全文获取类型
收费全文 | 3273篇 |
免费 | 341篇 |
专业分类
3614篇 |
出版年
2022年 | 29篇 |
2021年 | 51篇 |
2020年 | 24篇 |
2019年 | 42篇 |
2018年 | 39篇 |
2017年 | 35篇 |
2016年 | 66篇 |
2015年 | 110篇 |
2014年 | 149篇 |
2013年 | 173篇 |
2012年 | 249篇 |
2011年 | 229篇 |
2010年 | 164篇 |
2009年 | 127篇 |
2008年 | 168篇 |
2007年 | 185篇 |
2006年 | 162篇 |
2005年 | 161篇 |
2004年 | 130篇 |
2003年 | 137篇 |
2002年 | 135篇 |
2001年 | 67篇 |
2000年 | 91篇 |
1999年 | 54篇 |
1998年 | 50篇 |
1997年 | 32篇 |
1996年 | 47篇 |
1995年 | 32篇 |
1994年 | 32篇 |
1993年 | 41篇 |
1992年 | 48篇 |
1991年 | 42篇 |
1990年 | 40篇 |
1989年 | 29篇 |
1988年 | 41篇 |
1987年 | 23篇 |
1986年 | 29篇 |
1985年 | 28篇 |
1984年 | 30篇 |
1983年 | 16篇 |
1981年 | 13篇 |
1979年 | 14篇 |
1978年 | 16篇 |
1977年 | 15篇 |
1974年 | 15篇 |
1973年 | 15篇 |
1972年 | 17篇 |
1970年 | 15篇 |
1967年 | 13篇 |
1966年 | 12篇 |
排序方式: 共有3614条查询结果,搜索用时 15 毫秒
101.
Banke IJ Arlt MJ Pennington C Kopitz C Steinmetzer T Schweinitz A Gansbacher B Quigley JP Edwards DR Stürzebecher J Krüger A 《Biological chemistry》2003,384(10-11):1515-1525
Although tumors frequently show elevated protease activities, the concept of anti-proteolytic cancer therapy has lost momentum after failure of clinical trials with broad-spectrum matrix metalloproteinase inhibitors. Thus we need to adapt our design strategies for protease inhibitors. Here, we employed a series of seven structurally fine-modulated and pharmacokinetically closely related synthetic 4-amidinobenzylamine-based inhibitors with distinct selectivity for prototypical serine proteases in a murine T cell lymphoma liver metastasis model. This in vivo screening revealed efficacy of urokinase inhibitors but no correlation between urokinase selectivity or affinity and anti-metastatic effect. In contrast, factor Xa-selective inhibitors were more potent, demonstrating factor Xa or a factor Xa-like serine protease likely to be more determinant in this model. Factor Xa selectivity, but not affinity, significantly improved anti-metastatic efficacy. For example, factor Xa inhibitors CJ-504 and CJ-510 exert similar affinity for factor Xa (K(i)=14 nM versus 8.8 nM) but CJ-504 was 70-fold more selective for factor Xa. This correlated with higher anti-metastatic efficacy (58.8% with CJ-504; 28.2% with CJ-510). Our results show that among the protease inhibitors employed that have affinities in the nanomolar range, the strategy of selectivity-optimization is superior to further improvement of affinity to significantly enhance anti-metastatic efficacy. This appreciation may be important for the future rational design of new anti-proteolytic agents for cancer therapy. 相似文献
102.
103.
Stefan Schleifenbaum Torsten Prietzel Gabriela Aust Andreas Boldt Sebastian Fritsch Isabel Keil Holger Koch Robert M?bius Holger A. Scheidt Martin F. X. Wagner Niels Hammer 《PloS one》2016,11(3)
Introduction
Though xenogeneic acellular scaffolds are frequently used for surgical reconstruction, knowledge of their mechanical properties is lacking. This study compared the mechanical, histological and ultrastructural properties of various native and acellular specimens.Materials and Methods
Porcine esophagi, ureters and skin were tested mechanically in a native or acellular condition, focusing on the elastic modulus, ultimate tensile stress and maximum strain. The testing protocol for soft tissues was standardized, including the adaption of the tissue’s water content and partial plastination to minimize material slippage as well as templates for normed sample dimensions and precise cross-section measurements. The native and acellular tissues were compared at the microscopic and ultrastructural level with a focus on type I collagens.Results
Increased elastic modulus and ultimate tensile stress values were quantified in acellular esophagi and ureters compared to the native condition. In contrast, these values were strongly decreased in the skin after acellularization. Acellularization-related decreases in maximum strain were found in all tissues. Type I collagens were well-preserved in these samples; however, clotting and a loss of cross-linking type I collagens was observed ultrastructurally. Elastins and fibronectins were preserved in the esophagi and ureters. A loss of the epidermal layer and decreased fibronectin content was present in the skin.Discussion
Acellularization induces changes in the tensile properties of soft tissues. Some of these changes appear to be organ specific. Loss of cross-linking type I collagen may indicate increased mechanical strength due to decreasing transverse forces acting upon the scaffolds, whereas fibronectin loss may be related to decreased load-bearing capacity. Potentially, the alterations in tissue mechanics are linked to organ function and to the interplay of cells and the extracellular matrix, which is different in hollow organs when compared to skin. 相似文献104.
