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61.
Conotoxin GI: disulfide bridges, synthesis, and preparation of iodinated derivatives 总被引:3,自引:0,他引:3
W R Gray F A Luque R Galyean E Atherton R C Sheppard B L Stone A Reyes J Alford M McIntosh B M Olivera 《Biochemistry》1984,23(12):2796-2802
The 13 amino acid toxic peptide from the marine snail Conus geographus, conotoxin GI, blocks the acetylcholine receptor at the neuromuscular junction. In this report, we describe a method for analyzing disulfide bonding in nanomole amounts of small cystine-rich peptides. The procedure involves partial reduction and a double-label alkylation of cysteine residues. Using this method, we show that the natural conotoxin GI has a (2-7, 3-13) disulfide configuration. The structure of conotoxin GI has been confirmed by chemical synthesis. The preparation and purification of molecularly homogeneous, iodinated derivatives of this toxin are also described. All derivatives, including the [diiodohistidine,diiodotyrosine]conotoxin GI, retained at least half of the biological activity of unmodified toxin. Since the tetraiodinated toxin, which is greater than 25% by weight iodine, retains considerable toxicity, unmodified histidine and tyrosine residues in conotoxin GI are not crucial for biological activity. 相似文献
62.
Rittig MG Shaw B Letley DP Thomas RJ Argent RH Atherton JC 《Cellular microbiology》2003,5(12):887-899
Following reports that a VacA+cag+ toxigenic but not a VacA-cag- non-toxigenic Helicobacter pylori strain induced homotypic phagosome fusion in murine macrophages, we addressed that phenomenon in human cells. Mononuclear phagocytes and epitheloid cells were challenged with H. pylori strains of different vacA and cag genotypes and with VacA- and Cag- isogenic mutants, and chased in the absence or presence of signal transduction modulators. Electron microscopy revealed that, in monocytes: (i) homotypic phagosome fusion was frequently induced by all live H. pylori strains investigated but not by exogenous VacA; (ii) phagosomes containing bacteria fused, but not those containing latex beads; (iii) fusion resulted in communal compartments resembling giant multivesicular bodies; and (iv) formation of these compartments was blocked by inhibiting the host cell regulators PI 3-kinase, phospholipase C and p42 MAP kinase. Whereas some internalized bacteria remained viable 1 h after uptake, none survived a 24 h period. In contrast to monocytes, infected epitheloid cells rarely developed communal compartments. In combination, these results demonstrate that, in human monocytes, the H. pylori-induced homotypic phagosome fusion depends on neither the vacuolating cytotoxin VacA nor the cag pathogenicity island of H. pylori and does not result in prolonged intracellular survival. 相似文献
63.
The murid rodent subfamily Sigmodontinae contains 79 genera which are
distributed throughout the New World. The time of arrival of the first
sigmodontines in South America and the estimated divergence time(s) of the
different lineages of South American sigmodontines have been controversial
due to the lack of a good fossil record and the immense number of extant
species. The "early-arrival hypothesis" states that the sigmodontines must
have arrived in South America no later than the early Miocene, at least 20
MYA, in order to account for their vast present-day diversity, whereas the
"late-arrival hypothesis" includes the sigmodontines as part of the
Plio-Pleistocene Great American Interchange, which occurred approximately
3.5 MYA. The phylogenetic relationships among 33 of these genera were
reconstructed using mitochondrial DNA (mtDNA) sequence data from the ND3,
ND4L, arginine tRNA, and ND4 genes, which we show to be evolving at the
same rate. A molecular clock was calibrated for these genes using published
fossil dates, and the genetic distances were estimated from the DNA
sequences in this study. The molecular clock was used to estimate the dates
of the South American sigmodontine origin and the main sigmodontine
radiation in order to evaluate the "early-" and "late-arrival" scenarios.
We estimate the time of the sigmodontine invasion of South America as
between approximately 5 and 9 MYA, supporting neither of the scenarios but
suggesting two possible models in which the invading lineage was either (1)
ancestral to the oryzomyines, akodonts, and phyllotines or (2) ancestral to
the akodonts and phyllotines and accompanied by the oryzomyines. The
sigmodontine invasion of South America provides an example of the advantage
afforded to a lineage by the fortuitous invasion of a previously
unexploited habitat, in this case an entire continent.
相似文献
64.
