全文获取类型
收费全文 | 13585篇 |
免费 | 1443篇 |
国内免费 | 2266篇 |
出版年
2024年 | 17篇 |
2023年 | 244篇 |
2022年 | 380篇 |
2021年 | 701篇 |
2020年 | 512篇 |
2019年 | 722篇 |
2018年 | 651篇 |
2017年 | 533篇 |
2016年 | 669篇 |
2015年 | 927篇 |
2014年 | 1111篇 |
2013年 | 1153篇 |
2012年 | 1371篇 |
2011年 | 1250篇 |
2010年 | 816篇 |
2009年 | 740篇 |
2008年 | 848篇 |
2007年 | 748篇 |
2006年 | 670篇 |
2005年 | 569篇 |
2004年 | 486篇 |
2003年 | 412篇 |
2002年 | 368篇 |
2001年 | 230篇 |
2000年 | 187篇 |
1999年 | 162篇 |
1998年 | 121篇 |
1997年 | 97篇 |
1996年 | 75篇 |
1995年 | 45篇 |
1994年 | 53篇 |
1993年 | 33篇 |
1992年 | 48篇 |
1991年 | 43篇 |
1990年 | 52篇 |
1989年 | 33篇 |
1988年 | 20篇 |
1987年 | 18篇 |
1986年 | 30篇 |
1985年 | 16篇 |
1984年 | 17篇 |
1983年 | 20篇 |
1982年 | 12篇 |
1981年 | 13篇 |
1980年 | 7篇 |
1979年 | 17篇 |
1978年 | 6篇 |
1977年 | 9篇 |
1976年 | 9篇 |
1975年 | 7篇 |
排序方式: 共有10000条查询结果,搜索用时 359 毫秒
931.
Genomic integrity is maintained by checkpoints that guard against undesired replication after DNA damage. Here, we show that CDT1, a licensing factor of the pre-replication complex (preRC), is rapidly proteolysed after UV- or gamma-irradiation. The preRC assembles on replication origins at the end of mitosis and during G1 to license DNA for replication in S phase. Once the origin recognition complex (ORC) binds to origins, CDC6 and CDT1 associate with ORC and promote loading of the MCM2-7 proteins onto chromatin, generating the preRC. We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage. 相似文献
932.
The availability of genome sequences for several organisms, including humans, and the resulting first-approximation lists of genes, have allowed a transition from molecular biology to 'modular biology'. In modular biology, biological processes of interest, or modules, are studied as complex systems of functionally interacting macromolecules. Functional genomic and proteomic ('omic') approaches can be helpful to accelerate the identification of the genes and gene products involved in particular modules, and to describe the functional relationships between them. However, the data emerging from individual omic approaches should be viewed with caution because of the occurrence of false-negative and false-positive results and because single annotations are not sufficient for an understanding of gene function. To increase the reliability of gene function annotation, multiple independent datasets need to be integrated. Here, we review the recent development of strategies for such integration and we argue that these will be important for a systems approach to modular biology. 相似文献
933.
Expression,purification and functional characterization of a recombinant scorpion venom peptide BmTXKbeta 总被引:1,自引:0,他引:1
BmTXKbeta, a scorpion toxin isolated from the Chinese scorpion Buthus martensii Karsch (BmK), was expressed as a GST fusion protein in BL21 (DE3) strain. The recombinant GST-BmTXKbeta protein was purified by affinity chromatography. When treated with enterokinase, the GST-BmTXKbeta fusion protein released an approximate 6.5kDa protein which was the expected size for correctly processed. About 2mg purified recombinant BmTXKbeta protein (rBmTXKbeta) was produced from 1l bacterial culture, using this expression and purification system. The function of rBmTXKbeta was studied on the rabbit atrial myocyte by whole-cell patch clamp technique. The results showed that rBmTXKbeta inhibited the transient outward current (I(to)) of rabbit atrial myocyte with recovery after washout and the inhibition was concentration-dependent. The rBmTXKbeta prolonged the action potential duration of rabbit atrial myocyte in a concentration-dependent manner, whereas it did not affect the action potential amplitude. 相似文献
934.
