Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.

High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors.

Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection.

Background And Aims: Interferon and nucleotide/nucleoside analogues are the main treatments for chronic hepatitis B. These drugs effectively reduce serum hepatitis B virus (HBV) DNA titers but fail to sufficiently reduce hepatitis B surface antigen (HBsAg) levels. Following the recent identification of sodium taurocholate cotransporting polypeptide as a receptor for HBV entry, inhibition of HBV entry has become an attractive therapeutic target for chronic hepatitis B treatment.

Efficacy and safety of daclatasvir plus asunaprevir therapy for chronic hepatitis C patients with renal dysfunction.

Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known.

Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C.

Background: Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown.

Methods: One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus asunaprevir.

Foucault imaging and small-angle electron diffraction in controlled external magnetic fields.

We report a method for acquiring Foucault images and small-angle electron diffraction patterns in external magnetic fields using a conventional transmission electron microscope without any modification. In the electron optical system that we have constructed, external magnetic fields parallel to the optical axis can be controlled using the objective lens pole piece under weak excitation conditions in the Foucault mode and the diffraction mode. We observe two ferromagnetic perovskite-type manganese oxides, LaSrMnO (LSMO) and NdSrMnO, in order to visualize magnetic domains and their magnetic responses to external magnetic fields.

Real-world efficacy and safety of daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients.

Background And Aims: Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown.

Methods: A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of daclatasvir and asunaprevir combination therapy.

Heterogeneous phase fibrinolysis rates by damped oscillation rheometry.

Background: Devices gauging viscoelastic properties of blood during coagulation like the thromboelastograph support fundamental research as well as point of care needs. Associated fibrinolysis data are based on endogenous species or plasminogen activator added to a homogeneous sample prior to clot formation. Digestion in a monolithic structure differs from the physical situation of thrombolytic therapy where surface reactions dominate.

X-ray studies of neutron stars and their magnetic fields.

Utilizing results obtained over the past quarter century mainly with Japanese X-ray astronomy satellites, a review is given to some aspects of neutron stars (NSs), with a particular emphasis on the magnetic fields (MFs) of mass-accreting NSs and magnetars. Measurements of electron cyclotron resonance features in binary X-ray pulsars, using the Ginga and Suzaku observatories, clarified that their surface MFs are concentrated in a narrow range of (1-7) × 10(8) T. Extensive studies of magnetars with Suzaku reinforced their nature as neutron stars with truly strong MFs, and revealed several important clues to their formation, evolution, and physical states.

Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice.

Background: Peptidylarginine deiminase type 4 (PADI4) has been identified as a susceptibility gene for rheumatoid arthritis (RA) by genome-wide association studies. PADI4 is highly expressed in the bone marrow, macrophages, neutrophils, and monocytes. Peptidyl citrulline is an interesting molecule in RA because it is a target antigen for anti-citrullinated peptide antibodies, and only PADs (translated proteins from PADI genes) can provide peptidyl citrulline via the modification of protein substrates.

Optogenetic activation of axon guidance receptors controls direction of neurite outgrowth.

Growth cones of extending axons navigate to correct targets by sensing a guidance cue gradient via membrane protein receptors. Although most signaling mechanisms have been clarified using an in vitro approach, it is still difficult to investigate the growth cone behavior in complicated extracellular environment of living animals due to the lack of tools. We develop a system for the light-dependent activation of a guidance receptor, Deleted in Colorectal Cancer (DCC), using Arabidopsis thaliana Cryptochrome 2, which oligomerizes upon blue-light absorption.

IFNL4 polymorphism effects on outcome of simeprevir, peginterferon, and ribavirin therapy for older patients with genotype 1 chronic hepatitis C.

Aim: Older patients with chronic hepatitis C have a lower virological response to interferon (IFN)-based treatments compared to younger patients. A single nucleotide polymorphism in the IFN-λ-4 (IFNL4) gene has a potent predictive effect on treatment response to IFN-based treatments. The efficacy of simeprevir (SMV) plus pegylated-IFN (PEG-IFN) and ribavirin therapy and the predictive value of IFNL4 on the outcome of therapy for older patients have not been addressed.

