Severe Neurological Disease Research Articles

HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43

Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.

Curculigoside Regulates Apoptosis and Oxidative Stress Against Spinal Cord Injury by Modulating the Nrf-2/NQO-1 Signaling Pathway In Vitro and In Vivo.

Spinal cord injury (SCI) is a severe neurological disorder that can lead to paralysis or death. Oxidative stress during SCI is a critical phase causing extensive nerve cell damage and apoptosis, thereby impairing spinal cord healing. Thus, a primary goal of SCI drug therapy is to mitigate oxidative stress. Curculigoside (CUR), a phenolic glucoside extracted from the dried root and rhizome of Curculigo orchioides Gaertn, possesses neuroprotective and antioxidant properties. This study aimed to investigate whether CUR effectively promotes the recovery of spinal cord tissue following SCI and elucidate its mechanism. We employed a hydrogen peroxide (H2O2)-induced PC12 cell model and an SCI rat model to observe the effects of CUR on oxidation and apoptosis. The results demonstrated that CUR significantly reduced the expression of apoptosis-related proteins (Bax and Caspase-3), Annexin V/propidium iodide (PI), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), while increasing the expression of the anti-apoptotic protein Bcl-2. Moreover, CUR effectively enhanced levels of antioxidants (glutathione [GSH)] and decreased reactive oxygen species (ROS) in vitro. Furthermore, CUR facilitated functional recovery through its anti-apoptotic and anti-oxidative stress effects on spinal cord tissues in SCI rats. These effects were mediated via the Nrf2/NQO1 signaling pathway. Therefore, our study showed that CUR acted as an anti-apoptotic and anti-oxidative stress agent, inhibiting astrocyte activation and promoting neuronal reconstruction and functional recovery. These findings may contribute significantly to the development of SCI treatments and advance the field of SCI drug therapy.

Knowledge and attitude among Bangladeshi healthcare workers regarding the management and infection prevention and control of Nipah virus

BackgroundThe Nipah virus (NiV) is a zoonotic pathogen that belongs to the Paramyxoviridae family. It can cause severe respiratory and neurological diseases in humans, with varying clinical symptoms. Recognized as a critical public health concern by the World Health Organization, it requires concerted efforts in research and development to prevent outbreaks. MethodologyAn analytical cross-sectional study was conducted on 455 healthcare workers across four major regions in Bangladesh from April 2022 to May 2023. Using multistage convenient sampling and face-to-face interviews with a semi-structured questionnaire, we have examined the level of knowledge, attitudes, and individual perceptions of the preparedness for NiV. Data analysis included univariate and bivariate analyses, followed by binary logistic regression to ascertain the association with demographic factors. ResultsThe study identified a gender disparity favoring female healthcare workers (HCWs). Approximately 46.15 % of participants demonstrated a good knowledge about NiV, with doctors showing significantly higher knowledge odds (OR = 5.197, p < 0.001). Interestingly, graduate and post-graduate education levels did not yield a statistically significant correlation with knowledge. Specific training received was positively associated with knowledge levels (OR = 1.832, p = 0.014), highlighting the gap in routine infection prevention education. Regional differences were notable, with participants from Chittagong having a lower level of knowledge compared to Dhaka (OR = 0.307, p = 0.004). Attitudes towards NiV were predominantly positive, although higher education inversely correlated with positive attitudes, suggesting a potential gap between theoretical knowledge and practical attitudes. ConclusionWhile the attitude towards NiV is generally positive among Bangladeshi HCWs, there is a need to enhance knowledge levels, especially in primary care settings and certain regions. To effectively prepare for NiV outbreaks, it is crucial to prioritize continuous education and practical training. The study underscores the importance of implementing uniform educational strategies to equip HCWs across all categories and regions with adequate NiV knowledge and preparedness.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Poor neurodevelopment, nutritional and physical growth outcomes among children born to mothers with nodding syndrome

