Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate,Fenofibric Acid,and Pemafibrate

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.     

Application of step‐response test for evaluation of uncertainty of standard measuring system for lightning‐impulse high voltage

In evaluating the uncertainty of the standard measuring system for lightning‐impulse high voltages, which is composed of a standard voltage divider, a digital recorder, and calibrators, step‐response tests of the standard voltage divider may be useful. In this paper, a convolution algorithm is employed to calculate the output impulse voltage waveforms from measured step‐response waveforms. The uncertainties of peak‐value measurement due to the influence of the nominal epoch, uncertainty of the peak‐value measurement due to dispersion of the AC scale factor, and uncertainty of the virtual front‐time measurement due to long‐term stability are evaluated. Furthermore, the error of the virtual front time of the output waveforms is discussed. The front part of the step‐response waveform, t≤ T₃₀%, does not influence the error of the virtual front time. Therefore, for the standard voltage divider, the step‐response parameters, that is, the experimental response time, partial response time, settling time, and overshoot, have almost nothing to do with the error of the virtual front time. © 2012 Wiley Periodicals, Inc. Electr Eng Jpn, 180(2): 24–32, 2012; Published online in Wiley Online Library ( wileyonlinelibrary.com ). DOI 10.1002/eej.21279     

Measurement invariance of the Gifted Rating Scales—School Form across five cultural groups.

This study examined measurement invariance of the Gifted Rating Scales—School Form (GRS–S) across the United States, Puerto Rico, China, South Korea, and Turkey, using multigroup confirmatory factor analysis. A total of 1,817 students were rated by 287 teachers using either translated versions of GRS–S or the original English GRS–S. Results indicate a similar factor structure for the GRS–S across the five locations; six factors with each of the 72 items equivalently loaded to the same latent variable across groups. The metric invariance test and the factor variance and covariance invariance tests reveal that the patterns of factor loadings and the factor variances and covariances are invariant across the five groups. Moreover, the scalar invariance test indicates that item means are equivalent across the groups. These results suggest that the GRS–S has intercultural utility and can be similarly interpreted. Implications and limitations of the present research for gifted identification are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Determination of number-average and weight-average molecular weights of polymer sample from diffusion and sedimentation velocity measurements in theta solvent

Several methods to determine number-average molecular weight M_n and weight-average molecular weight M_w, of a polymer sample are proposed from diffusion and sedimentation velocity measurements at the θ point. According to these methods, M_n and M_w are determined from the diffusion constant vs. molecular weight relationship, and also from the equations of Svedberg and Flory–Mandelkern, using the 2nd-order and the –2nd-order diffusion constants. These methods have been applied to four samples of polydisperse polystyrene in the θ solvent, cyclohexane at 35°C. It was experimentally ascertained that M_n and M_w of each sample determined by the present methods were in good agreement with the results of column fractionation, light scattering, and calculated values from molecular weight distribution curve within experimental errors. It is concluded that the present methods are useful for determining M_n and M_w, since the reliabilities of M_n and M_w values, which are fundamental quantities of polymer characterization, can be raised by comparing the experimental data observed by conventional methods such as osmotic pressure, light scattering, and the Archibald method with those observed by the present methods.     

Corrosion characteristics of reduced activation ferritic steel, JLF-1 (8.92Cr–2W) in molten salts Flibe and Flinak

Static corrosion tests were performed in molten salts, LiF–BeF₂ (Flibe) and LiF–NaF–KF (Flinak), at 500 °C and 600 °C for 1000 h. The purpose is to investigate the corrosion characteristics of reduced activation ferritic steels, JLF-1 (8.92Cr–2W) in the fluids. The concentration of hydrogen fluoride (HF) in the fluids was measured by slurry pH titration method before and after the exposure. The HF concentration determined the fluoridation potential. The corrosion was mainly caused by dissolution of Fe and Cr into the fluids due to fluoridation and/or electrochemical corrosion. Carbon on the surface might be dissolved into the fluids due to the corrosion, and this resulted to the decrease of carbide on the surface. The corrosion depth of the JLF-1 specimen, which was obtained from the weight losses, was 0.637 μm in Flibe at 600 °C and 6.73 μm in Flinak at 600 °C.     

An Additional Insight into the Correlation between the Distribution Ratios and the Aqueous Acidity of the TODGA System

Abstract

Extraction of Eu(III) and Am(III) from HNO₃ into the organic solvents using N,N,N′,N′‐tetraoctyl‐diglycolamide (TODGA) was investigated in order to study the detailed extraction reaction. The chemical species: 1:2 for metal:TODGA complex is present in polar diluents. On the other hand, the metal complexes need three or more TODGA molecules to remain stable in non‐polar diluents. The HNO₃ concentration dependence on the distribution ratio suggests that HNO₃ participates in the metal extraction. Infrared spectra indicate that the carbonyl oxygen coordinates with Eu(III), and luminescence lifetimes suggest that there are no water molecules in the inner coordination sphere of the extracted Eu‐complex.     

A Moment Method for Evaporation Using a Logarithmic Size Distribution with the Smallest Size

A moment method of the log-normal distribution with the smallest size is applied to evaporation by newly introducing correction factors obtained from the error function. In this article, the improved moment method is tested for the evaporation, and is compared with the exact solutions calculated by the CIP semi-Lagrangian (CIP-SL) method. In small particle regime, the size distributions and the time histories of the total number and volume per unit volume are reproduced by the moment method for the evaporation near the smallest size. In large particle regime, however, the differences between the moment and exact solutions are larger with time, after the exact distribution spreads to the smallest size. This new moment solver can reproduce the evaporation near the smallest size even when large time step size is given, and thus is expected to be used for the parameterization of the evaporation of small particles in aerosol-transport model.     

Osteoinduction by Functionally Graded Apatites of Bovine Origin Loaded with Bone Morphogenetic Protein-2

Bioresorbable and functionally graded apatites (fg-HAp) ceramics, which are characterized by gradations in crystallinity and the grain size of hydroxyapatite (HAp:Ca₁₀(PO₄)₆(OH)₂), were designed using bovine bone by the calcination and partial dissolution–precipitation method. The fg-HAp ceramics had macropores of 100–600 μm originated from spongy bone, and micropores of 10–160 nm. Fg-HAp ceramics loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2/fg-HAp) were implanted into the subcutaneous tissue of rats. Eight weeks after the implantation, the surface and bulk degradations of the fg-HAp-containing body fluid occured, and small pieces of fg-HAp were incorporated into the induced bone and fatty marrow, suggesting that osteoinduction occurred in conjunction with bone remodeling. The rhBMP-2/fg-HAp ceramics developed could become a resorbable biomimetic material with fast bioresorption and osteoinduction characteristics.     

Effective Coke Removal in Methane to Benzene (MTB) Reaction on Mo/HZSM-5 Catalyst by H2 and H2O Co-addition to Methane

The catalytic dehydro-aromatization reaction over Mo/HZSM-5 catalyst was drastically stabilized by the co-addition of 5.4% H₂ and 1.8% H₂O to methane feed at 750 °C, 0.3 MPa and methane space velocity of 3000 mL g⁻¹ h⁻¹, suppressing the coke formation effectively, compared with single hydrogen or steam addition.