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Evidence of Borna disease virus 1 infection in humans is limited; in this report, donor-derived Borna virus encephalitis is shown to occur in three solid-organ transplant recipients.

Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.Zambusi, Novoselc et al. show that granulin-mediated clearance of cytoplasmic TDP-43+ condensates and lipid droplets in injury-activated microglia is required for their return to the homeostatic state and successful brain regeneration.

Borna disease virus 1 (BoDV-1) has long been recognized as a cause of fatal encephalitis in animals and was only recently identified as a zoonotic pathogen causing a similar disease in humans. This study provides the first comprehensive comparative analysis of BoDV-1-induced neuropathology in human and animal end hosts, including horses, sheep, and alpacas. Using immunohistochemical analyses, we investigated the topographical distribution of BoDV-1 and inflammatory responses in the central nervous system across 19 cases. Key findings reveal distinct differences and overlaps between humans and animals. While humans exhibited heterogeneous patterns especially of the lymphocyte infiltration, animals displayed more species-specific inflammation and viral spread patterns. In horses, the hippocampus and basal ganglia were consistently affected, whereas sheep showed predominant involvement of the frontal cortex and stria olfactoria. Alpacas demonstrated a less uniform distribution but highlighted the brainstem and basal ganglia as critical sites. Intriguingly, across all species, a negative association was observed between lymphocyte infiltration and the number of BoDV-1-infected cells. These findings enhance our understanding of BoDV-1 pathogenesis and is a first step of cross-species comparison in unraveling disease mechanisms in BoDV-1 infection. Further research is warranted to elucidate the implications of these findings for therapeutic strategies and to explore the entry and dissemination routes of BoDV-1 in different hosts.

IntroductionGlioblastoma multiforme (GBM) is a highly malignant glial tumor, affecting men more often than women. The reason for this gender-specific predominance remains unclear, raising the question whether these effects are subject to hormonal control. The purpose of this study was to examine the expression of estrogen receptor alpha (ERα) and aromatase in human GBM tissue samples in relation to patient survival and furthermore to investigate the effect of standard chemotherapy in combination with estradiol treatment on glioblastoma tumor cell lines in vitro.Methods60 tissue samples (31 male, 29 female) of GBM patients were analysed with immunohistochemistry for ERα and aromatase for survival analyses. The cell lines LN18 and LN229 were treated with 17β-estradiol (E2) in different dosing regimens and the cell viability was measured with MTT assay. After estradiol pre-treatment Temozolomide was added and tested again.ResultsHigh expression of ERα and aromatase in the GBM tissue samples was associated with significantly longer survival times of GBM patients, regardless of gender and body-mass-index. The treatment with high concentrations of estradiol resulted in lower tumor cell viability, compared to control. The cells significantly showed a stronger sensitivity against Temozolomid (TMZ) after estradiol pre-treatment.ConclusionERα-expression of glial tumour cells seems to play an important prognostic role as a biomarker in GBM, as well as the expression of the enzyme Aromatase. The combined treatment of GBM with standard chemotherapy and estradiol may be beneficial to patient’s survival.

Raman spectroscopy provides comprehensive biochemical information on a sample’s composition, yet it is often used to analyze aggregated spectra rather than specific shifts. We introduce Fluorescence Guided Raman Spectroscopy (FGRS) as a methodology enabling the isolation of proteins’ spectral signatures and the training of classifiers that generalize across cell lines. We demonstrate the utility of this approach using connexin 43, a marker protein of glioblastoma tumour microtubes. By screening eGFP, sodium fluorescein, and mTagBFP2 for their compatibility with a Raman system operating at 532 nm, we selected mTagBFP2 as the most Raman-compatible fluorophore, whereas the other fluorophores emitting near 532 nm caused spectral interference. mTagBFP2 was cloned into a connexin 43 expression vector, allowing fluorescent tracking and Raman interrogation with subsequent peak identification and correlation to an I-TASSER protein prediction model. We then trained two support vector machines (SVMs) for the classification of cells based on their connexin 43 content and highlighted the impact of different spectral ranges (full spectrum vs. most significant Raman shifts) on specificity and sensitivity in glioblastoma target cell lines. Connexin 43 expression led to a loss of the peaks at 600, 1253, and 1401 cm⁻¹, consistent with an increased α-helical content as predicted by I-TASSER. SVMs achieved up to 79% accuracy on unseen glioblastoma lines, with full-spectrum models reaching 98.7% sensitivity. Thus, FGRS enables the spectral isolation of tumour marker proteins and the development of robust classifiers across cell lines. By focusing on key Raman shifts, this method holds the potential to improve diagnostic accuracy and sensitivity, offering a customizable tool for tumour detection.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite multimodal treatments including surgery, chemotherapy and radiotherapy the prognosis remains poor and relapse occurs regularly. The alkylating agent temozolomide (TMZ) has been shown to improve the overall survival in patients with malignant gliomas, especially in tumors with methylated promoter of the O6-methylguanine-DNA-methyltransferase (MGMT) gene. However, intrinsic and acquired resistance towards TMZ makes it crucial to find new therapeutic strategies aimed at improving the prognosis of patients suffering from malignant gliomas. Cold atmospheric plasma is a new auspicious candidate in cancer treatment. In the present study we demonstrate the anti-cancer properties of different dosages of cold atmospheric plasma (CAP) both in TMZ-sensitive and TMZ-resistant cells by proliferation assay, immunoblotting, cell cycle analysis, and clonogenicity assay. Importantly, CAP treatment restored the responsiveness of resistant glioma cells towards TMZ therapy. Concomitant treatment with CAP and TMZ led to inhibition of cell growth and cell cycle arrest, thus CAP might be a promising candidate for combination therapy especially for patients suffering from GBMs showing an unfavorable MGMT status and TMZ resistance.