Effects of ITPA polymorphism on decrease of hemoglobin during simeprevir, peg-interferon, and ribavirin combination treatment for chronic hepatitis C.

Aim: Polymorphisms in the ITPA gene influence anemia during peg-interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with simeprevir, PEG-IFN, and RBV are not sufficiently known.

Methods: We analyzed 212 patients with genotype 1 chronic hepatitis C, who were treated with simeprevir plus PEG-IFN/RBV triple therapy, and assessed the effect of the ITPA polymorphism on hemoglobin levels and RBV dose reduction. ITPA (rs1127354) and IFNL4 (ss469415590) polymorphisms were genotyped using the Invader assay.

Brief hind paw stimulation is sufficient to induce delayed somatosensory discrimination learning in C57BL/6 mice.

Somatosensory learning and memory studies in rodents have primarily focused on the role of whiskers and the barrel structure of the sensory cortex, characteristics unique to rodents. In contrast, whether associative learning can occur in animals (and humans) via foot stimulation remains unclear. The sensory cortex corresponding to the plantar foot surface is localized in the centroparietal area, providing relatively easy access for studying somatosensory learning and memory.

Improvement of renal dysfunction in a patient with hepatitis C virus-related liver cirrhosis by daclatasvir and asunaprevir combination therapy: A case report.

Recently, treatments for chronic hepatitis C virus (HCV) infection have been drastically improved by the development of direct-acting antiviral agents. In September 2014, dual oral therapy using daclatasvir (DCV) and asunaprevir (ASV) was approved for the treatment of chronic HCV infection in Japan. We treated a patient with HCV-related liver cirrhosis with severe leg edema due to chronic renal dysfunction using this dual oral therapy.

Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir and BMS-788329 combination therapy in human hepatocyte chimeric mice.

We previously reported that interferon (IFN)-free direct-acting antiviral combination treatment succeeded in eradicating genotype 1b hepatitis C virus (HCV) in human hepatocyte chimeric mice. In this study, we examined the effect of vaniprevir (MK7009, NS3/4A protease inhibitor) and BMS-788329 (NS5A inhibitor) combination treatment on HCV genotype 1b and the expression of IFN-stimulated genes (ISGs) using a subgenomic replicon system and the same animal model. Combination treatment with vaniprevir and BMS-788329 significantly reduced HCV replication compared to vaniprevir monotherapy in HCV replicon cells (Huh7/Rep-Feo cells).

Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones.

Background & Aims: Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci).

HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy.

Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure.

Direct Growth and Controlled Coalescence of Thick AlN Template on Micro-circle Patterned Si Substrate.

High-density micro-circle patterned Si substrates were successfully fabricated for the direct overgrowth of thick AlN templates by using NH3 pulsed-flow multilayer AlN growth and epitaxial lateral overgrowth techniques. The experimental results show that an 8-μm-thick AlN template was grown at a very high growth rate on the substrates. The AlN template had full widths at half maximum of 0.

The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia.

Epidermal lipids are important for skin homeostasis. However, the entire picture of the roles of lipids, particularly nonceramide lipid species, in epidermal biology still remains obscure. Here, we report that PLA2G2F, a functionally orphan-secreted phospholipase A2 expressed in the suprabasal epidermis, regulates skin homeostasis and hyperplasic disorders.

Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice.

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.

Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice.

Unlabelled: Hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) are critical in eliminating infection. We developed an animal model in which HBV-infected human hepatocytes are targeted by HBV-specific CTLs. After HBV inoculation in human hepatocyte-transplanted herpes simplex virus type-1 thymidine kinase-NOG mice, human peripheral blood mononuclear cells (PBMCs) were administered, and albumin, HBV DNA, alanine aminotransferase (ALT), and cytokine levels were analyzed.

Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population.

We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population.