全文获取类型
收费全文 | 147篇 |
免费 | 7篇 |
国内免费 | 1篇 |
专业分类
155篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 5篇 |
2019年 | 2篇 |
2018年 | 2篇 |
2017年 | 3篇 |
2016年 | 1篇 |
2015年 | 4篇 |
2014年 | 9篇 |
2013年 | 4篇 |
2012年 | 10篇 |
2011年 | 5篇 |
2010年 | 10篇 |
2009年 | 6篇 |
2008年 | 10篇 |
2007年 | 9篇 |
2006年 | 14篇 |
2005年 | 10篇 |
2004年 | 11篇 |
2003年 | 12篇 |
2002年 | 10篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 3篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1991年 | 1篇 |
1986年 | 2篇 |
1983年 | 1篇 |
1980年 | 2篇 |
排序方式: 共有155条查询结果,搜索用时 15 毫秒
121.
Liu Q Kirubakaran S Hur W Niepel M Westover K Thoreen CC Wang J Ni J Patricelli MP Vogel K Riddle S Waller DL Traynor R Sanda T Zhao Z Kang SA Zhao J Look AT Sorger PK Sabatini DM Gray NS 《The Journal of biological chemistry》2012,287(13):9742-9752
An intensive recent effort to develop ATP-competitive mTOR inhibitors has resulted in several potent and selective molecules such as Torin1, PP242, KU63794, and WYE354. These inhibitors are being widely used as pharmacological probes of mTOR-dependent biology. To determine the potency and specificity of these agents, we have undertaken a systematic kinome-wide effort to profile their selectivity and potency using chemical proteomics and assays for enzymatic activity, protein binding, and disruption of cellular signaling. Enzymatic and cellular assays revealed that all four compounds are potent inhibitors of mTORC1 and mTORC2, with Torin1 exhibiting ~20-fold greater potency for inhibition of Thr-389 phosphorylation on S6 kinases (EC(50) = 2 nM) relative to other inhibitors. In vitro biochemical profiling at 10 μM revealed binding of PP242 to numerous kinases, although WYE354 and KU63794 bound only to p38 kinases and PI3K isoforms and Torin1 to ataxia telangiectasia mutated, ATM and Rad3-related protein, and DNA-PK. Analysis of these protein targets in cellular assays did not reveal any off-target activities for Torin1, WYE354, and KU63794 at concentrations below 1 μM but did show that PP242 efficiently inhibited the RET receptor (EC(50), 42 nM) and JAK1/2/3 kinases (EC(50), 780 nM). In addition, Torin1 displayed unusually slow kinetics for inhibition of the mTORC1/2 complex, a property likely to contribute to the pharmacology of this inhibitor. Our results demonstrated that, with the exception of PP242, available ATP-competitive compounds are highly selective mTOR inhibitors when applied to cells at concentrations below 1 μM and that the compounds may represent a starting point for medicinal chemistry efforts aimed at developing inhibitors of other PI3K kinase-related kinases. 相似文献
122.
K Ando JL Kernan PH Liu T Sanda E Logette J Tschopp AT Look J Wang L Bouchier-Hayes S Sidi 《Molecular cell》2012,47(5):681-693
Biochemical evidence implicates the death-domain (DD) protein PIDD as a molecular switch capable of?signaling cell survival or death in response to genotoxic stress. PIDD activity is determined by binding-partner selection at its DD: whereas recruitment of RIP1 triggers prosurvival NF-κB signaling, recruitment of RAIDD activates proapoptotic caspase-2 via PIDDosome formation. However, it remains unclear how interactor selection, and thus fate decision, is regulated at the PIDD platform. We show that the PIDDosome functions in the "Chk1-suppressed" apoptotic response to DNA damage, a conserved ATM/ATR-caspase-2 pathway antagonized by Chk1. In this pathway, ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury. 相似文献
123.
Three binding sites for stalk protein dimers are generally present in ribosomes from archaeal organism 总被引:1,自引:0,他引:1
Maki Y Hashimoto T Zhou M Naganuma T Ohta J Nomura T Robinson CV Uchiumi T 《The Journal of biological chemistry》2007,282(45):32827-32833
Ribosomes have a characteristic protuberance termed the stalk, which is indispensable for ribosomal function. The ribosomal stalk has long been believed to be a pentameric protein complex composed of two sets of protein dimers, L12-L12, bound to a single anchor protein, although ribosomes carrying three L12 dimers were recently discovered in a few thermophilic bacteria. Here we have characterized the stalk complex from Pyrococcus horikoshii, a thermophilic species of Archaea. This complex is known to be composed of proteins homologous to eukaryotic counterparts rather than bacterial ones. In truncation experiments of the C-terminal regions of the anchor protein Ph-P0, we surprisingly observed three Ph-L12 dimers bound to the C-terminal half of Ph-P0, and the binding site for the third dimer was unique to the archaeal homologs. The stoichiometry of the heptameric complex Ph-P0(Ph-L12)(2)(Ph-L12)(2)(Ph-L12)(2) was confirmed by mass spectrometry of the intact complex. In functional tests, ribosomes carrying a single Ph-L12 dimer had significant activity, but the addition of the second and third dimers increased the activity. A bioinformatics analysis revealed the evidence that ribosomes from all archaeal and also from many bacterial organisms may contain a heptameric complex at the stalk, whereas eukaryotic ribosomes seem to contain exclusively a pentameric stalk complex, thus modifying our view of the stalk structure significantly. 相似文献
124.
