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971.
Kreutter KD Lu T Lee L Giardino EC Patel S Huang H Xu G Fitzgerald M Haertlein BJ Mohan V Crysler C Eisennagel S Dasgupta M McMillan M Spurlino JC Huebert ND Maryanoff BE Tomczuk BE Damiano BP Player MR 《Bioorganic & medicinal chemistry letters》2008,18(9):2865-2870
2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (Ki = 1.2 nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration. 相似文献
972.
Marsault E Hoveyda HR Gagnon R Peterson ML Vézina M Saint-Louis C Landry A Pinault JF Ouellet L Beauchemin S Beaubien S Mathieu A Benakli K Wang Z Brassard M Lonergan D Bilodeau F Ramaseshan M Fortin N Lan R Li S Galaud F Plourde V Champagne M Doucet A Bhérer P Gauthier M Olsen G Villeneuve G Bhat S Foucher L Fortin D Peng X Bernard S Drouin A Déziel R Berthiaume G Dory YL Fraser GL Deslongchamps P 《Bioorganic & medicinal chemistry letters》2008,18(16):4731-4735
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported. 相似文献
973.
Travins JM Ali F Huang H Ballentine SK Khalil E Hufnagel HR Pan W Gushue J Leonard K Bone RF Soll RM DesJarlais RL Crysler CS Ninan N Kirkpatrick J Cummings MD Huebert N Molloy CJ Gaul M Tomczuk BE Subasinghe NL 《Bioorganic & medicinal chemistry letters》2008,18(5):1603-1606
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described. 相似文献
974.
Karen H. Beard Deane Wang Carl E. Waite Kelly L. M. Decker Gary J. Hawley Donald D. DeHayes Jeffery W. Hughes Jonathan R. Cumming 《Ecosystems》2005,8(2):210-224
The complexity of natural ecosystems makes it difficult to compare the relative importance of abiotic and biotic factors and to assess the effects of their interactions on ecosystem development. To improve our understanding of ecosystem complexity, we initiated an experiment designed to quantify the main effects and interactions of several factors that are thought to affect nutrient export from developing forest ecosystems. Using a replicated 2 × 2 × 4 factorial experiment, we quantified the main effects of these factors and the factor interactions on annual calcium, magnesium, and potassium export from field mesocosms over 4 years for two Vermont locations, two soils, and four different tree seedling communities. We found that the main effects explained 56%–97% of total variation in nutrient export. Abiotic factors (location and soil) accounted for a greater percentage of the total variation in nutrient export (47%–94%) than the biotic factor (plant community) (2%–15%). However, biotic control over nutrient export was significant, even when biomass was minimal. Factor interactions were often significant, but they explained less of the variation in nutrient export (1%–33%) than the main effects. Year-to-year fluctuations influenced the relative importance of the main effects in determining nutrient export and created factor interactions between most of the explanatory variables. Our study suggests that when research is focused on typically used main effects, such as location and soil, and interactions are aggregated into overall error terms, important information about the factors controlling ecosystem processes can be lost. 相似文献
975.
Marcio Carvalho de Moretzsohn Mark S Hopkins Sharon E Mitchell Stephen Kresovich Jose Francisco Montenegro Valls Marcio Elias Ferreira 《BMC plant biology》2004,4(1):11
Background
The genus Arachis is native to a region that includes Central Brazil and neighboring countries. Little is known about the genetic variability of the Brazilian cultivated peanut (Arachis hypogaea, genome AABB) germplasm collection at the DNA level. The understanding of the genetic diversity of cultivated and wild species of peanut (Arachis spp.) is essential to develop strategies of collection, conservation and use of the germplasm in variety development. The identity of the ancestor progenitor species of cultivated peanut has also been of great interest. Several species have been suggested as putative AA and BB genome donors to allotetraploid A. hypogaea. Microsatellite or SSR (Simple Sequence Repeat) markers are co-dominant, multiallelic, and highly polymorphic genetic markers, appropriate for genetic diversity studies. Microsatellite markers may also, to some extent, support phylogenetic inferences. Here we report the use of a set of microsatellite markers, including newly developed ones, for phylogenetic inferences and the analysis of genetic variation of accessions of A. hypogea and its wild relatives. 相似文献976.
