolone: Revisiting Anti-inflammatory and Remyelinating Treatment in a Murine Model of Multiple Sclerosis"],"prefix":"10.31083","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5946-5318","authenticated-orcid":true,"given":"Iv\u00e1n Nicol\u00e1s","family":"P\u00e9rez-Osorio","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9455-4500","authenticated-orcid":true,"given":"Jos\u00e9 Alejandro","family":"Espinosa-Cer\u00f3n","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"\u00c1lvarez-Guti\u00e9rrez","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-0792","authenticated-orcid":true,"given":"Rodrigo","family":"Gonzalez-Flores","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7149-0471","authenticated-orcid":true,"given":"Hugo","family":"Besedovsky","sequence":"first","affiliation":[{"name":"Research Group Immunophysiology, Division of Neurophysiology, Institute of Physiology and Pathophysiology, Philipps Universit\u00e4t, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3885-1858","authenticated-orcid":true,"given":"Gladis","family":"Fragoso","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8900-4037","authenticated-orcid":true,"given":"M\u00f3nica A.","family":"Torres-Ramos","sequence":"first","affiliation":[{"name":"Research Directorate, National Institute of Neurology and Neurosurgery Manuel Velasco Su\u00e1rez, Tlalpan, 14269 Mexico City, Mexico"},{"name":"Laboratory 4 Translational Sciences, Center for Research on Aging, CINVESTAV South Headquarters, 14330, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5608-5355","authenticated-orcid":true,"given":"Edda","family":"Sciutto","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Research Universidad Nacional Aut\u00f3noma de M\u00e9xico, UNAM, 04510 Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Jakimovski D, Bittner S, Zivadinov R, Morrow SA, Benedict RH, Zipp F, et al. Multiple sclerosis. Lancet (London, England). 2024; 403: 183\u2013202.","DOI":"10.1016\/S0140-6736(23)01473-3."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Tagge IJ, Leppert IR, Fetco D, Campbell JS, Rudko DA, Brown RA, et al. Permanent tissue damage in multiple sclerosis lesions is associated with reduced pre-lesion myelin and axon volume fractions. Multiple Sclerosis (Houndmills, Basingstoke, England). 2022; 28: 2027\u20132037.","DOI":"10.1177\/13524585221110585."},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet (London, England). 2015; 386: 974\u2013981.","DOI":"10.1016\/S0140-6736(15)61137-0."},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Franklin RJM, Simons M. CNS remyelination and inflammation: From basic mechanisms to therapeutic opportunities. Neuron. 2022; 110: 3549\u20133565.","DOI":"10.1016\/j.neuron.2022.09.023."},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Saied A, Elsaid N, Azab A. Long term effects of corticosteroids in multiple sclerosis in terms of the \u201cno evidence of disease activity\u201d (NEDA) domains. Steroids. 2019; 149: 108401.","DOI":"10.1016\/j.steroids.2019.04.006."},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"\u00d6merhoca S, Ha\u015fimo\u011flu ZY, Erdo\u011fan S, Kale N. The Adverse Effects of High-Dose Corticosteroids with Early and Late Severe Morbidity in the Treatment of Patients with Multiple Sclerosis: Long-Term Observation Results. Turkish Journal of Neurology. 2019; 25: 71\u201375.","DOI":"10.4274\/tnd.2019.75725."},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Rassy D, B\u00e1rcena B, P\u00e9rez-Osorio IN, Espinosa A, Pe\u00f3n AN, Terrazas LI, et al. Intranasal Methylprednisolone Effectively Reduces Neuroinflammation in Mice with Experimental Autoimmune Encephalitis. Journal of Neuropathology and Experimental Neurology. 2020; 79: 226\u2013237.","DOI":"10.1093\/jnen\/nlz128."},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"P\u00e9rez-Osorio IN, Espinosa A, Giraldo Vel\u00e1zquez M, Padilla P, B\u00e1rcena B, Fragoso G, et al. Nose-to-Brain Delivery of Dexamethasone: Biodistribution Studies in Mice. The Journal of Pharmacology and Experimental Therapeutics. 2021; 378: 244\u2013250.","DOI":"10.1124\/jpet.121.000530."},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Diviccaro S, Cioffi L, Falvo E, Giatti S, Melcangi RC. Allopregnanolone: An overview on its synthesis and effects. Journal of Neuroendocrinology. 2022; 34: e12996.","DOI":"10.1111\/jne.12996."},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Noorbakhsh F, Baker GB, Power C. Allopregnanolone and neuroinflammation: a focus on multiple sclerosis. Frontiers in Cellular Neuroscience. 2014; 8: 134.","DOI":"10.3389\/fncel.2014.00134."},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Altmann DM. Neuroimmunology and neuroinflammation in autoimmune, neurodegenerative and psychiatric disease. Immunology. 