Z-Selectivity in Olefin Metathesis with Chelated Ru Catalysts: Computational Studies of Mechanism and Selectivity

The mechanism and origins of Z-selectivity in olefin metathesis with chelated Ru catalysts were explored using density functional theory. The olefin approaches from the “side” position of the chelated Ru catalysts, in contrast to reactions with previous unchelated Ru catalysts that favor the bottom-bound pathway. Steric repulsions between the substituents on the olefin and the N-substituent on the N-heterocyclic carbene ligand lead to highly selective formation of the Z product

The interaction of core-collapse supernova ejecta with a companion star

The progenitors of many CCSNe are expected to be in binary systems. After the SN explosion, the companion may suffer from mass stripping and be shock heated as a result of the impact of the SN ejecta. If the binary system is disrupted, the companion is ejected as a runaway and hypervelocity star. By performing a series of 3D hydrodynamical simulations of the collision of SN ejecta with the companion star, we investigate how CCSN explosions affect their companions. We use the BEC code to construct the detailed companion structure at the time of SN explosion. The impact of the SN blast wave on the companion is followed by means of 3D SPH simulations using the Stellar GADGET code. For main-sequence (MS) companions, we find that the amount of removed mass, impact velocity, and chemical contamination of the companion that results from the impact of the SN ejecta, strongly increases with decreasing binary separation and increasing explosion energy. Their relationship can be approximately fitted by power laws, which is consistent with the results obtained from impact simulations of SNe~Ia. However, we find that the impact velocity is sensitive to the momentum profile of the outer SN ejecta and, in fact, may decrease with increasing ejecta mass, depending on the modeling of the ejecta. Because most companions to Ib/c CCSNe are in their MS phase at the moment of the explosion, combined with the strongly decaying impact effects with increasing binary separation, we argue that the majority of these SNe lead to inefficient mass stripping and shock heating of the companion star following the impact of the ejecta. Our simulations show that the impact effects of Ib/c SN ejecta on the structure of MS companions, and thus their long-term post-explosion evolution, is in general not dramatic. We find that at most 10% of their mass is lost, and their resulting impact velocities are less than 100 km/s.Comment: Accepted for publication in Astronomy and Astrophysics, some minor typographical errors are fixed, the affiliation of second author is correcte

BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities

BindingDB () is a publicly accessible database currently containing ∼20 000 experimentally determined binding affinities of protein–ligand complexes, for 110 protein targets including isoforms and mutational variants, and ∼11 000 small molecule ligands. The data are extracted from the scientific literature, data collection focusing on proteins that are drug-targets or candidate drug-targets and for which structural data are present in the Protein Data Bank. The BindingDB website supports a range of query types, including searches by chemical structure, substructure and similarity; protein sequence; ligand and protein names; affinity ranges and molecular weight. Data sets generated by BindingDB queries can be downloaded in the form of annotated SDfiles for further analysis, or used as the basis for virtual screening of a compound database uploaded by the user. The data in BindingDB are linked both to structural data in the PDB via PDB IDs and chemical and sequence searches, and to the literature in PubMed via PubMed IDs

Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney.

BackgroundExcess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout.MethodssUA levels, fractional excretion of uric acid (FEUA), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity.ResultsAfter 6 hours, a single 200-mg dose of lesinurad elevated FEUA 3.6-fold (p < 0.001) and reduced sUA levels by 33 % (p < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting.ConclusionThe pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout

Fluctuations of the Condensate in Ideal and Interacting Bose Gases

We investigate the fluctuations of the condensate in the ideal and weakly interacting Bose gases confined in a box of volume V within canonical ensemble. Canonical ensemble is developed to describe the behavior of the fluctuations when different methods of approximation to the weakly interacting Bose gases are used. Research shows that the fluctuations of the condensate exhibit anomalous behavior for the interacting Bose gas confined in a box.Comment: RevTex, 4 Figs,E-mail:[email protected], corrected typo

Lateral Sharpening of Cortical Frequency Tuning by Approximately Balanced Inhibition

SummaryCortical inhibition plays an important role in shaping neuronal processing. The underlying synaptic mechanisms remain controversial. Here, in vivo whole-cell recordings from neurons in the rat primary auditory cortex revealed that the frequency tuning curve of inhibitory input was broader than that of excitatory input. This results in relatively stronger inhibition in frequency domains flanking the preferred frequencies of the cell and a significant sharpening of the frequency tuning of membrane responses. The less selective inhibition can be attributed to a broader bandwidth and lower threshold of spike tonal receptive field of fast-spike inhibitory neurons than nearby excitatory neurons, although both types of neurons receive similar ranges of excitatory input and are organized into the same tonotopic map. Thus, the balance between excitation and inhibition is only approximate, and intracortical inhibition with high sensitivity and low selectivity can laterally sharpen the frequency tuning of neurons, ensuring their highly selective representation

Microbial Resistance Mechanisms to the Antibiotic and Phytotoxin Fusaric Acid

Fusaric acid (FA) produced by Fusarium oxysporum plays an important role in disease development in plants, including cotton. This non-specific toxin also has antibiotic effects on microorganisms. Thus, one expects a potential pool of diverse detoxification mechanisms of FA in nature. Bacteria and fungi from soils infested with Fusarium and from laboratory sources were evaluated for their ability to grow in the presence of FA and to alter the structure of FA into less toxic compounds.None of the bacterial strains were able to chemically modify FA. Highly FA resistant strains were found only in Gram-negative bacteria, mainly in the genus of Pseudomonas. The FA resistance of the Gram-negative bacteria was positively correlated with the number of predicted genes for FA efflux pumps present in the genome. Phylogenetic analysis of predicted FA resistance proteins (FUSC, an inner membrane transporter component of the efflux pump) revealed that FUSC proteins having high sequence identities with the functionally characterized FA resistance protein FusC or Fdt might be the major contributors of FA resistance. In contrast, most fungi converted FA to less toxic compounds regardless of the level of FA resistance they exhibited. Five derivatives were detected, and the detoxification of FA involved either oxidative reactions on the butyl side chain or reductive reactions on the carboxylic acid group. The production of these metabolites from widely different phyla indicates that resistance to FA by altering its structure is highly conserved. A few FA resistant saprophytic or biocontrol strains of fungi were incapable of altering FA, indicating a possible involvement of efflux transporters. Deployment of both efflux and derivatization mechanisms may be a common feature of fungal FA resistance