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11.
Allosteric activation mechanism of the alpha1beta2gamma2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine 下载免费PDF全文
A conserved leucine residue in the midpoint of the second transmembrane domain (M2) of the ligand-activated ion channel family has been proposed to play an important role in receptor activation. In this study, we assessed the importance of this leucine in the activation of rat alpha1beta2gamma2 GABA receptors expressed in Xenopus laevis oocytes by site-directed mutagenesis and two-electrode voltage clamp. The hydrophobic conserved M2 leucines in alpha1(L263), beta2(L259), and gamma2(L274) subunits were mutated to the hydrophilic amino acid residue serine and coexpressed in all possible combinations with their wild-type and/or mutant counterparts. The mutation in any one subunit decreased the EC(50) and created spontaneous openings that were blocked by picrotoxin and, surprisingly, by the competitive antagonist bicuculline. The magnitudes of the shifts in GABA EC(50) and picrotoxin IC(50) as well as the degree of spontaneous openings were all correlated with the number of subunits carrying the leucine mutation. Simultaneous mutation of the GABA binding site (beta2Y157S; increased the EC(50)) and the conserved M2 leucine (beta2L259S; decreased the EC(50)) produced receptors with the predicted intermediate agonist sensitivity, indicating the two mutations affect binding and gating independently. The results are discussed in light of a proposed allosteric activation mechanism. 相似文献
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S Patyar R Joshi DS Prasad Byrav A Prakash B Medhi BK Das 《Journal of biomedical science》2010,17(1):21
Resistance to conventional anticancer therapies in patients with advanced solid tumors has prompted the need of alternative
cancer therapies. Moreover, the success of novel cancer therapies depends on their selectivity for cancer cells with limited
toxicity to normal tissues. Several decades after Coley's work a variety of natural and genetically modified non-pathogenic
bacterial species are being explored as potential antitumor agents, either to provide direct tumoricidal effects or to deliver
tumoricidal molecules. Live, attenuated or genetically modified non-pathogenic bacterial species are capable of multiplying
selectively in tumors and inhibiting their growth. Due to their selectivity for tumor tissues, these bacteria and their spores
also serve as ideal vectors for delivering therapeutic proteins to tumors. Bacterial toxins too have emerged as promising
cancer treatment strategy. The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy.
Although it has shown successful results in vivo yet further investigation about the targeting mechanisms of the bacteria are required to make it a complete therapeutic approach
in cancer treatment. 相似文献
14.
Phylogenetic evidence for horizontal transmission of group I introns in the nuclear ribosomal DNA of mushroom-forming fungi 总被引:7,自引:3,他引:4
Group I introns were discovered inserted at the same position in the
nuclear small-subunit ribosomal DNA (nuc-ssu-rDNA) in several species of
homobasidiomycetes (mushroom-forming fungi). Based on conserved intron
sequences, a pair of intron-specific primers was designed for PCR
amplification and sequencing of intron-containing rDNA repeats. Using the
intron-specific primers together with flanking rDNA primers, a PCR assay
was conducted to determine presence or absence of introns in 39 species of
homobasidiomycetes. Introns were confined to the genera Panellus,
Clavicorona, and Lentinellus. Phylogenetic analyses of nuc-ssu-rDNA and
mitochondrial ssu-rDNA sequences suggest that Clavicorona and Lentinellus
are closely related, but that Panellus is not closely related to these. The
simplest explanation for the distribution of the introns is that they have
been twice independently gained via horizontal transmission, once on the
lineage leading to Panellus, and once on the lineage leading to Lentinellus
and Clavicorona. BLAST searches using the introns from Panellus and
Lentinellus as query sequences retrieved 16 other similar group I introns
of nuc-ssu-rDNA and nuclear large-subunit rDNA (nuc-lsu-rDNA) from fungal
and green algal hosts. Phylogenetic analyses of intron sequences suggest
that the mushroom introns are monophyletic, and are nested within a clade
that contains four other introns that insert at the same position as the
mushroom introns, two from different groups of fungi and two from green
algae. The distribution of host lineages and insertion sites among the
introns suggests that horizontal and vertical transmission, homing, and
transposition have been factors in intron evolution. As distinctive,
heritable features of nuclear rDNAs in certain lineages, group I introns
have promise as phylogenetic markers. Nevertheless, the possibility of
horizontal transmission and homing also suggest that their use poses
certain pitfalls.
相似文献
15.
