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991.
Laura J. Mares Alvaro Garcia Helge H. Rasmussen Flemming Cornelius Yasser A. Mahmmoud Joshua R. Berlin Bogdan Lev Toby W. Allen Ronald J. Clarke 《Biophysical journal》2014
The charge-transporting activity of the Na+,K+-ATPase depends on its surrounding electric field. To isolate which steps of the enzyme’s reaction cycle involve charge movement, we have investigated the response of the voltage-sensitive fluorescent probe RH421 to interaction of the protein with BTEA (benzyltriethylammonium), which binds from the extracellular medium to the Na+,K+-ATPase’s transport sites in competition with Na+ and K+, but is not occluded within the protein. We find that only the occludable ions Na+, K+, Rb+, and Cs+ cause a drop in RH421 fluorescence. We conclude that RH421 detects intramembrane electric field strength changes arising from charge transport associated with conformational changes occluding the transported ions within the protein, not the electric fields of the bound ions themselves. This appears at first to conflict with electrophysiological studies suggesting extracellular Na+ or K+ binding in a high field access channel is a major electrogenic reaction of the Na+,K+-ATPase. All results can be explained consistently if ion occlusion involves local deformations in the lipid membrane surrounding the protein occurring simultaneously with conformational changes necessary for ion occlusion. The most likely origin of the RH421 fluorescence response is a change in membrane dipole potential caused by membrane deformation. 相似文献
992.
993.
Brooks SA Makvandi-Nejad S Chu E Allen JJ Streeter C Gu E McCleery B Murphy BA Bellone R Sutter NB 《Animal genetics》2010,41(Z2):159-165
Horses, like many domesticated species, have been selected for broad variation in skeletal size. This variation is not only an interesting model of rapid evolutionary change during domestication, but is also directly applicable to the horse industry. Breeders select for complex traits like body size and skeletal conformation to improve marketability, function, soundness and performance in the show ring. Using a well-defined set of 35 measurements, we have identified and quantified skeletal variation in the horse species. We collected measurements from 1215 horses representing 65 breeds of diverse conformation such as the American Miniature, Shetland Pony, Arabian Horse, Thoroughbred, Shire and Clydesdale. Principal components analysis has identified two key dimensions of skeletal variation in the horse. Principal component 1 is positively correlated with every measurement and quantifies overall body size. Principal component 2 captures a pattern of bone widths vs. lengths and thus quantifies variation in overall bone thickness. By defining these complex skeletal traits, we have created a framework for whole genome association studies to identify quantitative trait loci that contribute to this variation. 相似文献
994.
Richard E. Baird Phillip A. Wadl Thomas Allen David McNeill Xinwang Wang John K. Moulton Timothy A. Rinehart Hamed K. Abbas Thomas Shier Robert N. Trigiano 《Mycopathologia》2010,170(3):169-180
Twelve simple sequence repeat (SSRs) loci were used to evaluate genetic diversity of 109 isolates of Macrophomina phaseolina collected from different geographical regions and host species throughout the United States (US). Genetic diversity was assessed using Nei’s minimum genetic distance, and the usefulness of each locus was determined by calculating the polymorphism information content (PIC). A total of 98 alleles were detected and of these 31 were unique to individual genotypes. Eight of twelve loci were highly informative with PIC values greater than 0.50. The majority of pairwise comparisons of genetic distance were greater than 0.60 indicating moderate to high genetic diversity. Dendrograms based on the genetic dissimilarities were created for the 109 isolates of which 79 were from soybean. Some clustering by host and geography was noted, but, the dendrograms generally grouped isolates independent of host or geography. Additionally, sequencing of the internal transcribed spacer region (ITS) for 10 isolates revealed that all of these isolates were 99% similar. Three SSR loci from M. phaseolina were cross amplified in other genera in the Botryosphaeriaceae. This was the first study of genotyping and assessing genetic diversity of M. phaseolina isolates collected from a widespread host and geographic range across the US with SSRs. With an additional 34 loci publically available for M. phaseolina, the results indicate that previously developed SSRs from one species can be used in future population, ecological, and genetic studies of M. phaseolina and other genera within the Botryosphaeriaceae. 相似文献
995.