125.
126.
127.
Wang J Ohno-Matsui K Yoshida T Kojima A Shimada N Nakahama K Safranova O Iwata N Saido TC Mochizuki M Morita I 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(1):712-720
The results of recent studies have implicated local inflammation and complement activation as the processes involved in the pathogenesis of age-related macular degeneration (AMD). We have demonstrated that amyloid beta (Abeta), which is deposited in drusen, causes an imbalance in the angiogenesis-related factors in retinal pigment epithelial cells. We have also shown that neprilysin gene-disrupted mice accumulate Abeta, and develop several features of AMD. The purpose of this study was to investigate the mechanisms involved in the development of AMD that are triggered by Abeta. Our results showed that Abeta binds to complement factor I which inhibits the ability of factor I to cleave C3b to inactivated iC3b. Factor H and factor I are soluble complement-activation inhibitors, and preincubation of factor I with Abeta in the presence of factor H abolished the ability of Abeta to cleave C3b, and also abolished the ability of factor I to cleave FGR-AMC. In contrast, Abeta did not affect the function of factor H even after binding. The production of iC3b was significantly decreased when C3b and factor H were incubated with the eyes from neprilysin gene-disrupted mice as compared with when C3b and factor H were incubated with eyes from age-matched wild-type mice. These results suggest that Abeta activates the complement system within drusen by blocking the function of factor I leading to a low-grade, chronic inflammation in subretinal tissues. These findings link four factors that have been suggested to be associated with AMD: inflammation, complement activation, Abeta deposition, and drusen. 相似文献
128.
Nakagawa K Kitazume S Oka R Maruyama K Saido TC Sato Y Endo T Hashimoto Y 《Journal of neurochemistry》2006,96(4):924-933
Alzheimer's disease (AD) is characterized by amyloid-beta peptide (Abeta) deposition in the brain. Abeta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1: beta-site APP-cleaving enzyme 1) and gamma-secretase. Previously, we demonstrated that BACE1 also cleaves beta-galactoside alpha2,6-sialyltransferase (ST6Gal-I) and down-regulates its transferase activity. Here, we report that overexpression of ST6Gal-I in Neuro2a cells enhanced alpha2,6-sialylation of endogenous APP and increased the extracellular levels of its metabolites [Abeta by two-fold, soluble APPbeta (sAPPbeta) by three-fold and sAPPalpha by 2.5-fold). Sialylation-deficient mutant (Lec-2) cells secreted half as much Abeta as wild-type Chinese hamster ovary (CHO) cells. Furthermore, wild-type CHO cells showed enhanced secretion of the APP metabolites upon ST6Gal-I overexpression, whereas Lec-2 cells did not, indicating that the secretion enhancement requires sialylation of cellular protein(s). Secretion of metabolites from a mutant APP (APP-Asn467,496Ala) that lacked N-glycosylation sites was not enhanced upon ST6Gal-I overexpression, suggesting that the N-glycans on APP itself are required for the enhanced secretion. In the mouse brain, the amount of alpha2,6-sialylated APP appeared to be correlated with the sAPPbeta level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD. 相似文献
129.
Synopsis We studied the life histories of the ninespine sticklebacks, Pungitius pungitius and Pungitius tymensis, collected from Japanese freshwater and brackish (sea) water habitats by examining the strontium (Sr) and calcium (Ca) concentrations
in their otoliths. The Sr:Ca ratios in the otoliths changed with the salinity of the habitat regardless of identification
as freshwater or brackish water type based on morphological characteristics. The ninespine sticklebacks living in a freshwater
environment showed consistently low Sr:Ca ratios throughout the otolith. These samples were identified as a standard freshwater
type. In contrast, all freshwater-type fishes collected from the intertidal zone showed higher otolith Sr:Ca ratios than those
in the standard freshwater type, and the ratios fluctuated with the growth phase. All brackish water-type fishes collected
in the intertidal zone showed the highest otolith Sr:Ca ratio throughout the otolith. In the present study, besides the two
representative life history types of P. pungitius, i.e., freshwater and brackish water life history types, other sticklebacks had an anadromous life history type. These findings
clearly indicate that the ninespine stickleback has a flexible migration strategy with a high degree of behavioral plasticity
and an ability to utilize the full range of salinity in its life history. 相似文献
130.
Piccini A Russo C Gliozzi A Relini A Vitali A Borghi R Giliberto L Armirotti A D'Arrigo C Bachi A Cattaneo A Canale C Torrassa S Saido TC Markesbery W Gambetti P Tabaton M 《The Journal of biological chemistry》2005,280(40):34186-34192
The mechanism of neurodegeneration caused by beta-amyloid in Alzheimer disease is controversial. Neuronal toxicity is exerted mostly by various species of soluble beta-amyloid oligomers that differ in their N- and C-terminal domains. However, abundant accumulation of beta-amyloid also occurs in the brains of cognitively normal elderly people, in the absence of obvious neuronal dysfunction. We postulated that neuronal toxicity depends on the molecular composition, rather than the amount, of the soluble beta-amyloid oligomers. Here we show that soluble beta-amyloid aggregates that accumulate in Alzheimer disease are different from those of normal aging in regard to the composition as well as the aggregation and toxicity properties. 相似文献