Ischemic stroke (IS) is a severe neurological disease with limited treatment options. Subcutaneous adipose tissue-derived small extracellular vesicles (SAT-sEVs), which are readily accessible and abundant, have emerged as promising biomarkers and therapeutic agents in various diseases. The objective of this research is to uncover the roles and regulatory mechanisms of proteins and miRNAs contained within SAT-sEVs in middle cerebral artery occlusion (MCAO) rats, aiming to discover innovative approaches and insights for IS treatment. To evaluate the therapeutic efficacy of SAT-sEVs, we intravenously administered them to MCAO rats and assessed neurological function and cerebral infarction 24h after SAT-sEVs administration using behavioral scoring and TTC staining. To elucidate the potential mechanisms and ischemia-induced alterations in SAT-sEVs, we conducted integrated transcriptomic and proteomic analyses on vesicles isolated from both MCAO rats (24-h post-ischemia) and normal controls. SAT-sEVs markedly alleviated neurological impairments and decreased the volume of cerebral infarcts in MCAO rats. Significant alterations were also observed in the miRNAs and proteins within SAT-sEVs following ischemic injury. This comprehensive analysis enhances our understanding of SAT-sEVs-mediated protective mechanisms and functional alterations in IS. It establishes a solid experimental basis for the potential clinical use of SAT-sEVs in stroke rehabilitation and other related diseases.

Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration.

Human brain development is highly regulated by several spatiotemporal processes, which disruption can result in severe neurological disorders. Emerging evidence highlights the pivotal role of mitochondrial function as one of these fundamental pathways involved in neurodevelopment. Our study investigates the role of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) protein in cortical neurogenesis and mitochondrial activity, since mutations in the HPDL gene are associated with a childhood-onset form of hereditary spastic paraplegia characterized by corticospinal tract degeneration and cortical abnormalities. Starting from mutant neuroblastoma cells, we demonstrated that HPDL is important to respiratory chain supercomplex assembly and cellular redox balance. Moreover, RNA-seq studies revealed dysregulated pathways related to brain development. Generation of cortical neurons and organoids from HPDL patient-derived induced pluripotent stem cells exhibited premature neurogenesis at early differentiation stages, likely leading to depletion of cortical progenitors, as evidenced by decreased proliferation, slight increase of apoptosis, and unbalanced cortical type composition at later stages. Cortical organoids showed failure to grow at a normal rate, a feature highly reminiscent of the "microcephaly" observed in severe HPDL children. Mitochondrial morpho-functional characterization in mutant neurons confirmed disruption of OxPhos chain functionality in neuroblastoma knock-out model cells and HPDL mutant cortical progenitors also displayed defects in respirasome assembly and increased ROS generation rate. Treatment of mutant cortical cells with antioxidants and CoQ10 intermediates partially rescued premature neurogenesis depending on the mutational context, suggesting potential future personalized therapeutic strategies. Our findings reveal a critical role for HPDL in coordinating cortical progenitor proliferation, neurogenesis, and mitochondrial function, shedding light on a better understanding of the related clinical presentations.

Background: Transcranial direct current stimulation (tDCS) is an emerging, non-invasive neuromodulation technique with massive potential in neurocritical care settings. This review covers the applications, mechanisms, and outcomes of tDCS in patients with severe neurological disorders. Methods: tDCS uses low-intensity direct current to modulate cortical excitability and induce neuroplasticity, which aids in recovering motor, cognitive, and sensory functions. Its simplicity and noninvasive nature enable bedside use, making it a good alternative to invasive interventions. Results: The evidence suggests that tDCS improves recovery in stroke, TBI, and DOC by affecting synaptic plasticity, releasing neurotrophic factors, and improving cerebral perfusion. However, due to the variability in the methodology and stimulation parameters of the studies, further research is required to determine standardized protocols. Safety appears minimal, with most side effects including mild discomfort. Conclusion: This review underlines the promise of tDCS as an adjunctive therapy in neurocritical care and recommends its integration into traditional rehabilitative strategies to enhance patient outcomes. Future studies should investigate optimizing stimulation parameters, long-term efficacy, and condition-specific applications to exploit tDCS's therapeutic benefits

