全文获取类型
收费全文 | 1950篇 |
免费 | 136篇 |
出版年
2023年 | 3篇 |
2022年 | 15篇 |
2021年 | 43篇 |
2020年 | 20篇 |
2019年 | 29篇 |
2018年 | 50篇 |
2017年 | 44篇 |
2016年 | 46篇 |
2015年 | 64篇 |
2014年 | 70篇 |
2013年 | 146篇 |
2012年 | 155篇 |
2011年 | 164篇 |
2010年 | 90篇 |
2009年 | 88篇 |
2008年 | 127篇 |
2007年 | 145篇 |
2006年 | 139篇 |
2005年 | 133篇 |
2004年 | 125篇 |
2003年 | 110篇 |
2002年 | 125篇 |
2001年 | 33篇 |
2000年 | 11篇 |
1999年 | 19篇 |
1998年 | 19篇 |
1997年 | 14篇 |
1996年 | 14篇 |
1995年 | 10篇 |
1994年 | 6篇 |
1993年 | 8篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1988年 | 2篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 6篇 |
1979年 | 4篇 |
1972年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有2086条查询结果,搜索用时 546 毫秒
171.
Zhu Xu Lei Zhang Wenjun Zhang Du Meng Hongxia Zhang Ying Jiang Xiaojun Xu Michael Van Meter Andrei Seluanov Vera Gorbunova Zhiyong Mao 《Cell cycle (Georgetown, Tex.)》2015,14(2):269-276
In principle, a decline in base excision repair (BER) efficiency with age should lead to genomic instability and ultimately contribute to the onset of the aging phenotype. Although multiple studies have indicated a negative link between aging and BER, the change of BER efficiency with age in humans has not been systematically analyzed. Here, with foreskin fibroblasts isolated from 19 donors between 20 and 64 y of age, we report a significant decline of BER efficiency with age using a newly developed GFP reactivation assay. We further observed a very strong negative correlation between age and the expression levels of SIRT6, a factor which is known to maintain genomic integrity by improving DNA double strand break (DSB) repair. Our mechanistic study suggests that, similar to the regulatory role that SIRT6 plays in DNA DSB repair, SIRT6 regulates BER in a PARP1-depdendent manner. Moreover, overexpression of SIRT6 rescues the decline of BER in aged fibroblasts. In summary, our results uncovered the regulatory mechanisms of BER by SIRT6, suggesting that SIRT6 reactivation in aging tissues may help delay the process of aging through improving BER. 相似文献
172.
Hill S Hirano K Shmanai VV Marbois BN Vidovic D Bekish AV Kay B Tse V Fine J Clarke CF Shchepinov MS 《Free radical biology & medicine》2011,50(1):130-138
The facile abstraction of bis-allylic hydrogens from polyunsaturated fatty acids (PUFAs) is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. The products of these autoxidation reactions can form cross-links to other membrane components and damage proteins and nucleic acids. We report that PUFAs deuterated at bis-allylic sites are much more resistant to autoxidation reactions, because of the isotope effect. This is shown using coenzyme Q-deficient Saccharomyces cerevisiae coq mutants with defects in the biosynthesis of coenzyme Q (Q). Q functions in respiratory energy metabolism and also functions as a lipid-soluble antioxidant. Yeast coq mutants incubated in the presence of the PUFA α-linolenic or linoleic acid exhibit 99% loss of colony formation after 4 h, demonstrating a profound loss of viability. In contrast, coq mutants treated with monounsaturated oleic acid or with one of the deuterated PUFAs, 11,11-D2-linoleic or 11,11,14,14-D4-α-linolenic acid, retain viability similar to wild-type yeast. Deuterated PUFAs also confer protection to wild-type yeast subjected to heat stress. These results indicate that isotope-reinforced PUFAs are stabilized compared to standard PUFAs, and they protect coq mutants and wild-type yeast cells against the toxic effects of lipid autoxidation products. These findings suggest new approaches to controlling ROS-inflicted cellular damage and oxidative stress. 相似文献
173.
Neitz RJ Konradi AW Sham HL Zmolek W Wong K Qin A Lorentzen C Nakamura D Quinn KP Sauer JM Powell K Ruslim L Chereau D Ren Z Anderson J Bard F Yednock TA Griswold-Prenner I 《Bioorganic & medicinal chemistry letters》2011,21(12):3726-3729
In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for substitution of the naphthalene ring, as well as for inhibitors adopting different central scaffolds. Significant potency gains were appreciated by inverting the polarity of the thione of the parent triazolothione 1, resulting in potent compounds with attractive pharmacokinetic profiles. 相似文献
174.
175.
176.
Pingping Jia Chi Zhang Yuanyuan Jia Keith A Webster Xupei Huang Andrei A Kochegarov Sharon L Lemanski Larry F Lemanski 《Journal of biomedical science》2011,18(1):46
Background
Methionine Sulfoxide Reductase A (MsrA), an enzyme in the Msr gene family, is important in the cellular anti-oxidative stress defense mechanism. It acts by reducing the oxidized methionine sulfoxide in proteins back to sulfide and by reducing the cellular level of reactive oxygen species. MsrA, the only enzyme in the Msr gene family that can reduce the S-form epimers of methionine sulfoxide, has been located in different cellular compartments including mitochondria, cytosol and nuclei of various cell lines. 相似文献177.
Cheng Z Elias DR Kamat NP Johnston ED Poloukhtine A Popik V Hammer DA Tsourkas A 《Bioconjugate chemistry》2011,22(10):2021-2029
Block copolymer-based vesicles have recently garnered a great deal of interest as nanoplatforms for drug delivery and molecular imaging applications due to their unique structural properties. These nanovesicles have been shown to direct their cargo to disease sites either through enhanced permeability and retention or even more efficiently via active targeting. Here, we show that the efficacy of nanovesicle targeting can be significantly improved when prepared from polymer-lipid blends compared with block copolymer alone. Polymer-lipid hybrid nanovesicles were produced from the aqueous coassembly of the diblock copolymer, poly(ethylene oxide)-block-polybutadiene (PEO-PBD), and the phospholipid, hydrogenated soy phosphatidylcholine (HSPC). The PEG-based vesicles, 117 nm in diameter, were functionalized with either folic acid or anti-HER2/neu affibodies as targeting ligands to confer specificity for cancer cells. Our results revealed that nanovesicles prepared from polymer-lipid blends led to significant improvement in cell binding compared to nanovesicles prepared from block copolymer alone in both in vitro cell studies and murine tumor models. Therefore, it is envisioned that nanovesicles composed of polymer-lipid blends may constitute a preferred embodiment for targeted drug delivery and molecular imaging applications. 相似文献
178.
179.