Martinladefoged5051

In both models, treatment with 30mg/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was due to cholestasis-independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP-305 at therapeutic doses promoted ductular proliferation in healthy mice and favored differentiation of primary HPC towards cholangiocyte lineage in vitro. CONCLUSIONS EDP-305 potently improved pre-established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP-305 in fibrotic liver diseases including cholangiopathies and NASH. This article is protected by copyright. All rights reserved.A concise and asymmetric total synthesis of five kopsane alkaloids which share a unique heptacyclic caged ring system was accomplished. The key transformation in our sequence involved a remarkable PtCl 2 catalyzed intramolecular [3+2] cycloaddition, which allowed for the rapid assembly of pentacyclic carbon skeletons bearing 2,3-quaternary functionalized indoline. Expeditious construction of diverse indoline scaffolds with excellent control of diastereoselectivity demonstrated the broad scope and versatility of this key transformation. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.We present for the first time how transient changes in the coordination number of zinc ion affects the rate determining step in the enzyme human carbonic anhydrase (HCA) II. The latter involves an intramolecular proton transfer between a zinc-bound water and a distant histidine residue (His-64). In the absence of time-resolved experiments, results from classical and QM-MM molecular dynamics and transition path sampling simulations are presented. The catalytic zinc ion is found to be present in two possible coordination states; viz. a stable tetra-coordinated state, T and a less stable penta-coordinated state, P with tetrahedral and trigonal bipyramidal coordination geometries, respectively. A fast dynamical inter-conversion occurs between T and P along due to  reorganization of active site water molecules making the zinc ion more positively charged in state P. When initiated from different coordination environments, the most probable mechanism of proton transfer is found to be deprotonation of the equatorial water molecule from state P and transfer of the excess proton via a short path formed by hydrogen bonded network of active site water molecules. We estimate the rate constant of proton transfer as kP = 1.29 X 10 6 s -1 from P and kT = 437 X10 4 s -1 from T. A quantitative match of estimated kP with the experimental value, (kexp ~ 0.8 X10 6 s -1 ) suggests that  dynamics of Zn coordination triggers the rate determining proton transfer step in HCA II. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.The stability of luminescent materials is a key factor for the practical application in white light-emitting diodes (LEDs). Poor chemical stability of narrow-band green-emitting RbLi(Li 3 SiO 4 ) 2 Eu 2+ (RLSOEu 2+ ) phosphor hinders its further commercialization even if it possesses excellent stability against thermal quenching. Herein, we propose an efficient protection scheme by combining the surface coating of amorphous Al 2 O 3 and hydrophobic modification by octadecyltrimethoxysilane (ODTMS) to construct the moisture-resistant dual-shelled RLSOEu 2+ @Al 2 O 3 @ODTMS composite. The growth mechanisms of both Al 2 O 3 inorganic layer and silane organic layer on the phosphor surface are investigated, which can remarkably improve the water-stability of this narrow-band green emitter. The evaluation result of the white LED by employing this composite as green component demonstrates that RLSOEu 2+ @Al 2 O 3 @ODTMS is a promising candidate for the high-performance display backlights, and this dual-shelled strategy provides an alternative method to improve the moisture-resistant property of humidity-sensitive phosphors. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.An unprecedented cationic supramolecule [(CpFe(η5- P5))12CuNCMe8]8+ of 2.66 nm in diameter was selectively isolated as a salt of the weakly coordinating anion [AlOC(CF3)34]- for the first time and characterized by X-ray structure analysis, PXRD, NMR spectroscopy and mass spectrometry. Its metal-deficient core contains the lowest possible number of Cu atoms to connect 12 pentaphosphaferrocene units providing a supramolecule with fullerene topology which, topologically, also represents the simplest homologue in the family of metal-deficient pentaphosphaferrocenebased supramolecules [CpRFe(η5-P5)12(CuX)20-n]. The largest so far attainable 12 vacant metal sites between cyclo-P5 rings make this compound a facile precursor for potential inner and outer modifications of the core as well as for the functionalization via the substitution of labile acetonitrile ligands. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Superstructures have attracted extensive attention because of their potential applications in materials science and biology. Herein, we fabricate the first centimeter-sized porous superstructure of carbon nanosheets (SCNS) by using metal-organic framework (MOF) nanoparticles as a template and polyvinylpyrrolidone as an additional carbon source. The SCNS shows an obviously honeycomb-like morphology with wall-sharing carbon cages, in each cavity of which a porous carbon sphere is encapsulated. A single piece of SCNS is directly used as the electrode for a two-electrode symmetrical supercapacitor cell without any binders and supports, benefiting from its advantage in ultra-large geometric size, and the Fe-immobilized SCNS exhibits excellent catalytic performances for oxygen reduction reaction and Zn-air battery. This synthetic strategy presents a facile approach to prepare functional SCNS at centimetric scale with controllable morphologies and compositions favoring the fabrication of energy devices. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.BACKGROUND For public health policies to be effective, it is critical that they are acceptable to the public as acceptance levels impact success rate. OBJECTIVE To explore public acceptance of public health statements and examine differences in acceptability across socio-demographics, health behaviours (physical activity, diet, binge drinking and smoking), health status and well-being. APX-115 molecular weight METHOD A cross-sectional survey was conducted with a nationally representative sample (N = 1001) using a random stratified sampling method. Face-to-face interviews were conducted at homes of residents in Wales aged 16+ years. Individuals reported whether they agreed, had no opinion, or disagreed with 12 public health statements. RESULTS More than half of the sample were supportive of 10 out of 12 statements. The three statements with the greatest support (>80% agreement) reflected the importance of a safe and loving childhood to becoming a healthy adult, schools teaching about health, and healthier foods costing less. Individuals who engaged in unhealthy behaviours were less likely to agree with some of the statements (eg 39.