Porcine teschoviruses (PTV) are enteric pathogens affecting suids. Although ubiquitous in healthy domestic pig (Sus scrofa domesticus) populations, some virulent strains can cause severe neurological disorders known as Teschen-Talfan disease. Wild boars (Sus scrofa) can host PTV, but little is known about their epidemiological role in the dynamic of the pathogens. Until recently, PTV had not been reported in wild boars in France. However, in 2019 and 2020, serological evidence of PTV infection was detected in hunted wild boars from Drôme and Marne, some of which exhibited neurological and reproductive disorders. As a result, a combined serological, virological, and phylogenic screening was implemented. Results revealed high seroprevalence rates, up to 38%, suggesting endemic circulation of PTV in these populations. Genetic sequencing of PCR-positive samples suggests the presence of a novel PTV genotype. These findings raise questions about the pathogenicity of this new PTV strain as well as of the potential role of wild boars in the epidemiology of PTV in France, and highlight the need for further investigation into the interactions between domestic pigs and wild boar and the dynamics of the spread of PTV between them.

The conducted research highlights a little – studied aspect of the interaction between wildlife and humans - the role of parasitic invasions in the occurrence of road accidents involving wild ungulates, in particular moose. Using the example of the Republic of Tatarstan, it is shown that all 17 examined moose that died in an accident in the first half of 2024 were infected with larvae of the nasopharyngeal gadfly Cephenemyia ulrichii . On average, 68 larvae were found in one animal, localized in the nasopharynx, soft palate, nasal sinuses and cranial region. A pathological and anatomical autopsy revealed macroscopic signs of meningoencephalitis, which indicates the development of estrogenic encephalitis. This pathology, causing severe pain, neurological disorders, disorientation and depression of consciousness, is a significant factor provoking inappropriate behavior of animals and their access to highways. The work also provides a comparative analysis with other parasitic diseases affecting the behavior of wild ungulates, such as Eleaophora schneideri and parasitization of the nematode Parelaphostrongylus tenuis ("brainworm") in North America. The lack of systematic work in Russia on the prevention of animal deaths on transport routes and the diagnosis of parasitosis in victims of road accidents is emphasized. The use of saline slime molds with 4% ivermectin is proposed as a practical preventive measure for cephenomyosis. It is concluded that it is necessary to carry out mandatory parasitological examinations of all animals killed on the roads in order to accurately assess the contribution of parasitic invasions to accidents and develop comprehensive legislative and preventive measures.

Orthoflaviviruses, such as tick-borne encephalitis virus (TBEV) and West Nile virus (WNV), can cause severe neurological disease and remain without specific antiviral treatments. We found that orthoflavivirus envelope (E) and non-structural protein 1 (NS1) interact with heat shock protein 70 (Hsp70) chaperones, key regulators of protein homeostasis and existing cancer drug targets. We examined how Hsp70 and endoplasmic reticulum–resident BiP contribute to viral protein secretion and infectivity of tick and mosquito-borne orthoflaviviruses. Targeting the Hsp70 nucleotide-binding domain with small-molecule inhibitor YM-1 significantly reduced infectivity of multiple orthoflaviviruses, while substrate-binding domain inhibitor PES-Cl specifically impaired NS1 secretion of tick-borne orthoflaviviruses. Protein degradation inhibitors restored NS1 expression in BiP-deficient cells but failed to rescue NS1 secretion. These data indicate that while BiP is essential for secretion of tick-borne orthoflavivirus NS1, it is not required for infectivity. The antiviral effect of YM-1 likely reflects inhibition of other chaperones or additional cellular targets.