IntroductionNodding syndrome (NS), a poorly understood severe neurological disorder develops in children. In Uganda, some NS cases have grown into child-bearing adults. Babies born to mothers with NS may be prone to impaired neurodevelopmental outcomes. Cognitive deficits in mothers with NS may further inhibit care offered to their children hence compromising neurocognitive development, physical growth, and behaviour. ObjectivesThe study aimed to determine the neurodevelopmental, behavioural, nutritional, and physical growth outcomes of children whose mothers have nodding syndrome. MethodsA comparative cross-sectional study was conducted between May 2021 and April 2022 in Northern Uganda. Children aged 0-5 years of mothers with NS were compared to those of mothers without NS, matched by age, gender and neighbouring residence. Neurodevelopment, behaviour, nutrition, and physical growth were assessed using standardized measures and t-tests employed for group comparisons of outcomes. ResultsOverall,106 children participated. Fifty-three (53) were offspring of mothers with NS and 53 of mothers without NS; having a mean age of 26.9 (2.22) and 27.5(2.12) months respectively. Children whose mothers have NS had significantly lower neurodevelopmental scores than those of NS-unaffected mothers in fine motor (37.5(12.1) vs 44.2(14.3), p = 0.011), receptive language (37.8(10.8) vs 43.9(12.9), p = 0.010), overall cognitive development (74.36(17.8) vs 83.34(19.6), p = 0.015), and attention (0.64(0.20) vs 0.76(0.15), p = 0.001). There were no differences in the behaviour scores. Children of mothers with NS also had significantly lower weight-for-age z scores (WAZ) (p = 0.003) and length/height-for-age z scores (LAZ/HAZ) (p = 0.001); with 19(35.9 %) of them stunted. ConclusionChildren whose mothers have NS have poorer neurodevelopmental, nutritional, and physical growth outcomes. Interventions to improve outcomes in these children are warranted.

Immunogenicity and Neutralization of Recombinant Vaccine Candidates Expressing F and G Glycoproteins against Nipah Virus.

Nipah virus (NiV), of the Paramyxoviridae family, causes highly fatal infections in humans and is associated with severe neurological and respiratory diseases. Currently, no commercial vaccine is available for human use. Here, eight structure-based mammalian-expressed recombinant proteins harboring the NiV surface proteins, fusion glycoprotein (F), and the major attachment glycoprotein (G) were produced. Specifically, prefusion NiV-F and/or NiV-G glycoproteins expressed in monomeric, multimeric (trimeric F and tetra G), or chimeric forms were evaluated for their properties as sub-unit vaccine candidates. The antigenicity of the recombinant NiV glycoproteins was evaluated in intramuscularly immunized mice, and the antibodies in serum were assessed. Predictably, all homologous immunizations exhibited immunogenicity, and neutralizing antibodies to VSV-luciferase-based pseudovirus expressing NiV-GF glycoproteins were found in all groups. Comparatively, neutralizing antibodies were highest in vaccines designed in their multimeric structures and administered as bivalent (GMYtet + GBDtet) and trivalent (Ftri + GMYtet + GBDtet). Additionally, while all adjuvants were able to elicit an immunogenic response in vaccinated groups, bivalent (GMYtet + GBDtet) and trivalent (Ftri + GMYtet + GBDtet) induced more potent neutralizing antibodies when administered with oil-in-water nano-emulsion adjuvant, AddaS03. For all experiments, the bivalent GMYtet + GBDtet was the most immunogenic vaccine candidate. Results from this study highlight the potential use of these mammalian-expressed recombinant NiV as vaccine candidates, deserving further exploration.

Neurovirulence of Usutu virus in human fetal organotypic brain slice cultures partially resembles Zika and West Nile virus

Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. We determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2′C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers, and all primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of all arboviruses, while 2′C-methyl-cytidine reduced only USUV and ZIKV titers. Collectively, USUV can infect human brain tissue, showing similarities in tropism and neurovirulence as WNV and ZIKV. These data suggest that a blockade to infection of the human brain may not be the explanation for the low clinical incidence of USUV-associated neurological disease. However, USUV replicated more slowly and to lower titers than WNV, which could help to explain the reduced severity of neurological disease resulting from USUV infection.

