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排序方式: 共有9596条查询结果,搜索用时 15 毫秒
991.
992.
ML Curtin SK Davidsen HR Heyman RB Garland GS Sheppard AS Florjancic L Xu GM Carrera DH Steinman JA Trautmann DH Albert TJ Magoc P Tapang DA Rhein RG Conway G Luo JF Denissen KC Marsh DW Morgan JB Summers 《Canadian Metallurgical Quarterly》1998,41(1):74-95
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development. 相似文献
993.
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995.
JA Hamilton 《Canadian Metallurgical Quarterly》1998,39(3):467-481
Transport of unesterified fatty acids (FA) into cells has been viewed either as a simple diffusion process regulated mainly by lipid physical chemistry or as a more complex process involving protein catalysis. In this review FA transport in cell membranes is broken down into three essential steps: adsorption, transmembrane movement, and desorption. The physical properties of FA in aqueous, membrane, and protein environments relevant to transport mechanisms are discussed, with emphasis on recent information derived from NMR and fluorescence studies. Because of their low solubility in water and high hydrophobicity, FA bind rapidly and avidly to model membranes (phospholipid bilayers); if albumin is a donor, FA desorb rapidly to reach their equilibrium distribution between the membrane and albumin. The ionization properties of FA in a phospholipid bilayer result in a high population of the un-ionized form (approximately 50%) at pH 7.4, which diffuses across the lipid bilayer (flip-flops) rapidly (t(1/2) < 1 sec). Desorption of FA from a phospholipid surface is slower than transmembrane movement and dependent on the FA chain length and unsaturation, but is rapid for typical dietary FA. These physical properties of FA in model systems predict that proteins are not essential for transport of FA through membranes. The only putative FA transport protein to be purified and reconstituted into phospholipid bilayers, the mitochondrial uncoupling protein (UCP1), was shown to transport the FA anion in response to FA flip-flop. New experiments with cells have found that FA movement into cells acidifies the cytosol, as predicted by the flip-flop model. 相似文献
996.
We have used a spin column assay to study the detergent-solubilized levamisole receptor, a nicotinic acetylcholine receptor of the nematode Caenorhabditis elegans. The receptor can be successfully solubilized in detergent solutions of Triton X-100, Lubrol PX, or sodium cholate. Centrifugal gel filtration assay using the tritiated ligand [3H]meta-aminolevamisole ([3H]MAL) provides a greater signal and a better signal-to-noise ratio for soluble levamisole receptor binding than either polyethylene glycol precipitation or DEAE filter assay with the same ligand. As for membrane-bound receptor, the detergent-solubilized levamisole receptor consists of more than one affinity state. Detergent solubilization appears to increase the affinity of all states for [3H]MAL (Kd for the highest affinity solubilized [3H]MAL binding state, 41 +/- 5 pM). Data is presented on the equilibrium binding and the association and dissociation reaction rates of the receptor. The similar relative efficacy with which various compounds inhibit specific [3H]MAL binding and deficiencies in solubilizable high affinity specific [3H]MAL binding in two receptor mutants show that the solubilized receptor is the same nicotinic acetylcholine receptor that is detected by assaying membrane-bound specific [3H]MAL binding. The detergent-solubilized levamisole receptor is stable at 0 degree to 4 degrees C, making receptor purification feasible. 相似文献
997.
TE Burris DK Holmes-Higgin TA Silvestrini JA Scholl RA Proudfoot PC Baker 《Canadian Metallurgical Quarterly》1997,13(6):556-567
The endogenous circadian rhythm of melatonin in humans provides information regarding the resetting response of the human circadian timing system to changes in the light-dark (LD) cycle. Alterations in the LD cycle have both acute and chronic effects on the observed melatonin rhythm. Investigations to date have firmly established that the melatonin rhythm can be reentrained following an inversion of the LD cycle. Exposure to bright light and darkness given over a series of days can rapidly induce large-magnitude phase shifts of the melatonin rhythm. Even single pulses of bright light can shift the timing of the melatonin rhythm. Recent data have demonstrated that lower light intensities than originally believed are capable of resetting the melatonin rhythm and that stimulation of photopically sensitive photoreceptors (i.e., cones) is sufficient to reset the endogenous circadian melatonin rhythm. In addition to phase resetting, exposure to light of critical timing, strength, and duration can attenuate the amplitude of the endogenous circadian rhythm of melatonin. Measurement of melatonin throughout resetting trials provides a dynamic view of the resetting response of the human circadian pacemaker to light. Future studies of the melatonin rhythm in humans may further characterize the resetting response of the human circadian timing system to light. 相似文献
998.
The understanding of the effect of impeller‐sparger configurations on gas dispersion and mass transfer is very important to improve the performance of gas/liquid contactor systems. The influence of the impeller positions, the upper turbine diameter, the sparger ring diameter and its location in regard to the lower impeller on the power consumption, the volumetric mass‐transfer coefficient and the overall oxygen transfer efficiency were studied in a nonstandard curved bottomed reactor with an agitated system with dual disk style turbines. In the range of the gas flow rates studied, the most efficient impeller‐sparger arrangement for the oxygen transfer is the impeller system with turbines of different diameters located at C = 0.25 and IC = 0.5, and with the sparger of smaller diameter than the lower impeller settled below the impeller. A new model to estimate the kLa with an average relative error of 8 %, which takes the reactor operation conditions and the influence of the impeller‐sparger geometry into account, was also proposed. 相似文献
999.
1000.