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.     

Direct Formation of Crystalline Gadolinium-Doped Ceria Powder via Polymerized Precursor Solution

Synthesis of Ce_0.9Gd_0.1O_1.95 (CGO) powder from a polymeric precursor solution containing a mixture of nitrates, nitric acid, and ethylene glycol was investigated with emphasis on the effect of polymerization of the precursor solution on the crystallization and morphology of the derived solid intermediate and the final oxide powder. It is shown for the first time in this work that the solid intermediate derived from the polymerized solution is present in the form of well-crystallized cerium-gadolinium formate solid solution, Ce_{1− x} Gd _x (HCOO)₃, exhibiting anisotropic growth. Further polymerization of the precursor solution resulted in the direct formation of loosely agglomerated nanoscaled CGO oxide powder from the polymerized solution at temperatures as low as 130°C.     

Carbon Nitride Loaded with an Ultrafine,Monodisperse, Metallic Platinum-Cluster Cocatalyst for the Photocatalytic Hydrogen-Evolution Reaction

For the realization of a next-generation energy society, further improvement in the activity of water-splitting photocatalysts is essential. Platinum (Pt) is predicted to be the most effective cocatalyst for hydrogen evolution from water. However, when the number of active sites is increased by decreasing the particle size, the Pt cocatalyst is easily oxidized and thereby loses its activity. In this study, a method to load ultrafine, monodisperse, metallic Pt nanoclusters (NCs) on graphitic carbon nitride is developed, which is a promising visible-light-driven photocatalyst. In this photocatalyst, a part of the surface of the Pt NCs is protected by sulfur atoms, preventing oxidation. Consequently, the hydrogen-evolution activity per loading weight of Pt cocatalyst is significantly improved, 53 times, compared with that of a Pt-cocatalyst loaded photocatalyst by the conventional method. The developed method is also effective to enhance the overall water-splitting activity of other advanced photocatalysts such as SrTiO₃ and BaLa₄Ti₄O₁₅.     

Determination of atomistic deformation of tricalcium silicate paste with high-volume fly ash

We examined the effect of incorporating high-volume fly ash on the atomic arrangement and interatomic deformation behavior of calcium silicate hydrates in tricalcium silicate paste upon exposure to external forces. The interatomic structural changes and strains under compressive load were assessed using synchrotron in situ high-energy X-ray scattering-based atomic pair distribution function analysis. Three different types of strains, which were (a) macroscopic strains from gauges on the surfaces of specimen, (b) strains in a reciprocal space (Bragg peak shift), and (c) strains in real space (PDF peak shift), were compared to each other. All monitored and calculated strains for tricalcium silicate-fly ash (50 wt% fly ash) paste were compared with the counterparts of the pure tricalcium silicate paste. Pair distribution function analysis in the range of r < 10 Å indicated that the atomic arrangement of tricalcium silicate-fly ash was similar to that of synthetic calcium silicate hydrates followed by that of pure tricalcium silicate paste. Moreover, the pair distribution function refinement results revealed that the calcium silicate hydrate structure in tricalcium silicate-fly ash paste was similar to tobermorite 11 Å, unlike that in pure tricalcium silicate paste. The interatomic strain of tricalcium silicate-fly ash in the real space (r < 20 Å) was smaller than that of tricalcium silicate under compression, which suggested that the incompressibility of calcium silicate hydrates at atomistic scale was enhanced by the incorporation of fly ash into it. This was likely to be caused by the increased silicate polymerization of calcium silicate hydrates, which was attributed to the increase in the amount of silicate in their structure via the addition of fly ash.     

Robust Linear Interpolation and Extrapolation of Stationary Time Series in Lp

To deal with uncertainty of the spectral distribution, we consider minimax interpolation and extrapolation problems in L^p for stationary processes. The interpolation and extrapolation problems can be regarded as a linear approximation problem on the unit disk in the complex plane. Although the robust one-step-ahead predictor and interpolator has already been considered separately in the previous literature, we give two conditions for the uncertainty class to find the minimax interpolator and extrapolator in the general framework from both the point of view of the observation set and the point of view of evaluation on the interpolation and extrapolation error under the L^p-norm. We show that there exists a minimax interpolator and extrapolator for the class of spectral densities ε-contaminated by unknown spectral densities under our conditions. When the uncertainty class contains spectral distribution functions which are not absolutely continuous to the Lebesgue measure, we show that there exists an approximate interpolator and extrapolator in L^p such that its maximal interpolation and extrapolation error is arbitrarily close to the minimax error when the spectral distributions have densities. Our results are applicable to the stationary harmonizable stable processes.     

Models for circular data from time series spectra

Circular data are those for which the natural support is the unit circle and its toroidal extensions. Numerous constructions have been proposed which can be used to generate models for such data. We propose a new, very general, one based on the normalization of the spectra of complex-valued stationary processes. As illustrations of the new construction's application, we study models for univariate circular data obtained from the spectra of autoregressive moving average models and relate them to existing models in the literature. We also propose and investigate multivariate circular models obtained from the high-order spectra of stationary stochastic processes generated using linear filtering with an autoregressive moving average response function. A new family of distributions for a Markov process on the circle is also introduced. Results for asymptotically optimal inference for dependent observations on the circle are presented which provide a new paradigm for inference with circular models. The application of one of the new families of spectra-generated models is illustrated in an analysis of wind direction data.     

Indentation-induced ductile behavior of glass–ceramics involving layered aluminosilicates

Contact damage in materials is critical in engineering applications because it influences mechanical resistance, such as wear, erosion, and impact failure. Indentation tests were performed using a tungsten carbide ball indenter (Hertzian contact) on the surfaces of glass–ceramics containing hexagonal CaAl₂Si₂O₈ or mica crystals (fluorophlogopite), both of which have a layered structure. The stress–strain relation and the permanent deformation on the surface, as well as the observation of the microcrack zone by X-ray computed tomography using synchrotron radiation, revealed that the glass–ceramic with hexagonal CaAl₂Si₂O₈ showed ductility similar to the quasi-plastic behavior previously observed in the mica glass–ceramic. The yield stresses of the glass–ceramics were estimated from the stress deviating from the stress–strain relation assuming complete elastic response between the ball and the sample. The ratio of the yield stress to Young modulus (Y/E) of the glass–ceramic with hexagonal CaAl₂Si₂O₈ was determined to be higher than that of the mica glass–ceramic.