Differential dynamics specify MeCP2 function at nucleosomes and methylated DNA.

Methyl-CpG-binding protein 2 (MeCP2) is an essential chromatin-binding protein whose mutations cause Rett syndrome (RTT), a severe neurological disorder that primarily affects young females. The canonical view of MeCP2 as a DNA methylation-dependent transcriptional repressor has proven insufficient to describe its dynamic interaction with chromatin and multifaceted roles in genome organization and gene expression. Here we used single-molecule correlative force and fluorescence microscopy to directly visualize the dynamics of wild-type and RTT-causing mutant MeCP2 on DNA. We discovered that MeCP2 exhibits distinct one-dimensional diffusion kinetics when bound to unmethylated versus CpG methylated DNA, enabling methylation-specific activities such as co-repressor recruitment. We further found that, on chromatinized DNA, MeCP2 preferentially localizes to nucleosomes and stabilizes them from mechanical perturbation. Our results reveal the multimodal behavior of MeCP2 on chromatin that underlies its DNA methylation- and nucleosome-dependent functions and provide a biophysical framework for dissecting the molecular pathology of RTT mutations.

Dried Blood Spot Metabolome Features of Ischemic-Hypoxic Encephalopathy: A Neonatal Rat Model.

Hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by perinatal asphyxia with significant consequences. Early recognition and intervention are crucial, with therapeutic hypothermia (TH) being the primary treatment, but its efficacy depends on early initiation of treatment. Accurately assessing the HIE severity in neonatal care poses challenges, but omics approaches have made significant contribution to understanding its complex pathophysiology. Our study further explores the impact of HIE on the blood metabolome over time and investigated changes associated with hypothermia's therapeutic effects. Using a rat model of hypoxic-ischemic brain injury, we comprehensively analyzed dried blood spot samples for fat-soluble compounds using HPLC-MS. Our research shows significant changes in the blood metabolome after HIE, with a particularly rapid recovery of lipid metabolism observed. Significant changes in lipid metabolites were observed after 3 h of HIE, including increases in ceramides, carnitines, certain fatty acids, phosphocholines, and phosphoethanolamines, while sphingomyelins and N-acylethanolamines (NAEs) decreased (p < 0.05). Furthermore, NAEs were found to be significant features in the OPLS-DA model for HIE diagnosis, with an area under the curve of 0.812. TH showed a notable association with decreased concentrations of ceramides. Enrichment analysis further corroborated these observations, showing modulation in several key metabolic pathways, including arachidonic acid oxylipin metabolism, eicosanoid metabolism via lipooxygenases, and leukotriene C4 synthesis deficiency. Our study reveals dynamic changes in the blood metabolome after HIE and the therapeutic effects of hypothermia, which improves our understanding of the pathophysiology of HIE and could lead to the development of new rapid diagnostic approaches for neonatal HIE.

Effect of pseudorabies virus infection on NMDA receptor expression in mice and its role in immunosuppression

Pseudorabies virus (PRV), an α-herpesvirus, induces immunosuppression and can lead to severe neurological diseases. N-methyl-D-aspartate receptor (NMDAR), an important excitatory nerve receptor in the central nervous system, is linked to various nervous system pathologies. The link between NMDAR and PRV-induced neurological diseases has not been studied. In vivo studies revealed that PRV infection triggers a reduction in hippocampal NMDAR expression, mediated by inflammatory processes. Extensive hippocampal neuronal degeneration was found in mice on the 6th day by hematoxylin-eosin staining, which was strongly correlated with increased NMDAR protein expression. In vitro studies utilizing the CCK-8 assay demonstrated that treatment with an NMDAR antagonist significantly heightened the cytotoxic effects of PRV on T lymphocytes. Notably, NMDAR inhibition did not affect the replication ability of PRV. However, it facilitated the accumulation of pro-inflammatory cytokines in PRV-infected T cells and enhanced the transcription of the CD25 gene through the secretion of interleukin-2 (IL-2), consequently exacerbating immunosuppression. In this study, we found that NMDAR has functional activity in T lymphocytes and is crucial for the inflammatory and immune responses triggered by PRV infection. These discoveries highlight the significant role of NMDAR in PRV-induced neurological disease pathogenesis.

