全文获取类型
收费全文 | 110篇 |
免费 | 2篇 |
专业分类
112篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2018年 | 2篇 |
2017年 | 1篇 |
2016年 | 1篇 |
2015年 | 5篇 |
2014年 | 2篇 |
2013年 | 1篇 |
2012年 | 5篇 |
2011年 | 2篇 |
2010年 | 2篇 |
2009年 | 3篇 |
2008年 | 4篇 |
2007年 | 4篇 |
2006年 | 9篇 |
2005年 | 1篇 |
2004年 | 5篇 |
2003年 | 1篇 |
2002年 | 3篇 |
2001年 | 11篇 |
2000年 | 1篇 |
1999年 | 9篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1970年 | 1篇 |
1928年 | 1篇 |
1909年 | 1篇 |
排序方式: 共有112条查询结果,搜索用时 10 毫秒
61.
Affinity and specificity requirements for the first Src homology 3 domain of the Crk proteins. 总被引:3,自引:2,他引:3 下载免费PDF全文
B S Knudsen J Zheng S M Feller J P Mayer S K Burrell D Cowburn H Hanafusa 《The EMBO journal》1995,14(10):2191-2198
The specificity of SH3 domain complex formation plays an important role in determining signal transduction events. We have previously identified a highly specific interaction between the first CrkSH3 domain [CrkSH3(1)] and proline-rich sequences in the guanine nucleotide exchange factor C3G. A 10 amino acid peptide derived from the first proline-rich sequence (P3P4P5A6L7P8P9K10K11R12) bound with a Kd of 1.89 +/- 0.06 microM and fully retained the high affinity and unique selectivity for the CrkSH3(1) domain. Mutational analysis showed that P5, P8, L7 and K10 are critical for high affinity binding. A conservative mutation, K10R, significantly decreased the affinity for the CrkSH3(1) domain while increasing the affinity for Grb2. Comparative binding studies with the K10R and K10A mutant peptides to c-Crk and v-Crk further suggested that K10 binds via a charge-dependent and a charge-independent interaction to the RT loop of the CrkSH3(1) domain. Besides determining important structural features necessary for high affinity and specificity binding to the CrkSH3(1) domain, our results also demonstrate that a conservative mutation in a single amino acid can significantly alter the specificity of an SH3 binding peptide. 相似文献
62.
Zheng L Terman A Hallbeck M Dehvari N Cowburn RF Benedikz E Kågedal K Cedazo-Minguez A Marcusson J 《Autophagy》2011,7(12):1528-1545
Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days), and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration. 相似文献
63.
Characterisation, Density, and Distribution of Kainate Receptors in Normal and Alzheimer''s Diseased Human Brain 总被引:1,自引:0,他引:1
Richard F. Cowburn John A. Hardy Roger S. Briggs Peter J. Robertsdagger 《Journal of neurochemistry》1989,52(1):140-147
The specific binding of [3H]kainic acid was investigated in membrane preparations from human parietal cortex obtained postmortem. Saturation studies revealed that binding occurred to a single population of sites with a KD of 15 nM and a Bmax of 110 fmol/mg of protein. The kinetically determined dissociation constant for these sites agreed well with that obtained from saturation analyses. Pharmacological characterisation of these sites gave a profile consistent with those reported for kainate receptor sites in animal brain. The integrity of kainate receptors was studied in several brain regions from six patients who had died of Alzheimer's disease and from six closely matched control subjects. No change in either the affinity or the number of kainate receptors was seen in any of the regions studied, despite the loss of neocortical and hippocampal glutamatergic terminals in the Alzheimer's diseased brains, as previously reported. 相似文献
64.
Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease 总被引:3,自引:0,他引:3
Akterin S Cowburn RF Miranda-Vizuete A Jiménez A Bogdanovic N Winblad B Cedazo-Minguez A 《Cell death and differentiation》2006,13(9):1454-1465
Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Abeta) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on Abeta neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that Abeta causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Abeta toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, Abeta neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis. 相似文献
65.
Fabien Ferrage Kaushik Dutta Alexander Shekhtman David Cowburn 《Journal of biomolecular NMR》2010,47(1):41-54
Protein interactions are important for understanding many molecular mechanisms underlying cellular processes. So far, interfaces
between interacting proteins have been characterized by NMR spectroscopy mostly by using chemical shift perturbations and
cross-saturation via intermolecular cross-relaxation. Although powerful, these techniques cannot provide unambiguous estimates
of intermolecular distances between interacting proteins. Here, we present an alternative approach, called REDSPRINT (REDduced/Standard
PRoton density INTerface identification), to map protein interfaces with greater accuracy by using multiple NMR probes. Our
approach is based on monitoring the cross-relaxation from a source protein (or from an arbitrary ligand that need not be a
protein) with high proton density to a target protein (or other biomolecule) with low proton density by using isotope-filtered
nuclear Overhauser spectroscopy (NOESY). This methodology uses different isotropic labeling for the source and target proteins
to identify the source-target interface and also determine the proton density of the source protein at the interface for protein-protein
or protein-ligand docking. Simulation indicates significant gains in sensitivity because of the resultant relaxation properties,
and the utility of this technique, including a method for direct determination of the protein interface, is demonstrated for
two different protein–protein complexes. 相似文献
66.