Andrea Trevino Todd P. Coleman Jont Allen 《Journal of computational neuroscience》2010,29(1-2):193-201
In this paper, we develop a dynamical point process model for how complex sounds are represented by neural spiking in auditory nerve fibers. Although many models have been proposed, our point process model is the first to capture elements of spontaneous rate, refractory effects, frequency selectivity, phase locking at low frequencies, and short-term adaptation, all within a compact parametric approach. Using a generalized linear model for the point process conditional intensity, driven by extrinsic covariates, previous spiking, and an input-dependent charging/discharging capacitor model, our approach robustly captures the aforementioned features on datasets taken at the auditory nerve of chinchilla in response to speech inputs. We confirm the goodness of fit of our approach using the Time-Rescaling Theorem for point processes. 相似文献
996.
Thomas P. Matthews Tatiana McHardy Suki Klair Kathy Boxall Martin Fisher Michael Cherry Charlotte E. Allen Glynn J. Addison John Ellard G. Wynne Aherne Isaac M. Westwood Rob van Montfort Michelle D. Garrett John C. Reader Ian Collins 《Bioorganic & medicinal chemistry letters》2010,20(14):4045-4049
A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold. 相似文献
997.
Manisha Sathe Mariliza Derveni Marjorie Allen David C. Cullen 《Bioorganic & medicinal chemistry letters》2010,20(5):1792-1795
Polystyrene-supported 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (PS-IIDQ), a polymer-supported covalent coupling reagent, was successfully employed for the first time in the bioconjugation of an example hapten (phytanic acid derivative) to a carrier protein (bovine serum albumin (BSA)) within the context of immunogen preparation for antibody development. The ability of the prepared example phytanic acid derivative–BSA conjugate to bind an anti-phytanic acid antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA). 相似文献
998.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
999.
Douglas B. Craig Allison M. Haslam Harlyn J. Silverstein Miki Chikamatsu Elnaz Shadabi Ellert R. Nichols 《The protein journal》2010,29(6):398-406
Single enzyme molecule assays were performed using capillary electrophoresis-based protocols on β-galactosidase from Lactobacillus delbrueckii, Lactobacillus reuteri, Lactobacillus helveticus
and Bacillus circulans. The enzyme was found to show static heterogeneity with respect to catalytic rate and the variance in rate increased with
protein size. This is consistent with the proposal that random errors in translation may be an important underlying component
of enzyme heterogeneity. Additionally these enzymes were found to show static heterogeneity with respect to electrophoretic
mobility. Comparison of wild-type and rpsL E. coli β-galactosidase expressed in the presence and absence of streptomycin suggested that increases in error do not result in
detectable increases in the dynamic heterogeneity of activity with increasing temperature. Finally, a method was developed
to measure the dynamic heterogeneity in electrophoretic mobility. 相似文献
1000.
Xunbao Duan Steve G. Kelsen Allen B. Clarkson Jr Rong Ji Salim Merali 《Proteomics》2010,10(11):2165-2174
To better understand lung oxidant stress responses, we examined A549 lung cells exposed to H2O2 using “stable isotope labeling by amino acids.” We identified 466 cytosolic and 387 nuclear proteins; H2O2 exposure produced ≥twofold differences in 31, all were downregulations. None were previously reported as oxidant stress response proteins, although they share common functions. One of the responders, treacle, was linked to p53, an important oxidative stress response. The Treacher Collins–Franceschetti syndrome can result from treacle mutation and insufficiency was suggested to cause increased p53 leading to the syndrome. However, results here indicate p53 and treacle responses to H2O2 are independent: treacle remains suppressed after p53 recovery; the threshold for treacle reduction is well above that for p53 induction; and treacle suppression by short interfering RNA does not modify the p53 response. Evidence of treacle antioxidant activity include reduction being driven by proteasome degradation independently of mRNA, typical for oxidant‐absorbing proteins, and increased sensitivity to H2O2 consequent to short interfering RNA suppression. Data here show a link between oxidative stress and treacle reduction, demonstrate that treacle does not control p53, provide evidence of a treacle oxidant defense role, support the hypothesis that oxidant stress plays a role in the Treacher Collins–Franceschetti syndrome, and raise the possibility that treacle plays an anti‐oxidant role in lungs. 相似文献