全文获取类型
收费全文 | 8233篇 |
免费 | 828篇 |
国内免费 | 3篇 |
出版年
2024年 | 9篇 |
2023年 | 68篇 |
2022年 | 149篇 |
2021年 | 311篇 |
2020年 | 168篇 |
2019年 | 245篇 |
2018年 | 201篇 |
2017年 | 212篇 |
2016年 | 332篇 |
2015年 | 556篇 |
2014年 | 630篇 |
2013年 | 628篇 |
2012年 | 818篇 |
2011年 | 749篇 |
2010年 | 430篇 |
2009年 | 366篇 |
2008年 | 476篇 |
2007年 | 449篇 |
2006年 | 378篇 |
2005年 | 356篇 |
2004年 | 316篇 |
2003年 | 220篇 |
2002年 | 209篇 |
2001年 | 97篇 |
2000年 | 100篇 |
1999年 | 78篇 |
1998年 | 28篇 |
1997年 | 35篇 |
1996年 | 26篇 |
1995年 | 27篇 |
1994年 | 28篇 |
1993年 | 26篇 |
1992年 | 34篇 |
1991年 | 36篇 |
1990年 | 29篇 |
1989年 | 20篇 |
1988年 | 18篇 |
1986年 | 13篇 |
1985年 | 12篇 |
1984年 | 19篇 |
1983年 | 9篇 |
1982年 | 13篇 |
1980年 | 14篇 |
1979年 | 14篇 |
1977年 | 10篇 |
1976年 | 8篇 |
1975年 | 9篇 |
1974年 | 12篇 |
1973年 | 8篇 |
1970年 | 8篇 |
排序方式: 共有9064条查询结果,搜索用时 137 毫秒
931.
932.
Gresko E Roscic A Ritterhoff S Vichalkovski A del Sal G Schmitz ML 《The EMBO journal》2006,25(9):1883-1894
The serine/threonine kinase HIPK2 phosphorylates the p53 protein at Ser 46, thus promoting p53-dependent gene expression and subsequent apoptosis. Here, we show that DNA damaging chemotherapeutic drugs cause degradation of endogenous HIPK2 dependent on the presence of a functional p53 protein. Early induced p53 allows caspase-mediated cleavage of HIPK2 following aspartic acids 916 and 977. The resulting C-terminally truncated HIPK2 forms show an enhanced induction of the p53 response and cell death, thus allowing the rapid amplification of the p53-dependent apoptotic program during the initiation phase of apoptosis by a regulatory feed-forward loop. The active HIPK2 fragments are further degraded during the execution and termination phase of apoptosis, thus ensuring the occurrence of HIPK2 signaling only during the early phases of apoptosis induction. 相似文献
933.
The NF-kappaB p50 is the N-terminal processed product of the precursor, p105. It has been suggested that p50 is generated not from full-length p105 but cotranslationally from incompletely synthesized molecules by the proteasome. We show that the 20S proteasome endoproteolytically cleaves the fully synthesized p105 and selectively degrades the C-terminus of p105, leading to p50 generation in a ubiquitin-independent manner. As small as 25 residues C-terminus to the site of processing are sufficient to promote processing in vivo. However, any p105 mutant that lacks complete ankyrin repeat domain (ARD) is processed aberrantly, suggesting that native processing must occur from a precursor, which extends beyond the ARD. Remarkably, the mutant p105 that lacks the internal region including the glycine-rich region (GRR) is completely degraded by 20S proteasome in vitro. This suggests that the GRR impedes the complete degradation of the p105 precursor, thus contributing to p50 generation. 相似文献
934.
Coecke S Ahr H Blaauboer BJ Bremer S Casati S Castell J Combes R Corvi R Crespi CL Cunningham ML Elaut G Eletti B Freidig A Gennari A Ghersi-Egea JF Guillouzo A Hartung T Hoet P Ingelman-Sundberg M Munn S Janssens W Ladstetter B Leahy D Long A Meneguz A Monshouwer M Morath S Nagelkerke F Pelkonen O Ponti J Prieto P Richert L Sabbioni E Schaack B Steiling W Testai E Vericat JA Worth A 《Alternatives to laboratory animals : ATLA》2006,34(1):49-84
935.
936.
Schäffer AA Pfannstiel J Webster AD Plebani A Hammarström L Grimbacher B 《Human genetics》2006,118(6):725-729
Common variable immunodeficiency (CVID) is an antibody deficiency syndrome that often co-occurs in families with selective
IgA deficiency (IgAD). Vořechovsky et al. (Am J Hum Genet 64:1096–1109, 1999; J Immunol 164:4408–4416, 2000) ascertained and genotyped 101 multiplex IgAD families and used them to identify and fine map the IGAD1 locus on chromosome 6p. We analyzed the original genotype data in a subset of families with at least one case of CVID and
present evidence of a CVID locus on chromosome 16q with autosomal dominant inheritance. The peak (model-based) LOD score for
the best marker D16S518 is 2.83 at θ=0.07, and a 4-marker LOD score under heterogeneity peaks at 3.00 with α=0.68. The (model-free) NPL score using the same markers peaks at the same location with a value of 3.38 (P=0.0001). 相似文献
937.
