ラスムッセン脳炎

Herpes simplex virus type 1 (HSV-1) causes severe neurological complications such as herpes simplex encephalitis and Alzheimer's disease (AD). Its entry is mediated by glycoproteins gD and gB, which regulate receptor binding and membrane fusion. Targeting these entry glycoproteins represents a promising therapeutic strategy to limit HSV-1 infection and its contribution to AD pathogenesis. Therefore, this study aimed to identify natural dual inhibitors of HSV-1 glycoproteins gB and gD from Ginkgo biloba using an integrated computational approach involving molecular docking, pharmacokinetic, toxicity, and bioactivity profiling, molecular dynamics simulations, and MM-GBSA binding free energy analyses to evaluate binding stability and therapeutic potential. A total of 39 phytochemicals were retrieved from IMPPAT 2.0 and PubChem databases and docked against HSV-1 glycoproteins gB and gD. Pharmacokinetics and toxicity were assessed using admetSAR 3.0, SwissADME, Deep-PK, and pKCSM. Molecular docking revealed several phytochemicals with strong binding affinities to HSV-1 glycoproteins gB and gD, compared to docosanol. Among these, β-sitosterol and ginkgolide A exhibited favorable drug-likeness, acceptable oral bioavailability, no mutagenic and hepatotoxic effects, and biologically active. Molecular dynamic simulation confirmed their greatest binding stability compared to docosanol. MM-GBSA binding free energy analysis further validated their strong and stable interactions within the active sites of HSV-1 glycoproteins gB and gD. These findings identify β-sitosterol and ginkgolide A as promising dual-target inhibitors of HSV-1 glycoproteins gB and gD in context of HSV-1-associated AD pathogenesis. However, experimental validation is required to confirm their antiviral efficacy and potential relevance to AD.

Phlebotomine sand flies are important vectors of various pathogens, including the Chandipura virus (CHPV), a neurotropic rhabdovirus associated with fatal pediatric encephalitis outbreaks in India. Gujarat, a CHPV-endemic region, lacks comprehensive molecular data on sand fly species. Accurate species identification is important for effective vector surveillance and control strategies. 2950 sand flies were collected from 14 districts using aspirators and traps. Morphological identification was performed by using standard taxonomic keys. DNA barcoding of the mitochondrial cytochrome c oxidase subunit I (COI) gene was performed using universal barcoding primers. Sequence alignment, phylogenetic analysis, and genetic divergence calculations were performed through MEGA and BOLD Systems databases. Seven species were identified: Sergentomyia babu, Se. punjabensis, Se. insularis, Se. bailyi, Se. shorttii, Phlebotomus argentipes, and Ph. papatasi. Phylogenetic clustering showed strong bootstrap support (>90%), confirming congruence between morphological and molecular identification. Intraspecific divergence was low (0.5 to 2.0%), while interspecific divergence was comparatively higher (5.4 to 18.9%), indicating a clear "barcode gap" that validated species boundaries. COI DNA barcoding reliably distinguished sand fly species from CHPV-endemic Gujarat. The study highlights the presence of epidemiologically relevant vectors, supports the use of molecular taxonomy in entomological surveillance, and emphasizes the need to expand DNA barcode reference libraries for Indian sand flies.

Epilepsy has long been conceptualised as a disorder in which aberrant brain dynamics extend beyond the epileptogenic zone. Evidence demonstrates that loss of entropy is a generic feature of pathological dynamics in the brain, including the ictal state. However, the impact of recurrent seizures on entropy in the interictal state remains unknown. Resting state magnetoencephalography (MEG) scans and resection masks of 32 individuals with epilepsy who had Engel I outcome post-surgery were retrospectively retrieved. Using co-registered FreeSurfer parcellations, we reconstructed the source localised MEG time series and computed sample entropy for 114 regions of interest. We then tested the association of entropy with the resected volume of the brain, and additional clinical variables including the age of seizure onset, seizure frequency and duration of epilepsy. To further understand the temporal relationship between seizure onset and entropy in the interictal state, we collected and computed sample entropy for week-long EEG traces from leucine-rich glioma inactivated 1 monoclonal antibody (LGI1-mAb) rodent models of autoimmune encephalitis (n=5) and control rats (n=5). We found that in individuals with epilepsy, a lower age of seizure onset was associated with lower mean sample entropy of the whole cortex (Spearman's rho =0.60, p<0.001; partial correlation =0.41, p=0.021). Entropy did not differ between the resected and non-resected regions of the brain. Furthermore, in an exploratory analysis, LGI1-mAb treated rodents showed lower sample entropy as compared to control rats, after the onset of seizures. Together, these results suggest that cortical entropy may serve as a marker of long-term alterations in cortical dynamics associated with recurrent seizures.

West Nile virus (WNV) is the most common cause of domestic human arboviral infection in the contiguous United States. WNV surveillance across the United States is not comprehensive and is limited. Nonclinical WNV surveillance is variable, and WNV surveillance in humans is limited by the percentage of symptomatic human infections and time it takes to seek healthcare and diagnosis. Wastewater surveillance has been used to detect viruses shed from asymptomatic and symptomatic persons; therefore, we assessed wastewater as a surveillance tool for WNV tracking. We tested archived RNA and raw wastewater from 6 states with documented human illness during the 2023 WNV transmission season for WNV RNA. WNV RNA was detected in 18% (n = 29/158) of samples from Arizona, California, Colorado, Illinois, Indiana, and Nebraska. Our results highlight the ability to detect WNV in wastewater and the potential of wastewater surveillance to augment current surveillance data.

Tick-borne encephalitis virus (TBEV), a prominent orthoflavivirus transmitted by ticks, poses a risk of potentially fatal encephalitis in humans. Currently, the only available inactivated vaccines have limited usage, underscoring the need for developing novel vaccine strategies. The 3' untranslated region (UTR) of TBEV can be divided into variable and conserved regions, where structured RNA elements play crucial roles in viral replication and virulence. In this study, we found that deleting sequences in both the variable region and most of the conserved region within the 3'UTR eliminated viral replication. However, inserting a poly(A) tract effectively restored viral propagation. Notably, the recovered virus variants, Δ1-642/poly(A), exhibited high attenuation in mice. A single-dose immunization with Δ1-642/poly(A) induced robust TBEV-specific IgG, neutralizing antibody, and T-cell immune responses, providing complete protection against lethal challenges with wild-type virus. Collectively, our findings demonstrate that poly(A) replacement represents a viable strategy for developing live-attenuated TBEV vaccines.IMPORTANCEOrthoflaviviruses, encompassing mosquito-borne dengue virus (DENV), yellow fever virus (YFV), Zika virus (ZIKV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV), represent a substantial global public health and economic burden. The 3' UTR is critical for viral replication and pathogenesis, as exemplified by the ongoing clinical development of the tetravalent Butantan dengue vaccine (with deletion in 3' UTR). Our previous study on WNV-poly(A) variants proposed a novel live-attenuated vaccine design via 3' UTR engineering, yet its broad applicability remained unclear due to extensive 3' UTR heterogeneity. In this study, we successfully rescued a TBEV poly(A) virus using an analogous strategy. This virus was highly attenuated in mice, and a single immunization provided long-term complete protection against lethal wild-type virus challenge. Collectively, our data validate the poly(A) replacement approach as a potentially universal platform for developing live-attenuated vaccines against both mosquito-borne and tick-borne orthoflaviviruses.