全文获取类型
收费全文 | 771篇 |
免费 | 62篇 |
国内免费 | 1篇 |
出版年
2022年 | 4篇 |
2021年 | 17篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 10篇 |
2017年 | 16篇 |
2016年 | 21篇 |
2015年 | 27篇 |
2014年 | 35篇 |
2013年 | 56篇 |
2012年 | 49篇 |
2011年 | 45篇 |
2010年 | 30篇 |
2009年 | 19篇 |
2008年 | 33篇 |
2007年 | 35篇 |
2006年 | 28篇 |
2005年 | 27篇 |
2004年 | 23篇 |
2003年 | 26篇 |
2002年 | 20篇 |
2001年 | 16篇 |
2000年 | 33篇 |
1999年 | 19篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 10篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 5篇 |
1992年 | 15篇 |
1991年 | 13篇 |
1990年 | 15篇 |
1989年 | 25篇 |
1988年 | 12篇 |
1987年 | 12篇 |
1986年 | 12篇 |
1985年 | 10篇 |
1984年 | 8篇 |
1983年 | 12篇 |
1979年 | 5篇 |
1977年 | 5篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 5篇 |
1971年 | 6篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1927年 | 2篇 |
排序方式: 共有834条查询结果,搜索用时 31 毫秒
71.
72.
Uddin MJ Schulte MI Maddukuri L Harp J Marnett LJ 《Nucleosides, nucleotides & nucleic acids》2010,29(11):831-840
An efficient enzymatic synthesis of 6-chloropurine-2'-deoxyriboside from the reaction of 6-chloropurine with 2'-deoxycytidine catalyzed by nucleoside-2'-deoxyribosyltransferase (E.C. 2.4.2.6) followed by chemical conversion into the 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino) phosphoramidite derivative is described. The phosphoramidite derivative was incorporated site-specifically into an oligonucleotide and used for the introduction of a tethered tetramethylrhodamine-cadaverine conjugate. The availability of an efficient route to 6-chloropurine-2'-deoxyriboside 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite enables the facile synthesis of oligonucleotides containing a range of functional groups tethered to deoxyadenosine residues. 相似文献
73.
74.
The current view of canonical Wnt signalling is that following Wnt binding to its receptors (Frizzled-Lrp5/6), dishevelled (Dvl) becomes hyperphosphorylated, and the signal is transduced to the APC-GSK3beta-axin-beta-catenin multiprotein complex, which subsequently dissociates. As a result beta-catenin is not phosphorylated, escapes proteosomal degradation and activates its target genes after translocation to the nucleus. Here, we analyzed the importance of the Wnt-3a-induced phosphorylation and shift in electrophoretic migration of Dvl (PS-Dvl) for the activation of beta-catenin. Analysis of Wnt-3a time- and dose-responses in a dopaminergic cell line showed that beta-catenin is activated rapidly (within minutes) and at a low dose of Wnt-3a (1 ng/ml). Surprisingly, PS-Dvl appeared only after 30 min and at greater doses (> or =20 ng/ml) of Wnt-3a. Moreover, we found that a casein kinase 1 inhibitor (D4476) or siRNA for casein kinase 1 delta/epsilon (CK1delta/epsilon) blocked the Wnt-3a-induced PS-Dvl. Interestingly, CK1 inhibition or siRNA for CK1delta/epsilon did not ablate the activation of beta-catenin by Wnt-3a, indicating that there is a PS-Dvl-independent path to activate beta-catenin. The increase in beta-catenin activation by Wnt-3a (PS-Dvl-dependent or -independent) were blocked by Dickkopf1 (Dkk1), suggesting that the effect of Wnt-3a is in both cases mediated by Lrp5/6 receptors. Thus, our results show that Wnt-3a rapidly induce a partial activation of beta-catenin in the absence of PS-Dvl at low doses, while at high doses induce a full activation of beta-catenin in a PS-Dvl-dependent manner. 相似文献
75.
Dentinogenesis imperfecta is a congenital dentin dysplasia that occurs either isolated or associated with a genetic disorder known as osteogenesis imperfecta. Dentinogenesis imperfecta is inherited in an autosomal dominant pattern. Clinically the teeth color of both dentitions varies from brown to a translucent gray with an opalescent sheen. Shields et al. (1973) proposed a classification of Dentinogenesis imperfecta into three types: type I, associated with osteogenesis imperfecta; type II, hereditary opalescent dentin; type III Brandywine-type. The phenotypes of Dentinogenesis imperfecta are described in regard to their genetic defects, pathology, radiology and histopathology as well as their dental treatment. 相似文献
76.
77.
78.
Jacomijn P. Dijksterhuis Bolormaa Baljinnyam Karen Stanger Hakki O. Sercan Yun Ji Osler Andres Jeffrey S. Rubin Rami N. Hannoush Gunnar Schulte 《The Journal of biological chemistry》2015,290(11):6789-6798
The seven-transmembrane-spanning receptors of the FZD1–10 class are bound and activated by the WNT family of lipoglycoproteins, thereby inducing a complex network of signaling pathways. However, the specificity of the interaction between mammalian WNT and FZD proteins and the subsequent signaling cascade downstream of the different WNT-FZD pairs have not been systematically addressed to date. In this study, we determined the binding affinities of various WNTs for different members of the FZD family by using bio-layer interferometry and characterized their functional selectivity in a cell system. Using purified WNTs, we show that different FZD cysteine-rich domains prefer to bind to distinct WNTs with fast on-rates and slow off-rates. In a 32D cell-based system engineered to overexpress FZD2, FZD4, or FZD5, we found that WNT-3A (but not WNT-4, -5A, or -9B) activated the WNT-β-catenin pathway through FZD2/4/5 as measured by phosphorylation of LRP6 and β-catenin stabilization. Surprisingly, different WNT-FZD pairs showed differential effects on phosphorylation of DVL2 and DVL3, revealing a previously unappreciated DVL isoform selectivity by different WNT-FZD pairs in 32D cells. In summary, we present extensive mapping of WNT-FZD cysteine-rich domain interactions complemented by analysis of WNT-FZD pair functionality in a unique cell system expressing individual FZD isoforms. Differential WNT-FZD binding and selective functional readouts suggest that endogenous WNT ligands evolved with an intrinsic natural bias toward different downstream signaling pathways, a phenomenon that could be of great importance in the design of FZD-targeting drugs. 相似文献
79.
80.