全文获取类型
收费全文 | 284416篇 |
免费 | 29510篇 |
国内免费 | 536篇 |
出版年
2018年 | 2582篇 |
2016年 | 3382篇 |
2015年 | 4824篇 |
2014年 | 5474篇 |
2013年 | 8062篇 |
2012年 | 8703篇 |
2011年 | 8909篇 |
2010年 | 5855篇 |
2009年 | 5406篇 |
2008年 | 7860篇 |
2007年 | 7903篇 |
2006年 | 7488篇 |
2005年 | 7199篇 |
2004年 | 7058篇 |
2003年 | 6814篇 |
2002年 | 6553篇 |
2001年 | 11880篇 |
2000年 | 11912篇 |
1999年 | 9400篇 |
1998年 | 3385篇 |
1997年 | 3596篇 |
1996年 | 3470篇 |
1995年 | 3188篇 |
1994年 | 3184篇 |
1993年 | 3163篇 |
1992年 | 7925篇 |
1991年 | 7903篇 |
1990年 | 7564篇 |
1989年 | 7516篇 |
1988年 | 6873篇 |
1987年 | 6626篇 |
1986年 | 6035篇 |
1985年 | 6225篇 |
1984年 | 5150篇 |
1983年 | 4346篇 |
1982年 | 3378篇 |
1981年 | 3144篇 |
1980年 | 2944篇 |
1979年 | 4950篇 |
1978年 | 3813篇 |
1977年 | 3719篇 |
1976年 | 3433篇 |
1975年 | 3785篇 |
1974年 | 4172篇 |
1973年 | 4092篇 |
1972年 | 3664篇 |
1971年 | 3430篇 |
1970年 | 3084篇 |
1969年 | 2994篇 |
1968年 | 2745篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
Abeba Demelash Lukas W. Pfannenstiel Charles S. Tannenbaum Xiaoxia Li Matthew F. Kalady Jennifer DeVecchio Brian R. Gastman 《The Journal of biological chemistry》2015,290(36):21962-21975
Unlike other antiapoptotic Bcl-2 family members, Mcl-1 also mediates resistance to cancer therapy by uniquely inhibiting chemotherapy-induced senescence (CIS). In general, Bcl-2 family members regulate apoptosis at the level of the mitochondria through a common prosurvival binding groove. Through mutagenesis, we determined that Mcl-1 can inhibit CIS even in the absence of its apoptotically important mitochondrion-localizing domains. This finding prompted us to generate a series of Mcl-1 deletion mutants from both the N and C termini of the protein, including one that contained a deletion of all of the Bcl-2 homology domains, none of which impacted anti-CIS capabilities. Through subsequent structure-function analyses of Mcl-1, we identified a previously uncharacterized loop domain responsible for the anti-CIS activity of Mcl-1. The importance of the loop domain was confirmed in multiple tumor types, two in vivo models of senescence, and by demonstrating that a peptide mimetic of the loop domain can effectively inhibit the anti-CIS function of Mcl-1. The results from our studies appear to be highly translatable because we discerned an inverse relationship between the expression of Mcl-1 and of various senescence markers in cancerous human tissues. In summary, our findings regarding the unique structural properties of Mcl-1 provide new approaches for targeted cancer therapy. 相似文献
2.
3.
Dayanjan S. Wijesinghe Matthew Brentnall Jennifer A. Mietla L. Alexis Hoeferlin Robert F. Diegelmann Lawrence H. Boise Charles E. Chalfant 《Journal of lipid research》2014,55(7):1298-1309
In these studies, the role of ceramide-1-phosphate (C1P) in the wound-healing process was investigated. Specifically, fibroblasts isolated from mice with the known anabolic enzyme for C1P, ceramide kinase (CERK), ablated (CERK−/− mice) and their wild-type littermates (CERK+/+) were subjected to in vitro wound-healing assays. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrated steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK−/− fibroblasts. This observed difference was reflected in scratch-induced eicosanoid levels. Similar, but somewhat less intense, changes were observed in a more complex system utilizing skin biopsies obtained from CERK-null mice. Importantly, C1P levels increased during the early stages of human wound healing correlating with the transition from the inflammatory stage to the peak of the fibroplasia stage (e.g., proliferation and migration of fibroblasts). Finally, the loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK−/−. As the proper migration of fibroblasts is one of the necessary steps of wound healing, these studies demonstrate a novel requirement for the CERK-derived C1P in the proper healing response of wounds. 相似文献
4.
Sinisa Bjelic Yakov Kipnis Ling Wang Zbigniew Pianowski Sergey Vorobiev Min Su Jayaraman Seetharaman Rong Xiao Gregory Kornhaber John F. Hunt Liang Tong Donald Hilvert David Baker 《Journal of molecular biology》2014
Designed retroaldolases have utilized a nucleophilic lysine to promote carbon–carbon bond cleavage of β-hydroxy-ketones via a covalent Schiff base intermediate. Previous computational designs have incorporated a water molecule to facilitate formation and breakdown of the carbinolamine intermediate to give the Schiff base and to function as a general acid/base. Here we investigate an alternative active-site design in which the catalytic water molecule was replaced by the side chain of a glutamic acid. Five out of seven designs expressed solubly and exhibited catalytic efficiencies similar to previously designed retroaldolases for the conversion of 4-hydroxy-4-(6-methoxy-2-naphthyl)-2-butanone to 6-methoxy-2-naphthaldehyde and acetone. After one round of site-directed saturation mutagenesis, improved variants of the two best designs, RA114 and RA117, exhibited among the highest kcat (> 10− 3 s− 1) and kcat/KM (11–25 M− 1 s− 1) values observed for retroaldolase designs prior to comprehensive directed evolution. In both cases, the > 105-fold rate accelerations that were achieved are within 1–3 orders of magnitude of the rate enhancements reported for the best catalysts for related reactions, including catalytic antibodies (kcat/kuncat = 106 to 108) and an extensively evolved computational design (kcat/kuncat > 107). The catalytic sites, revealed by X-ray structures of optimized versions of the two active designs, are in close agreement with the design models except for the catalytic lysine in RA114. We further improved the variants by computational remodeling of the loops and yeast display selection for reactivity of the catalytic lysine with a diketone probe, obtaining an additional order of magnitude enhancement in activity with both approaches. 相似文献
5.
Binnur Eroglu Donald E. Kimbler Junfeng Pang Justin Choi Demetrius Moskophidis Nathan Yanasak Krishnan M. Dhandapani Nahid F. Mivechi 《Journal of neurochemistry》2014,130(5):626-641
Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat‐related activities. The heat‐shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of reactive oxygen species‐induced p53 target genes Pig1, Pig8, and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP‐15. In contrast to Hsp110‐ or Hsp70i‐deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild‐type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement in contextual and cued fear conditioning tests and beam balance in wild‐type mice that were treated with Celastrol or BGP‐15 following TBI compared to TBI‐treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI.
6.
7.
8.
9.
10.
Rui André Saraiva Raposo Mohamed Abdel-Mohsen Xutao Deng Frederick M. Hecht Christopher D. Pilcher Satish K. Pillai Douglas F. Nixon 《Journal of virology》2014,88(19):11624-11629
In this study, we investigated the expression levels of host restriction factors in six untreated HIV-1-positive patients over the course of infection. We found that the host restriction factor gene expression profile consistently increased over time and was significantly associated with CD4+ T cell activation and viral load. Our data are among the first to demonstrate the dynamic nature of host restriction factors in vivo over time. 相似文献