105.
Bader G Schiffmann S Herrmann A Fischer M Gütlich M Auerbach G Ploom T Bacher A Huber R Lemm T 《Journal of molecular biology》2001,312(5):1051-1057
Tetrahydrobiopterin, the cofactor required for hydroxylation of aromatic amino acids regulates its own synthesis in mammals through feedback inhibition of GTP cyclohydrolase I. This mechanism is mediated by a regulatory subunit called GTP cyclohydrolase I feedback regulatory protein (GFRP). The 2.6 A resolution crystal structure of rat GFRP shows that the protein forms a pentamer. This indicates a model for the interaction of mammalian GTP cyclohydrolase I with its regulator, GFRP. Kinetic investigations of human GTP cyclohydrolase I in complex with rat and human GFRP showed similar regulatory effects of both GFRP proteins. 相似文献
106.
Weingärtner O Lütjohann D Vanmierlo T Müller S Günther L Herrmann W Böhm M Laufs U Herrmann M 《Chemistry and physics of lipids》2011,(6):451-456
Objective
Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), and diabetes mellitus and statin treatment affect cholesterol metabolism. The aim of the present study was to evaluate markers of cholesterol metabolism and determine their relationship with CVD in patients without diabetes mellitus who were not receiving statin treatment.Methods
In addition to conventional CVD risk factors, plasma levels of campesterol and sitosterol (indicators of cholesterol absorption) and lathosterol (an indicator of cholesterol synthesis) were determined in 835 consecutive patients referred for coronary angiography. Coronary artery disease was evaluated by coronary angiograms, carotid atherosclerosis and peripheral vascular disease were assessed by Doppler ultrasound, and cerebrovascular accidents and transient ischemic attacks were identified by medical history.Results
After excluding patients with known diabetes mellitus and those receiving statin treatment, 177 patients were included in the analysis. Compared to patients without CVDs (n = 111), patients with concomitant CVDs (n = 66) had a reduced lathosterol-to-cholesterol ratio (1.25 ± 0.61 vs. 1.38 ± 0.63, P < 0.05) and an increased campesterol-to-cholesterol ratio (1.81 ± 1.04 vs. 1.50 ± 0.69, P < 0.05), indicating that enhanced absorption and reduced synthesis of cholesterol is associated with CVD development. Logistic regression analysis including all established cardiovascular risk factors (age, sex, total cholesterol, arterial hypertension, body mass index and smoking) revealed that campesterol and the campesterol-to-cholesterol ratio were significant predictors of concomitant CVD in this patient population.Conclusion
In patients without diabetes mellitus, markers of enhanced cholesterol absorption were a strong predictor for concomitant CVD. 相似文献107.
Tracie Pennimpede Stefanie Wolter Lars Wittler Anne‐Karoline Ebert Wolfgang Rösch Raimund Stein Enrika Bartels Dominik Schmidt Thomas M. Boemers Eberhard Schmiedeke Per Hoffmann Susanne Moebus Bernhard G. Herrmann Markus M. Nöthen Heiko Reutter Michael Ludwig 《Birth defects research. Part A, Clinical and molecular teratology》2013,97(3):133-139
108.
Unlocking the diversity and biotechnological potential of marine surface associated microbial communities 总被引:3,自引:0,他引:3
Marine sessile eukaryotic hosts provide a unique surface for microbial colonisation. Chemically mediated interactions between the host and colonising microorganisms, interactions between microorganisms in the biofilm community and surface-specific physical and chemical conditions impact differently on the diversity and function of surface-associated microbial assemblages compared with those in planktonic systems. Understanding the diversity and ecology of surface-associated microbial communities will greatly contribute to the discovery of next-generation, bioactive compounds. On the basis of recent conceptual and technological advances insights into the microbiology of marine living surfaces are improving and novel bioactives, including those previously ascribed as host derived, are now revealed to be produced by members of the surface-associated microbial community. 相似文献
109.
110.
Carolin Lechtermann Berthold P. Hauffa Ralf Herrmann Michael M. Schündeln Alexandra Gellhaus Markus Schmidt Corinna Grasemann 《PloS one》2014,9(8)
Preeclampsia, a hypertensive disorder in pregnancy develops in 2–8% of pregnancies worldwide. Winter season and vitamin D deficiency have been associated with its onset.