A Novel Cerium Oxide/Gold/Carbon Nanocomposite-Based Electrochemical Sensor for Detecting Hydroxyl Radicals

Hydroxyl radicals (•OH), a type of reactive oxygen species (ROS), play a crucial role in maintaining the normal physiological processes of human cells. Nevertheless, an excessive accumulation of these radicals may perturb cellular mechanisms, so triggering the onset of severe diseases, including cancer, neurological disorders, and heart disease. The detection of •OH is thus of utmost importance in the early diagnosis of these disorders. The combination of an electrochemical methodology with a recognition system is considered as a promising approach for the detection of •OH. This is primarily due to its capacity to provide fast and direct readings without the need for any preliminary sample preparation. This study presents the development of a new electrochemical sensor for the detection of •OH. The sensor was developed by modifying a screen-printed carbon electrode (SPCE) with a nanocomposite consisting of cerium oxide nanoclusters (CeOx), gold nanoparticles (AuNPs), and a highly conductive carbon. The synthesis of AuNPs supported by carbon was carried out using a deposition-precipitation process. Subsequently, the meticulous deposition of CeOx nanoclusters onto the AuNPs was achieved by the use of surface organometallic chemistry (SOMC). Energy dispersive X-ray spectroscopy (EDS) and transmission electron microscopy (TEM) were applied to assess the distribution of AuNPs on the carbon substrate and their subsequent embellishment with CeOx nanoclusters. The actual loadings of Ce and Au present in the nanocomposite were measured using inductively coupled plasma optical emission spectroscopy (ICP-OES). Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were employed to analyze the electrochemical responses resulting from the interaction of the CeOx-Au/Carbon nanocomposite with •OH. The CV results demonstrated that the proposed sensor exhibited the capability to effectively identify the presence of •OH in the Fenton reaction, with a notably low limit of detection of 58 µM. The sensor demonstrated a linear correlation between the current response and the concentration of •OH, within the range of 0.05 to 5 mM. Compared to a sensor modified with CeOx/Carbon, the CeOx-Au/Carbon-modified sensor exhibited enhanced electrochemical performance, as demonstrated by an increased current response and a reduced peak potential difference when detecting •OH radicals. Furthermore, the EIS studies showed that the sensor could distinguish •OH from other comparable ROS, such as hydrogen peroxide (H2O2).

Examining Clinical Features and Severe Neurologic Disease of Parechovirus Infection in Young Infants: A Multi-State Cohort Study.

Human parechovirus (HPeV) infection can result in severe disease in infants, including sepsis, seizures, brain injury, and death. In 2022, a resurgence of HPeV was noted in young infants. Spectrum of illness and outcomes remain to be fully described. A multi-state retrospective cohort study was conducted to evaluate hospitalizations and outcomes of infants aged ≤6 months admitted in 2022 with laboratory-confirmed HPeV infection. Infants with severe disease were defined as having clinical seizures, or abnormalities on MRI or EEG during admission. Infants with severe vs non-severe disease were compared using descriptive statistics. 124 U.S. infants were identified with HPeV in 11 states. Cases of HPeV peaked in May and presented at a median of 25.8 days of life (0-194 d) with fever, fussiness, and poor feeding. Bacterial and other viral co-infections were rare. 33 (27%) of infants had severe neurologic disease, were more likely to present at an earlier age (13.9 vs 30 days of life, p<0.01), have preterm gestation (12% vs. 1%, p = 0.02), and present with respiratory symptoms (26% vs. 8%, p = 0.01) or apnea (41% vs. 1%, p <0.001). Subcortical white matter cytoxic cerebral edema was common in severe cases. Two infants with HPeV died during admission with severe neurologic HPeV disease; no infant with mild HPeV disease died. This is the largest, geographically-diverse U.S. study to describe the 2022 HPeV outbreak among infants. Longitudinal follow up of infants is needed to define predictors and outcomes of severe HPeV disease.

