全文获取类型
收费全文 | 2715篇 |
免费 | 249篇 |
专业分类
2964篇 |
出版年
2023年 | 9篇 |
2022年 | 23篇 |
2021年 | 58篇 |
2020年 | 29篇 |
2019年 | 34篇 |
2018年 | 39篇 |
2017年 | 29篇 |
2016年 | 64篇 |
2015年 | 124篇 |
2014年 | 109篇 |
2013年 | 172篇 |
2012年 | 188篇 |
2011年 | 205篇 |
2010年 | 125篇 |
2009年 | 119篇 |
2008年 | 156篇 |
2007年 | 177篇 |
2006年 | 169篇 |
2005年 | 164篇 |
2004年 | 146篇 |
2003年 | 182篇 |
2002年 | 147篇 |
2001年 | 39篇 |
2000年 | 28篇 |
1999年 | 37篇 |
1998年 | 38篇 |
1997年 | 20篇 |
1996年 | 10篇 |
1995年 | 26篇 |
1994年 | 18篇 |
1993年 | 12篇 |
1992年 | 23篇 |
1991年 | 17篇 |
1990年 | 14篇 |
1989年 | 13篇 |
1988年 | 10篇 |
1987年 | 15篇 |
1985年 | 10篇 |
1984年 | 19篇 |
1983年 | 16篇 |
1982年 | 10篇 |
1981年 | 12篇 |
1980年 | 10篇 |
1979年 | 6篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 5篇 |
1974年 | 6篇 |
1973年 | 13篇 |
1972年 | 9篇 |
排序方式: 共有2964条查询结果,搜索用时 15 毫秒
241.
242.
Ritter B Denisov AY Philie J Allaire PD Legendre-Guillemin V Zylbergold P Gehring K McPherson PS 《The EMBO journal》2007,26(18):4066-4077
AP-2 is a key regulator of the endocytic protein machinery driving clathrin-coated vesicle (CCV) formation. One critical function, mediated primarily by the AP-2 alpha-ear, is the recruitment of accessory proteins. NECAPs are alpha-ear-binding proteins that enrich on CCVs. Here, we have solved the structure of the conserved N-terminal region of NECAP 1, revealing a unique module in the pleckstrin homology (PH) domain superfamily, which we named the PHear domain. The PHear domain binds accessory proteins bearing FxDxF motifs, which were previously thought to bind exclusively to the AP-2 alpha-ear. Structural analysis of the PHear domain reveals the molecular surface for FxDxF motif binding, which was confirmed by site-directed mutagenesis. The reciprocal analysis of the FxDxF motif in amphiphysin I identified distinct binding requirements for binding to the alpha-ear and PHear domain. We show that NECAP knockdown compromises transferrin uptake and establish a functional role for NECAPs in clathrin-mediated endocytosis. Our data uncover a striking convergence of two evolutionarily and structurally distinct modules to recognize a common peptide motif and promote efficient endocytosis. 相似文献
243.
Wakefield L Cornish V Long H Griffiths WJ Sim E 《Biochemical and biophysical research communications》2007,364(3):556-560
The mouse arylamine N-acetyltransferase 2 (Nat2) and its homologue (NAT1) in humans are known to detoxify xenobiotic arylamines and are also thought to play a role in endogenous metabolism. Human NAT1 is highly over-expressed in estrogen receptor positive breast tumours and is implicated in susceptibility to neural tube defects. In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking. Mouse Nat2 provides a good model to study human NAT1 as it shows similar expression profiles and substrate specificities. We have generated transgenic mice lacking a functional Nat2 gene and compared the urinary levels of acetylated folate metabolite para-aminobenzoylglutamate in Nat2 knockout and Nat2 wild-type mice. These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described. 相似文献
244.
Trostchansky A Souza JM Ferreira A Ferrari M Blanco F Trujillo M Castro D Cerecetto H Baker PR O'Donnell VB Rubbo H 《Biochemistry》2007,46(15):4645-4653
Nitrated fatty acids (nitroalkenes) have been recently detected and quantified in cell membranes and human plasma. However, nitration of arachidonate (AA), that could redirect AA-dependent cell signaling pathways, has not been studied in detail. Herein, we synthesized and determined for the first time the isomer distribution of nitroarachidonate (AANO2) and demonstrate its ability to modulate inflammation. Synthesis of AANO2 was achieved by AA treatment with sodium nitrite in acidic conditions following HPLC separation. Mass spectrometry (MS) analysis showed the characteristic MS/MS transition of AANO2 (m/z 348/301). Moreover, the IR signal at 1378.3 cm(-1) and NMR studies confirmed the presence of mononitrated nitroalkenes. Positional isomer distribution was determined by NMR and MS fragmentation with lithium; four major isomers (9-, 12-, 14-, and 15-AANO2) were identified, which exhibited key anti-inflammatory properties. These include their ability to release biologically relevant amounts of nitric oxide, induce cGMP-dependent vasorelaxation, and down-regulate inducible nitric oxide synthase (NOS2) expression during macrophage activation, providing unique structural evidence and novel regulatory signaling properties of AANO2. 相似文献
245.
246.
Liu X Simpson JA Brunt KR Ward CA Hall SR Kinobe RT Barrette V Tse MY Pang SC Pachori AS Dzau VJ Ogunyankin KO Melo LG 《American journal of physiology. Heart and circulatory physiology》2007,293(1):H48-H59
We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 x 10(11) particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure. 相似文献
247.
Ghosh AK Xi K Grum-Tokars V Xu X Ratia K Fu W Houser KV Baker SC Johnson ME Mesecar AD 《Bioorganic & medicinal chemistry letters》2007,17(21):5876-5880
Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic severe acute respiratory syndrome-coronavirus chymotrypsin-like protease inhibitors are described. These inhibitors were designed and synthesized based upon our X-ray crystal structure of inhibitor 1 bound to SARS-CoV 3CLpro. Incorporation of Boc-Ser as the P(4)-ligand resulted in enhanced SARS-CoV 3CLpro inhibitory activity. Structural analysis of the inhibitor-bound X-ray structure revealed high binding affinity toward the enzyme. 相似文献
248.
Parker MF Bronson JJ Barten DM Corsa JA Du W Felsenstein KM Guss VL Izzarelli D Loo A McElhone KE Marcin LR Padmanabha R Pak R Polson CT Toyn JH Varma S Wang J Wong V Zheng M Roberts SB 《Bioorganic & medicinal chemistry letters》2007,17(21):5790-5795
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported. 相似文献
249.
Larsen SD Poel TJ Filipski KJ Kohrt JT Pfefferkorn JA Sorenson RJ Tait BD Askew V Dillon L Hanselman JC Lu GH Robertson A Sekerke C Kowala MC Auerbach BJ 《Bioorganic & medicinal chemistry letters》2007,17(20):5567-5572
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. 相似文献
250.