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901.
Potter A Oldfield V Nunns C Fromont C Ray S Northfield CJ Bryant CJ Scrace SF Robinson D Matossova N Baker L Dokurno P Surgenor AE Davis B Richardson CM Murray JB Moore JD 《Bioorganic & medicinal chemistry letters》2010,20(22):6483-6488
Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential. 相似文献
902.
Christine E. Brotherton-Pleiss Michael P. Dillon Anthony P.D.W. Ford Joel R. Gever David S. Carter Shelley K. Gleason Clara J. Lin Amy G. Moore Anthony W. Thompson Marzia Villa Yansheng Zhai 《Bioorganic & medicinal chemistry letters》2010,20(3):1031-1036
Despite the extensive literature describing the role of the ATP-gated P2X3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. 相似文献
903.
904.
João S. Soares Kumbakonam R. Rajagopal James E. Moore Jr. 《Biomechanics and modeling in mechanobiology》2010,9(2):177-186
A thermodynamically consistent framework for describing the response of materials undergoing deformation-induced degradation
is developed and applied to a particular biodegradable polymer system. In the current case, energy is dissipated through the
mechanism of hydrolytic degradation and its effects are incorporated in the constitutive model by appropriately stipulating
the forms for the rate of dissipation and for the degradation-dependent Helmholtz potential which changes with the extent
of the degradation of the material. When degradation does not occur, the response of the material follows the response of
a power-law generalized neo-Hookean material that fits the response of the non-degraded poly(l-lactic acid) under uniaxial extension. We study the inflation and extension of a degrading cylindrical annulus and the influence
of the deformation on the mechanism of degradation and its consequent mechanical response. Depreciation of mechanical properties
due to degradation confers time-dependent characteristics to the response of the biodegradable material: the material creeps
when subjected to constant loads and stresses necessary to keep a fixed deformation relax. 相似文献
905.
Jessica Hernandez Catherine Hucul Emily Reasor Taryn Smith Joel W. McGlothlin David C. Haak Lisa K. Belden Ignacio T. Moore 《Ecology and evolution》2021,11(16):11398
Sexually transmitted microbes are hypothesized to influence the evolution of reproductive strategies. Though frequently discussed in this context, our understanding of the reproductive microbiome is quite nascent. Indeed, testing this hypothesis first requires establishing a baseline understanding of the temporal dynamics of the reproductive microbiome and of how individual variation in reproductive behavior and age influence the assembly and maintenance of the reproductive microbiome as a whole. Here, we ask how mating activity, breeding stage, and age influence the reproductive microbiome. We use observational and experimental approaches to explain variation in the cloacal microbiome of free‐living, female tree swallows (Tachycineta bicolor). Using microsatellite‐based parentage analyses, we determined the number of sires per brood (a proxy for female mating activity). We experimentally increased female sexual activity by administering exogenous 17ß‐estradiol. Lastly, we used bacterial 16S rRNA amplicon sequencing to characterize the cloacal microbiome. Neither the number of sires per brood nor the increased sexual activity of females significantly influenced female cloacal microbiome richness or community structure. Female age, however, was positively correlated with cloacal microbiome richness and influenced overall community structure. A hypothesis to explain these patterns is that the effect of sexual activity and the number of mates on variation in the cloacal microbiome manifests over an individual''s lifetime. Additionally, we found that cloacal microbiome alpha diversity (Shannon Index, Faith''s phylogenetic distance) decreased and community structure shifted between breeding stages. This is one of few studies to document within‐individual changes and age‐related differences in the cloacal microbiome across successive breeding stages. More broadly, our results contribute to our understanding of the role that host life history and behavior play in shaping the cloacal microbiomes of wild birds. 相似文献
906.
Investigating the phase behavior of sugars in ice and lyophilized solids is of significant interest in the pharmaceutical industry. In this study, Raman and near infrared (NIR) spectroscopy are used to characterize and quantitate trehalose crystallization using several chemometric models. The predictive behaviors of partial least squares (PLS), principal component analysis (PCA), and multiple linear regression (MLR) models are compared. In general, PLS and PCA outperform linear and MLR models. Changes in specific vibrational modes associated with several coupled motions are described and assigned as a function of crystal content. In addition to characterization and quantitation, our method may be used to localize gradients of amorphous and/or crystallized trehalose within a sample. 相似文献
907.
The alternative oxidase (AOX) is a non-protonmotive ubiquinol oxidase that is found in all plants, some fungi, green algae, bacteria and pathogenic protozoa. The lack of AOX in the mammalian host renders this protein an important potential therapeutic target in the treatment of pathogenic protozoan infections. Bioinformatic searches revealed that, within a putative ubiquinol-binding crevice in AOX, Gln242, Asn247, Tyr253, Ser256, His261 and Arg262 were highly conserved. To confirm that these amino-acid residues are important for ubiquinol-binding and hence activity substitution mutations were generated and characterised. Assessment of AOX activity in isolated Schizosaccharomyces pombe mitochondria revealed that mutation of either Gln242, Ser256, His261 and Arg262 resulted in >90% inhibition of antimycin A-insensitive respiration suggesting that hydroxyl, guanidino, imidazole groups, polar and charged residues in addition to the size of the amino-acid chain are important for ubiquinone-binding. Substitution of Asn247 with glutamine or Tyr253 with phenylalanine had little effect upon the respiratory rate indicating that these residues are not critical for AOX activity. However replacement of Tyr253 by alanine resulted in a 72% loss of activity suggesting that the benzoquinone group and not hydroxyl group is important for quinol binding. These results provide important new insights into the ubiquinol-binding site of the alternative oxidase, the identity of which maybe important for future rational drug design. 相似文献
908.
John J Kavanagh Charles F Levenback Pedro T Ramirez Judith L Wolf Carla L Moore Marsha R Jones Lisa Meng Gail L Brown Robert C Bast Jr 《Journal of hematology & oncology》2010,3(1):1-11
We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site. 相似文献
909.
Habitat structure at many scales influences faunal communities. Although habitat structure at different scales often covaries, studies rarely examine the relative effects of structure at multiple scales on faunal density and diversity. In shallow‐water seagrass systems, epifaunal density at local scales generally increases with increased habitat structural complexity (e.g. shoot density per unit area). In turn, structural complexity often varies with other aspects of habitat structure at patch scales, such as proximity to patch edges, which itself modifies ecological processes that structure epifaunal communities. We conducted surveys and a manipulative experiment in the eelgrass Zostera marina beds of San Diego Bay, California, USA, to determine (1) whether eelgrass structural complexity, epifaunal density and diversity, and fish (predator) density and diversity vary with proximity to patch edges, and (2) the relative influences of structural complexity, proximity to patch edges and predator presence on epifaunal distribution. Seagrass structural complexity generally increased from patch edges to patch interiors at all sites and in all sampling periods. However, patterns of epifaunal density, diversity, and biomass varied among sites and sampling periods, with density and biomass increasing from patch edges to interiors at some sites and decreasing at others. In the manipulative experiment, we allowed epifauna to colonize sparse or dense artificial seagrass habitat at both the edge and interior of a seagrass patch, and enclosed a subset of experimental units in predator exclusion cages. Overall, proximity to patch edges had a larger influence on epifaunal density and community structure than did structural complexity or predation, with the exception of some common taxa which responded more strongly to either complexity or predator exclusion. Our results emphasize the importance of addressing and evaluating habitat structure at multiple scales to better understand the distribution and interactions of organisms in a particular environment. 相似文献