Background
Host parasitism by Trichomonas vaginalis is complex. Adherence to vaginal epithelial cells (VECs) is mediated by surface proteins. We showed before that antisense down-regulation of expression of adhesin AP65 decreased amounts of protein, which lowered levels of T. vaginalis adherence to VECs. We now perform antisense down-regulation of expression of the ap33 gene to evaluate and confirm a role for AP33 in adherence by T. vaginalis. We also used an established transfection system for heterologous expression of AP33 in T. foetus as an additional confirmatory approach. 相似文献65.
66.
67.
The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system. 相似文献
68.
Coro J Atherton R Little S Wharton H Yardley V Alvarez A Súarez M Pérez R Rodríguez H 《Bioorganic & medicinal chemistry letters》2006,16(5):1312-1315
The effect of several alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) on Leishmania donovani, Trypanosoma brucei rhodesiense, and Plasmodium falciparum is reported. Most of the compounds exhibited a potent activity against the three parasitic strains but the best in vitro activity profiles were found against T. b. rhodesiense with IC(50) values ranging between 0.3 and 4 microM for the most active compounds. 相似文献
69.
Louisa Jackson John Britton Sarah A. Lewis Tricia M. McKeever John Atherton Donna Fullerton Andrew W. Fogarty 《Helicobacter》2009,14(5):460-465
Background: Infection with Helicobacter pylori is associated with a variety of non-gastrointestinal sequelae. These may be mediated by an increase in systemic inflammation. We assessed if serologic evidence of infection with H. pylori is associated with increased serum C-reactive protein (CRP) levels.
Methods: The study design consisted of a randomly selected, cross-sectional population-based study of 2633 individuals phenotyped in 1991, of whom 2361 participants provided serum samples to permit measurement of H. pylori 's serologic status and CRP levels.
Results: Male gender (odds ratio (OR): 1.65; 95% confidence interval (CI): 1.23–2.21), age (OR per year: 1.05; 95% CI: 1.04–1.06), height (OR per meter: 0.05; 95% CI: 0.01–0.24), current smoking habit (compared with never smokers, OR: 1.46; 95% CI: 1.13–1.88), and less affluent socioeconomic status were associated with increased odds of being seropositive for H. pylori . Helicobacter pylori infection was associated with increased risk of having an elevated serum CRP (above 3 mg/L) after adjustment for gender, age, height, smoking status, and socioeconomic status (OR: 1.32; 95% CI: 1.05–1.67). Similar associations were seen using a threshold for elevated serum CRP of greater than 1 mg/L.
Conclusions: Our data suggest that infection with H. pylori is associated with increased systemic inflammation. This suggests one potential mechanism to explain the extra-gastrointestinal conditions associated with H. pylori infection. 相似文献
Methods: The study design consisted of a randomly selected, cross-sectional population-based study of 2633 individuals phenotyped in 1991, of whom 2361 participants provided serum samples to permit measurement of H. pylori 's serologic status and CRP levels.
Results: Male gender (odds ratio (OR): 1.65; 95% confidence interval (CI): 1.23–2.21), age (OR per year: 1.05; 95% CI: 1.04–1.06), height (OR per meter: 0.05; 95% CI: 0.01–0.24), current smoking habit (compared with never smokers, OR: 1.46; 95% CI: 1.13–1.88), and less affluent socioeconomic status were associated with increased odds of being seropositive for H. pylori . Helicobacter pylori infection was associated with increased risk of having an elevated serum CRP (above 3 mg/L) after adjustment for gender, age, height, smoking status, and socioeconomic status (OR: 1.32; 95% CI: 1.05–1.67). Similar associations were seen using a threshold for elevated serum CRP of greater than 1 mg/L.
Conclusions: Our data suggest that infection with H. pylori is associated with increased systemic inflammation. This suggests one potential mechanism to explain the extra-gastrointestinal conditions associated with H. pylori infection. 相似文献
70.
Diane H. Boschelli Joan Subrath Chuansheng Niu Biqi Wu Yan Wang Julie Lee Agnes Brennan Melisa Ho Bijia Deng Xiaoke Yang Xin Xu Louis Leung Jianyao Wang James Atherton Divya Chaudhary 《Bioorganic & medicinal chemistry letters》2010,20(6):1965-1968
Analog 8, a 3-pyridinecarbonitrile with an (E)-2-{6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}vinyl group at C-5, had an IC50 value of 1.1 nM for the inhibition of PKCθ and potently blocked the production of IL-2 in both stimulated murine T cells (IC50 = 34 nM) and human whole blood (IC50 = 500 nM). 相似文献