Short interfering RNA-directed inhibition of hepatitis B virus replication

AbstractRNA interference (RNAi) is the process by which double-stranded RNA directs sequence-specific degradation of mRNA. In mammalian cells, RNAi can be triggered by 21-nucleotide duplexes of short interfering RNA (siRNA). We examined effects of siRNA on hepatitis B virus (HBV) replication. Human hepatoma cells were transfected with HBV DNA and siRNA against HBV-pregenome RNA. Transfection experiments demonstrated that the siRNA reduced the amount of HBV-pregenome RNA and resulted in reduction of the levels of replicative intermediates and viral protein. Our results indicate that siRNA-mediated gene silencing inhibits HBV replication through suppression of viral RNA, which may be useful as a potential therapeutic modality

Prospective association of soft drink consumption with depressive symptoms.

OBJECTIVE: Consumption of soft drinks has become a serious public health issue worldwide. However, prospective evidence is limited regarding the relationship between soft drink consumption and depression, especially in Asia. The aim of this study was to investigate the prospective association between soft drink consumption and the development of depressive symptoms. METHODS: We evaluated an occupational cohort of 935 adults in Japan (2012-2016), who were free from depressive symptoms at baseline and attended a 3-y follow-up assessment. Soft drink consumption was assessed using a self-administered diet history questionnaire. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multivariate logistic regression analysis controlling for sociodemographic, lifestyle, dietary, and occupational covariates. RESULTS: Over the 3-y study period, 16.9% (158 cases) of the study participants reported depressive symptoms. Higher soft drink consumption was associated with higher odds of depressive symptoms. The multivariable-adjusted OR was 1.91 (95% CI, 1.11-3.29; Ptrend = 0.015) when comparing soft drink consumption of ≥4 cups/wk with consumption of <1 cup/wk. CONCLUSION: The present results suggested that greater consumption of soft drinks would increase the likelihood of exhibiting depressive symptoms.This study was supported by JSPS KAKENHI Grant Numbers 25293146, 25702006, Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus (15ek0210021h0002) from the Japan Agency for Medical Research and Development, and the Industrial Health Foundation. F.I. was funded by the Medical Research Council Epidemiology Unit, United Kingdom (MC_UU_12015/5)

Attenuation of Responsiveness to Interferon-α Treatment by Preceded Overactivation of Interferon-mediated Pathway in Patients Chronically Infected by Hepatitis C Virus

The Interferon (IFN) receptor-mediated signal transduction pathways involve the two novel DNA-binding factors, interferon regulatory factor-1 (IRF-1) and IRF-2. Both recognize the same DNA sequence, in which the expression ratio of IRF-1 to IRF-2 is relevant to induction of IFN-inducible genes, because IRF-1 acts as a transcriptional activator and IRF-2 as a counterpart. In the present study, 54 patients with chronic hepatitis C and the age-and sex-matched 7 subjects with fatty liver as a control were subjected to analysis of the expression ratio of IRF-1 to IRF-2 mRNA in the liver tissue obtained at the time of livert biopsy by reverse transcription-polymerase chain reaction in combination with a restriction fragment length polymorphism assay. The expression ratio of IRF-1 to IRF-2 mRNA in the liver tissue in patients chronically infected by hepatitis C virus (HCV) was significantly higher than that in control, although the values did not correlate with the serum levels of HCV-RNA. Of 54 patients, 28 received IFN treatment, resulting in complete response in 8 patients. With respect to responsiveness to IFN treatment, patients who had complete response had the relatively lower ratios of IRF-1 to IRF-2 mRNA in the liver tissue, compared with those who did not. These results indicate that the IFN-mediated pathway is spontaneously activated in patients with chronic hepatitis C, and that its preceded overactivation counteracts on the efficacy of IFN treatment in these patients

Early SNS-based monitoring system for the COVID-19 outbreak in Japan: a population-level observational study

Background: The World Health Organization declared the novel coronavirus outbreak (COVID-19) to be a pandemic on March 11, 2020. Large-scale monitoring for capturing the current epidemiological situation of COVID-19 in Japan would improve preparation for and prevention of a massive outbreak. Methods: A chatbot-based healthcare system named COOPERA (COvid-19: Operation for Personalized Empowerment to Render smart prevention And care seeking) was developed using the LINE app to evaluate the current Japanese epidemiological situation. LINE users could participate in the system either though a QR code page in the prefecture’s website, or a banner at the top of the LINE app screen. COOPERA asked participants questions regarding personal information, preventive actions, and non-specific symptoms related to COVID-19 and their duration. We calculated daily cross correlation functions between the reported number of infected cases confirmed by PCR and the symptom-positive group captured by COOPERA. Results: We analyzed 206,218 participants from three prefectures reported between March 5 and 30, 2020. The mean (standard deviation) age of participants was 44.2 (13.2). No symptoms were reported by 96.93% of participants, but there was a significantly positive correlation between the reported number of COVID-19 cases and self-reported fevers, suggesting that massive monitoring of fever might help to estimate the scale of the COVID-19 epidemic in real time. Conclusions: COOPERA is the first real-time system being used to monitor trends in COVID-19 in Japan, and provides useful insights to assist political decisions to tackle the epidemic

