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排序方式: 共有161条查询结果,搜索用时 15 毫秒
81.
Ren L Ahrendt KA Grina J Laird ER Buckmelter AJ Hansen JD Newhouse B Moreno D Wenglowsky S Dinkel V Gloor SL Hastings G Rana S Rasor K Risom T Sturgis HL Voegtli WC Mathieu S 《Bioorganic & medicinal chemistry letters》2012,22(10):3387-3391
Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. 相似文献
82.
A distinct increase in fox populations, particularly in urban areas, has been observed in Europe. This is of particular concern in endemic regions of the small fox tapeworm Echinococcus multilocularis, the aetiological agent of human alveolar echinococcosis. Novel tools have facilitated the investigation of the ecology of urban foxes and have demonstrated the urban wildlife cycle of E. multilocularis. Such studies are essential for estimating the risk of transmission to humans and to determine the basics for the development of control strategies. 相似文献
83.
The use of sequence alignments to understand protein families is ubiquitous in molecular biology. High quality alignments are difficult to build and protein alignment remains one of the largest open problems in computational biology. Misalignments can lead to inferential errors about protein structure, folding, function, phylogeny, and residue importance. Identifying alignment errors is difficult because alignments are built and validated on the same primary criteria: sequence conservation. Local covariation identifies systematic misalignments and is independent of conservation. We demonstrate an alignment curation tool, LoCo, that integrates local covariation scores with the Jalview alignment editor. Using LoCo, we illustrate how local covariation is capable of identifying alignment errors due to the reduction of positional independence in the region of misalignment. We highlight three alignments from the benchmark database, BAliBASE 3, that contain regions of high local covariation, and investigate the causes to illustrate these types of scenarios. Two alignments contain sequential and structural shifts that cause elevated local covariation. Realignment of these misaligned segments reduces local covariation; these alternative alignments are supported with structural evidence. We also show that local covariation identifies active site residues in a validated alignment of paralogous structures. Loco is available at https://sourceforge.net/projects/locoprotein/files/. 相似文献
84.
cDNA sequence coding for a rat glia-derived nexin and its homology to members of the serpin superfamily 总被引:7,自引:0,他引:7
J Sommer S M Gloor G F Rovelli J Hofsteenge H Nick R Meier D Monard 《Biochemistry》1987,26(20):6407-6410
Rat glial cells release a neurite-promoting factor with serine protease inhibitory activity. By using a rat glioma cDNA clone as a probe, it was possible to isolate rat cDNAs containing the entire sequence coding for this neurite-promoting factor. The largest rat cDNA (approximately 2100 bp) was characterized by DNA sequencing. It contained the entire coding region, 135 bp of the 5' nontranslated region, and about 750 bp of the 3' nontranslated region. The open reading frame coded for 397 amino acids including a putative signal peptide of 19 amino acids. The correct identity of the coding sequence was substantiated by the fact that the sequence of tryptic peptides, derived from the purified rat factor, matched exactly with the deduced amino acid sequence. The rat protein sequence had 84% homology with the corresponding protein from human glioma cells. Both amino acid sequences indicated that the proteins belong to the protease nexins [Baker, B.J., Low, D. A., Simmer, R. L., & Cunningham, D.D. (1980) Cell (Cambridge, Mass.) 21, 37-45] and therefore can be defined as glia-derived nexins (GDNs). Further analysis showed that both rat and human GDN belong to the serpin superfamily and share 41%, 32%, and 25% homology with human endothelial-cell-type plasminogen activator inhibitor, antithrombin III, and alpha-1 proteinase inhibitor, respectively. 相似文献
85.
86.
Mohammad NS Yedluri R Addepalli P Gottumukkala SR Digumarti RR Kutala VK 《Molecular and cellular biochemistry》2011,356(1-2):159-167
Apoptosis, or programmed cell death, is a vital cellular process often impaired in diseases such as cancer. Aspartic acid-directed proteases known as caspases cleave a broad spectrum of cellular proteins and are central constituents of the apoptotic machinery. Caspases are regulated by a variety of mechanisms including protein phosphorylation. One intriguing mechanism by which protein kinases can modulate caspase pathways is by blocking substrate cleavage through phosphorylation of residues adjacent to caspase cleavage sites. To explore this mechanism in detail, we recently undertook a systematic investigation using a combination of bioinformatics, peptide arrays, and peptide cleavage assays to identify proteins with overlapping protein kinase and caspase recognition motifs (Duncan et al., Sci Signal 4:ra30, 2011). These studies implicated protein kinase CK2 as a global regulator of apoptotic pathways. In this article, we extend the analysis of proteins with overlapping CK2 and caspase consensus motifs to examine the convergence of CK2 with specific caspases and to identify CK2/caspase substrates known to be phosphorylated or cleaved in cells. Given its constitutive activity and elevated expression in cancer, these observations suggest that the ability of CK2 to modulate caspase pathways may contribute to a role in promoting cancer cell survival and raise interesting prospects for therapeutic targeting of CK2. 相似文献
87.