Temozolomide (TMZ) is standard treatment for glioblastoma (GBM); nonetheless, resistance and tumor recurrence are still major problems. In addition to its association with recurrent GBM and TMZ resistance, ALDH1A3 has a role in autophagy-dependent ferroptosis activation. In this study, we treated TMZ-resistant LN229 human GBM cells with the ferroptosis inducer RSL3. Remarkably, TMZ-resistant LN229 clones were also resistant to ferroptosis induction, although lipid peroxidation was induced by RSL3. By using Western blotting, we were able to determine that ALDH1A3 was down-regulated in TMZ-resistant LN229 cells. Most intriguingly, the cell viability results showed that only those clones that up-regulated ALDH1A3 after TMZ withdrawal became re-sensitized to ferroptosis induction. The recovery of ALDH1A3 expression appeared to be regulated by EGFR-dependent PI3K pathway activation since Akt was activated only in ALDH1A3 high clones. Blocking the EGFR signaling pathway with the EGFR inhibitor AG1498 decreased the expression of ALDH1A3. These findings shed light on the potential application of RSL3 in the treatment of glioblastoma relapse.

Borna disease virus 1 (BoDV-1) is the causative agent of Borna disease, a fatal neurologic disorder of domestic mammals and humans, resulting from spill-over infection from its natural reservoir host, the bicolored white-toothed shrew ( Crocidura leucodon ). The known BoDV-1-endemic area is remarkably restricted to parts of Germany, Austria, Switzerland and Liechtenstein. To gain comprehensive data on its occurrence, we analysed diagnostic material from suspected BoDV-1-induced encephalitis cases based on clinical and/or histopathological diagnosis. BoDV-1 infection was confirmed by RT-qPCR in 207 domestic mammals, 28 humans and seven wild shrews. Thereby, this study markedly raises the number of published laboratory-confirmed human BoDV-1 infections and provides a first comprehensive summary. Generation of 136 new BoDV-1 genome sequences from animals and humans facilitated an in-depth phylogeographic analysis, allowing for the definition of risk areas for zoonotic BoDV-1 transmission and facilitating the assessment of geographical infection sources. Consistent with the low mobility of its reservoir host, BoDV-1 sequences showed a remarkable geographic association, with individual phylogenetic clades occupying distinct areas. The closest genetic relatives of most human-derived BoDV-1 sequences were located at distances of less than 40 km, indicating that spill-over transmission from the natural reservoir usually occurs in the patient´s home region. Borna disease virus 1 (BoDV-1) is a zoonotic pathogen endemic in bicoloured white-toothed shrews in Central Europe that can cause fatal encephalitis in humans and other mammals. Here, the authors investigate the molecular epidemiology and phylogeography of BoDV-1 using newly collected and archived samples.

After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the first systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest–Degen inclusion bodies. While the composition of histopathological changes was constant, the inflammatory distribution pattern varied interindividually, affecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more diffuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease.

A final diagnosis in a horse with clinical signs of encephalopathy can be challenging despite the use of extensive diagnostics. Clinical signs are often not pathognomonic and need to be interpreted in combination with (specific) laboratory results and epidemiological data of the geographical region of the origin of the case(s). Here we describe the diagnostic pathway of tick-borne encephalitis virus infection in two horses using established molecular diagnostic methods and a novel in situ hybridization technique to differentiate between regionally important/emerging diseases for central Europe: (i) hepatoencephalopathy, (ii) Borna disease virus, and (iii) West Nile virus infections.