Tralokinumab for the Treatment of Adult Atopic Dermatitis in Special Populations.

Even if mild forms of atopic dermatitis (AD) are usually well controlled with topical prescription drugs and emollients, the management of severe forms of the disease may be challenging, especially in special populations (SPs). These patients include groups of disadvantaged people (elderly, patients with disabilities and serious medical conditions) who are usually excluded from clinical trials. As a consequence, most of the data about the efficacy and safety of a drug in these patients derives from post-marketing experiences. In this context, the aim of our study was to retrospectively investigate the effectiveness and safety of tralokinumab in the management of AD in SPs. A 24-weeks retrospective, dual-center study was performed enrolling patients with a diagnosis of moderate-to-severe AD undergoing treatment with tralokinumab at labelled dosage. Disease severity was assessed using Eczema Area Severity Index (EASI), Pruritus-Numerical Rating Scale (P-NRS), and Dermatology Life Quality Index (DLQI) score at baseline and after 4 weeks (W4), W16, and W24. Adverse events (AEs) were monitored at the same timepoints. Statistical significance of clinical improvement (EASI, P-NRS, DLQI) at week 4, week 16, and week 24 as compared with baseline was evaluated by using Student's t-test, considering significant a p-value <0.05. Our study enrolling 27 SPs patients showed a significant improvement in EASI and P-NRS since week 4, continuing to improve up to week 24. Similarly, DLQI significantly decreases at each timepoint as compared with baseline. Finally, no AEs were reported during the study period. Of interest, our cohort included oncologic patients, a patient with a history of severe infection, as well as subjects affected by severe neurological, psychiatric, pulmonary, and/or cardiovascular disease. Our experience showed that tralokinumab is effective and safe in elderly patients and subjects affected by severe comorbidities.

Application of advanced biosensors in nervous system diseases

AbstractNervous system diseases are among the most common diseases globally, posing a severe threat to patients' quality of life and placing a considerable burden on families and society. With improvements in miniaturization, intelligence, and the safety of biosensors, the combination of machinery and organisms is becoming increasingly common. In neuroscience research, biosensors of different macroscopic dimensions have been uniquely utilized to harness their relevant properties. One‐dimensional (1D) biosensors can achieve in situ real‐time monitoring of neural markers at the subcellular, single‐cell, ex vivo, and in vivo levels, with reduced impacts on organisms. Two‐dimensional (2D) biosensors can monitor the chemical behavior of cells and the neural activity of living animals. They are helpful for objectively identifying the characteristics of cells in response to external stimuli and studying the neural circuits of living animals. Three‐dimensional (3D) biosensors have shown unique advantages in point‐of‐care testing, liquid biopsy, drug screening, and mechanistic research. In clinical practice, brain‐computer interfaces (BCIs) and wearable devices have become important tools for monitoring and treatment. To date, there has been widespread adoption of BCIs in clinical practice. BCIs not only exhibit good efficacy in severe neurological and mental diseases but also provide a method for early diagnosis and treatment of these diseases. Wearable sensor devices can accurately assess the symptoms of movement disorders and play an active role in rehabilitation and treatment. In this review, we summarize the application of advanced biosensors in neuroscience research and clinical practice. The challenges and prospects of biosensors as applied to nervous system diseases under interdisciplinary promotion are also discussed in depth.

