{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T02:24:04Z","timestamp":1793154244555,"version":"4.5.0"},"reference-count":63,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:00:00Z","timestamp":1707350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation","award":["DFG"],"award-info":[{"award-number":["DFG"]}]},{"name":"German Research Foundation","award":["RTG2154"],"award-info":[{"award-number":["RTG2154"]}]},{"name":"German Research Foundation","award":["materials4brain"],"award-info":[{"award-number":["materials4brain"]}]},{"name":"German Research Foundation","award":["P7"],"award-info":[{"award-number":["P7"]}]},{"name":"Schleswig-Holstein","award":["DFG"],"award-info":[{"award-number":["DFG"]}]},{"name":"Schleswig-Holstein","award":["RTG2154"],"award-info":[{"award-number":["RTG2154"]}]},{"name":"Schleswig-Holstein","award":["materials4brain"],"award-info":[{"award-number":["materials4brain"]}]},{"name":"Schleswig-Holstein","award":["P7"],"award-info":[{"award-number":["P7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Brain diseases are oftentimes life-threatening and difficult to treat. The local administration of drug substances using brain implants can increase on-site concentrations and decrease systemic side effects. However, the biocompatibility of potential brain implant materials needs to be evaluated carefully as implants can trigger foreign body reactions, particularly by increasing the microglia and astrocyte reactivity. To date, these tests have been frequently conducted in very simple in vitro models, in particular not respecting the key players in glial cell reactions and the challenges of surgical implantation characterized by the disruption of oxygen and nutrient supply. Thus, we established an in vitro model in which we treated human glial cell lines with reduced oxygen and glucose levels. The model displayed cytokine and reactive oxygen species release from reactive microglia and an increase in a marker of reactive astrocytes, galectin-3. Moreover, the treatment caused changes in the cell survival and triggered the production of hypoxia-inducible factor 1\u03b1. In this comprehensive platform, we demonstrated the protective effect of the natural polyphenol resveratrol as a model substance, which might be included in brain implants to ease the undesired glial cell response. Overall, a glial-cell-based in vitro model of the initial challenges of local brain disease treatment may prove useful for investigating new therapy options.<\/jats:p>","DOI":"10.3390\/ijms25042078","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T09:00:02Z","timestamp":1707382802000},"page":"2078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Resveratrol Alleviates the Early Challenges of Implant-Based Drug Delivery in a Human Glial Cell Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-7327","authenticated-orcid":false,"given":"Luise","family":"Schlotterose","sequence":"first","affiliation":[{"name":"Institute of Anatomy, Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Cossais","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Lucius","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0490-0164","authenticated-orcid":false,"given":"Kirsten","family":"Hattermann","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Kiel University, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"ref_1","unstructured":"(2022, November 24). The Top 10 Causes of Death. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.4155\/tde.14.114","article-title":"Delivery of local therapeutics to the brain: Working toward advancing treatment for malignant gliomas","volume":"6","author":"Chaichana","year":"2015","journal-title":"Ther. Deliv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jneumeth.2018.10.015","article-title":"Drug targeting strategies into the brain for treating neurological diseases","volume":"311","author":"Barnabas","year":"2019","journal-title":"J. Neurosci. Methods"},{"key":"ref_4","unstructured":"(2022, November 25). Gliadel. Available online: https:\/\/gliadel.com\/hcp\/."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Schlotterose, L., Cossais, F., Lucius, R., and Hattermann, K. (2023). Breaking the circulus vitiosus of neuroinflammation: Resveratrol attenuates the human glial cell response to cytokines. Biomed. Pharmacother., 163.","DOI":"10.1016\/j.biopha.2023.114814"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1021\/cn500256e","article-title":"Brain tissue responses to neural implants impact signal sensitivity and intervention strategies","volume":"6","author":"Kozai","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s13311-018-0631-6","article-title":"Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses","volume":"15","author":"Orr","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s00429-012-0446-x","article-title":"Differential distribution and activation of microglia in the brain of male C57BL\/6J mice","volume":"218","author":"Yang","year":"2013","journal-title":"Brain Struct. Funct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0301-0082(89)90005-1","article-title":"Role of glial cells in the regulation of the brain ion microenvironment","volume":"33","author":"Walz","year":"1989","journal-title":"Prog. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.neuron.2013.10.034","article-title":"Evolving concepts of gliogenesis: A look way back and ahead to the next 25 years","volume":"80","author":"Freeman","year":"2013","journal-title":"Neuron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"66001","DOI":"10.1088\/1741-2560\/9\/6\/066001","article-title":"In vivo two-photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes","volume":"9","author":"Kozai","year":"2012","journal-title":"J. Neural Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41467-019-08446-0","article-title":"Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury","volume":"10","author":"Bretheau","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.neuron.2013.12.034","article-title":"Reactive gliosis and the multicellular response to CNS damage and disease","volume":"81","author":"Burda","year":"2014","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.tins.2009.08.002","article-title":"Molecular dissection of reactive astrogliosis and glial scar formation","volume":"32","author":"Sofroniew","year":"2009","journal-title":"Trends Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.expneurol.2007.05.014","article-title":"CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure","volume":"209","author":"Fitch","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41586-021-03960-y","article-title":"Neurotoxic reactive astrocytes induce cell death via saturated lipids","volume":"599","author":"Guttenplan","year":"2021","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nn.3278","article-title":"The smallest stroke: Occlusion of one penetrating vessel leads to infarction and a cognitive deficit","volume":"16","author":"Shih","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"242","DOI":"10.12688\/f1000research.51752.2","article-title":"A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model","volume":"10","author":"Gibson","year":"2021","journal-title":"F1000Research"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1007\/s12035-022-02745-2","article-title":"In Vitro Oxygen Glucose Deprivation Model of Ischemic Stroke: A Proteomics-Driven Systems Biological Perspective","volume":"59","author":"Babu","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1021\/jf0112973","article-title":"Plant foods and herbal sources of resveratrol","volume":"50","author":"Burns","year":"2002","journal-title":"J. Agric. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Salehi, B., Mishra, A.P., Nigam, M., Sener, B., Kilic, M., Sharifi-Rad, M., Fokou, P.V.T., Martins, N., and Sharifi-Rad, J. (2018). Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines, 6.","DOI":"10.3390\/biomedicines6030091"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Schlotterose, L., Pravdivtseva, M.S., Ellermann, F., Jansen, O., H\u00f6vener, J.-B., S\u00f6nnichsen, F.D., Cossais, F., Lucius, R., and Hattermann, K. (2023). Resveratrol Mitigates Metabolism in Human Microglia Cells. Antioxidants, 12.","DOI":"10.3390\/antiox12061248"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.neuropharm.2010.09.005","article-title":"Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats","volume":"60","author":"Li","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.brainresbull.2016.02.011","article-title":"Resveratrol provides neuroprotection by inhibiting phosphodiesterases and regulating the cAMP\/AMPK\/SIRT1 pathway after stroke in rats","volume":"121","author":"Wan","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1159\/000481611","article-title":"Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation\/Reoxygenation Injury","volume":"43","author":"Tang","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chiang, M.-C., Nicol, C.J.B., Lo, S.-S., Hung, S.-W., Wang, C.-J., and Lin, C.-H. (2022). Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911678"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Simpson, D.S.A., and Oliver, P.L. (2020). ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants, 9.","DOI":"10.3390\/antiox9080743"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.neulet.2003.07.002","article-title":"Resveratrol promotes differentiation and induces Fas-independent apoptosis of human medulloblastoma cells","volume":"351","author":"Wang","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10571-007-9152-2","article-title":"Resveratrol increases glutamate uptake, glutathione content, and S100B secretion in cortical astrocyte cultures","volume":"27","author":"Leite","year":"2007","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbagen.2011.10.005","article-title":"Effects of resveratrol on HepG2 cells as revealed by (1)H-NMR based metabolic profiling","volume":"1820","author":"Massimi","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8054","DOI":"10.1038\/s41598-021-85702-8","article-title":"Cromolyn inhibits the secretion of inflammatory cytokines by human microglia (HMC3)","volume":"11","author":"Wang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1002\/glia.22898","article-title":"Astrocyte reactivity after brain injury-: The role of galectins 1 and 3","volume":"63","author":"Sirko","year":"2015","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ribeiro, T.N., Delgado-Garc\u00eda, L.M., and Porcionatto, M.A. (2021). Notch1 and Galectin-3 Modulate Cortical Reactive Astrocyte Response After Brain Injury. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.649854"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2174\/1568007053005154","article-title":"Targeting hypoxia-inducible factor (HIF) as a therapeutic strategy for CNS disorders","volume":"4","author":"Freeman","year":"2005","journal-title":"Curr. Drug Targets CNS Neurol. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.pharmthera.2012.07.005","article-title":"Hypoxia-inducible factor as a therapeutic target for cardioprotection","volume":"136","author":"Ong","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.1038\/s41467-019-11707-7","article-title":"Moving beyond the glial scar for spinal cord repair","volume":"10","author":"Bradbury","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.biomaterials.2015.02.081","article-title":"BBB leakage, astrogliosis, and tissue loss correlate with silicon microelectrode array recording performance","volume":"53","author":"Nolta","year":"2015","journal-title":"Biomaterials"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1089\/ars.2007.1634","article-title":"Brain tissue oxygen concentration measurements","volume":"9","author":"Ndubuizu","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0034-5687(01)00306-1","article-title":"Tissue oxygen tension and brain sensitivity to hypoxia","volume":"128","author":"Erecinska","year":"2001","journal-title":"Respir. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.fct.2017.05.007","article-title":"Acrylamide-induced neurotoxicity in primary astrocytes and microglia: Roles of the Nrf2-ARE and NF-\u03baB pathways","volume":"106","author":"Zhao","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12974-018-1198-1","article-title":"Inflammatory and cytotoxic effects of bifenthrin in primary microglia and organotypic hippocampal slice cultures","volume":"15","author":"Gargouri","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rizor, A., Pajarillo, E., Johnson, J., Aschner, M., and Lee, E. (2019). Astrocytic Oxidative\/Nitrosative Stress Contributes to Parkinson\u2019s Disease Pathogenesis: The Dual Role of Reactive Astrocytes. Antioxidants, 8.","DOI":"10.3390\/antiox8080265"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/j.1471-4159.2010.07004.x","article-title":"Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses","volume":"115","author":"Kim","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.bbadis.2014.09.011","article-title":"Neuroprotective action of resveratrol","volume":"1852","author":"Bastianetto","year":"2015","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Liu, J., Liao, H., Chen, Y., Zhu, H., Li, X., Liu, J., Xiang, Q., Zeng, F., and Yang, Q. (2022). Resveratrol Inhibits Oxidative Stress and Regulates M1\/M2-Type Polarization of Microglia via Mediation of the Nrf2\/Shh Signaling Cascade after OGD\/R Injury In Vitro. J. Pers. Med., 12.","DOI":"10.3390\/jpm12122087"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.3389\/fnins.2019.01178","article-title":"Brain-Immune Interactions and Neuroinflammation After Traumatic Brain Injury","volume":"13","author":"Dinet","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s11064-013-1209-7","article-title":"Changes in microglial inflammation-related and brain-enriched MicroRNAs expressions in response to in vitro oxygen-glucose deprivation","volume":"39","author":"Kong","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Wang, R., Zhang, X., Zhang, J., Fan, Y., Shen, Y., Hu, W., and Chen, Z. (2012). Oxygen-glucose deprivation induced glial scar-like change in astrocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037574"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s10571-019-00687-3","article-title":"Neuroprotection of Resveratrol Against Focal Cerebral Ischemia\/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis","volume":"39","author":"Dou","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Calvello, R., Cianciulli, A., Porro, C., Moda, P., de Nuccio, F., Nicolardi, G., Giannotti, L., Panaro, M.A., and Lofrumento, D.D. (2021). Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model. Nutrients, 13.","DOI":"10.3390\/nu13051418"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Patabendige, A., Singh, A., Jenkins, S., Sen, J., and Chen, R. (2021). Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084280"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/jnc.13062","article-title":"Microglia and neuroprotection","volume":"136","author":"Chen","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"A577","DOI":"10.1016\/j.chest.2016.02.602","article-title":"Intermittent Hypoxia Reduces Microglia Proliferation and Induces DNA Damage In Vitro","volume":"149","author":"Liu","year":"2016","journal-title":"Chest"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s12031-013-0137-y","article-title":"Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids","volume":"52","author":"Habib","year":"2014","journal-title":"J. Mol. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/jnr.23336","article-title":"Activation of microglia and astrocytes in the nucleus tractus solitarius during ventilatory acclimatization to 10% hypoxia in unanesthetized mice","volume":"92","author":"Tadmouri","year":"2014","journal-title":"J. Neurosci. Res."},{"key":"ref_57","first-page":"1051","article-title":"Resveratrol inhibits the growth of tumor cells under chronic stress via the ADRB-2-HIF-1\u03b1 axis","volume":"41","author":"Ma","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7057","DOI":"10.2147\/OTT.S259016","article-title":"Resveratrol Suppresses Tumor Progression via Inhibiting STAT3\/HIF-1\u03b1\/VEGF Pathway in an Orthotopic Rat Model of Non-Small-Cell Lung Cancer (NSCLC)","volume":"13","author":"Wang","year":"2020","journal-title":"OncoTargets. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1186\/s12974-020-02028-4","article-title":"Neuroprotective epi-drugs quench the inflammatory response and microglial\/macrophage activation in a mouse model of permanent brain ischemia","volume":"17","author":"Mota","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_60","first-page":"11711","article-title":"Resveratrol alleviates oxygen\/glucose deprivation\/reoxygenation-induced neuronal damage through induction of mitophagy","volume":"23","author":"Ye","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7556","DOI":"10.1128\/JVI.00696-14","article-title":"The human fetal glial cell line SVG p12 contains infectious BK polyomavirus","volume":"88","author":"Henriksen","year":"2014","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1080\/13550280152058816","article-title":"CD4\/CXCR4-independent infection of human astrocytes by a T-tropic strain of HIV-1","volume":"7","author":"Schweighardt","year":"2001","journal-title":"J. Neurovirol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2078\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:57:14Z","timestamp":1760104634000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,8]]},"references-count":63,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25042078"],"URL":"https:\/\/doi.org\/10.3390\/ijms25042078","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,8]]}}}