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排序方式: 共有154条查询结果,搜索用时 296 毫秒
51.
Steven T. Staben Nicole Blaquiere Vickie Tsui Aleksandr Kolesnikov Steven Do Erin K. Bradley Jenna Dotson Richard Goldsmith Timothy P. Heffron John Lesnick Cristina Lewis Jeremy Murray Jim Nonomiya Alan G. Olivero Jodie Pang Lionel Rouge Laurent Salphati BinQing Wei Ping Wu 《Bioorganic & medicinal chemistry letters》2013,23(3):897-901
Substructural class effects surrounding replacement of a ‘cis’ N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability. 相似文献
52.
Yi CH Pan H Seebacher J Jang IH Hyberts SG Heffron GJ Vander Heiden MG Yang R Li F Locasale JW Sharfi H Zhai B Rodriguez-Mias R Luithardt H Cantley LC Daley GQ Asara JM Gygi SP Wagner G Liu CF Yuan J 《Cell》2011,146(4):607-620
Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation. 相似文献
53.
Molecular phylogeny of Neotropical bioluminescent beetles (Coleoptera: Elateroidea) in southern and central Brazil 下载免费PDF全文
Bioluminescence in beetles is found mainly in the Elateroidea superfamily (Elateridae, Lampyridae and Phengodidae). The Neotropical region accounts for the richest diversity of bioluminescent species in the world with about 500 described species, most occurring in the Amazon, Atlantic rainforest and Cerrado (savanna) ecosystems in Brazil. The origin and evolution of bioluminescence, as well as the taxonomic status of several Neotropical taxa in these families remains unclear. In order to contribute to a better understanding of the phylogeny and evolution of bioluminescent Elateroidea we sequenced and analyzed sequences of mitochondrial NADH2 and the nuclear 28S genes and of the cloned luciferase sequences of Brazilian species belonging to the following genera: (Lampyridae) Macrolampis, Photuris, Amydetes, Bicellonycha, Aspisoma, Lucidota, Cratomorphus; (Elateridae) Conoderus, Pyrophorus, Hapsodrilus, Pyrearinus, Fulgeochlizus; and (Phengodidae) Pseudophengodes, Phrixothrix, Euryopa and Brasilocerus. Our study supports a closer phylogenetic relationship between Elateridae and Phengodidae as other molecular studies, in contrast with previous morphologic and molecular studies that clustered Lampyridae/Phengodidae. Molecular data also supported division of the Phengodinae subfamily into the tribes Phengodini and Mastinocerini. The position of the genus Amydetes supports the status of the Amydetinae as a subfamily. The genus Euryopa is included in the Mastinocerini tribe within the Phengodinae/Phengodidae. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
54.
Philip W Fowler Murali K Bollepalli Markus Rapedius Ehsan Nematian-Ardestani Lijun Shang Mark SP Sansom Stephen J Tucker Thomas Baukrowitz 《Channels (Austin, Tex.)》2014,8(6):551-555
In a previous study we identified an extensive gating network within the inwardly rectifying Kir1.1 (ROMK) channel by combining systematic scanning mutagenesis and functional analysis with structural models of the channel in the closed, pre-open and open states. This extensive network appeared to stabilize the open and pre-open states, but the network fragmented upon channel closure. In this study we have analyzed the gating kinetics of different mutations within key parts of this gating network. These results suggest that the structure of the transition state (TS), which connects the pre-open and closed states of the channel, more closely resembles the structure of the pre-open state. Furthermore, the G-loop, which occurs at the center of this extensive gating network, appears to become unstructured in the TS because mutations within this region have a ‘catalytic’ effect upon the channel gating kinetics. 相似文献
55.
S. Aydin H Ozercan F. Dagli S. Aydin O. Dogru S. Celebi O. Akin SP Guzel 《Biotechnic & histochemistry》2005,80(3):163-168
Ghrelin (G-HH) synthesized in several tissues including salivary and stomach glands stimulates appetite in humans by modulating neuropeptide Y neurons in the hypothalamic arcuate nucleus. Loss of appetite is one of the most important symptoms of stomach cancer. We conducted a study using immunohistochemistry to determine whether salivary glands and stomach cancer tissues produce ghrelin. We determined that negative ghrelin immunohistochemistry discriminates tumors from normal tissues and may therefore further our understanding of the clinically important problem of reduced food intake and anorexia in cancer patients. Radioimmunoassay analyses confirmed that cancer cells do not produce a G-HH peptide, whereas normal cells yield this peptide. 相似文献
56.
