全文获取类型
收费全文 | 306篇 |
免费 | 21篇 |
专业分类
327篇 |
出版年
2021年 | 4篇 |
2020年 | 1篇 |
2019年 | 2篇 |
2018年 | 2篇 |
2017年 | 7篇 |
2016年 | 6篇 |
2015年 | 7篇 |
2014年 | 11篇 |
2013年 | 21篇 |
2012年 | 18篇 |
2011年 | 25篇 |
2010年 | 16篇 |
2009年 | 18篇 |
2008年 | 12篇 |
2007年 | 18篇 |
2006年 | 8篇 |
2005年 | 15篇 |
2004年 | 5篇 |
2003年 | 16篇 |
2002年 | 18篇 |
2001年 | 5篇 |
2000年 | 14篇 |
1999年 | 8篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1977年 | 4篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 3篇 |
1969年 | 1篇 |
1927年 | 1篇 |
1926年 | 1篇 |
排序方式: 共有327条查询结果,搜索用时 15 毫秒
11.
Effects on RNAi of the tight structure, sequence and position of the targeted region 总被引:34,自引:3,他引:31 下载免费PDF全文
RNA interference (RNAi) is a gene-silencing phenomenon that involves the double-stranded RNA-mediated cleavage of mRNA, and small interfering RNAs (siRNAs) can cause RNAi in mammalian cells. There have been many attempts to clarify the mechanism of RNAi, but information about the relationship between the sequence and structure, in particular, a tight structure, of the target RNA and the activities of siRNAs are limited. In the present study, we examined this relationship by introducing the TAR element, which adopts a very stable secondary structure, at different positions within target RNAs. Our results suggested that the activities of siRNAs were affected by the tight stem–loop structure of TAR. In contrast, the position of the target within the mRNA, the binding of the Tat protein to the TAR, and the location of the target within a translated or a noncoding region had only marginal effects on RNAi. When the target sequence was placed in two different orientations, only one orientation had a significant effect on the activities of siRNA, demonstrating that the presence of certain nucleotides at some specific positions was favorable for RNAi. Systematic analysis of 47 different sites within 47 plasmids under identical conditions indicated that it is the target sequence itself, rather than its location, that is the major determinant of siRNA activity. 相似文献
12.
Izumi T Sakaguchi J Takeshita M Tawara H Kato K Dose H Tsujino T Watanabe Y Kato H 《Bioorganic & medicinal chemistry》2003,11(12):2541-2550
Structural modification of imiquimod (1), which is known as an interferon-alpha (IFN-alpha) inducer, for the aim of finding a novel and small-molecule tumor necrosis factor-alpha (TNF-alpha) suppressor and structure-activity relationship (SAR) are described. Structural modification of a imiquimod analogue, 4-amino-1-[2-(1-benzyl-4-piperidyl)ethyl-1H-imidazo[4,5-c]quinoline (2), which had moderate TNF-alpha suppressing activity without IFN-alpha inducing activity, led to a finding of 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline (10) with potent TNF-alpha suppressing activity. The relation between conformational direction of 2-(4-piperidyl)ethyl group at position 1 and TNF-alpha suppressing activity is also demonstrated by NMR. 相似文献
13.
Kobayashi A Tanaka Y Shimada M 《Evolution; international journal of organic evolution》2003,57(11):2659-2664
The genetic variation of sex ratio and sex allocation were examined in a series of half-sib analyses on the sex ratio of braconid parasitoid wasp Heterospilus prosopidis populations collected in Hawaii and Arizona. The mean threshold value and the range of the threshold for change in the sex of offspring in response to resource quality (host size) were determined. Estimates of the narrow-sense heritability (h2) of sex ratio at a specific host size ranged from 0.185 to 0.315, and those of the sex changing point (threshold value) ranged from 0.220 to 0.342. The coefficient of variation (CV(A)) of sex ratio was significantly larger than CV(A) of body weight. We discuss factors that maintained the significant additive genetic variation of sex ratio. 相似文献
14.
Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice 总被引:23,自引:0,他引:23
Mutoh H Hakamata Y Sato K Eda A Yanaka I Honda S Osawa H Kaneko Y Sugano K 《Biochemical and biophysical research communications》2002,294(2):470-479
Gastric intestinal metaplasia occurs as a pathological condition in the gastric mucosa. To clarify how an intestine-specific homeobox gene, Cdx2, affects the morphogenesis of gastric mucosa, we generated transgenic mice expressing Cdx2 in parietal cells. Until Day 18 after birth, the number of parietal cells inthegastric mucosa of transgenic mice was the same as for their normal littermates. However, at Day 19, we detected several glands in which parietal cells disappeared and the proliferating zone moved from the isthmus to the base of the glands. Thereafter, parietal cells decreased gradually and disappeared at Day 37. All of the gastric mucosal cells, except for enterochromaffin-like (ECL) cells, were completely replaced by intestinal metaplasia, consisting of goblet cells, enteroendocrine cells, and absorptive cells expressing alkaline phosphatase. Pseudopyloric gland metaplasia was also formed. The transgenic mouse is a very useful model for clarifying physiological differentiation of gastric and intestinal cell lineages and analyzing the molecular events from intestinal metaplasia to adenocarcinoma. 相似文献
15.
