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131.
Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes 总被引:29,自引:0,他引:29
McDermott MF Aksentijevich I Galon J McDermott EM Ogunkolade BW Centola M Mansfield E Gadina M Karenko L Pettersson T McCarthy J Frucht DM Aringer M Torosyan Y Teppo AM Wilson M Karaarslan HM Wan Y Todd I Wood G Schlimgen R Kumarajeewa TR Cooper SM Vella JP Amos CI Mulley J Quane KA Molloy MG Ranki A Powell RJ Hitman GA O'Shea JJ Kastner DL 《Cell》1999,97(1):133-144
Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease. 相似文献
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B.?McCarthy A.?Daws D.?L.?MacmillanEmail author 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2004,190(4):291-299
Recordings were made from the nerve innervating the stretch receptors of the abdominal muscle receptor organs and slow extensor muscles of tethered crayfish, Cherax destructor, during so-called non-giant swimming. The stretch receptors were active during the flexor phase of swimming but the duration and pattern of activity varied from cycle to cycle. Their pattern of firing was modified by the activity of the large accessory neurons which make direct inhibitory synapses upon them. Neither the stretch receptors nor the accessory neurons were active during the extensor phase of the cycle. The timing and extent of tailfan movements during the period of stretch receptor activity were measured from video records before and after the stretch receptor nerves were cut in the second to fifth segments. The promotion of the tailfan during flexion was significantly delayed and the minimum angle to which the uropods were remoted at the end of flexion significantly larger in denervated animals. We propose that afferent information from the stretch receptors coordinates the timing and extent of tailfan movements according to variations in the positioning and movement of the abdominal segments such that the hydrodynamic efficiency of the tailfan is enhanced on a cycle by cycle basis during non-giant swimming.Abbreviations A# abdominal segment number - Acc accessory neuron - LUU large unidentified unit - MRO muscle receptor organ - NGS non-giant swimming - SEMN slow extensor motor neuron - SR stretch receptor neuron 相似文献
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P3 cap modified Phe*-Ala series BACE inhibitors 总被引:1,自引:0,他引:1
Chen SH Lamar J Guo D Kohn T Yang HC McGee J Timm D Erickson J Yip Y May P McCarthy J 《Bioorganic & medicinal chemistry letters》2004,14(1):245-250
With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM). 相似文献
139.
Webb TR Moran T Huang CQ McCarthy JR Grigoriadis DE Chen C 《Bioorganic & medicinal chemistry letters》2004,14(15):3869-3873
A series of benzoylpyrimidines derived from the anilinepyrimidine CRF(1) antagonists were synthesized. Several synthetic routes were developed to explore the SAR of this series of compounds. Compounds such as 8d (K(i) = 15 nM) exhibited high binding affinities at the human CRF(1) receptor. 相似文献
140.
Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes 总被引:11,自引:0,他引:11