2018; 154: 167\u2013168.","DOI":"10.1111\/imm.12943."},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Dai S, Qu L, Li J, Zhang Y, Jiang L, Wei H, et al. Structural insight into the ligand binding mechanism of aryl hydrocarbon receptor. Nature Communications. 2022; 13: 6234.","DOI":"10.1038\/s41467-022-33858-w."},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Wu PY, Chuang PY, Chang GD, Chan YY, Tsai TC, Wang BJ, et al. Novel Endogenous Ligands of Aryl Hydrocarbon Receptor Mediate Neural Development and Differentiation of Neuroblastoma. ACS Chemical Neuroscience. 2019; 10: 4031\u20134042.","DOI":"10.1021\/acschemneuro.9b00273."},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Dever DP, Adham ZO, Thompson B, Genestine M, Cherry J, Olschowka JA, et al. Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis. Developmental Neurobiology. 2016; 76: 533\u2013550.","DOI":"10.1002\/dneu.22330."},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Imran SJ, Vagaska B, Kriska J, Anderova M, Bortolozzi M, Gerosa G, et al. Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons. Pharmaceuticals (Basel, Switzerland). 2022; 15: 828.","DOI":"10.3390\/ph15070828."},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Juricek L, Carcaud J, Pelhaitre A, Riday TT, Chevallier A, Lanzini J, et al. AhR-deficiency as a cause of demyelinating disease and inflammation. Scientific Reports. 2017; 7: 9794.","DOI":"10.1038\/s41598-017-09621-3."},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Bittner S, Afzali AM, Wiendl H, Meuth SG. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL\/6 mice. Journal of Visualized Experiments: JoVE. 2014; 51275.","DOI":"10.3791\/51275."},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Hanson LR, Fine JM, Svitak AL, Faltesek KA. Intranasal administration of CNS therapeutics to awake mice. Journal of Visualized Experiments: JoVE. 2013; 4440.","DOI":"10.3791\/4440."},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Zolkowska D, Wu CY, Rogawski MA. Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery. Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics. 2021; 18: 544\u2013555.","DOI":"10.1007\/s13311-020-00985-5."},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nature Methods. 2012; 9: 676\u2013682.","DOI":"10.1038\/nmeth.2019."},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Rishi K, Rana N. Particle Size and Shape Analysis Using ImageJ with Customized Tools for Segmentation of Particles. International Journal of Engineering Research & Technology. 2015; 4: 247\u2013250. https:\/\/www.ijert.org\/particle-size-and-shape-analysis-using-imagej-with-customized-tools-for-segmentation-of-particles.","DOI":"10.17577\/IJERTV4IS110211"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Wu D, Potluri N, Kim Y, Rastinejad F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Molecular and Cellular Biology. 2013; 33: 4346\u20134356.","DOI":"10.1128\/MCB.00698-13."},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Liu Y, Grimm M, Dai WT, Hou MC, Xiao ZX, Cao Y. CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacologica Sinica. 2020; 41: 138\u2013144.","DOI":"10.1038\/s41401-019-0228-6."},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Liu Y, Yang X, Gan J, Chen S, Xiao ZX, Cao Y. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Research. 2022; 50: W159\u2013W164.","DOI":"10.1093\/nar\/gkac394."},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Bolte S, Cordeli\u00e8res FP. A guided tour into subcellular colocalization analysis in light microscopy. Journal of Microscopy. 2006; 224: 213\u2013232.","DOI":"10.1111\/j.1365-2818.2006.01706.x."},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Noorbakhsh F, Ellestad KK, Maingat F, Warren KG, Han MH, Steinman L, et al. Impaired neurosteroid synthesis in multiple sclerosis. Brain: a Journal of Neurology. 2011; 134: 2703\u20132721.","DOI":"10.1093\/brain\/awr200."},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Balan I, Boero G, Ch\u00e9ry SL, McFarland MH, Lopez AG, Morrow AL. Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders. Life (Basel, Switzerland). 2024; 14: 582.","DOI":"10.3390\/life14050582."},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Samuel S, Nguyen T, Choi HA. Pharmacologic Characteristics of Corticosteroids. Journal of Neurocritical Care. 2017; 10: 53\u201359.","DOI":"10.18700\/jnc.170035."},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Molecular and Cellular Endocrinology. 2011; 335: 2\u201313.","DOI":"10.1016\/j.mce.2010.04.005."