Neurotoxic effects of coronavirus: Potential implications in Alzheimer's onset and progression

The COVID-19, caused by SARS-CoV-2, first affects the respiratory tract but evidence is emerging that the virus, reaching the central nervous system (CNS), can lead to severe neurological disorders. In particular, CoV infection could cause an acceleration of the neurodegenerative process. On the other hand, patients diagnosed with Alzheimer's disease (AD) develop more serious forms of COVID-19 with worse relapses. Therefore, understanding the connection between the two pathologies, AD and infection by coronavirus, could help in the development of new therapeutic approaches to counter them.We used the SH-SY5Y cell line differentiated into neurons, as widely used in studies of AD if supplemented with exogenous fibrillary β-amyloid (Aβ). As a glial counterpart, human microglia (HMC3) and astrocytic (D54MG) cell lines were used to create co-cultures with neurons via transwell systems. In these experimental models, we generated infection with the Human Coronavirus OC43 (HCoV-OC43), a low-risk model of SARS-CoV-2.Our results suggest that the infection by HCoV-OC43 leads to a neurotoxic effect not depending on an already present event of Aβ deposition. Indeed, unlike microglia, neurons and even more astrocytes are susceptible to CoV infection and, although the infection does not show a cytotoxic effect in the neurons in the first few days, significant alterations at a biochemical and morphological level have been observed, suggesting that the neurons are reacting to a stressful condition, including the prodromal and neurodegenerative features of AD. Interestingly, the interaction of infected astrocytes with the neurons resulted in the manifestation of signs of neurodegeneration, such as amyloid-beta deposition.By using exogenous fibrillary Aβ, as an AD in vitro model, our data suggest that there is an aggravating effect both on the infection itself and on the neurological disease progression.In conclusion, the results of this study suggest a causal interplay between HCoV-OC43 and neurological diseases and demonstrate that the co-presence of different CNS cell populations is the necessary condition to study the pathogenic effects in vitro as a whole.

Corrigendum: Enterovirus-D68 – a reemerging non-polio enterovirus that causes severe respiratory and neurological disease in children

Corrigendum: Enterovirus-D68 – a reemerging non-polio enterovirus that causes severe respiratory and neurological disease in children

Usutu virus and West Nile virus use a transcellular route of neuroinvasion across an in vitro model of the human blood–brain barrier

West Nile virus (WNV) leads to thousands of cases of severe neurological disease in humans each year. Usutu virus (USUV) is closely related to WNV, but rarely induces disease in humans. We hypothesised that USUV is less able to cross the blood-brain barrier (BBB) and, consequently, is less likely to infect the brain. Therefore, we developed an in vitro BBB model consisting of primary human brain microvascular endothelial cells, pericytes and astrocytes. Both USUV and WNV invaded across the in vitro BBB via a transcellular mechanism in the absence of barrier disruption. USUV replicated to lower titres than WNV but induced a comparable cytokine and chemokine response, with modulation of key factors associated with barrier function and immune-cell migration. In conclusion, USUV appears attenuated in its ability to replicate at this interface compared with WNV, but further work must be done to identify key determinants underlying the differing clinical presentations.

JAK2/STAT3 signaling pathway mediates methylmercury toxicity in mouse astrocyte neuronal C8-D1A cell line.

Methylmercury (MeHg) is an environmental pollutant. Consumption of contaminated fish is the main exposure route in humans, leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes disrupting glutamate and calcium homeostasis and increasing oxidative stress. Despite extensive research, the molecular mechanisms underlying MeHg neurotoxicity remain incompletely understood. The induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role activating antioxidant responses during MeHg-induced oxidative injury have garnered significant attention as a potential therapeutic target against MeHg toxicity. However, recent studies indicate that the Nrf2 signaling pathway alone may not be sufficient to mitigate MeHg-induced damage, suggesting the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) plays a crucial role in cell growth and survival. Several studies have also highlighted its involvement in regulating redox homeostasis, thereby preventing oxidative stress through mechanisms that involve modulation of nuclear genes that encode electron transport complexes (ETC) and antioxidant enzymes. These characteristics suggest that STAT3 could serve as a viable mechanism to mitigate MeHg toxicity, either in conjunction with or as an alternative to Nrf2 signaling. Our previous findings demonstrated that MeHg activates the STAT3 signaling pathway in the GT1-7 hypothalamic neuronal cell line, suggesting its potential role in promoting neuroprotection. Here, to elucidate the role of the STAT3 signaling pathway in MeHg neurotoxicity, we pharmacologically inhibited STAT3 using AG490 in the C8D1A astrocytic cell line exposed to 10 µM MeHg. Our data demonstrated that pharmacological inhibition of STAT3 phosphorylation exacerbates MeHg-induced mortality, antioxidant responses, and ROS production, suggesting that STAT3 may contribute to neuroprotection against MeHg exposure in astrocytes.