We describe a high-throughput in-cell nuclear magnetic resonance (NMR)-based method for mapping the structural changes that accompany protein-protein interactions (STINT-NMR). The method entails sequentially expressing two (or more) proteins within a single bacterial cell in a time-controlled manner and monitoring the protein interactions using in-cell NMR spectroscopy. The resulting spectra provide a complete titration of the interaction and define structural details of the interacting surfaces at atomic resolution. 相似文献
67.
Anna Sandebring Kelly Jean Thomas Alexandra Beilina Marcel van der Brug Megan M. Cleland Rili Ahmad David W. Miller Ibardo Zambrano Richard F. Cowburn Homira Behbahani Angel Cedazo-Mínguez Mark R. Cookson 《PloS one》2009,4(5)
PTEN-induced novel kinase 1 (PINK1) mutations are associated with autosomal recessive parkinsonism. Previous studies have shown that PINK1 influences both mitochondrial function and morphology although it is not clearly established which of these are primary events and which are secondary. Here, we describe a novel mechanism linking mitochondrial dysfunction and alterations in mitochondrial morphology related to PINK1. Cell lines were generated by stably transducing human dopaminergic M17 cells with lentiviral constructs that increased or knocked down PINK1. As in previous studies, PINK1 deficient cells have lower mitochondrial membrane potential and are more sensitive to the toxic effects of mitochondrial complex I inhibitors. We also show that wild-type PINK1, but not recessive mutant or kinase dead versions, protects against rotenone-induced mitochondrial fragmentation whereas PINK1 deficient cells show lower mitochondrial connectivity. Expression of dynamin-related protein 1 (Drp1) exaggerates PINK1 deficiency phenotypes and Drp1 RNAi rescues them. We also show that Drp1 is dephosphorylated in PINK1 deficient cells due to activation of the calcium-dependent phosphatase calcineurin. Accordingly, the calcineurin inhibitor FK506 blocks both Drp1 dephosphorylation and loss of mitochondrial integrity in PINK1 deficient cells but does not fully rescue mitochondrial membrane potential. We propose that alterations in mitochondrial connectivity in this system are secondary to functional effects on mitochondrial membrane potential. 相似文献
68.
PTEN levels in Alzheimer's disease medial temporal cortex 总被引:3,自引:0,他引:3
Rickle A Bogdanovic N Volkmann I Zhou X Pei JJ Winblad B Cowburn RF 《Neurochemistry international》2006,48(2):114-123
Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a dual (protein tyrosine and lipid) phosphatase one of the functions of which is to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol-3,4-biphosphate thereby inhibiting phosphoinositide-dependent kinase activation of the cell survival kinase Akt. Akt activity is up regulated in Alzheimer's disease (AD) brain in parallel to the progression of neurofibrillary pathology. The present study determined whether altered expression of PTEN occurs in Alzheimer's disease brain. Western immunoblotting revealed no significant changes of PTEN protein levels in nuclear and membrane fractions of medial temporal cortex from a series of Alzheimer's disease and control cases. Similarly, no changes in PTEN protein levels, as determined by dot-blotting, were seen in temporal cortex homogenates from a separate series of Alzheimer's disease and control brains. A small but significant decrease in the levels of Ser(380) p-PTEN was seen in homogenates of Alzheimer's disease temporal cortex. Immunohistochemistry revealed PTEN immunoreactivity in a number of brain structures including neurons, capillaries and structures resembling oligodendrocytes and astrocytes. The majority of temporal cortex pyramidal neurons (93-100%) were PTEN immunopositive. The Alzheimer's disease cases had significantly lower numbers of total ( approximately 12% loss, P<0.02) and PTEN immunopositive ( approximately 15% loss, P<0.01) pyramidal neurons as compared to the control cases. 相似文献
69.
Summary This paper details the solid-phase synthesis by N
-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry of a series of bivalent consolidated ligands, branched peptides with lengths of 22 to 25 residues. The target peptides were designed to, and in fact do, interact with greater specificity and higher affinity with the SH2 and SH3 domains of Abelson kinase in an SH(32) dual domain construct. Fmoc-O-phospho-l-tyrosine[Fmoc-Tyr(PO3H2)-OH] was used to introduce the required phosphotyrosine residues, and Fmoc-N
-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl-l-lysine [Fmoc-Lys(Dde)-OH] was used to introduce a branch point that allowed proper orientation of individual ligands. The resultant product peptides were characterized by amino acid analyses and electrospray mass spectra.This paper is based on a presentation given at the Symposium on Peptide Structure and Design as part of the 31st Annual ACS Western Regional Meeting held in San Diego, CA, USA, October 18–21, 1995. 相似文献
70.
Ertan Eryilmaz Neel H. Shah Tom W. Muir David Cowburn 《The Journal of biological chemistry》2014,289(21):14506-14511
Protein splicing is a posttranslational modification where intervening proteins (inteins) cleave themselves from larger precursor proteins and ligate their flanking polypeptides (exteins) through a multistep chemical reaction. First thought to be an anomaly found in only a few organisms, protein splicing by inteins has since been observed in microorganisms from all domains of life. Despite this broad phylogenetic distribution, all inteins share common structural features such as a horseshoe-like pseudo two-fold symmetric fold, several canonical sequence motifs, and similar splicing mechanisms. Intriguingly, the splicing efficiencies and substrate specificity of different inteins vary considerably, reflecting subtle changes in the chemical mechanism of splicing, linked to their local structure and dynamics. As intein chemistry has widespread use in protein chemistry, understanding the structural and dynamical aspects of inteins is crucial for intein engineering and the improvement of intein-based technologies. 相似文献