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21.
Adams ME Wallace MB Kanouni T Scorah N O'Connell SM Miyake H Shi L Halkowycz P Zhang L Dong Q 《Bioorganic & medicinal chemistry letters》2012,22(7):2411-2414
The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy. 相似文献
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23.
This study considered a model for species abundance dynamics in two local community (or islands) connected to a regional metacommunity. The model was analyzed using continuous probabilistic technique that employs Kolmogorov-Fokker-Planck forward equation to derive the probability density of the species abundance in the two local communities. Using this technique, we proposed a classification for the species abundance dynamics in the local communities. This classification was made based on such characteristics as immigration intensity, species representation in the metacommunity and the size of local communities. We further distinguished several different scenarios for species abundance dynamics using different ecological characteristics such as species persistence, extinction and monodominance in one or both local communities. The similarity of the species abundance distributions between the two local communities was studied using the correlation coefficient between species abundances in two local communities. The correlation is a function of migration rates between local communities and between local and metacommunity. Immigration between local communities drives the homogenization of the local communities, while immigration from the metacommunity will differentiate them. This community subdivision model provides useful insights for studying the effect of landscape fragmentation on species diversity. 相似文献
24.
Julkunen P Wilson W Jurvelin JS Rieppo J Qu CJ Lammi MJ Korhonen RK 《Journal of biomechanics》2008,41(9):1978-1986
Mechanical properties of articular cartilage are controlled by tissue composition and structure. Cartilage function is sensitively altered during tissue degeneration, in osteoarthritis (OA). However, mechanical properties of the tissue cannot be determined non-invasively. In the present study, we evaluate the feasibility to predict, without mechanical testing, the stress-relaxation response of human articular cartilage under unconfined compression. This is carried out by combining microscopic and biochemical analyses with composition-based mathematical modeling. Cartilage samples from five cadaver patellae were mechanically tested under unconfined compression. Depth-dependent collagen content and fibril orientation, as well as proteoglycan and water content were derived by combining Fourier transform infrared imaging, biochemical analyses and polarized light microscopy. Finite element models were constructed for each sample in unconfined compression geometry. First, composition-based fibril-reinforced poroviscoelastic swelling models, including composition and structure obtained from microscopical and biochemical analyses were fitted to experimental stress-relaxation responses of three samples. Subsequently, optimized values of model constants, as well as compositional and structural parameters were implemented in the models of two additional samples to validate the optimization. Theoretical stress-relaxation curves agreed with the experimental tests (R=0.95-0.99). Using the optimized values of mechanical parameters, as well as composition and structure of additional samples, we were able to predict their mechanical behavior in unconfined compression, without mechanical testing (R=0.98). Our results suggest that specific information on tissue composition and structure might enable assessment of cartilage mechanics without mechanical testing. 相似文献
25.
Zacharia S. Cheruvallath Stephen L. Gwaltney Mark Sabat Mingnam Tang Haixia Wang Andy Jennings David Hosfield Bumsup Lee Yiqin Wu Petro Halkowycz Charles E. Grimshaw 《Bioorganic & medicinal chemistry letters》2017,27(12):2678-2682
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes. 相似文献
26.
Walter Keung Amogh Boloor Jason Brown Andre Kiryanov Anthony Gangloff J. David Lawson Robert Skene Isaac Hoffman Josephine Atienza Jason Kahana Ron De Jong Pamela Farrell Deepika Balakrishna Petro Halkowycz 《Bioorganic & medicinal chemistry letters》2017,27(4):1099-1104
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies. 相似文献
27.
Membrane rafts are discrete microdomains found in cell membranes that contain cholesterol and glycosphingolipids such as gangliosides.
As cholesterol is a major component of membrane rafts, its sequestration by the polyene filipin can be used to disrupt them.
In previous work we observed that membrane raft disruption by filipin treatment of murine neuroblastoma N2a cells led to changes
in expression of cell processes. In this study, we determined the type of process formation induced by filipin treatment as
well as whether their expression was accompanied by changes in ganglioside content or subcellular distribution. The results
indicate that the processes formed were axonal in nature and their expression was accompanied by changes in both ganglioside
content as well as the subcellular localization of GM1.