Microbiota restoration: natural and supplemented recovery of human microbial communities 总被引:1,自引:0,他引:1
Reid G Younes JA Van der Mei HC Gloor GB Knight R Busscher HJ 《Nature reviews. Microbiology》2011,9(1):27-38
In a healthy host, a balance exists between members of the microbiota, such that potential pathogenic and non-pathogenic organisms can be found in apparent harmony. During infection, this balance can become disturbed, leading to often dramatic changes in the composition of the microbiota. For most bacterial infections, nonspecific antibiotics are used, killing the non-pathogenic members of the microbiota as well as the pathogens and leading to a substantial delay in the restoration of a healthy microbiota. However, in some cases, infections can self-resolve without the intervention of antibiotics. In this Review, we explore the mechanisms underlying microbiota restoration following insult (antibiotic or otherwise) to the skin, oral cavity, and gastrointestinal and urogenital tracts, highlighting recovery by natural processes and after probiotic administration. 相似文献
88.
Hummelen R Macklaim JM Bisanz JE Hammond JA McMillan A Vongsa R Koenig D Gloor GB Reid G 《PloS one》2011,6(11):e26602
After menopause, many women experience vaginal dryness and atrophy of tissue, often attributed to the loss of estrogen. An understudied aspect of vaginal health in women who experience dryness due to atrophy is the role of the resident microbes. It is known that the microbiota has an important role in healthy vaginal homeostasis, including maintaining the pH balance and excluding pathogens. The objectives of this study were twofold: first to identify the microbiome of post-menopausal women with and without vaginal dryness and symptoms of atrophy; and secondly to examine any differences in epithelial gene expression associated with atrophy. The vaginal microbiome of 32 post-menopausal women was profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Sixteen subjects were selected for follow-up sampling every two weeks for 10 weeks. In addition, 10 epithelial RNA samples (6 healthy and 4 experiencing vaginal dryness) were acquired for gene expression analysis by Affymetrix Human Gene array. The microbiota abundance profiles were relatively stable over 10 weeks compared to previously published data on premenopausal women. There was an inverse correlation between Lactobacillus ratio and dryness and an increased bacterial diversity in women experiencing moderate to severe vaginal dryness. In healthy participants, Lactobacillus iners and L. crispatus were generally the most abundant, countering the long-held view that lactobacilli are absent or depleted in menopause. Vaginal dryness and atrophy were associated with down-regulation of human genes involved in maintenance of epithelial structure and barrier function, while those associated with inflammation were up-regulated consistent with the adverse clinical presentation. 相似文献
89.
Luiz E. O. C. Aragão Benjamin Poulter Jos B. Barlow Liana O. Anderson Yadvinder Malhi Sassan Saatchi Oliver L. Phillips Emanuel Gloor 《Biological reviews of the Cambridge Philosophical Society》2014,89(4):913-931
Extreme climatic events and land‐use change are known to influence strongly the current carbon cycle of Amazonia, and have the potential to cause significant global climate impacts. This review intends to evaluate the effects of both climate and anthropogenic perturbations on the carbon balance of the Brazilian Amazon and to understand how they interact with each other. By analysing the outputs of the Intergovernmental Panel for Climate Change (IPCC) Assessment Report 4 (AR4) model ensemble, we demonstrate that Amazonian temperatures and water stress are both likely to increase over the 21st Century. Curbing deforestation in the Brazilian Amazon by 62% in 2010 relative to the 1990s mean decreased the Brazilian Amazon's deforestation contribution to global land use carbon emissions from 17% in the 1990s and early 2000s to 9% by 2010. Carbon sources in Amazonia are likely to be dominated by climatic impacts allied with forest fires (48.3% relative contribution) during extreme droughts. The current net carbon sink (net biome productivity, NBP) of +0.16 (ranging from +0.11 to +0.21) Pg C year?1 in the Brazilian Amazon, equivalent to 13.3% of global carbon emissions from land‐use change for 2008, can be negated or reversed during drought years [NBP = ?0.06 (?0.31 to +0.01) Pg C year?1]. Therefore, reducing forest fires, in addition to reducing deforestation, would be an important measure for minimizing future emissions. Conversely, doubling the current area of secondary forests and avoiding additional removal of primary forests would help the Amazonian gross forest sink to offset approximately 42% of global land‐use change emissions. We conclude that a few strategic environmental policy measures are likely to strengthen the Amazonian net carbon sink with global implications. Moreover, these actions could increase the resilience of the net carbon sink to future increases in drought frequency. 相似文献
90.
Perturbations in the carbon budget of the tropics 总被引:1,自引:0,他引:1
The carbon budget of the tropics has been perturbed as a result of human influences. Here, we attempt to construct a ‘bottom‐up’ analysis of the biological components of the budget as they are affected by human activities. There are major uncertainties in the extent and carbon content of different vegetation types, the rates of land‐use change and forest degradation, but recent developments in satellite remote sensing have gone far towards reducing these uncertainties. Stocks of carbon as biomass in tropical forests and woodlands add up to 271 ± 16 Pg with an even greater quantity of carbon as soil organic matter. Carbon loss from deforestation, degradation, harvesting and peat fires is estimated as 2.01 ± 1.1 Pg annum?1; while carbon gain from forest and woodland growth is 1.85 ± 0.09 Pg annum?1. We conclude that tropical lands are on average a small carbon source to the atmosphere, a result that is consistent with the ‘top‐down’ result from measurements in the atmosphere. If they were to be conserved, they would be a substantial carbon sink. Release of carbon as carbon dioxide from fossil fuel burning in the tropics is 0.74 Pg annum?1 or 0.57 MgC person?1 annum?1, much lower than the corresponding figures from developed regions of the world. 相似文献