The research aims to apply and evaluate a standardized protocol for nutritional risk assessment and nutritional support management, and to assess its predictive value in individuals with severe neurological disorders who are at risk of malnutrition. A retrospective analysis was performed on 930 suitable patients hospitalized in the Neurology Intensive Care Unit (NICU) at Xuanwu Hospital, Capital Medical University, between January 2012 and December 2019. At discharge, patients were categorized based on modified Rankin Scale (mRS) results (excellent prognosis: mRS 0-2, n = 600; bad prognosis: mRS 3-6, n = 330) and survival status (survivor: n = 869; deceased: n = 61). The protocol included baseline characteristics and biochemical evaluations, admission Nutritional Risk Screening 2002 (NRS 2002) scores, identifying the nutritional support modality, estimation of typical energy intake throughout the first 7 days, and level of disease evaluation using standardized assessment instruments such as the Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation II (APACHE II), and National Institutes of Health Stroke Scale (NIHSS). Univariate studies, multivariate logistic regression estimation, and receiver operating characteristic (ROC) curve assessment were used to assess predictive significance. The standardized protocol enabled the systematic identification of nutritional risk, stratification of clinical severity, and early guidance for planning nutritional interventions. Key risk indicators, including elevated NRS 2002, APACHE II, and NIHSS scores, advanced age, and inadequate early energy intake, were associated with unfavorable outcomes. In contrast, higher GCS and adequate vitamin B12 levels demonstrated protective tendencies. ROC analysis confirmed that NRS 2002 provided the most effective predictive utility for both functional outcome and survival status. The findings demonstrate that structured nutritional risk assessment and standardized support implementation offer practical value for early prognostic judgment and Nutritional decision-making for severely ill individuals suffering from neurological diseases.

Leber’s Hereditary Optic Neuropathy (LHON) is a rare genetic condition and severe neurological disorder characterized by dysfunctional mitochondria under extreme oxidative stress, resulting in retinal ganglion cell death and subsequent rapid bilateral loss of central vision. The m.14484T>C mutation in the ND6 subunit of mitochondrial complex I is known for inducing LHON, and is a prevalent LHON-associated mutation, yet its mechanism of impairment at the molecular level is currently unresolved. In this study, we explore the biophysical underpinnings of this mutation and its role in LHON through disruption of human complex I function. We consider, using atomistic simulations, the differential thermodynamics and kinetics of coenzyme Q10 binding between the mutant and wild-type forms, altered dynamics of the complex upon mutation, and key interactions between coenzyme Q10 and complex I binding sites. The hydrogen bond network present near and within the coenzyme Q10 binding domain, along with proper hydration of E-channel residues that couple redox chemistry to proton pumping, is found to be critical for complex I stability and quinone binding, which the ND6-centered mutation disrupts.

Pseudorabies virus (PRV), an alphaherpesvirus, causes severe neurological and respiratory diseases in multiple mammalian species and poses an emerging threat to public health. Increasing evidence suggests that virus-induced inflammatory cell death plays a pivotal role in shaping host immune responses and disease outcomes. PANoptosis, a newly defined inflammatory programmed cell death pathway integrating pyroptosis, apoptosis, and necroptosis, has been implicated in host defense against diverse pathogens. However, whether PRV infection induces PANoptosis and contributes to inflammatory pathology remains largely unexplored. In this study, we demonstrate that PRV efficiently replicates in Human Acute Monocytic Leukemia Cells (THP-1)-derived macrophages and robustly induces PANoptosis, characterized by the concurrent activation of Gasdermin D, caspase-3, and Mixed Lineage Kinase Domain-Like (MLKL). Pharmacological inhibition of PANoptosis markedly attenuated PRV-induced inflammatory cytokine production in vitro. Furthermore, intranasal inoculation of PRV in Balb/c mice resulted in productive lung infection accompanied by pronounced pulmonary inflammation. Lung tissues from PRV-challenged mice exhibited molecular and histopathological hallmarks of PANoptosis. Importantly, drug-mediated suppression of PANoptosis significantly reduced lung inflammation and inflammatory cytokine expression in vivo. Collectively, our findings identify PANoptosis as a critical mechanism underlying PRV-induced inflammatory responses and suggest that targeting PANoptosis may represent a promising therapeutic strategy for PRV-associated inflammatory diseases.

ABSTRACT While the EV-A71 vaccine is available, its real-world effectiveness against severe neurological complications such as encephalitis and its influence on circulating enterovirus serotypes require further clarification. This single-center, retrospective study analyzed 7823 children hospitalized with enterovirus-associated hand, foot, and mouth disease or herpangina between 2016 and 2023. Among them, 414 children had received EV-A71 vaccination (376 fully, 38 partially) and 7409 were unvaccinated. Encephalitis, defined by clinical symptoms, neuroimaging evidence, and CSF pleocytosis (>5 WBC/mm3), occurred in 8.5% of vaccinated children compared to 16.7% in unvaccinated children, representing a 49% relative risk reduction (χ2 = 19.768, p < .001). Concurrently, a significant shift in serotype distribution was observed: the proportion of cases caused by EV-A71 decreased from 26.3% to 13.1% (p < .001), while non-EV-A71/CVA16 serotypes became dominant, accounting for 73.2% of cases by 2023. Taken together, these results indicate a dual benefit of EV-A71 vaccination: direct protection against severe neurological disease and an indirect impact on the local epidemiology of enteroviruses. These findings demonstrate that EV-A71 vaccination is highly effective in preventing severe encephalitis and is associated with an evolving enterovirus serotype landscape, underscoring the need to expand immunization programs and develop multivalent vaccines against emerging serotypes.

