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Dr. Jessica S. Kelsey Dr. Tamas Geczy Nancy E. Lewin Dr. Noemi Kedei Colin S. Hill Julia S. Selezneva Christopher J. Valle Wonhee Woo Dr. Inna Gorshkova Dr. Peter M. Blumberg 《Chembiochem : a European journal of chemical biology》2014,15(8):1131-1144
The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C δ C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure–activity relations for C1 domain ligands. Coexpressing pairs of C1‐containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain. 相似文献
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高压直流电缆实际运行过程中可能会有缺陷出现,使得电缆内部电场分布发生畸变,加速绝缘材料的老化。运用有限元分析的方法,对直流电缆电场分布进行了二维和三维建模和仿真分析,研究了不同电缆绝缘层温差、缺陷位置及尺寸情况下电缆中单个球形缺陷对周围绝缘材料的影响,得到了较为通用的直流电缆缺陷对电场畸变的计算公式。研究发现三维仿真更加适合对缺陷进行研究,稳态下缺陷对电场的加强决定于材料的电导率,且缺陷对绝缘材料的影响是局部的. 相似文献
4.
Pai-shan PA Digital Content Design Graduate School of Toy Game Design National Taipei University of Education Taipei City China 《中国有色金属学会会刊》2011,(Z1)
Color filters are produced using semiconductor production techniques although problems with low yield remain to be addressed. This study presents a new means of selective removal using excimer irradiation, chemical etching, or electrochemical machining on the fifth generation TFT LCDs. The selective removal of microstructure layers from the color filter surface of an optoelectronic flat panel display, as well as complete removal of the ITO thin-films, RGB layer, or resin black matrix (BM) layer from the sub... 相似文献
5.
Noga Gal Dr. Sofiya Kolusheva Dr. Noemi Kedei Dr. Andrea Telek Taiyabah A. Naeem Nancy E. Lewin Langston Lim Poonam Mannan Susan H. Garfield Dr. Saïd El Kazzouli Dr. Dina M. Sigano Dr. Victor E. Marquez Dr. Peter M. Blumberg Prof. Raz Jelinek 《Chembiochem : a European journal of chemical biology》2011,12(15):2331-2340
N‐methyl‐substituted diacylglycerol–indololactones (DAG–indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCα. We present a comprehensive analysis of membrane interactions and biological activities of several DAG–indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG–indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands. 相似文献
6.
Chris T. Freeman Muhammad Ali Alsubaie Zhonglun Cai Eric Rogers Paul L. Lewin 《International Journal of Adaptive Control and Signal Processing》2013,27(3):230-249
Previous work has shown that the structure of repetitive control (RC) and that of iterative learning control (ILC) differ only in the location of an internal model of the disturbance. In this paper, it is shown how this common setting permits derivation of controllers in one domain based on an existing controller in the other. This is illustrated using the following case studies: 1) an RC scheme using a state feedback structure is derived based on an existing ILC scheme, which also uses state feedback (the underlying structure is first extended to comprise both current‐error feedback and previous‐error feedforward implementations); and 2) an ILC scheme using an output injection structure is developed based on an existing RC scheme, which uses state feedback, but differs from 1) by containing only a single internal model representation. All controllers are shown to have similar equivalent representations, with parameters derived by using linear quadratic regulator analysis. This correspondence enables comparison of the effect of the structure (ILC or RC, state feedback or output injection), number of internal models, and use of error (feedback or feedforward) on subsequent performance. This is undertaken using experimental results obtained using a gantry robot. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
7.
PA Bretscher 《Canadian Metallurgical Quarterly》1999,96(1):185-190
I present here a new model for the primary activation of precursor helper T cells. Observations demonstrate that the immune system learns not to respond to extrathymic, organ-specific self-antigens because of their early appearance in development. The immune system thus discriminates between peripheral self-antigens and foreign antigens and, when mature, usually makes an immune response against only the latter. Contemporary models for the activation and inactivation of T helper (Th) function do not account for such discrimination. The model proposed here is consistent with contemporary findings and incorporates a mechanism of peripheral self-nonself discrimination. 相似文献
8.
OBJECTIVE: Cholelithiasis is a common problem in hospitals of the Peruvian Andes; however, its prevalence in Andean communities is unknown. To estimate the prevalence of gallstone disease in this locale, we conducted a cross-sectional community study in three high-altitude Peruvian rural villages (i.e., > 3000 m above sea level). METHODS: We examined 911 volunteers > 15 yr of age from three villages for gallstone disease by history and ultrasonography. Risk factors for gallstone disease were examined in 382 volunteers from one village. RESULTS: The age-adjusted prevalence of gallstone disease ranged from 4-10% in men and from 18-20% in women. Women had significantly higher age-adjusted prevalence rates than did men. The prevalence of gallstone disease increased significantly with age and decreased significantly with alcohol consumption. Although not statistically significant, we found a positive association between gallstone disease and body mass index. CONCLUSION: The results of this study indicate that gallstone disease, commonly perceived as a disease of the developed world, is also a common problem in high-altitude Peruvian communities. 相似文献
9.
P Sarti E Lendaro R Ippoliti A Bellelli PA Benedetti M Brunori 《Canadian Metallurgical Quarterly》1999,13(1):191-197
With the electro-driven import of rhodamine 123, we used single cell fluorescence microscopy to single out the contribution of nitric oxide (NO) in controlling mitochondrial membrane potential expressed by (stationary growing) rhabdomyosarcoma and neuroblastoma cells in culture. The experimental design and the computer-aided image analysis detected and quantitated variations of fluorescence signals specific to mitochondria. We observed that 1) the two cell lines display changes of fluorescence dependent on mitochondrial energization states; 2) mitochondrial fluorescence decreases after exposure of the cells to a NO releaser; 4) the different fluorescence intensity measured under stationary growing conditions, or after activation and inhibition of constitutive NO synthase, is consistent with a steady-state production of NO. Direct comparison of single cell fluorescence with bulk cytofluorimetry proved that the results obtained by the latter method may be misleading because of the intrinsic-to-measure lack of information about distribution of fluorescence within different cell compartments. The kinetic parameters describing the reactions between cytochrome oxidase, NO, and O2 may account for the puzzling (20-fold) increase of the KM for O2 reported for cells and tissues as compared to purified cytochrome c oxidase, allowing an estimate of in vivo NO flux. 相似文献
10.