Objective: The objective was to examine the role of total and beverage‐specific alcohol consumption on the incidence of type 2 diabetes mellitus (DM) among elderly men and women. Research Methods and Procedures: We studied prospectively 4655 participants of the Cardiovascular Health Study who were free of DM at baseline. Alcohol consumption was obtained at baseline and during follow‐up examinations. DM was defined using fasting glucose and/or use of hypoglycemic medications. We used Cox proportional hazard models to estimate adjusted relative risks of diabetes across alcohol categories. Results: During a mean follow‐up of 6.3 years, 234 incident cases of DM were documented. Compared with never drinkers, hazard ratios [95% confidence interval (CI)] for DM were 0.7 (0.3 to 1.4), 0.5 (0.3 to 0.9), 0.6 (0.4 to 1.1), and 0.8 (0.4 to 1.3) for former drinkers and current drinkers of <1, 1 to 6, and 7+ drinks per week, respectively, for men after adjustment for age, BMI, education, and smoking. Corresponding values for women were 1.2 (0.6 to 2.3), 0.7 (0.4 to 1.1), 0.6 (0.3 to 1.1), and 0.4 (0.2 to 1.0), respectively. A reduced risk of DM was observed with all types of beverage consumed. Similar findings were observed when we repeated the above analyses using simple or weighted cumulative alcohol update and covariates over time. Discussion: Light to moderate alcohol consumption was associated with a lower incidence of DM among elderly people, irrespective of the type of beverage consumed. 相似文献
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Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M. Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A. Enquobahrie James B. Meigs Pui Kwok Marie-France Hivert Ingrid B. Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I. Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S. Siscovick 《PLoS genetics》2015,11(10)
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits'' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits. 相似文献
17.
Repeated evolution of an acetate-crossfeeding polymorphism in long-term populations of Escherichia coli 总被引:1,自引:0,他引:1
Six out of 12 independent replicate populations of Escherichia coli
maintained in long-term glucose-limited continuous culture for up to
approximately 1,750 generations evolve polymorphisms maintained by acetate
crossfeeding. In all cases, the acetate-crossfeeding phenotype is
associated with semiconstitutive overexpression of acetyl CoA synthetase,
which allows for the enhanced uptake of low levels of exogenous acetate.
Mutations in the 5' regulatory region of the acetyl CoA synthetase locus
are responsible for all the acetate crossfeeding phenotypes found. These
changes were either transposable-element insertions or a single T-->A
nucleotide substitution at position -93 relative to the acs gene
translation start site.
相似文献
18.
Parent presence, delayed dispersal, and territory acquisition in the Seychelles warbler 总被引:1,自引:0,他引:1
The presence of parents in the natal territory may play an important,but often overlooked, role in natal dispersal and the consequentacquisition of a territory. Living with parents in a territorymay confer a fitness advantage to subordinates through, forexample, the nepotistic behavior of the parents or indirectbenefits gained by helping to raise nondescendent kin. Whena parent is replaced by a stepparent, such advantages are reducedor disappear and, as a result, subordinates may disperse. Subordinatesthat disperse after parent replacement may be constrained intheir timing of dispersal, which could have negative fitnessconsequences. In the cooperatively breeding Seychelles warbler,we show that when a parent was naturally replaced or experimentallyremoved and subsequently replaced by a stepparent from outsidethe territory, subordinates were more likely to disperse thanwhen both parents remained in the natal territory. Furthermore,subordinates dispersing from territories in which one or bothparents had been replaced were less likely to acquire a breederposition than subordinates dispersing when both parents werestill on the natal territory. Our findings suggest that thepresence of parents in the natal territory may promote delayeddispersal and facilitate the eventual acquisition of a breederposition outside the natal territory. Our results support theidea that the prolonged parental care, which long-lived speciesare able to provide, may have selected for family living. 相似文献
19.
Background
Extensive focus is placed on the comparative analyses of consensus genotypes in the study of West Nile virus (WNV) emergence. Few studies account for genetic change in the underlying WNV quasispecies population variants. These variants are not discernable in the consensus genome at the time of emergence, and the maintenance of mutation-selection equilibria of population variants is greatly underestimated. The emergence of lineage 1 WNV strains has been studied extensively, but recent epidemics caused by lineage 2 WNV strains in Hungary, Austria, Greece and Italy emphasizes the increasing importance of this lineage to public health. In this study we explored the quasispecies dynamics of minority variants that contribute to cell-tropism and host determination, i.e. the ability to infect different cell types or cells from different species from Next Generation Sequencing (NGS) data of a historic lineage 2 WNV strain.Results
Minority variants contributing to host cell membrane association persist in the viral population without contributing to the genetic change in the consensus genome. Minority variants are shown to maintain a stable mutation-selection equilibrium under positive selection, particularly in the capsid gene region.Conclusions
This study is the first to infer positive selection and the persistence of WNV haplotype variants that contribute to viral fitness without accompanying genetic change in the consensus genotype, documented solely from NGS sequence data. The approach used in this study streamlines the experimental design seeking viral minority variants accurately from NGS data whilst minimizing the influence of associated sequence error. 相似文献20.
Pim van Hooft Herbert HT Prins Wayne M Getz Anna E Jolles Sipke E van Wieren Barend J Greyling Paul D van Helden Armanda DS Bastos 《BMC evolutionary biology》2010,10(1):106