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401.
Synapsin I bundles F-actin in a phosphorylation-dependent manner 总被引:12,自引:0,他引:12
Synapsin I is a neuron-specific phosphoprotein localized to the cytoplasmic surface of synaptic vesicles. This phosphoprotein is a major substrate for cyclic AMP-dependent and calcium/calmodulin-dependent protein kinases. Its state of phosphorylation can be altered both in vivo and in vitro by a variety of physiological and pharmacological manipulations known to affect synaptic function. Recent direct evidence suggests that it may be involved in the regulation of neurotransmitter release from the nerve terminal. In the nerve terminal, synaptic vesicles are embedded in a cytoskeletal network, consisting in part of actin. We report here the ability of the dephospho-form of synapsin I to bundle F-actin. This bundling activity is reduced when synapsin I is phosphorylated by cAMP-dependent protein kinase and virtually abolished when it is phosphorylated by calcium/calmodulin-dependent protein kinase II or by both kinases. These results, demonstrating an interaction of synapsin I with actin in vitro, support the possibility that synapsin I is involved in clustering of synaptic vesicles at the presynaptic terminal and that the phosphorylation of synapsin I may be involved in regulating the translocation of synaptic vesicles to their sites of release. 相似文献
402.
RNAi-mediated gene silencing in non-human primates 总被引:2,自引:0,他引:2
Zimmermann TS Lee AC Akinc A Bramlage B Bumcrot D Fedoruk MN Harborth J Heyes JA Jeffs LB John M Judge AD Lam K McClintock K Nechev LV Palmer LR Racie T Röhl I Seiffert S Shanmugam S Sood V Soutschek J Toudjarska I Wheat AJ Yaworski E Zedalis W Koteliansky V Manoharan M Vornlocher HP MacLachlan I 《Nature》2006,441(7089):111-114
The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs. 相似文献
403.
Da Jiang Yinping Pan Shiyuan Wang Yishi Lin Connor M.Holland John R.Kirtley Xianhui Chen Jun Zhao Lei Chen Shaoyu Yin Yihua Wang 《科学通报(英文版)》2021,(5):425-432
The iron-chalcogenide high temperature superconductor Fe(Se,Te) (FST) has been reported to exhibit complex magnetic ordering and nontrivial band topology which ... 相似文献
404.
提出了可变频时钟写入方法和锁相环倍频时钟写入方法,给出了这两种写入法的读/写电路,并分析了其性能。结果证明,可变频时钟写入方法电路简单,刻写时钟周期短;锁相环倍频时钟写入过程较前者长,但其频率范围容易调整。两者均适合高密度小型温盘的时钟录写。 相似文献
405.
Inactivation of the apoptosis effector Apaf-1 in malignant melanoma 总被引:47,自引:0,他引:47
Soengas MS Capodieci P Polsky D Mora J Esteller M Opitz-Araya X McCombie R Herman JG Gerald WL Lazebnik YA Cordón-Cardó C Lowe SW 《Nature》2001,409(6817):207-211
Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type. 相似文献
406.
Hereditary spherocytosis (HS) is a common, clinically heterogeneous haemolytic anaemia in which the primary erythrocyte defect is believed to be some abnormality in the spectrin-actin membrane skeleton, leading to loss of surface membrane. Recessively inherited spectrin deficiency with extreme erythrocyte fragility and spherocytosis has been identified in certain mutant mice and two severely anaemic humans. Although suspected, deficiency of spectrin has not been demonstrated in less severe forms of human HS. We not report the quantitation of erythrocytes spectrin by radioimmunoassay. We found that normal erythrocytes contained 240,000 copies of spectrin heterodimer, whereas erythrocytes from 14 patients with a variety of types of HS were all partially deficient in spectrin (range 74,000-200,000 copies), the magnitude of the deficiency correlating with the severity of the disease. Spectrin deficiency of varying degrees is common in HS and probably represents the principal structural defect leading to loss of surface membrane. 相似文献
407.
肖人彬 《华中科技大学学报(自然科学版)》1994,(12)
阐述了人的建模思维机制。引入等价关系和划分作为问题粒度研究的基础,定义了逆商集,使之与商集一起,构成了对问题不同粒度的完整描述,并讨论了粒度的性质,借助拓扑分析,给出了问题可分解、可细化和粗化、细化等一系列定义,在问题簇和模型簇概念的基础上,提出了嵌套式建模(支持)作为面向复杂系统的建模支持方法论,具体给出了其实施步骤,这是一个人机交互的启发式过程,将嵌套式建模与传统式建模作了比较,此外还作了若干说明。 相似文献
408.
409.
A general model for ontogenetic growth. 总被引:36,自引:0,他引:36
Several equations have been proposed to describe ontogenetic growth trajectories for organisms justified primarily on the goodness of fit rather than on any biological mechanism. Here, we derive a general quantitative model based on fundamental principles for the allocation of metabolic energy between maintenance of existing tissue and the production of new biomass. We thus predict the parameters governing growth curves from basic cellular properties and derive a single parameterless universal curve that describes the growth of many diverse species. The model provides the basis for deriving allometric relationships for growth rates and the timing of life history events. 相似文献
410.
主要利用φ混合序列的矩不等式和随机变量的截尾技术,在适当的矩条件下,研究了φ混合序列的完全矩收敛性。本文的结果推广了独立序列和已有文献关于φ混合序列的相应结果,同时也将φ混合序列的完全收敛性改进到完全矩收敛性。 相似文献