Human non-polio enteroviruses (NPEVs) cause a plethora of infections in humans, ranging from mild to severe neurological diseases including aseptic meningitis. NPEVs are the leading cause of aseptic meningitis in both children and adults worldwide. In Russia, reports of NPEV infections have surged, especially in the post-COVID era starting in 2022, with elevated infection rates into 2023. A comprehensive examination of the whole genome is crucial for understanding the evolution of NPEV genes and for predicting potential outbreaks. This study focused on identifying the circulating NPEV strains in the Ural Federal District and Western Siberia, using Sanger sequencing and next-generation sequencing (NGS) methodologies. Biological samples were collected from (n = 225) patients diagnosed with aseptic meningitis. Bioinformatics analysis targeted the nucleotide sequences of the major capsid protein (partial VP1) gene fragment, and the assembly of whole NPEV genomes. A total of 159 NPEVs were characterized, representing 70.7% of the collected samples. The main capsid variants forming the predominant genotypic profile included E30 (n = 39, 24.3%), E6 (n = 31, 19.3%), and CVA9 (n = 25, 15.6%). Using NGS, we successfully assembled 13 whole genomes for E6, E30, EV-B80, CVA9, CVB5, E11, and EV-A71 and 3 partial genomes for E6 and EV-B87. This molecular-genetic analysis provides contemporary insights into the genotypic composition, circulation patterns, and evolutionary dynamics of the dominant NPEV associated with aseptic meningitis in the Ural Federal District and Western Siberia. The laboratory-based monitoring and epidemiological surveillance for genetic changes and evolutionary studies are important for improving prevention and healthcare.

BackgroundZika virus (ZIKV) can cause severe neurological disorders such as congenital microcephaly, and there are currently no approved prevention or treatment measures. Elucidating the antiviral mechanism of the host interferon-stimulated genes (ISGs) is crucial for the development of therapeutic strategies.MethodsThis study integrated multisystem transcriptomic data [human brain organoids, monocyte-derived dendritic cells (moDCs), and peripheral blood mononuclear cells (PBMCs) from infected patients], combined with cellular experiments and bioinformatics analysis, to systematically investigate the spatiotemporal regulation characteristics and functions of ISGs during ZIKV infection.ResultsThe results showed that treatment with interferon beta (IFN-β) significantly activated the ISGs (e.g., IRF7 and IFITM3) in the ZIKV-infected brain organoids, which were enriched in virus defense-related pathways. Single-cell transcriptomics revealed cellular heterogeneity in the IFN-β-driven ISG responses in moDCs. Transcriptomic analysis of the PBMCs identified 210 differentially expressed genes between the acute and convalescent phases. Core ISGs (e.g., RSAD2 and OAS3) were transiently upregulated in the acute phase. Through cross-analysis, 22 cross-system shared ISGs were screened out. Least absolute shrinkage and selection operator (LASSO) regression identified 11 potential diagnostic biomarkers for ZIKV infection. Small interfering RNA (siRNA) knockdown experiments confirmed that IFI35, IFI44, and OAS3 exerted antiviral effects by inhibiting ZIKV replication.ConclusionThis study reveals the functional plasticity of ISGs and provides key targets and theoretical support for the prevention and treatment of ZIKV.