Heffron JK Moerland TS 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2008,150(3):339-346
The Atlantic stingray, Dasyatis sabina found along the Gulf of Mexico and southeastern Atlantic coasts, is a euryhaline species of elasmobranch. This species is able to osmotically compensate for changing environmental salinity by altering plasma and intracellular solutes, including urea and counteracting methylamines (betaine and TMAO). Parvalbumin (PV) is an intracellular protein that facilitates muscle relaxation by sequestering calcium. Determining the effects that in situ concentrations of urea (146 mM), betaine (62 mM), and TMAO (11 mM) have on PV function in marine and freshwater adapted populations of D. sabina could provide insight into intracellular correlates of euryhaline tolerance for this species. PV from marine and freshwater populations of D. sabina was identified and purified by SDS-PAGE, western blot analysis, and full amino acid sequence analysis. Both populations exhibited two PV isoforms, PV I (approximately 12.18 kDa mw) and PV II (11.96 kDa mw). PV dissociation constants (K(D)) were determined in the presence and absence of physiological concentrations of urea, betaine, and TMAO by fluorescence spectroscopy using the fluorescent Ca(2+) indicator fluo-3 which competes with PV for Ca(2+). Functional studies revealed PV I showed no significant changes in calcium binding from in situ muscle conditions, except in the presence of betaine. In contrast, PV II's ability to bind calcium was increased relative to physiological conditions in the presence of each osmolyte independently. Thus, it appears that organic osmolytes have isoform specific effects on PV function. 相似文献
57.
In vivo analysis of the Saccharomyces cerevisiae HO nuclease recognition site by site-directed mutagenesis. 总被引:5,自引:6,他引:5 下载免费PDF全文
HO nuclease introduces a specific double-strand break in the mating-type locus (MAT) of Saccharomyces cerevisiae, initiating mating-type interconversion. To define the sequence recognized by HO nuclease, random mutations were produced in a 30-base-pair region homologous to either MAT alpha or MATa by a chemical synthesis procedure. The mutant sites were introduced into S. cerevisiae on a shuttle vector and tested for the ability to stimulate recombination in an assay that mimics mating-type interconversion. The results suggest that a core of 8 noncontiguous bases near the Y-Z junction of MAT is essential for HO nuclease to bind and cleave its recognition site. Other contacts must be required because substrates that contain several mutations outside an intact core reduce or eliminate cleavage in vivo. The results show that HO site recognition is a complex phenomenon, similar to promoter-polymerase interactions. 相似文献
58.
The Neisseria meningitidis haemoglobin receptor: its role in iron utilization and virulence 总被引:24,自引:8,他引:16
Igor Stojijkovic Vivian Hwa Luc de Saint Martin Peadar O'Gaora Xavier Nassif Fred Heffron Magdalene So 《Molecular microbiology》1995,15(3):531-541
The Neisseris meningitidis haemoglobin receptor gene, hmbR, was cloned by complementation in a porphyrin-requiring Escherichia coli mutant. hmbR encodes an 89.5 kDa outer membrane protein which shares amino acid homology with the TonB-dependent receptors of Gram-negative bacteria. HmbR had the highest similarity to Neisseria transferrin and lactoferrin receptors. The utilization of haemoglobin as an iron source required internalization of the haemin moiety by the cell. The mechanism of haemin internalization via the haemoglobin receptor was TonB-dependent in E. coli. A N. meningitidis hmbR mutant was unable to use haemoglobin but could still use haemin as a sole iron source. The existence of a second N. meningitidis receptor gene, specific for haemin, was shown by the isolation of cosmids which did not hybridize with the hmbR probe, but which were able to complement an E. coli hemA aroB mutant on haemin-supplemented plates. The N. meningitidis hmbR mutant was attenuated in an infant rat model for meningococcal infection, indicating that haemoglobin utilization is important for N. meningitidis virulence. 相似文献
59.
A site-specific endonuclease essential for mating-type switching in Saccharomyces cerevisiae 总被引:55,自引:0,他引:55
We have detected two site-specific endonucleases in strains of Saccharomyces cerevisiae. One endonuclease, which we call YZ endo, is present only in yeast strains that are undergoing mating-type interconversion. The site at which YZ endo cleaves corresponds to the in vivo double-strand break occurring at the mating-type locus in yeast undergoing mating-type interconversion. YZ endo generates a site-specific double-strand break having 4-base 3' extensions terminating in 3' hydroxyl groups. The site of cleavage occurs in the Z1 region near the YZ junction of the mating-type locus. Mutant mating-type loci known to decrease the frequency of mating-type interconversion are correspondingly poor substrates for YZ endo in vitro. In vitro analysis of a number of such altered recognition sites has delimited the sequences required for cleavage. The molecular genetics of mating-type interconversion is discussed in the context of this endonucleolytic activity. The second endonuclease, which we refer to as Sce II, is present in all strains of S. cerevisiae we have examined. The cleavage site of Sce II has been determined and proves to be unrelated to the cleavage site of YZ endo. 相似文献
60.
Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. 总被引:10,自引:0,他引:10 下载免费PDF全文
B M Manning K A Quane H Ording A Urwyler V Tegazzin M Lehane J O'Halloran E Hartung L M Giblin P J Lynch P Vaughan K Censier D Bendixen G Comi L Heytens K Monsieurs T Fagerlund W Wolz J J Heffron C R Muller T V McCarthy 《American journal of human genetics》1998,62(3):599-609
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype. 相似文献