全文获取类型
收费全文 | 1199篇 |
免费 | 116篇 |
出版年
2022年 | 5篇 |
2021年 | 21篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2018年 | 13篇 |
2017年 | 21篇 |
2016年 | 16篇 |
2015年 | 32篇 |
2014年 | 51篇 |
2013年 | 57篇 |
2012年 | 67篇 |
2011年 | 76篇 |
2010年 | 45篇 |
2009年 | 43篇 |
2008年 | 50篇 |
2007年 | 58篇 |
2006年 | 62篇 |
2005年 | 45篇 |
2004年 | 38篇 |
2003年 | 38篇 |
2002年 | 42篇 |
2001年 | 30篇 |
2000年 | 34篇 |
1999年 | 28篇 |
1998年 | 28篇 |
1997年 | 19篇 |
1996年 | 16篇 |
1995年 | 19篇 |
1994年 | 18篇 |
1993年 | 16篇 |
1992年 | 24篇 |
1991年 | 31篇 |
1990年 | 18篇 |
1989年 | 17篇 |
1988年 | 17篇 |
1987年 | 21篇 |
1986年 | 12篇 |
1985年 | 10篇 |
1984年 | 12篇 |
1983年 | 8篇 |
1982年 | 8篇 |
1981年 | 7篇 |
1980年 | 11篇 |
1979年 | 13篇 |
1978年 | 11篇 |
1977年 | 17篇 |
1976年 | 5篇 |
1975年 | 7篇 |
1974年 | 7篇 |
1973年 | 7篇 |
排序方式: 共有1315条查询结果,搜索用时 31 毫秒
991.
Mark K. N?hr Anete Dudele Morten M. Poulsen Lene H. Ebbesen Yulia Radko Lars P. Christensen Niels Jessen Bj?rn Richelsen Sten Lund Steen B. Pedersen 《PloS one》2016,11(1)
Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin / delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. In conclusion: Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion. 相似文献
992.
993.
Poulsen KR Sørensen TK Duroux L Petersen EI Petersen SB Wimmer R 《Biochemistry》2006,45(30):9163-9171
We here present a study of the interaction between the Fusarium solani pisi cutinase mutant S120A and spin-labeled 4,4-dimethyloxazoline-N-oxyl-(DOXYL)-stearoyl-glycerol substrates in a micellar system. The interaction is detected by NMR measuring changes in chemical shift for 1H and 15N as well as relaxation parameters for backbone 1H (T1) and 15N (T1, T2) atoms as well as for side chain methyl groups 1H (T1). The detected interaction shows a weak binding of cutinase to the lipid micelles. Structural and mobility changes are located inside and around the active site, its flanking loops, and the oxyanion hole, respectively. Relaxation changes in the amino acid pairs Ser 92, Ala 93 and Thr 173, Gly 174 positioned at the edge of each of the active site flanking loops make these residues prime candidates for hinges, allowing for structural rearrangement during substrate binding. The cutinase mutant S120A used carries a 15 amino acid pro-peptide; the significance of this pro-peptide was so far undetermined. We show here that the pro-peptide is affected by the presence of the micellar substrate. Relaxation enhancements indicative of spatial proximity between the DOXYL group in the lipid chain and some hydrophobic residues surrounding the active site could be found. 相似文献
994.
Jacob Andersen Lars Olsen Kasper B. Hansen Olivier Taboureau Flemming S. J?rgensen Anne Marie J?rgensen Benny Bang-Andersen Jan Egebjerg Kristian Str?mgaard Anders S. Kristensen 《The Journal of biological chemistry》2010,285(3):2051-2063
The serotonin transporter (SERT) regulates extracellular levels of the neurotransmitter serotonin (5-hydroxytryptamine) in the brain by facilitating uptake of released 5-hydroxytryptamine into neuronal cells. SERT is the target for widely used antidepressant drugs, including imipramine, fluoxetine, and (S)-citalopram, which are competitive inhibitors of the transport function. Knowledge of the molecular details of the antidepressant binding sites in SERT has been limited due to lack of structural data on SERT. Here, we present a characterization of the (S)-citalopram binding pocket in human SERT (hSERT) using mutational and computational approaches. Comparative modeling and ligand docking reveal that (S)-citalopram fits into the hSERT substrate binding pocket, where (S)-citalopram can adopt a number of different binding orientations. We find, however, that only one of these binding modes is functionally relevant from studying the effects of 64 point mutations around the putative substrate binding site. The mutational mapping also identify novel hSERT residues that are crucial for (S)-citalopram binding. The model defines the molecular determinants for (S)-citalopram binding to hSERT and demonstrates that the antidepressant binding site overlaps with the substrate binding site. 相似文献
995.
996.
997.
998.
Plasmids carrying the mioC promoter region with its two DnaA boxes are as efficient in titration of DnaA protein as plasmids carrying a replication-inactivated oriC region with its five DnaA boxes. The two DnaA boxes upstream of the mioC promoter were mutated in various ways to study the cooperativity between the DnaA boxes, and to study in vivo the in vitro-defined 9mer DnaA box consensus sequence (TT(A)/(T)TNCACA). The quality and cooperativity of the DnaA boxes were determined in two complementary ways: as titration of DnaA protein leading to derepression of the dnaA promoter, and as repression of the mioC promoter caused by the DnaA protein binding to the DnaA boxes. Titration of DnaA protein correlated with repression of the mioC promoter. The level of titration and repression with the normal promoter-proximal box (TTTTCCACA) depends strongly on the presence and the quality of a DnaA box in the promoter-distal position, whereas a promoter-proximal DnaA box with the sequence TTATCCACA titrated DnaA protein and caused significant repression of the mioC promoter without a promoter-distal DnaA box. The quality of the eight different consensus DnaA boxes located in the promoter-proximal position was determined: TTATCCACA had the highest affinity for DnaA protein. In the third position, A was better than T, and the four possibilities in the fifth position could be ranked as C >A >or=G >T. Parallel in vitro experiments using a purified DNA-binding domain of DnaA protein gave the same ranking of the binding affinities of the eight DnaA boxes. 相似文献
999.
1000.
Chas. E. S. Flemming 《BMJ (Clinical research ed.)》1922,1(3198):621-622