Fission yeast Mrc1 (mediator of replication checkpoint 1) is an adaptor checkpoint protein required for Rad3-dependent activation of the checkpoint kinase Cds1 in response to arrest of replication forks. Here we report studies on the regulation of Mrc1 by phosphorylation. Replication arrest induced by hydroxyurea (HU) induces Mrc1 phosphorylation that is detected by a change in Mrc1 electrophoretic mobility. Phosphorylation is maintained in cds1Delta, rad3Delta, and tel1Delta single mutants but eliminated in a rad3Delta tel1Delta double mutant. Mrc1 has two clusters of S/TQ motifs that are potential Rad3/Tel1 phosphorylation sites. Mutation of six S/TQ motifs in these two clusters strongly impairs Mrc1 phosphorylation. Two motifs located at S604 and T645 are vital for HU resistance. The T645A mutation strongly impairs a Cds1-Mrc1 yeast two-hybrid interaction that is dependent on a functional forkhead-associated (FHA) domain in Cds1, indicating that phosphorylation of T645 mediates Mrc1's association with Cds1. Consistent with this model, the T645 region of Mrc1 effectively substitutes for the T11 region of Cds1 that is thought to be phosphorylated by Rad3 and to mediate FHA-dependent oligomerization of Cds1. The S/TQ cluster that includes S604 is needed for Mrc1's increased association with chromatin in replication-arrested cells. These data indicate that Rad3 and Tel1 regulate Mrc1 through differential phosphorylation to control Cds1. 相似文献
935.
Horiuchi K Weskamp G Lum L Hammes HP Cai H Brodie TA Ludwig T Chiusaroli R Baron R Preissner KT Manova K Blobel CP 《Molecular and cellular biology》2003,23(16):5614-5624
ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15(-/-) mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15(-/-) mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15(-/-) mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15(-/-) mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization. 相似文献
936.
It is found that the helix parameter (HP), which favors clustering of non-polar residues, is linearly correlated with the logarithms of rate constants of folding of small two-state alpha-helical proteins. The definition is HP = N(H)(-1) sigma [f(i)+ (f(i-1)+f(i+1))/2], where f(i)=1 or -1, if the i'th residue is hydrophobic or hydrophilic, respectively, N(H) is the number of hydrophobic residues and the summation is taken over the hydrophobic residues. 相似文献
937.
938.
Fei X Zheng QH Liu X Wang JQ Sun HB Mock BH Stone KL Miller KD Sledge GW Hutchins GD 《Bioorganic & medicinal chemistry letters》2003,13(13):2217-2222
Novel matrix metalloproteinase (MMP) inhibitor radiotracers, (S)-3-methyl-2-(2',3',4'-methoxybiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1a-c), (S)-3-methyl-2-(2',3',4'-fluorobiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1d-f), and (S)-3-methyl-2-(4'-nitrobiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1g), a series of substituted biphenylsulfonamide derivatives, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer imaging agents. 相似文献
939.
940.
Middlekauff HR Yu JL Hui K 《American journal of physiology. Regulatory, integrative and comparative physiology》2001,280(5):R1462-R1468
In animal studies, acupuncture has been shown to be sympathoinhibitory, but it is unknown if acupuncture is sympathoinhibitory in humans. Nineteen healthy volunteers underwent mental stress testing pre- and postacupuncture. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate during mental stress were compared pre- and postacupuncture. Control acupuncture consisted of acupuncture at nonacupoints and "no-needle" acupuncture. Acupuncture had no effect on resting MSNA, blood pressure, or heart rate. After real acupuncture, the increase in mean arterial pressure (pre- vs. postacupuncture 4.5 vs. 1.7 mmHg, P < 0.001), but not MSNA or heart rate, was blunted during mental stress. Similarly, following nonacupoint acupuncture, the increase in mean arterial pressure was blunted during mental stress (5.4 vs. 2.9 mmHg, P < 0.0003). No-needle acupuncture had no effect on these variables. In conclusion, acupuncture at traditional acupoints, nonacupoints, and no-needle acupuncture does not modulate baseline MSNA or MSNA responses to mental stress in normal humans. Acupuncture significantly attenuates the increase in blood pressure during mental stress. Needling nonacupoints, but not "no-needle" acupuncture, have a similar effect on blood pressure. 相似文献