Saori Haga

Although ubiquitination has been shown to play important roles in the HCV life cycle, the roles of deubiquitinating enzymes (DUBs), which cleave ubiquitin chains from their substrates, in HCV propagation have not been investigated. Here, we identified USP15 as a DUB regulating HCV propagation. USP15 showed no interaction with viral proteins and no participation in innate immune responses. Deficiency of USP15 in Huh7 cells resulted in suppression of the translation of HCV RNA and reduction in the amounts of lipid droplets, and the addition of fatty acids partially restored the production of infectious HCV particles. These data suggest that USP15 participates in HCV propagation in hepatic cells through the regulation of viral RNA translation and lipid metabolism.

Significance The mechanism by which hepatitis C virus (HCV) evades immune surveillance and causes chronic infection is unclear. We demonstrate here that HCV core protein interferes with the maturation of major histocompatibility complex (MHC) class I catalyzed by signal peptide peptidase (SPP) and induces degradation via HMG-CoA reductase degradation 1 homolog. In addition, we found that the core protein transmembrane domain is homologous to the human cytomegalovirus US2 protein, whose transmembrane region also targets SPP to impair MHC class I molecule expression in a similar manner. Therefore, our data suggest that SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.

Dengue is a mosquito-borne disease that has spread to over 100 countries. Its symptoms vary from the relatively mild acute febrile illness called dengue fever to the much more severe dengue shock syndrome. Dengue is caused by dengue virus (DENV), which belongs to the Flavivirus genus of the family Flaviviridae. There are four serotypes of DENV, i.e., DENV1 to DENV4, and each serotype is divided into distinct genotypes. Thailand is an endemic area where all four serotypes of DENV co-circulate. Genome sequencing of the DENV2 that was isolated in Thailand in 2016 and 2017 revealed the emergence of the Cosmopolitan genotype and its co-circulation with the Asian-I genotype. However, it was unclear whether different genotypes have different levels of viral replication and pathogenicity. Focus-forming assay (FFA) results showed that clinical isolates of these genotypes differed in focus size and proliferative capacity. Using circular polymerase extension reaction, we generated parental and chimeric viruses with swapped genes between these two DENV2 genotypes, and compared their focus sizes and infectivity titers using FFA. The results showed that the focus size was larger when the structural proteins and/or non-structural NS1-NS2B proteins were derived from the Cosmopolitan virus. The infectious titers were consistent with the focus sizes. Single-round infectious particle assay results confirmed that chimeric viruses with Cosmopolitan type structural proteins, particularly prM/E, had significantly increased luciferase activity. Replicon assay results showed that Cosmopolitan NS1-NS2B proteins had increased reporter gene expression levels. Furthermore, in interferon-receptor knock-out mice, viruses with Cosmopolitan structural and NS1-NS2B proteins had higher titers in the blood, and caused critical disease courses. These results suggested that differences in the sequences within the structural and NS1-NS2B proteins may be responsible for the differences in replication, pathogenicity, and infectivity between the Asian-I and Cosmopolitan viruses.

Introduction Metacognitive training (MCT) is a group program for improving cognitive bias in patients with schizophrenia. MCT has a reported positive effect on psychiatric symptoms and cognitive bias in patients with schizophrenia, but the effect of the intervention on patients with schizophrenia in the early recovery stage during hospitalization is not comprehensible. Therefore, this study aimed to investigate the efficacy of MCT in the early recovery stage of patients with schizophrenia in a Japanese emergency psychiatric ward. Method This unblinded, pilot randomized controlled trial recruited 24 patients with schizophrenia aged 20–65 years. Patients were randomly divided into two groups: occupational therapy (OT) + MCT group and OT-only group. Using the two-way repeated-measures analysis of variance (ANOVA), changes in cognitive function, psychiatric symptoms, cognitive insight, and intrinsic motivation were compared between those at baseline and post-intervention and between the two groups. Furthermore, patient readmission during the year after discharge was compared between the groups. Results The final analysis included eight patients in each group, owing to the withdrawal of some patients from the study. The two-way repeated-measures analysis of variance revealed significant differences in cognitive function in several domains within subjects. However, no significant differences between subjects were observed. Psychiatric symptoms showed significant within-subject improvement, and interaction was found for general psychopathology ( p = 0.03). The variable of cognitive insight and self-reflectiveness was significantly different between subjects ( p = 0.03). There was no significant difference in intrinsic motivation. Readmission within a year was significantly lower in the OT + MCT group than in the OT-only group (2 [25%] vs. 6 [75%]; p = 0.046). Conclusion In a Japanese emergency psychiatric ward, this pilot randomized controlled study was the first attempt to investigate the efficacy of MCT in patients with schizophrenia suggesting that MCT may be effective in preventing psychiatric symptoms, poor self-reflectiveness, and readmissions. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; UMIN000034106).