Ap-2 and Ikaros regulate transcription of human placental leucine aminopeptidase/oxytocinase gene. 总被引:4,自引:0,他引:4
16.
Kashiwakura I Inanami O Takahashi K Takahashi TA Kuwabara M Takagi Y 《Radiation research》2003,160(2):210-216
In previous studies we characterized the radiosensitivity of CFU-megakaryocytes from human placental and umbilical cord blood and the effects of various early-acting cytokines. We found that the maximal clonal growth of CFU-megakaryocytes in vitro and maximal protection against X-ray damage were supported by a combination of thrombopoietin and stem cell factor. However, the mechanism by which the two cytokines exert a synergistic effect remained unclear, so we extended these studies to investigate the radioprotective action of synergistic thrombopoietin and stem cell factor on the survival of X-irradiated CD34(+) CFU-megakaryocytes. A combination of thrombopoietin and stem cell factor led to activation of mitogen-activated protein kinase and extracellular signal-regulated protein kinase and to suppression of caspase 3 in X-irradiated CD34(+) cells. When PD98059 and various synthetic substrates-specific inhibitors of these proteins-were used, the combination had less effect on the clonal growth of X-irradiated CD34(+) CFU-megakaryocytes. However, the addition of wortmannin, a specific inhibitor of the phosphatidylinositol-3 kinase pathway, did not alter the synergistic action of thrombopoietin plus stem cell factor. We suggest that part of this synergistic effect can be explained by activation of mitogen-activated protein kinase and extracellular signal-regulated protein kinase and by suppression of the caspase cascade. 相似文献
17.
18.
In vivo gene gun-mediated DNA delivery into rodent brain tissue 总被引:1,自引:0,他引:1
Sato H Hattori S Kawamoto S Kudoh I Hayashi A Yamamoto I Yoshinari M Minami M Kanno H 《Biochemical and biophysical research communications》2000,270(1):163-170
Various types of gene transfer into live tissues have been tried. However, in vivo gene transfer into brain tissue or neuronal cells without virus vector has required a great effort. Particle-mediated gene transfer into live brain tissue was thought to be impossible because of its fragility and the mechanical problem of a previous type of gene gun. In addition, particle-mediated DNA transfer into monolayer-cultured cells without mechanical damage has been difficult. We successfully transferred DNA into rodent live brain tissue and also into monolayer-cultured cells without mechanical damage by using a new type of gene gun and also confirmed gene expression in the brain. This new method represents another variation of gene transfer into the brain. 相似文献
19.
20.
A further investigation and reappraisal of the thio effect in the cleavage reaction catalyzed by a hammerhead ribozyme 总被引:4,自引:3,他引:1 下载免费PDF全文
We synthesized three types of 11mer substrate, namely the natural substrate S11O and the thiosubstituted substrates S11SpS and S11RpS, in which the respective pro-Sp and pro-Rp oxygen atoms were replaced by sulfur, and subjected them to detailed kinetic analysis in the cleavage reaction catalyzed by a hammerhead ribozyme. In agreement with previous findings, in the presence of Mg2+ or Ca2+ ions the rate of ribozyme-catalyzed cleavage of S11SpS was as high as that of S11O, whereas the corresponding rate for S11RpS was nearly four orders of magnitude lower than that for either S11O or S11SpS. However, the rate of the ribozyme-catalyzed reaction with each of the three substrates was enhanced by Cd2+ ions. Such results have generally been taken as evidence that supports the direct interaction of the sulfur atom at the Rp position of the cleavage site with the added Cd2+ ion. However, our present analysis demonstrates that (i) the added Cd2+ ion binds at the P9 site; (ii) the bound Cd2+ ion at the P9 site replaces two Mg2+ or two Ca2+ ions, an observation that suggests a different mode of interaction with the added Cd2+ ion; and, most importantly and in contrast to the conclusion reached by other investigators, (iii) the Cd2+ ion does not interact with the sulfur atom at the Rp position of the scissile phosphate either in the ground state or in the transition state. 相似文献