全文获取类型
收费全文 | 1055篇 |
免费 | 72篇 |
国内免费 | 1篇 |
出版年
2023年 | 10篇 |
2022年 | 23篇 |
2021年 | 57篇 |
2020年 | 29篇 |
2019年 | 35篇 |
2018年 | 27篇 |
2017年 | 33篇 |
2016年 | 35篇 |
2015年 | 42篇 |
2014年 | 55篇 |
2013年 | 80篇 |
2012年 | 81篇 |
2011年 | 72篇 |
2010年 | 41篇 |
2009年 | 41篇 |
2008年 | 52篇 |
2007年 | 54篇 |
2006年 | 54篇 |
2005年 | 60篇 |
2004年 | 47篇 |
2003年 | 31篇 |
2002年 | 30篇 |
2001年 | 17篇 |
2000年 | 20篇 |
1999年 | 9篇 |
1997年 | 4篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1993年 | 3篇 |
1992年 | 7篇 |
1991年 | 5篇 |
1990年 | 8篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1985年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 4篇 |
1974年 | 3篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1969年 | 1篇 |
1968年 | 4篇 |
1967年 | 4篇 |
1966年 | 3篇 |
1965年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有1128条查询结果,搜索用时 171 毫秒
91.
92.
Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Brian T Weinert Tarek Moustafa Vytautas Iesmantavicius Rudolf Zechner Chunaram Choudhary 《The EMBO journal》2015,34(21):2620-2632
Acetylation is frequently detected on mitochondrial enzymes, and the sirtuin deacetylase SIRT3 is thought to regulate metabolism by deacetylating mitochondrial proteins. However, the stoichiometry of acetylation has not been studied and is important for understanding whether SIRT3 regulates or suppresses acetylation. Using quantitative mass spectrometry, we measured acetylation stoichiometry in mouse liver tissue and found that SIRT3 suppressed acetylation to a very low stoichiometry at its target sites. By examining acetylation changes in the liver, heart, brain, and brown adipose tissue of fasted mice, we found that SIRT3‐targeted sites were mostly unaffected by fasting, a dietary manipulation that is thought to regulate metabolism through SIRT3‐dependent deacetylation. Globally increased mitochondrial acetylation in fasted liver tissue, higher stoichiometry at mitochondrial acetylation sites, and greater sensitivity of SIRT3‐targeted sites to chemical acetylation in vitro and fasting‐induced acetylation in vivo, suggest a nonenzymatic mechanism of acetylation. Our data indicate that most mitochondrial acetylation occurs as a low‐level nonenzymatic protein lesion and that SIRT3 functions as a protein repair factor that removes acetylation lesions from lysine residues. 相似文献
93.
94.
Initial analysis of copy number variations in cattle selected for resistance or susceptibility to intestinal nematodes 总被引:1,自引:0,他引:1
95.
96.
97.
Hjelmeland AB Wu Q Heddleston JM Choudhary GS MacSwords J Lathia JD McLendon R Lindner D Sloan A Rich JN 《Cell death and differentiation》2011,18(5):829-840
Malignant gliomas are lethal cancers that display cellular hierarchies with cancer stem cells at the apex. Glioma stem cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer stem cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer stem cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer stem cell phenotype, and that culturing cancer cells at lower pH reflective of endogenous tumor conditions may better retain the cellular heterogeneity found in tumors. 相似文献
98.
Bacteriorhodopsin (BR) is an integral membrane protein found in "purple membrane" (the Archaea cell membrane) mainly in Halobacteria. This protein absorbs green light (wavelength 500-650 nm, with the absorption maximum at 568 nm) and converts it into an electrochemical gradient. This gradient in turn is used for ATP production. The ability of BR to convert light energy into chemical energy or sunlight into electricity has been used in different applications mainly optical appliances but also for therapeutic/medical applications and research. This review surveys some of these applications that have been patented in the last five years. 相似文献
99.
Chou JL Shenoy DV Thomas N Choudhary PK Laferla FM Goodman SR Breen GA 《Journal of Proteomics》2011,74(4):466-479
Mitochondrial structural and functional alterations appear to play to an important role in the pathogenesis of Alzheimer's disease (AD). In the present study, we used a quantitative comparative proteomic profiling approach to analyze changes in the mitochondrial proteome in AD. A triple transgenic mouse model of AD (3xTg-AD) which harbors mutations in three human transgenes, APP(Swe), PS1(M146V) and Tau(P301L), was used in these experiments. Quantitative differences in the mitochondrial proteome between the cerebral cortices of 6-month-old male 3xTg-AD and non-transgenic mice were determined by using two-dimensional difference gel electrophoresis (2D-DIGE) and tandem mass spectrometry. We identified 23 different proteins whose expression levels differed significantly between triple transgenic and non-transgenic mitochondria. Both down-regulated and up-regulated mitochondrial proteins were observed in transgenic AD cortices. Proteins which were dysregulated in 3xTg-AD cortices functioned in a wide variety of metabolic pathways, including the citric acid cycle, oxidative phosphorylation, pyruvate metabolism, glycolysis, oxidative stress, fatty acid oxidation, ketone body metabolism, ion transport, apoptosis, and mitochondrial protein synthesis. These alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice occurred before the development of significant amyloid plaque and neurofibrillary tangles, indicating that mitochondrial dysregulation is an early event in AD. 相似文献
100.
Schmidt-Arras DE Böhmer A Markova B Choudhary C Serve H Böhmer FD 《Molecular and cellular biology》2005,25(9):3690-3703
Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPalpha promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants. 相似文献