Determining Interdomain Structure and Dynamics of a Retroviral Capsid Protein in the Presence of Oligomerization: Implication for Structural Transition in Capsid Assembly

Capsid (CA) proteins from all retroviruses, including HIV-1, are structurally homologous dual-domain helical proteins. They form a capsid lattice composed of unitary symmetric CA hexamers. X-ray crystallography has shown that within each hexamer a monomeric CA adopts a single conformation, where most helices are parallel to the symmetry axis. In solution, large differences in averaged NMR spin relaxation rates for the two domains were observed, suggesting they are dynamically independent. One relevant question for the capsid assembly remains: whether the interdomain conformer within a hexamer unit needs to be induced or pre-exists within the conformational space of a monomeric CA. The latter seems more consistent with the relaxation data. However, possible CA protein oligomerization and the structure of each domain will affect relaxation measurements and data interpretation. This study, using CA proteins from equine infectious anemia virus (EIAV) as an example, demonstrates a linear extrapolation approach to obtain backbone ¹⁵N spin relaxation time ratios <i>T</i>₁/<i>T</i>₂ for a monomeric EIAV-CA in the presence of oligomerization equilibrium. The interdomain motion turns out to be limited. The large difference in the domain averaged ⟨<i>T</i>₁/<i>T</i>₂⟩ for a CA monomer is a consequence of the orthogonal distributions of helices in the two domains. The new monomeric interdomain conformation in solution is significantly different from that in CA hexamer. Therefore, if capsid assembly follows a nucleation–propagation process, the interdomain conformational change might be a key step during the nucleation, as the configuration in hexagonal assembly is never formed by diffusion of its two domains in solution

Local climate change governance in China: an analysis of social network and cross-sector collaboration in capacity development

No description supplie

Selective Single C(sp³)–F Bond Cleavage in Trifluoromethylarenes: Merging Visible-Light Catalysis with Lewis Acid Activation

The conversion of easily available trifluoromethylarenes into aryldifluoromethyl compounds, which are valuable motifs in the pharmaceutical chemistry, is highly atom- and step-economical. However, the single C­(sp³)–F bond cleavage of ArCF₃ is a great challenge because of the chemical inertness of the C­(sp³)–F bond and the difficult selectivity control of monodefluorination. We report here the first example of single C­(sp³)–F functionalization of trifluoromethylarenes via visible-light catalysis merged with Lewis acid activation. The method allows good chemoselectivity control and shows good functional group tolerance. Mechanistic studies suggest an in situ-generated borenium cationic species as the key intermediate for C­(sp³)–F bond cleavage in this reaction

Silver-Catalyzed Decarboxylative Remote Fluorination via a Zwitterion-Promoted 1,4-Heteroaryl Migration

A silver-catalyzed decarboxylative remote fluorination via a zwitterion-promoted 1,4-heteroaryl migration has been developed. A variety of heteroaryl-tethered benzyl fluorides have been readily synthesized with good regioselectivity under mild conditions. The zwitterion of the substrate is suggested to accelerate the 1,4-heteroaryl migration, which determines the regioselectivity of this transformation

Efficacy and Safety of Alfuzosin as Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>Alfuzosin has been widely used to treat benign prostatic hyperplasia and prostatitis, and is claimed to be a selective agent for the lower urinary tract with low incidence of adverse side-effects and hypotensive changes. Recently, several randomized controlled trials have reported using Alfuzosin as an expulsive therapy of ureteral stones. Tamsulosin, another alpha blocker, has also been used as an agent for the expulsive therapy for ureteral stones. It is unclear whether alfuzosin has similar efficacy as Tamsulosin in the management of ureteral stones.</p><p>Objective</p><p>To perform a systematic review and analysis of literatures comparing Alfuzosin with Tamsulosin or standard conservative therapy for the treatment of ureteral stones less than 10 mm in diameter.</p><p>Methods</p><p>A systematic literature review was performed in December 2014 using Pubmed, Embase, and the Cochrane library databases to identify relevant studies. All randomized and controlled trials were included. A subgroup analysis was performed comparing Alfuzosin with control therapy on the management of distal ureteral stones.</p><p>Results</p><p>Alfuzosin provided a significantly higher stone-free rate than the control treatments (RR: 1.85; 95% confidence interval [CI], 1.35–2.55; p<0.001), and a shorter stone expulsion time (Weighted mean difference [WMD]: -4.20 d, 95%CI, -6.19 to -2.21; p<0.001), but it has a higher complication rate (RR: 2.02; 95% CI, 1.30–3.15; p<0.01). When Alfuzosin was compared to Tamsulosin, there was no significant difference in terms of stone-free rate (RR: 0.90; 95% CI, 0.79–1.02; p = 0.09) as well as the stone expulsion time (WMD: 0.52 d, 95%CI, -1.61 to 2.64; p = 0.63). The adverse effects of Alfuzosin were similar to those of Tamsulosin (RR: 0.88; 95% CI, 0.61–1.26; p = 0.47).</p><p>Conclusions</p><p>Alfuzosin is a safe and effective agent for the expulsive therapy of ureteral stones smaller than 10 mm in size. It is more effective than therapeutic regiment without alpha blocker. It is equivalent to Tamsulosin in its effectiveness and safety profile. Adverse effects should always be kept in mind when use this class of drugs.</p></div

Effect of Acylated and Nonacylated Anthocyanins on Urine Metabolic Profile during the Development of Type 2 Diabetes in Zucker Diabetic Fatty Rats

The effect of nonacylated and acylated anthocyanins on urinary metabolites in diabetic rats was investigated. Nonacylated anthocyanins extract from bilberries (NAAB) or acylated anthocyanins extract from purple potatoes (AAPP) was given to Zucker diabetic fatty (ZDF) rats for 8 weeks at daily doses of 25 and 50 mg/kg body weight. 1H NMR metabolomics was applied to study alterations in urinary metabolites from three time points (weeks 1, 4, and 8). Both types of anthocyanins modulated the metabolites associated with the tricarboxylic acid cycle, gut microbiota metabolism, and renal function at weeks 1 and 4, such as 2-oxoglutarate, fumarate, alanine, trigonelline, and hippurate. In addition, only a high dose of AAPP decreased monosaccharides, formate, lactate, and glucose levels at week 4, suggesting improvement in energy production in mitochondria, glucose homeostasis, and oxidative stress. This study suggested different impacts of AAPP and NAAB on the metabolic profile of urine in diabetes

Flow diagram for reference search and selection of studies for analysis.

<p>Flow diagram for reference search and selection of studies for analysis.</p

Forest plot of Alfuzosin versus Tamsulosin therapy.

<p>Refer to legend in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134589#pone.0134589.g002" target="_blank">Fig 2</a> for explanation.</p

Forest plot of subgroup analysis categorized by stone locations.

<p>Refer to legend in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134589#pone.0134589.g002" target="_blank">Fig 2</a> for explanation.</p

Funnel plot of Alfuzosin versus control therapy.

<p>Funnel plot for evaluation of publication bias. Vertical solid line represents the logarithmic transformation of the overall estimated treatment effect (ie, log [RR]), diagonal dotted lines represent pseudo–95% confidence limits for estimated treatment effect, and the circles represent treatment effects of each of the 9 studies. In the absence of publication bias, graph should represent a funnel, with individual studies clustered around the overall estimated treatment effect symmetrically.</p