Pappa G Lichtenberg M Iori R Barillari J Bartsch H Gerhäuser C 《Mutation research》2006,599(1-2):76-87
The isothiocyanates sulforaphane and PEITC (beta-phenethyl isothiocyanate) as well as the indoles indole-3-carbinol and its condensation product 3,3'-diindolylmethane are known to inhibit cancer cell proliferation and induce apoptosis. In this study, we compared the cell growth inhibitory potential of the four compounds on the p53 wild type human colon cancer cell line 40-16 (p53(+/+)) and its p53 knockout derivative 379.2 (p53(-/-)) (both derived from HCT116). Using sulforhodamin B staining to assess cell proliferation, we found that the isothiocyanates were strongly cytotoxic, whereas the indoles inhibited cell growth in a cytostatic manner. Half-maximal inhibitory concentrations of all four compounds in both cell lines ranged from 5-15 microM after 24, 48 and 72 h of treatment. Apoptosis induction was analyzed by immunoblotting of poly(ADP-ribose)polymerase (PARP). Treatment with sulforaphane (15 microM), PEITC (10 microM), indole-3-carbinol (10 microM) and 3,3'-diindolylmethane (10 microM) induced PARP cleavage after 24 and 48 h in both 40-16 and the 379.2 cell lines, suggestive of a p53-independent mechanism of apoptosis induction. In cultured 40-16 cells, activation of caspase-9 and -7 detected by Western blotting indicated involvement of the mitochondrial pathway. We detected time- and concentration-dependent changes in protein expression of anti-apoptotic Bcl-x(L) as well as pro-apoptotic Bax and Bak proteins. Of note is that for sulforaphane only, ratios of pro- to anti-apoptotic Bcl-2 family protein levels directly correlated with apoptosis induction measured by PARP cleavage. Taken together, we demonstrated that the glucosinolate breakdown products investigated in this study have distinct profiles of cell growth inhibition, potential to induce p53-independent apoptosis and to modulate Bcl-2 family protein expression in human colon cancer cell lines. 相似文献
938.
939.
Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis 总被引:7,自引:0,他引:7
Activity deprivation in neurons induces a slow compensatory scaling up of synaptic strength, reflecting a homeostatic mechanism for stabilizing neuronal activity. Prior studies have focused on the loss of action potential (AP) driven neurotransmission in synaptic homeostasis. Here, we show that the miniature synaptic transmission that persists during AP blockade profoundly shapes the time course and mechanism of homeostatic scaling. A brief blockade of NMDA receptor (NMDAR) mediated miniature synaptic events ("minis") rapidly scales up synaptic strength, over an order of magnitude faster than with AP blockade alone. The rapid scaling induced by NMDAR mini blockade is mediated by increased synaptic expression of surface GluR1 and the transient incorporation of Ca2+-permeable AMPA receptors at synapses; both of these changes are implemented locally within dendrites and require dendritic protein synthesis. These results indicate that NMDAR signaling during miniature synaptic transmission serves to stabilize synaptic function through active suppression of dendritic protein synthesis. 相似文献
940.
Schmitz S Hoffmann A Szekat C Rudd B Bierbaum G 《Applied and environmental microbiology》2006,72(11):7270-7277
The lantibiotic (lanthionine-containing antibiotic) mersacidin is an antimicrobial peptide consisting of 20 amino acids and is produced by Bacillus sp. strain HIL Y-85,54728. The structural gene (mrsA) and the genes for producer self-protection, modification enzymes, transport proteins, and regulator proteins are organized in a 12.3-kb biosynthetic gene cluster on the chromosome of the producer strain. Mersacidin is produced in stationary phase in a synthetic medium (K. Altena, A. Guder, C. Cramer, and G. Bierbaum, Appl. Environ. Microbiol. 66:2565-2571, 2000). To investigate the influence of the alternative sigma factor H on mersacidin biosynthesis, a SigH knockout was constructed. The knockout mutant was asporogenous, and a comparison to the wild-type strain indicated no significant differences concerning mersacidin production and immunity. Characterization of the mrsA promoter showed that the gene is transcribed by the housekeeping sigma factor A. The biosynthesis of some lantibiotic peptides like nisin or subtilin is regulated in a cell-density-dependent manner (M. Kleerebezem, Peptides 25:1405-1414, 2004). When mersacidin was added at a concentration of 2 mg/liter to an exponentially growing culture, an earlier production of antibacterial activity against Micrococcus luteus ATCC 4698 in comparison to that of the control culture was observed, suggesting that mersacidin itself functions as an autoinducer. In real-time PCR experiments, the expression of mrsA was remarkably increased in the induced culture compared to the control. In conclusion, mersacidin is yet another lantibiotic peptide whose biosynthesis can be regulated by an autoinducing mechanism. 相似文献