A Serine Palmitoyltransferase Inhibitor Blocks Hepatitis C Virus Replication in Human Hepatocytes

Background & AimsHost cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice.MethodsWe tested the ability of NA808 to inhibit SPT’s enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors.ResultsNA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors.ConclusionsThe SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors

Verification of Implant Surface Modification by a Novel Processing Method

Metals have been used clinically as biomaterials, especially in the orthopaedic and dental fields. Metals used as implants wear at contact surfaces, producing metal particles and metal ions that may be harmful. Newly developed metal implants and methods of implant surface modification are currently under scrutiny. We evaluated the use of electrolytic in-process dressing (ELID) as a surface finishing method for metal implants. Metal implants processed using the ELID method (ELID group) or not processed (Non-ELID group) were inserted surgically into rabbit femurs. The rabbits were sacrificed postoperatively over a 24-week period. We assessed the concentrations of the cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, the resistance to implant pull-out, and histopathology at the implant site. There was no significant difference between the groups regarding the cytokine concentrations or implant pull-out resistance. Many particles indicating wear around the implant were noted in the Non-ELID group (n=10) but not the ELID group (n=13), while a fibrous membrane adhering to the every implant was noted in the ELID group. The formation of a fibrous membrane rather than metal particles in the ELID group may indicate improved biocompatibility, and it suggests that ELID may prevent corrosion in the areas of contact

Random regression for modeling soybean plant response to irrigation changes using time-series multispectral data

Plant response to drought is an important yield-related trait under abiotic stress, but the method for measuring and modeling plant responses in a time series has not been fully established. The objective of this study was to develop a method to measure and model plant response to irrigation changes using time-series multispectral (MS) data. We evaluated 178 soybean (Glycine max (L.) Merr.) accessions under three irrigation treatments at the Arid Land Research Center, Tottori University, Japan in 2019, 2020 and 2021. The irrigation treatments included W5: watering for 5 d followed by no watering 5 d, W10: watering for 10 d followed by no watering 10 d, D10: no watering for 10 d followed by watering 10 d, and D: no watering. To capture the plant responses to irrigation changes, time-series MS data were collected by unmanned aerial vehicle during the irrigation/non-irrigation switch of each irrigation treatment. We built a random regression model (RRM) for each of combination of treatment by year using the time-series MS data. To test the accuracy of the information captured by RRM, we evaluated the coefficient of variation (CV) of fresh shoot weight of all accessions under a total of nine different drought conditions as an indicator of plant’s stability under drought stresses. We built a genomic prediction model (MTRRM model) using the genetic random regression coefficients of RRM as secondary traits and evaluated the accuracy of each model for predicting CV. In 2020 and 2021,the mean prediction accuracies of MTRRM models built in the changing irrigation treatments (r = 0.44 and 0.49, respectively) were higher than that in the continuous drought treatment (r = 0.34 and 0.44, respectively) in the same year. When the CV was predicted using the MTRRM model across 2020 and 2021 in the changing irrigation treatment, the mean prediction accuracy (r = 0.46) was 42% higher than that of the simple genomic prediction model (r =0.32). The results suggest that this RRM method using the time-series MS data can effectively capture the genetic variation of plant response to drought

Syntheses and Characterization of New Nickel Coordination Polymers with 4,4′-Dipyridylsulfide. Dynamic Rearrangements of One-Dimensional Chains Responding to External Stimuli: Temperature Variation and Guest Releases/Re-Inclusions

Crystal structures and dynamic rearrangements of one-dimensional coordination polymers with 4,4′-dipyridylsulfide (dps) have been studied. Reaction of Ni(NO3)2·6H2O with dps in EtOH yielded [Ni(dps)2(NO3)2] ·EtOH (1), which had channels filled with guest EtOH molecules among the four Ni(dps)2 chains. This coordination polymer reversibly transformed the channel structure responding to temperature variations. Immersion of 1 in m-xylene released guest EtOH molecules to yield a guest-free coordination polymer [Ni(dps)2(NO3)2] (2a), which was also obtained by treatment of Ni(NO3)2·6H2O with dps in MeOH. On the other hand, removal of the guest molecules from 1 upon heating at 130 °C under reduced pressure produced a guest-free coordination polymer [Ni(dps)2(NO3)2] (2b). Although the 2a and 2b guest-free coordination polymers have the same formula, they showed differences in the assembled structures of the one-dimensional chains. Exposure of 2b to EtOH vapor reproduced 1, while 2a did not convert to 1 in a similar reaction. Reaction of Ni(NO3)2·6H2O with dps in acetone provided [Ni(dps)(NO3)2(H2O)] ·Me2CO (4) with no channel structure. When MeOH or acetone was used as a reaction solvent, the [Ni(dps)2(NO3)2] · (guest molecule) type coordination polymer, which was observed in 1, was not formed. Nevertheless, the reaction of Ni(NO3)2·6H2O with dps in MeOH/acetone mixed solution produced [Ni(dps)2(NO3)2]·0.5(MeOH·acetone) (5), which has an isostructural Ni-dps framework to 1

De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and β-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/β-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions. © The Author(s) 2017

De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity

Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30C>G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and β-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/β-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions