In Vivo and In Vitro Pharmacological Studies of Methoxycarbonyl-Carboetomidate

Background—We previously developed two etomidate analogs that retain etomidate’s favorable hemodynamic properties, but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl-etomidate (MOC-etomidate) is rapidly metabolized and ultra-short acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11?-hydroxylase. We hypothesized that MOC-etomidate’s labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of methoxycarbonyl-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a “soft” analog of carboetomidate. Methods—MOC-carboetomidate’s octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate’s EC50 and ED50 for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on gamma-aminobutyric acid A (GABAA) receptor function was assessed using two-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. Results—MOC-carboetomidate’s octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate’s EC50 for LORR in tadpoles was 9 ± 1 µM and its EC50 for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABAA receptor currents by 400 ± 100%. Its metabolic half-life in pooled rat blood was 1.3 minutes. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs. 15 ± 3, respectively; p = 0. 0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. Conclusions—MOC-carboetomidate is a GABAA receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function

Microplasma Processed Ultrathin Boron Nitride Nanosheets for Polymer Nanocomposites with Enhanced Thermal Transport Performance

This Research Article reports on the enhancement of the thermal transport properties of nanocomposite materials containing hexagonal boron nitride in poly(vinyl alcohol) through room-temperature atmospheric pressure direct-current microplasma processing. Results show that the microplasma treatment leads to exfoliation of the hexagonal boron nitride in isopropyl alcohol, reducing the number of stacks from amp;gt;30 to a few or single layers. The thermal diffusivity of the resulting nanocomposites reaches 8.5 mm(2) s(-1) times greater than blank poly(vinyl alcohol) and twice that of nanocomposites containing nonplasma treated boron nitride nanosheets. From TEM analysis, we observe much less aggregation Of the nanosheets after plasma processing along with indications of an amorphous carbon interfacial layer, which may contribute to stable dispersion of boron nitride nanosheets in the resulting plasma treated colloids.Funding Agencies|National Natural Science Foundation of China [51203135, 51173174]; Invest NI PoC award [325]; COST Action [TD1208]; Engineering &amp; Physical Sciences Research Council (EPSRC) [EP/M024938/1, EP/K022237/1]</p

Nano-structured magnetic metamaterial with enhanced nonlinear properties

Nano-structuring can significantly modify the properties of materials. We demonstrate that size-dependent modification of the spin-wave spectra in magnetic nano-particles can affect not only linear, but also nonlinear magnetic response. The discretization of the spectrum removes the frequency degeneracy between the main excitation mode of a nano-particle and the higher spin-wave modes, having the lowest magnetic damping, and reduces the strength of multi-magnon relaxation processes. This reduction of magnon-magnon relaxation for the main excitation mode leads to a dramatic increase of its lifetime and amplitude, resulting in the intensification of all the nonlinear processes involving this mode. We demonstrate this experimentally on a two-dimensional array of permalloy nano-dots for the example of parametric generation of a sub-harmonic of an external microwave signal. The characteristic lifetime of this sub-harmonic is increased by two orders of magnitude compared to the case of a continuous magnetic film, where magnon-magnon relaxation limits the lifetime

Microbes as engines of ecosystem function : When does community structure enhance predictions of ecosystem processes?

FUNDING This work was supported by NSF grant DEB-1221215 to DN, as well as grants supporting the generation of our datasets as acknowledged in their original publications and in Supplementary Table S1. ACKNOWLEDGMENT We thank the USGS Powell Center ‘Next Generation Microbes’ working group, anonymous reviews, Brett Melbourne, and Alan Townsend for valuable feedback on this project.Peer reviewedPublisher PD

More on FOX News: FOXA1 on the horizon of estrogen receptor function and endocrine response

Estrogen receptor α (ER) is a major driver of breast cancer and the target of endocrine therapy. Full disclosure of the cofactors regulating ER interactions with chromatin and its transcriptional regulatory activity is still elusive. Novel genome-wide profiling tools have mapped ER binding events in breast cancer cells and delineated cofactors important in ER activity. Among these, the Forkhead protein FOXA1 is emerging as a key factor dictating global chromatin structure and the transcriptional function of ER in breast and non-breast cancer cells. The significance of FOXA1 in the chromatin interactions and transcriptional regulation of both estrogen- and tamoxifen-bound ER, and in supporting tamoxifen-resistant cell growth, may impact current endocrine therapies

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

An extensible framework for multicore response time analysis

In this paper, we introduce a multicore response time analysis (MRTA) framework, which decouples response time analysis from a reliance on context independent WCET values. Instead, the analysis formulates response times directly from the demands placed on different hardware resources. The MRTA framework is extensible to different multicore architectures, with a variety of arbitration policies for the common interconnects, and different types and arrangements of local memory. We instantiate the framework for single level local data and instruction memories (cache or scratchpads), for a variety of memory bus arbitration policies, including: Round-Robin, FIFO, Fixed-Priority, Processor-Priority, and TDMA, and account for DRAM refreshes. The MRTA framework provides a general approach to timing verification for multicore systems that is parametric in the hardware configuration and so can be used at the architectural design stage to compare the guaranteed levels of real-time performance that can be obtained with different hardware configurations. We use the framework in this way to evaluate the performance of multicore systems with a variety of different architectural components and policies. These results are then used to compose a predictable architecture, which is compared against a reference architecture designed for good average-case behaviour. This comparison shows that the predictable architecture has substantially better guaranteed real-time performance, with the precision of the analysis verified using cycle-accurate simulation

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations