Ruthenium(II)-Catalyzed Synthesis of Hydroxylated Arenes with Ester as an Effective Directing Group

An unprecedented Ru(II) catalyzed <i>ortho</i>-hydroxylation has been developed for the facile synthesis of a variety of multifunctionalized arenes from easily accessible ethyl benzoates with ester as an efficient directing group. Both the TFA/TFAA cosolvent system and oxidants serve as the critical success factors in this transformation. The reaction demonstrates excellent reactivity, good functional group tolerance, and high yields

SnO₂@C@VO₂ Composite Hollow Nanospheres as an Anode Material for Lithium-Ion Batteries

Porous SnO₂@C@VO₂ composite hollow nanospheres were ingeniously constructed through the combination of layer-by-layer deposition and redox reaction. Moreover, to optimize the electrochemical properties, SnO₂@C@VO₂ composite hollow nanospheres with different contents of the external VO₂ were also studied. On the one hand, the elastic and conductive carbon as interlayer in the SnO₂@C@VO₂ composite can not only buffer the huge volume variation during repetitive cycling but also effectively improve electronic conductivity and enhance the utilizing rate of SnO₂ and VO₂ with high theoretical capacity. On the other hand, hollow nanostructures of the composite can be consolidated by the multilayered nanocomponents, resulting in outstanding cyclic stability. In virtue of the above synergetic contribution from individual components, SnO₂@C@VO₂ composite hollow nanospheres exhibit a large initial discharge capacity (1305.6 mAhg^–1) and outstanding cyclic stability (765.1 mAhg^–1 after 100 cycles). This design of composite hollow nanospheres may be extended to the synthesis of other nanomaterials for electrochemical energy storage

Folding-Degradation Relationship of a Membrane Protein Mediated by the Universally Conserved ATP-Dependent Protease FtsH

ATP-dependent protein degradation mediated by AAA+ proteases is one of the major cellular pathways for protein quality control and regulation of functional networks. While a majority of studies of protein degradation have focused on water-soluble proteins, it is not well understood how membrane proteins with abnormal conformation are selectively degraded. The knowledge gap stems from the lack of an in vitro system in which detailed molecular mechanisms can be studied as well as difficulties in studying membrane protein folding in lipid bilayers. To quantitatively define the folding-degradation relationship of membrane proteins, we reconstituted the degradation using the conserved membrane-integrated AAA+ protease FtsH as a model degradation machine and the stable helical-bundle membrane protein GlpG as a model substrate in the lipid bilayer environment. We demonstrate that FtsH possesses a substantial ability to actively unfold GlpG, and the degradation significantly depends on the stability and hydrophobicity near the degradation marker. We find that FtsH hydrolyzes 380–550 ATP molecules to degrade one copy of GlpG. Remarkably, FtsH overcomes the dual-energetic burden of substrate unfolding and membrane dislocation with the ATP cost comparable to that for water-soluble substrates by robust ClpAP/XP proteases. The physical principles elucidated in this study provide general insights into membrane protein degradation mediated by ATP-dependent proteolytic systems

Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of <i>Plasmodium falciparum</i> (<i>Pf</i>NDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of <i>Plasmodium falciparum</i> (<i>Pf</i>NDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on <i>Pf</i>NDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the <i>Pf</i>NDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The <i>Pf</i>NDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial <i>Pf</i>NDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as <i>Mycobacterium tuberculosis</i>

Kaplan-Meier survival curves by timing of maternal ARV initiation.

<p>Kaplan-Meier survival curves by timing of maternal ARV initiation.</p

Factors associated with MTCT (n = 1452)^*.

<p>Factors associated with MTCT (n = 1452)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138104#t003fn001" target="_blank">^*</a>.</p

Description of women is study sample (n = 1548).

<p>Description of women is study sample (n = 1548).</p

Factors associated with infant mortality (n = 1553).

<p>Factors associated with infant mortality (n = 1553).</p

Factors associated with late initiation of maternal ARV.

<p>Factors associated with late initiation of maternal ARV.</p

A Novel TGR5 Activator WB403 Promotes GLP-1 Secretion and Preserves Pancreatic β-Cells in Type 2 Diabetic Mice

<div><p>The G protein-coupled receptor TGR5 is a membrane receptor for bile acids. Its agonism increases energy expenditure and controls blood glucose through secretion of glucagon-like peptide-1 in enteroendocrine cells. In this study, we explored the therapeutic potential of WB403, a small compound activating TGR5 which was identified by combining TGR5 targeted luciferase assay and active GLP-1 assay, in treating type 2 diabetes. After confirmation of TGR5 and GLP-1 stimulating activities in various cell systems, WB403 was examined in oral glucose tolerance test, and tested on different mouse models of type 2 diabetes for glycemic control and pancreatic β-cell protection effect. As a result, WB403 exhibited a moderate TGR5 activation effect while promoting GLP-1 secretion efficiently. Interestingly, gallbladder filling effect, which was reported for some known TGR5 agonists, was not detected in this novel compound. <i>In vivo</i> results showed that WB403 significantly improved glucose tolerance and decreased fasting blood glucose, postprandial blood glucose and HbA1c in type 2 diabetic mice. Further analysis revealed that WB403 increased pancreatic β-cells and restored the normal distribution pattern of α-cell and β-cell in islets. These findings demonstrated that TGR5 activator WB403 effectively promoted GLP-1 release, improved hyperglycemia and preserved the mass and function of pancreatic β-cells, whereas it did not show a significant side effect on gallbladder. It may represent a promising approach for future type 2 diabetes mellitus drug development.</p></div