全文获取类型
收费全文 | 64996篇 |
免费 | 6352篇 |
国内免费 | 25篇 |
出版年
2022年 | 477篇 |
2021年 | 1053篇 |
2020年 | 663篇 |
2019年 | 850篇 |
2018年 | 1041篇 |
2017年 | 906篇 |
2016年 | 1555篇 |
2015年 | 2551篇 |
2014年 | 2836篇 |
2013年 | 3334篇 |
2012年 | 4445篇 |
2011年 | 4255篇 |
2010年 | 2721篇 |
2009年 | 2477篇 |
2008年 | 3580篇 |
2007年 | 3624篇 |
2006年 | 3456篇 |
2005年 | 3276篇 |
2004年 | 3211篇 |
2003年 | 2945篇 |
2002年 | 2880篇 |
2001年 | 1070篇 |
2000年 | 906篇 |
1999年 | 975篇 |
1998年 | 934篇 |
1997年 | 694篇 |
1996年 | 613篇 |
1995年 | 556篇 |
1994年 | 585篇 |
1993年 | 581篇 |
1992年 | 737篇 |
1991年 | 611篇 |
1990年 | 625篇 |
1989年 | 610篇 |
1988年 | 540篇 |
1987年 | 520篇 |
1986年 | 499篇 |
1985年 | 499篇 |
1984年 | 523篇 |
1983年 | 469篇 |
1982年 | 496篇 |
1981年 | 449篇 |
1980年 | 470篇 |
1979年 | 396篇 |
1978年 | 369篇 |
1977年 | 324篇 |
1976年 | 332篇 |
1975年 | 271篇 |
1974年 | 305篇 |
1973年 | 282篇 |
排序方式: 共有10000条查询结果,搜索用时 406 毫秒
141.
Carwyn Davies Linda A Hogarth Karen L Mackenzie Andrew G Hall Richard B Lock 《Cell cycle (Georgetown, Tex.)》2015,14(22):3602-3612
p21WAF1 is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21WAF1 in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21WAF1 was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21WAF1 in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21WAF1 silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21WAF1 expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21WAF1 regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat. 相似文献
142.
143.
144.
Chiara Tyndall Hansjo¨rg Lehnherr Ursula Sandmeier Eva Kulik & Thomas A. Bickle 《Molecular microbiology》1997,23(4):729-736
Eco R124I, Eco DXXI and Eco prrI are the known members of the type IC family of DNA restriction and modification systems. The first three are carried on large, conjugative plasmids, while Eco prrI is chromosomally encoded. The enzymes are coded by three genes, hsdR , hsdM and hsdS . Analysis of the DNA sequences upstream and downstream of the type IC hsd loci shows that all are highly homologous to each other and also to sequences present in the bacteriophage P1 genome. The upstream sequences include functional phd and doc genes, which encode an addiction system that stabilizes the P1 prophage state, and extend to and beyond pac , the site at which phage DNA packaging begins. Downstream of the hsd loci, P1 DNA sequences begin at exactly the same place for all of the systems. For Eco DXXI and Eco prrI the P1 homology extends for thousands of base pairs while for Eco R124I an IS 1 insertion and an associated deletion have removed most of the P1-homologous sequences. The significance of these results for the evolution of DNA restriction and modification systems is discussed. 相似文献
145.
The assembly of high voltage-activated Ca2+ channels with different β subunits influences channel properties and possibly subcellular targeting. We studied β subunit expression in the somata and axon terminals of the magnocellular neurosecretory cells, which are located in the supraoptic nucleus (SON) and neurohypophysis, respectively. Antibodies directed against the 4 CaVβ subunits (CaVβ1-CaVβ4) were used for immunoblots and for immunostaining of slices of these two tissues. We found that all 4 β subunits are expressed in both locations, but that CaVβ2 had the highest relative expression in the neurohypophysis. These data suggest that the CaVβ2 subunit is selectively targeted to axon terminals and may play a role in targeting and/or regulating the properties of Ca2+ channels. 相似文献
146.
147.
Immobilization of lipoxygenase in an alginate-silicate solgel matrix: formation of fatty acid hydroperoxides 总被引:3,自引:0,他引:3
A method for the immobilization of lipoxygenase (LOX) in an alginate-silicate gel matrix was developed. In this method, a mixture of calcium alginate beads and LOX in borate buffer are dispersed into a hexane solution of tetramethoxy-ortho-silicate (TMOS). Hydrolysis of the TMOS gives products that permeate and co-polymerize with the alginate gel to form a colloid within the beads that entraps the LOX. Optimum reaction conditions for sol-gel entrapment of LOX are at pH 9.0 in 0.2M borate buffer. The composite gel, after isolation and vacuum drying, had excellent protein retention that has good enzyme activity and stability at room temperature. The activity of the entrapped LOX was less than the activity of the free enzyme. However, the activity of the immobilized LOX can be restored by the addition of borate buffer and glycerol, or borate buffer saturated with an organic solvent. In contrast to the free enzyme in solution, which loses its activity in less than one day, sol-gel entrapped LOX retains its activity at ambient temperature for at least 25 days and can be recycled. This report demonstrates that the sol-gel entrapment method for immobilizing LOX can be useful in developing a process for the oxidation of polyunsaturated fatty acids. 相似文献
148.
149.
Mathieu Lefèvre Daniel J. Felmlee Marie Parnot Thomas F. Baumert Catherine Schuster 《PloS one》2014,9(4)
Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE’s HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection. 相似文献
150.