Background/Objectives: Patients with acute severe neurological disorders often receive a transurethral indwelling catheter (TUIC) during their initial treatment. These TUICs often remain in place until the transfer to a rehabilitation or a long-term care facility. There are no systematic concepts for bladder management and no data regarding the impact on the catheter associated, health-related quality of life (HRQoL) in this patient group. The aim of this study was to investigate the impact of successful TUIC removal on the HRQoL of those affected and to contribute to the development of systematic bladder management. Methods: A prospective longitudinal study was conducted on 33 patients treated at a neurological rehabilitation centre due to acute severe neurological disorders. The HRQoL was assessed using the SF-36 Health Survey prior to and following the TUIC removal. The influence of urinary incontinence was analysed. The mean differences were determined using a one-sample t-test adjusted for age and gender. Results: TUIC removal was successful in 61.8% (21/33). The SF-36 Health Survey showed the following improvements (adj. mean diff., 95% CI, p-value): Mental Component Summary measure (4.36, 0.34; 8.38, p = 0.035), Role-Emotional (20.89, 0.54; 41.24, p = 0.045), Physical Functioning (10.03, 3.18; 16.88, p = 0.007). The comparison between incontinent and continent patients showed a poorer HRQoL for the incontinent group. Conclusions: Successful TUIC removal has a positive influence on psychological/emotional aspects and physical functioning. Structured bladder management that considers the physical and psychological aspects of patients and nursing staff, as well as medical and economic aspects, should be pursued with vigour.

BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.

Identification and characterization of two novel linear B cell epitopes on the envelope protein of Japanese encephalitis virus.

Zika virus (ZIKV) causes severe neurological disease, including microcephaly and Guillain-Barré syndrome, through complex interactions with host cell proteins. This review synthesizes the 2015-2025 published literature on ZIKV-host protein interactions and their therapeutic targeting. ZIKV enters cells via multiple receptor pathways: adhesion receptors (DC-SIGN, Hsp70), high-affinity entry receptors (ITGB4, GRP78, NCAM1), internalization receptors (integrin αvβ5, sialic acid), and endosomal receptors (AXL, TIM-1, CD300a). Viral structural proteins direct virion assembly, while nonstructural proteins NS1-NS5 suppress immune responses, remodel cellular membranes, and dysregulate gene expression. NS5 uniquely suppresses neurodevelopmental genes and disrupts ciliary function through nuclear localization, directly driving microcephaly pathogenesis. Therapeutic strategies include receptor antagonists, protease inhibitors, and polymerase inhibitors. However, receptor redundancy, viral protein multifunctionality, and pregnancy safety constraints limit clinical translation. This review identifies ZIKV-host protein interactions as therapeutic targets and highlights barriers to drug development.

Serological evidence of tick-borne encephalitis virus in limousin, france.

Ischemic stroke, a severe neurological disorder with a multifactorial pathogenesis, presents significant therapeutic challenges. Calycosin, a natural flavonoid, has diverse biological activities, including antioxidant, anti-inflammatory, and antitumor effects. In this study we investigate the protective effects of calycosin against blood-brain barrier (BBB) damage following cerebral ischemia-reperfusion injury (CIRI) and explore the underlying mechanisms. We employ middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation (OGD) in bEnd.3 brain microvascular endothelial cells to assess neurological function, BBB integrity, the expression of pyroptosis-related proteins, inflammatory mediator release, endothelial barrier permeability, and cell viability. The results reveal that calycosin significantly ameliorates CIRI-induced BBB damage, as evidenced by improved neurological scores, reduced brain water content, and decreased infarct volume. Calycosin suppresses NLRP3-mediated pyroptosis by downregulating HMGB1, NLRP3, caspase 1, GSDMD, N-GSDMD, and IL-18 expression while reducing the secretion of HMGB1, IL-1β, and IL-18. Additionally, calycosin enhances BBB integrity by decreasing MMP9 and AQP-4 expression and upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-5). In OGD-treated bEnd.3 cells, calycosin inhibits NLRP3-mediated pyroptosis, reduces inflammatory mediator release, and improves cell viability and barrier function. Notably, molecular docking and molecular dynamics simulations demonstrate that calycosin stably binds to NLRP3 with high affinity, supporting its potential as an NLRP3 inhibitor. These findings indicate that calycosin protects against CIRI-induced BBB damage by inhibiting NLRP3-mediated pyroptosis and modulating tight junction protein expression, indicating that calycosin is a potential therapeutic option for ischemic stroke.

Implications of immune responses to DENV, JEV, and ZIKV Infections for cross-reactivity and considerations for vaccine evaluation