},{"key":"ref30","unstructured":"Li L, Xu Q, Wu Y, Hu W, Gu P, Fu Z. Combined therapy of methylprednisolone and brain-derived neurotrophic factor promotes axonal regeneration and functional recovery after spinal cord injury in rats. Chinese Medical Journal. 2003; 116: 414\u2013418."},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Liu WL, Lee YH, Tsai SY, Hsu CY, Sun YY, Yang LY, et al. Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytes. Glia. 2008; 56: 1390\u20131400.","DOI":"10.1002\/glia.20706."},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Popescu BFG, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneapolis, Minn.). 2013; 19: 901\u2013921.","DOI":"10.1212\/01.CON.0000433291.23091.65."},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Lafrenaye AD, Mondello S, Wang KK, Yang Z, Povlishock JT, Gorse K, et al. Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI. Scientific Reports. 2020; 10: 13369.","DOI":"10.1038\/s41598-020-70266-w."},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Grimaldi A, Pediconi N, Oieni F, Pizzarelli R, Rosito M, Giubettini M, et al. Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer\u2019s Disease Patients, Possible Biomarkers for Early Diagnosis. Frontiers in Neuroscience. 2019; 13: 925.","DOI":"10.3389\/fnins.2019.00925."},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Abdelhak A, Foschi M, Abu-Rumeileh S, Yue JK, D\u2019Anna L, Huss A, et al. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nature Reviews. Neurology. 2022; 18: 158\u2013172.","DOI":"10.1038\/s41582-021-00616-3."},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Peng W, Xie Y, Liao C, Bai Y, Wang H, Li C. Spatiotemporal patterns of gliosis and neuroinflammation in presenilin 1\/2 conditional double knockout mice. Frontiers in Aging Neuroscience. 2022; 14: 966153.","DOI":"10.3389\/fnagi.2022.966153."},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Jurga AM, Paleczna M, Kuter KZ. Overview of General and Discriminating Markers of Differential Microglia Phenotypes. Frontiers in Cellular Neuroscience. 2020; 14: 198.","DOI":"10.3389\/fncel.2020.00198."},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Kalakh S, Mouihate A. The Effects of Neuroactive Steroids on Myelin in Health and Disease. Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre. 2024; 33: 198\u2013214.","DOI":"10.1159\/000537794."},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Barroso A, Mahler JV, Fonseca-Castro PH, Quintana FJ. The aryl hydrocarbon receptor and the gut-brain axis. Cellular & molecular immunology. 2021; 18: 259\u2013268.","DOI":"10.1038\/s41423-020-00585-5."},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Juricek L, Coumoul X. The Aryl Hydrocarbon Receptor and the Nervous System. International Journal of Molecular Sciences. 2018; 19: 2504.","DOI":"10.3390\/ijms19092504."},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Wang Y, Sun J, Zhu K, Wang D, Zhao X, Zhang H, et al. Microglial aryl hydrocarbon receptor enhances phagocytic function via SYK and promotes remyelination in the cuprizone mouse model of demyelination. Journal of Neuroinflammation. 2023; 20: 83.","DOI":"10.1186\/s12974-023-02764-3."},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Cannon AS, Nagarkatti PS, Nagarkatti M. Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases. International Journal of Molecular Sciences. 2021; 23: 288.","DOI":"10.3390\/ijms23010288."},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D, Juricek L, et al. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. 2018; 115: E1319\u2013E1328.","DOI":"10.1073\/pnas.1715999115."},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Haidar R, Shabo R, Moeser M, Luch A, Kugler J. The nuclear entry of the aryl hydrocarbon receptor (AHR) relies on the first nuclear localization signal and can be negatively regulated through IMP\u03b1\/\u03b2 specific inhibitors. Scientific Reports. 2023; 13: 19668.","DOI":"10.1038\/s41598-023-47066-z."},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Zhou Y, Zhang J. Neuronal activity and remyelination: new insights into the molecular mechanisms and therapeutic advancements. Frontiers in Cell and Developmental Biology. 2023; 11: 1221890.","DOI":"10.3389\/fcell.2023.1221890."}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/29\/12\/10.31083\/j.fbl2912420","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T11:53:56Z","timestamp":1735559636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/29\/12\/10.31083\/j.fbl2912420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,18]]},"references-count":45,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024]]}},"alternative-id":["S2768-6701(24)01552-1"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2912420","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,18]]},"article-number":"420"}}