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81.
Guo Z Wu D Zhu YF Tucci FC Regan CF Rowbottom MW Struthers RS Xie Q Reijmers S Sullivan SK Sai Y Chen C 《Bioorganic & medicinal chemistry letters》2005,15(16):3685-3690
SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM. 相似文献
82.
Prioritizing multiple-use landscapes for conservation: methods for large multi-species planning problems 总被引:2,自引:0,他引:2
Moilanen A Franco AM Early RI Fox R Wintle B Thomas CD 《Proceedings. Biological sciences / The Royal Society》2005,272(1575):1885-1891
Across large parts of the world, wildlife has to coexist with human activity in highly modified and fragmented landscapes. Combining concepts from population viability analysis and spatial reserve design, this study develops efficient quantitative methods for identifying conservation core areas at large, even national or continental scales. The proposed methods emphasize long-term population persistence, are applicable to both fragmented and natural landscape structures, and produce a hierarchical zonation of regional conservation priority. The methods are applied to both observational data for threatened butterflies at the scale of Britain and modelled probability of occurrence surfaces for indicator species in part of Australia. In both cases, priority landscapes important for conservation management are identified. 相似文献
83.
84.
By facilitating reproducible first dimension separations, commercial immobilized pH gradient (IPG) strips enable high throughput and high-resolution proteomic analyses using two-dimensional gel electrophoresis (2DE). Amersham, Biorad, Invitrogen, and Sigma all market linear pH 3-10 IPG strips. We have applied optimized 2DE protocols with both membrane and soluble brain protein extracts to critically evaluate all four products. Resolved protein spots were quantitatively evaluated after carrying out these protocols using IPG strips from the four companies. Biorad and Amersham IPG strips resolved a high number of membrane and soluble proteins, respectively. Furthermore, Amersham IPG strips eluted the largest amount of protein into the second dimension gels and had the most protein remaining in the strip after 2DE. Biorad and Amersham IPG strips maintained a consistent linear pH 3-10 gradient, whereas those from Invitrogen appeared nonlinear or "compressed" within the central pH region. The gradient range within Sigma IPG strips appeared to be slightly less than pH 3-10, due to one extended pH unit within the gradient. Overall, all four commercially available IPG strips have the ability to resolve both membrane and soluble brain proteomes. The difference is that Amersham and Biorad do so more consistently and with better spot resolution. It appears that the physical/chemical nature of commercially available IPG strips can vary considerably, leading to marked differences in subsequent protein resolution in 2DE. These differences likely reflect variations in the uptake of proteins into the strips, and differences in the focusing and elution of proteins from the first to the second dimension. These differences would appear, in part, to underlie some inter-lab variations in the effective resolution of proteomes. 相似文献
85.
86.
HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells 总被引:4,自引:0,他引:4
Basuroy S Bhattacharya S Tcheranova D Qu Y Regan RF Leffler CW Parfenova H 《American journal of physiology. Cell physiology》2006,291(5):C897-C908
Tumor necrosis factor- (TNF-) causes oxidative stress and apoptosis in a variety of cell types. Heme oxygenase (HO) degrades heme to bilirubin, an antioxidant, and carbon monoxide (CO), a cell cycle modulator, and a vasodilator. Newborn pig cerebral microvascular endothelial cells (CMVEC) highly express constitutive HO-2. We investigated the role of HO-2 in protection against TNF--induced apoptosis in cerebral vascular endothelium. In CMVEC from mice and newborn pigs, 15 ng/ml TNF- alone, or with 10 µg/ml cycloheximide (CHX) caused apoptosis detected by nuclear translocation of p65 NF-B, caspase-3 activation, DNA fragmentation, cell-cell contact destabilization, and cell detachment. TNF- did not induce HO-1 expression in CMVEC. CMVEC from HO-2 knockout mice showed greater sensitivity to apoptosis caused by serum deprivation and TNF- than did wild-type mice. TNF- increased reactive oxygen species generation, including hydrogen peroxide and superoxide radicals, as detected by dihydrorhodamine-123 and dihydroethidium. The TNF- response was inhibited by superoxide dismutase and catalase suggesting apoptosis is oxidative stress related. Inhibition of endogenous HO-2 in newborn pig CMVEC increased oxidative stress and exaggerated apoptosis caused by serum deprivation and TNF-. In HO-1-overexpressing CMVEC (HO-1 selective induction by cobalt portophyrin), TNF- did not cause apoptosis. A CO-releasing compound, CORM-A1, and bilirubin blocked TNF--induced reactive oxygen species accumulation and apoptosis consistent with the antioxidant and antiapoptotic roles of the end products of HO activity. We conclude that HO-2 is critical for protection of cerebrovascular endothelium against apoptotic changes induced by oxidative stress and cytokine-mediated inflammation. carbon monoxide; bilirubin; vascular injury; reactive oxygen species; heme oxygenase; cycloheximide 相似文献
87.
We compared the efficacy of artificial and natural selection processes in purging the genetic load of perpetually small populations.
We subjected replicate lines of the housefly (Musca domestica L.), recently derived from the wild, to artificial selection for increased mating propensity (i.e., the proportion of male–female
pairs initiating copulation within 30 min) in efforts to cull out the inbreeding depression effects of long-term small population
size (as determined by a selection protocol for increased assortative mating). We also maintained parallel non-selection lines
for assessing the spontaneous purge of genetic load due to inbreeding alone. We thus evaluated the fitness of artificially
and ‘naturally’ purging populations held at census sizes of 40 individuals over the course of 18 generations. We found that
the artificially selected lines had significant increases in mating propensity (up to 46% higher from the beginning of the
protocol) followed by reversed selection responses back to the initial levels, resulting in non-significant heritabilities.
Nevertheless, the ‘naturally’ selected lines had significantly lower fitness overall (a 28% reduction from the beginning of
the protocol), although lower effective population sizes could have contributed to this effect. We conclude that artificial
selection bolstered fitness, but only in the short-term, because the inadvertent fixation of extant genetic load later resulted
in pleiotropic fitness declines. Still, the short-term advantage of the selection protocol likely contributed to the success
of the speciation experiment since our recently-derived housefly populations are particularly vulnerable to inbreeding depression
effects on mating behavior. 相似文献
88.
89.
Schmidt LJ Duncan K Yadav N Regan KM Verone AR Lohse CM Pop EA Attwood K Wilding G Mohler JL Sebo TJ Tindall DJ Heemers HV 《Molecular endocrinology (Baltimore, Md.)》2012,26(5):716-735
Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa. 相似文献
90.
In this review we highlight recent accomplishments in the design of materials from proteins and peptides. Examples include hydrogels made from aggregating designed β-hairpin peptides, whose physical properties respond to small changes in the amino acid composition of the peptide; materials that combine different segments of natural elastomeric proteins - such as elastin, resilin, silk fibroin whose bulk properties are dictated in unanticipated ways by their composition; and hydrogels formed by strings or arrays of protein modules, which are cross-linked by multivalent versions of their peptide ligands, and which may exhibit exquisite stimuli-responsive behavior. The suitability of the unique properties of such new materials for practical applications is also considered. 相似文献