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S Kim U Boege S Krishnaswamy I Minor T J Smith M Luo D G Scraba M G Rossmann 《Virology》1990,175(1):176-190
The structure of Mengo virus had been determined from crystals grown in the presence of 100 mM phosphate buffer at pH 7.4. It is shown that Mengo virus is poorly infectious at the phosphate concentration similar to that in which it was crystallized. Maximal infectivity is achieved at 10 mM phosphate or less in physiological saline. The phosphate effect is ameliorated when the pH is lowered to 4.6. Although it has not been possible to study the crystal structure of the virus at low phosphate concentrations, it is shown that increasing the Cl- concentration at pH 6.2 or decreasing the pH to 4.6 causes substantial conformational changes confined to the "pit," a deep surface depression. These structural changes involve a movement of the "FMDV loop" (GH loop) in VP1, an ordering of the "VP3 loop" (GH loop in VP3) between 3176 and 3182, the displacement of a bound phosphate near the "FMDV loop" (GH loop in VP1), and movement of the carboxy terminus of VP2. The changes in conformation are correlated with the dissociation of the virion into pentamers at pH 6.2 and 150 mM Cl-. The localization of the conformational changes and the correlated role of the phosphate in controlling infectivity support the hypothesis that the "pit" is the receptor attachment site. 相似文献
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Rodent models of rheumatoid arthritis (RA) are useful tools to study the pathogenic process of RA. Among the most widely used models of RA are the streptococcal cell wall (SCW) arthritis model and the collagen-induced arthritis (CIA). Both innate and adaptive immune mechanisms are involved in these rodent models. While no models perfectly duplicate the condition of human RA, they are easily reproducible, well defined and have proven useful for development of new therapies for arthritis, as exemplified by cytokine blockade therapies. Besides SCW and CIA models, there are numerous others including transgenic models such as K/BxN, induced models such as adjuvant-induced and pristane models, and spontaneous models in certain mouse strains, that have been used to help understand some of the underlying mechanisms. This review provides an update and analysis of RA models in mice and rats. The array of models has provided rheumatologists and immunologists a means to understand the multifactorial disease in humans, to identify new drug targets, and to test new therapies. 相似文献
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Raghavan Krishnaswamy S. Gray David B. Scholz Thomas H. Nemeth Gregory A. Hussain Munir A. 《Pharmaceutical research》1996,13(12):1815-1820
Purpose. The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development.
Methods. The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples.
Results. The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves -lactam ring opening. The -lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the k
OH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the -lactam nitrogen making it a good leaving group.
Conclusions. The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible. 相似文献
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N H Wadia V S Trikannad P R Krishnaswamy 《Journal of neurology, neurosurgery, and psychiatry》1981,44(9):849-851
The infrequency of multiple sclerosis in India may have genetic implications. We found (a) the HLA-A3 and HLA-B7 haplotypes amongst Indians to be lower than those reported in Caucasians, (b) no excess of HLA-A3 and HLA-B7 amongst our 27 multiple sclerosis patients compared to 330 controls; instead it was the reverse, (c) HLA-B12 as high as 74% in the "clinically definite" cases, against only 9% in controls, (d) a significant relative risk of MS amongst Indians with HLA-B12 haplotype. Attention is drawn to th higher incidence of MS amongst the small Parsee community and the high association of HLA-B12 in these patients. 相似文献
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Soundararajan Krishnaswamy Su X Duan Lisa L Von Moltke David J Greenblatt Michael H Court 《Drug metabolism and disposition》2003,31(1):133-139
Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n = 54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of 7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative human liver microsomes (n = 7) and pooled human kidney, intestinal and lung microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis-Menten kinetics. Serotonin glucuronidation activity in these human liver microsomes had widely varying V(max) values ranging from 0.62 to 51.3 nmol/min/mg of protein but very similar apparent K(m) values ranging from 5.2 to 8.8 mM. Pooled human kidney, intestine, and lung microsomes had V(max) values (mean +/- standard error of the estimates) of 8.8 +/- 0.4, 0.22 +/- 0.00, and 0.03 +/- 0.00 nmol/min/mg of protein (respectively) and apparent K(m) values of 6.5 +/- 0.9, 12.4 +/- 2.0, and 4.9 +/- 3.3 mM (respectively). In comparison, recombinant UGT1A6 had a V(max) of 4.5 +/- 0.1 nmol/min/mg of protein and an apparent K(m) of 5.0 +/- 0.4 mM. A highly significant correlation was found between immunoreactive UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin concentration in human liver microsomes (R(s) = 0.769; P < 0.001) (n = 52). In conclusion, these results indicate that serotonin is a highly selective in vitro probe substrate for human UGT1A6. 相似文献
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