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排序方式: 共有4137条查询结果,搜索用时 15 毫秒
941.
Virginia M. Tanis Genesis M. Bacani Jonathan M. Blevitt Christa C. Chrovian Shelby Crawford Aimee De Leon Anne M. Fourie Laurent Gomez Cheryl A. Grice Krystal Herman Aaron M. Kearney Adrienne M. Landry-Bayle Alice Lee-Dutra Jay Nelson Jason P. Riley Alejandro Santillán John J.M. Wiener Xiaohua Xue Arlene L. Young 《Bioorganic & medicinal chemistry letters》2012,22(24):7504-7511
Previously, benzthiazole containing LTA4H inhibitors were discovered that were potent (1–3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering c Log D) a new benzthiazole series was designed, congeners of 1–3, which led to compounds 7a, 7c, 12a–d which exhibited LTA4H IC50 = 3–6 nM and hERG Dofetilide Binding IC50 = 8.9–> >10 μM. 相似文献
942.
943.
Rudenko IN Kaganovich A Hauser DN Beylina A Chia R Ding J Maric D Jaffe H Cookson MR 《The Biochemical journal》2012,446(1):99-111
Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2-3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD. 相似文献
944.
Alzheimer's disease (AD) is accompanied by oxidative stress in the brain. Because the brain tissue is rich in polyunsaturated fatty acids, it is prone to the free radical attack resulting in lipid peroxidation. Intermediates of lipid peroxidation may diffuse from the primary site, cross the blood-brain barrier and modify erythrocyte membranes in the bloodstream. We exposed isolated erythrocyte membranes from patients with AD and the control group to in vitro free radical damage and monitored the accumulation of the end products of lipid peroxidation, lipofuscin-like pigments (LFPs), by fluorescence spectroscopy. LFPs were analyzed by means of tridimensional and synchronous fluorescence spectroscopy. The levels of LFP formed during in vitro peroxidation were significantly higher in erythrocyte membranes from patients with AD compared with the control group. Furthermore, the chemical composition of LFP in AD was different from the control group. The analysis of the specific modifications of erythrocyte membranes in AD is of great medical importance regarding the need of a diagnostic blood biomarker. 相似文献
945.
The endemic Tahiti reed‐warbler Acrocephalus caffer occurs in two distinct morphs, a typical or ‘yellow’ morph and a melanic or ‘dark’ morph, which are found together in the valleys of the eastern and central parts of the island of Tahiti (Society Islands, French Polynesia). We investigated the molecular basis of the plumage colour polymorphism in this species using sequences of the melanocortin‐1 receptor (MC1R), a gene often found associated to melanism in birds. We found that the MC1R genotype was perfectly associated with plumage colour in the Tahiti reed‐warbler, with the same nonsynonymous substitution that showed a correlation with phenotype in the Caribbean bananaquit Coereba flaveola. An heterozygous reed‐warbler at this site presented a melanic phenotype, suggesting that the melanic allele is dominant. All other Polynesian reed‐warbler species, which do not have a melanic morph, shared the ‘yellow’ nucleotide at this position. These results suggested that the same mutation point was linked to a melanic polymorphism in two unrelated passerine birds. 相似文献
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947.
Influenza A viruses are single-stranded RNA viruses capable of evolving rapidly to adapt to environmental conditions. Examples include the establishment of a virus in a novel host or an adaptation to increasing immunity within the host population due to prior infection or vaccination against a circulating strain. Knowledge of the viral protein regions under positive selection is therefore crucial for surveillance. We have developed a method for detecting positively selected patches of sites on the surface of viral proteins, which we assume to be relevant for adaptive evolution. We measure positive selection based on dN/dS ratios of genetic changes inferred by considering the phylogenetic structure of the data and suggest a graph-cut algorithm to identify such regions. Our algorithm searches for dense and spatially distinct clusters of sites under positive selection on the protein surface. For the hemagglutinin protein of human influenza A viruses of the subtypes H3N2 and H1N1, our predicted sites significantly overlap with known antigenic and receptor-binding sites. From the structure and sequence data of the 2009 swine-origin influenza A/H1N1 hemagglutinin and PB2 protein, we identified regions that provide evidence of evolution under positive selection since introduction of the virus into the human population. The changes in PB2 overlap with sites reported to be associated with mammalian adaptation of the influenza A virus. Application of our technique to the protein structures of viruses of yet unknown adaptive behavior could identify further candidate regions that are important for host-virus interaction. 相似文献
948.
Endoplasmic reticulum (ER) stress may be both a trigger and consequence of chronic inflammation. Chronic inflammation is often associated with diseases that arise because of primary misfolding mutations and ER stress. Similarly, ER stress and activation of the unfolded protein response (UPR) is a feature of many chronic inflammatory and autoimmune diseases. In this review, we describe how protein misfolding and the UPR trigger inflammation, how environmental ER stressors affect antigen presenting cells and immune effector cells, and present evidence that inflammatory factors exacerbate protein misfolding and ER stress. Examples from both animal models of disease and human diseases are used to illustrate the complex interactions between ER stress and inflammation, and opportunities for therapeutic targeting are discussed. Finally, recommendations are made for future research with respect to the interaction of ER stress and inflammation. 相似文献
949.
Cardiomyocytes are the fundamental cells of the heart and play an important role in engineering of tissue constructs for regenerative medicine and drug discovery. Therefore, the development of culture conditions that can be used to generate functional cardiomyocytes to form cardiac tissue may be of great interest. In this study, isolated neonatal rat cardiomyocytes were cultured with several culture conditions in vitro and characterized for cell proliferation, myofibril organization, and cardiac functionality by assessing cell morphology, immunocytochemical staining, and time-lapse confocal scanning microscopy. When cardiomyocytes were cultured in liver cell line derived conditioned medium without exogenous growth factors and cytokines, the cell proliferation increased, cell morphology was highly elongated, and subsequent myofibril organization was highly developed. These developed myofibril organization also showed high level of contractibility and synchronization, representing high functionality of cardiomyocytes. Interestingly, many of the known factors in hepatic conditioned medium, such as insulin-like growth factor II (IGFII), macrophage colony-stimulating factor (MCSF), leukemia inhibitory factor (LIF), did not show similar effects as the hepatic conditioned medium, suggesting the possibility of synergistic activity of the several soluble factors or the presence of unknown factors in hepatic conditioned medium. Finally, we demonstrated that our culture system could provide a potentially powerful tool for in vitro cardiac tissue organization and cardiac function study. 相似文献
950.