977.
David A Leavens Autumn B Hostetter Michael J Wesley William D Hopkins 《Animal behaviour》2004,67(3):467-476
Do chimpanzees tailor their communication in accordance with the attentional status of a human observer? We presented 57 chimpanzees with three experimental conditions in randomized order: an experimenter offered a banana to the focal subject (Focal), to a cagemate of the focal subject (In-Cage) and to a chimpanzee in an adjacent cage (Adjacent) while a second experimenter recorded the first and second responses of the focal subject in all three conditions. The chimpanzees' behaviour was mostly visual or bimodal in the Focal condition, changing to auditory behaviour or disengagement in the In-Cage and Adjacent conditions. Thus, with no explicit training and on their first trials in all instances, the chimpanzees tactically deployed their communicative behaviours in the visual and auditory domains in accordance with the manipulated attentional and intentional status of a human observer. 相似文献
978.
René R Balandrán-Quintana Ana Ma Mendoza-Wilson Gerardo Alvarez-Manilla Carl W Bergmann Irasema Vargas-Arispuro Miguel Angel Martínez-Téllez 《Biochemical and biophysical research communications》2002,290(1):577-584
The effect of pectic oligomers (OG) on ethylene biosynthesis, electrolyte leakage (EL), and CO(2) production was studied in discs excised from zucchini fruit (Cucurbita pepo L.) and stored at 20 or 2.5 degrees C. At 20 degrees C, OG enhanced ethylene biosynthesis and had a transient effect on decreasing EL, but showed little effect on respiratory rate; both the amount and size of the oligomer were important in changing both ethylene synthesis and EL. At 2.5 degrees C, OG increased both ethylene biosynthesis and respiratory rate with a maximum effect at 100 microg of oligomer and peaking at 6 h; shorter oligomers demonstrated an even greater effect on ethylene biosynthesis, but differences were smaller in respiratory rate. EL at 2.5 degrees C was affected most by 1 microg of OG and by monomeric galacturonic acid, with transient increases that peaked at 8 h. We suggest a signaling role for OG in the early steps of cold acclimation or chilling injury. 相似文献
979.
Sharon C Francis Carl Sunshine Kevin L Kirk 《The Journal of biological chemistry》2002,277(10):7816-7823
Previously we observed that rab3 GTPases modulate both the secretion of catecholamines from PC12 neuroendocrine cells and the steady-state accumulation of exogenous norepinephrine (NE) into these cells (Weber, E., Jilling, T., and Kirk, K. L. (1996) J. Biol. Chem. 271, 6963-6971). Here we addressed the mechanisms by which these monomeric GTPases stimulate NE uptake by PC12 cells including their effects on uptake kinetics, their sites of action (secretory granule membrane versus plasma membrane), and the involvement of rab3-interacting proteins in this process. We observed that rab3B stimulated the rate and maximal accumulation of radiolabeled NE into large dense core vesicles within intact PC12 cells. rab3A and rab3B also increased NE uptake into large dense core vesicles in digitonin-permeabilized PC12 cells, which indicates that these GTPases stimulate catecholamine uptake at the level of the secretory granule membrane. In an attempt to identify rab3B targets that may mediate this effect on NE uptake, we found that rab3B interacts directly with phosphoinositide 3-kinase (PI3K) in a GTP-dependent fashion and that PI3K activity was elevated in PC12 cells overexpressing rab3B. Furthermore, two structurally distinct inhibitors of PI3K (wortmannin and LY294002) inhibited NE uptake in intact as well as digitonin-permeabilized PC12 cells, but had no effect on calcium-evoked NE secretion. Our results indicate that rab3 and PI3K positively and coordinately regulate NE uptake in PC12 neuroendocrine cells at least in part by stimulating the secretory vesicle uptake step. 相似文献