Special issue article in honor of Dr. George DeVries. 相似文献
28.
In this paper a spatially implicit neutral model for explaining the edge effects between habitats is proposed. To analyze this model we use two different approaches: a discrete approach that is based on the Master equation for a one step jump process and a continuous approach based on the approximation of the discrete jump process with the Kolmogorov-Fokker-Planck forward and backward equations. The discrete and continuous approaches are applied to analyze the species abundance distributions and the time to species extinction. Moreover, with the aid of the continuous approach a realistic classification of the behavior of species in local communities is developed. The species abundance dynamics at the edge between two distinct habitats is compared with those located in the homogeneous interior habitats using species abundance distributions and the first time to species extinction. We show that the structure of the links between local community and the metacommunity plays an important role on species persistence. Specifically, species at the edge between two distinct metacommunities have higher extinction rate than those in the interior habitats connected only to one metacommunity. Moreover, the same species might be persistent in the homogeneous interior habitat, but its probability of extinction from the edge local community could be very high. 相似文献
29.
Eryngium regnellii Malme belongs to the largest genera in the Apiaceae family, with 250 species worldwide and 65 represented in South America. It is a herbaceous species typical of hill plant communities, which, along with remnant grassland patches, are the most relevant natural habitats for the maintenance of diversity in the Southern Pampas. Eryngium regnellii is key to the maintenance of pollination mutualisms, being a generalist (displaying a diverse assemblage of pollinators) and ubiquitous species (present in all studied sierras). However, fragmentation of the Pampean landscape due to agricultural intensification has led to the loss of natural environments. Therefore, the reintroduction of E. regnellii in strategic places would facilitate the occurrence of wild pollinators, while favoring pollination services in the agroecosystem. The germination requirements of E. regnellii were studied because a better knowledge of the reproductive biology of this species would provide information relevant to its reproduction and reintroduction into degraded areas. Germination percentages and mean time to germination were evaluated, using one control and two pre-germination treatments: chemical scarification with sulfuric acid, and mechanical scarification with sand paper. Chemical scarified seeds did not germinate. Mechanically scarified and control seed groups showed no significant differences either in germination percentages (49% and 59% respectively) or in mean germination time (13 and 14 days, respectively). Results indicate that E. regnellii shows no physical dormancy, and does not require specific pre-germination treatments for germination under the studied laboratory conditions. The high germination capacity of E. regnellii, along with its ecological attributes, make it a potential species for restoring plant-pollinator interactions in the fragmented landscapes of the Southern Pampas. 相似文献
30.
Hernández-Cruz AE E Sánchez P Preciado-Rangel M L García-Bañuelos A Palomo-Gil A Espinoza-Banda 《Phyton》2015,84(2):454-460
In the production of cotton (Gossypium hirsutum L.), nitrogen fertilization is one of the most costly crop practices, but important to reach high yields. However, high nitrogen (N) content in plants does not always translate into a high fibre production. One way of assessing the efficiency of the N fertilizer is through the enzymatic activity of the nitrate reductase (NR). This is a key enzyme in N assimilation, whose activity is regulated by a number of endogenous and exogenous factors that determine yield. The aim of this study was to assess the effect of N fertilization on yield, fibre quality, biomass, and NR enzymatic activity in vivo in the cotton variety Fiber Max 989. The evaluated application rates were 0, 50, 100, and 150 kg/ha of N, using urea as a source (46% N) in a randomizedblock design with three replicates. At harvest, the maximum yield of seed cotton and the greatest accumulation of total foliar biomass through time was reached after applying 150 kg N/ha. The different N-application rates did not affect the components of cotton-fibre quality. The activity of endogenous NR was greater on plants where 150 kg N/ha were applied. The highest cotton yield and N contents were obtained on these plants. Therefore, the NR activity in vivo could be used as a bioindicator of the N nutritional level in cotton. 相似文献