Exploring Microorganisms Associated to Acute Febrile Illness and Severe Neurological Disorders of Unknown Origin: A Nanopore Metagenomics Approach.

Acute febrile illness (AFI) and severe neurological disorders (SNDs) often present diagnostic challenges due to their potential origins from a wide range of infectious agents. Nanopore metagenomics is emerging as a powerful tool for identifying the microorganisms potentially responsible for these undiagnosed clinical cases. In this study, we aim to shed light on the etiological agents underlying AFI and SND cases that conventional diagnostic methods have not been able to fully elucidate. Our approach involved analyzing samples from fourteen hospitalized patients using a comprehensive nanopore metagenomic approach. This process included RNA extraction and enrichment using the SMART-9N protocol, followed by nanopore sequencing. Subsequent steps involved quality control, host DNA/cDNA removal, de novo genome assembly, and taxonomic classification. Our findings in AFI cases revealed a spectrum of disease-associated microbes, including Escherichia coli, Streptococcus sp., Human Immunodeficiency Virus 1 (Subtype B), and Human Pegivirus. Similarly, SND cases revealed the presence of pathogens such as Escherichia coli, Clostridium sp., and Dengue virus type 2 (Genotype-II lineage). This study employed a metagenomic analysis method, demonstrating its efficiency and adaptability in pathogen identification. Our investigation successfully identified pathogens likely associated with AFI and SNDs, underscoring the feasibility of retrieving near-complete genomes from RNA viruses. These findings offer promising prospects for advancing our understanding and control of infectious diseases, by facilitating detailed genomic analysis which is critical for developing targeted interventions and therapeutic strategies.

Magnetic Resonance Imaging in Uremic Encephalopathy: Identifying Key Imaging Patterns and Clinical Correlations.

Background/Objectives: Magnetic Resonance Imaging (MRI) is essential in diagnosing neurological conditions, offering detailed insights into brain pathology. Uremic encephalopathy (UE) is a severe neurological disorder resulting from renal failure, characterized by cognitive impairments and brain abnormalities due to the accumulation of uremic toxins (UTs). Despite extensive research on UTs, there is a significant gap in the detailed characterization of MRI findings in UE patients. This study aims to bridge this gap by conducting a comprehensive literature review of cerebral MRI findings in UE. We hypothesize that specific MRI patterns correlate with the severity and clinical manifestations of UE, thereby enhancing diagnostic accuracy and improving patient outcomes. Methods: A literature review was performed using PubMed, Cochrane Library, and Google Scholar. The search terms included "uremic encephalopathy MRI", "uremia and kidney failure MRI", and "toxic and metabolic or acquired encephalopathies MRI". The inclusion criteria were original articles on UE and MRI findings published in English. Results: Common MRI sequences include T1-weighted, T2-weighted, FLAIR, and DWI. Frequent MRI findings in UE are cytotoxic and vasogenic brain edema in regions such as the basal ganglia and periventricular white matter. Patterns like the "lentiform fork sign" and basal ganglia involvement are key indicators of UE. Conclusions: MRI plays a crucial role in diagnosing UE by identifying characteristic brain edema and specific patterns. A comprehensive diagnostic approach, incorporating clinical, laboratory, and imaging data, is essential for accurate diagnosis and management. The study calls for larger well-designed cohorts with long-term follow-up to improve the understanding and treatment of UE.