Non-Abelian Walls in Supersymmetric Gauge Theories

The Bogomol'nyi-Prasad-Sommerfield (BPS) multi-wall solutions are constructed in supersymmetric U(N_C) gauge theories in five dimensions with N_F(>N_C) hypermultiplets in the fundamental representation. Exact solutions are obtained with full generic moduli for infinite gauge coupling and with partial moduli for finite gauge coupling. The generic wall solutions require nontrivial configurations for either gauge fields or off-diagonal components of adjoint scalars depending on the gauge. Effective theories of moduli fields are constructed as world-volume gauge theories. Nambu-Goldstone and quasi-Nambu-Goldstone scalars are distinguished and worked out. Total moduli space of the BPS non-Abelian walls including all topological sectors is found to be the complex Grassmann manifold SU(N_F) / [SU(N_C) x SU(N_F-N_C) x U(1)] endowed with a deformed metric.Comment: 62 pages, 17 figures, the final version in PR

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure : a sub analysis of the CANDLE trial

Background: Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods: Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results: The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′ < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66–1.04). Conclusions: In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction

Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment

Ability to form cellular aggregations such as tumorspheres and spheroids have been used as a morphological marker of malignant cancer cells and in particular cancer stem cells (CSC). However, the common definition of the types of cellular aggregation formed by cancer cells has not been available. We examined morphologies of 67 cell lines cultured on three dimensional morphology enhancing NanoCulture Plates (NCP) and classified the types of cellular aggregates that form. Among the 67 cell lines, 49 cell lines formed spheres or spheroids, 8 cell lines formed grape-like aggregation (GLA), 8 cell lines formed other types of aggregation, and 3 cell lines formed monolayer sheets. Seven GLA-forming cell lines were derived from adenocarcinoma among the 8 lines. A neuroendocrine adenocarcinoma cell line PC-3 formed asymmetric GLA with ductal structures on the NCPs and rapidly growing asymmetric tumors that metastasized to lymph nodes in immunocompromised mice. In contrast, another adenocarcinoma cell line DU-145 formed spheroids in vitro and spheroid-like tumors in vivo that did not metastasize to lymph nodes until day 50 after transplantation. Culture in the 3D nanoenvironment and in a defined stem cell medium enabled the neuroendocrine adenocarcinoma cells to form slowly growing large organoids that expressed multiple stem cell markers, neuroendocrine markers, intercellular adhesion molecules, and oncogenes in vitro. In contrast, the more commonly used 2D serum-contained environment reduced intercellular adhesion and induced mesenchymal transition and promoted rapid growth of the cells. In addition, the 3D stemness nanoenvironment promoted secretion of HSP90 and EpCAM-exosomes, a marker of CSC phenotype, from the neuroendocrine organoids. These findings indicate that the NCP-based 3D environment enables cells to form stem cell tumoroids with multipotency and model more accurately the in vivo tumor status at the levels of morphology and gene expression

Optimal waist circumference cut-off points and ability of different metabolic syndrome criteria for predicting diabetes in Japanese men and women: Japan Epidemiology Collaboration on Occupational Health Study

Abstract Background We sought to establish the optimal waist circumference (WC) cut-off point for predicting diabetes mellitus (DM) and to compare the predictive ability of the metabolic syndrome (MetS) criteria of the Joint Interim Statement (JIS) and the Japanese Committee of the Criteria for MetS (JCCMS) for DM in Japanese. Methods Participants of the Japan Epidemiology Collaboration on Occupational Health Study, who were aged 20–69 years and free of DM at baseline (n = 54,980), were followed-up for a maximum of 6 years. Time-dependent receiver operating characteristic analysis was used to determine the optimal cut-off points of WC for predicting DM. Time-dependent sensitivity, specificity, and positive and negative predictive values for the prediction of DM were compared between the JIS and JCCMS MetS criteria. Results During 234,926 person-years of follow-up, 3180 individuals developed DM. Receiver operating characteristic analysis suggested that the most suitable cut-off point of WC for predicting incident DM was 85 cm for men and 80 cm for women. MetS was associated with 3–4 times increased hazard for developing DM in men and 7–9 times in women. Of the MetS criteria tested, the JIS criteria using our proposed WC cut-off points (85 cm for men and 80 cm for women) had the highest sensitivity (54.5 % for men and 43.5 % for women) for predicting DM. The sensitivity and specificity of the JCCMS MetS criteria were ~37.7 and 98.9 %, respectively. Conclusion Data from the present large cohort of workers suggest that WC cut-offs of 85 cm for men and 80 cm for women may be appropriate for predicting DM for Japanese. The JIS criteria can detect more people who later develop DM than does the JCCMS criteria

Flavor Neutrino Masses giving sin\theta_{13}=0

Among neutrino mixings, the reactor mixing angle, \theta_{13}, is observed to be almost vanishing and is consistent with \theta_{13}=0. We discuss how the condition of \theta_{13}=0 constrains models of neutrino mixings and show that, for flavor neutrino masses given by M_{ij} (i,j=e,\mu,\tau), two conditions of M_{e\tau}=-e^{2i\gamma}tan(\theta_{23})M_{e\mu} and M_{\tau\tau}=e^{4i\gamma}M_{\mu\mu}+e^{2i\gamma}[2/tan(2\theta_{23})]M_{\mu\tau} lead to \theta_{13}=0, where \theta_{23} is the atmospheric neutrino mixing angle and \gamma is its associated phase. The rephasing invariance can select two phases provided by \alpha=arg(M_{e\mu}) and \beta=arg(M_{e\tau}), giving \gamma=(\beta-\alpha)/2.Comment: 5 pages, typos corrected and references update