全文获取类型
收费全文 | 1037篇 |
免费 | 18篇 |
国内免费 | 15篇 |
专业分类
化学 | 626篇 |
晶体学 | 3篇 |
力学 | 26篇 |
数学 | 181篇 |
物理学 | 234篇 |
出版年
2022年 | 7篇 |
2020年 | 12篇 |
2019年 | 13篇 |
2018年 | 9篇 |
2017年 | 8篇 |
2016年 | 21篇 |
2015年 | 10篇 |
2014年 | 20篇 |
2013年 | 38篇 |
2012年 | 32篇 |
2011年 | 61篇 |
2010年 | 24篇 |
2009年 | 30篇 |
2008年 | 61篇 |
2007年 | 44篇 |
2006年 | 58篇 |
2005年 | 55篇 |
2004年 | 37篇 |
2003年 | 33篇 |
2002年 | 44篇 |
2001年 | 33篇 |
2000年 | 24篇 |
1999年 | 19篇 |
1998年 | 13篇 |
1997年 | 14篇 |
1996年 | 23篇 |
1995年 | 17篇 |
1994年 | 19篇 |
1993年 | 18篇 |
1992年 | 23篇 |
1991年 | 15篇 |
1990年 | 14篇 |
1989年 | 8篇 |
1988年 | 13篇 |
1987年 | 10篇 |
1986年 | 11篇 |
1985年 | 10篇 |
1984年 | 9篇 |
1983年 | 9篇 |
1982年 | 8篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 8篇 |
1976年 | 6篇 |
1975年 | 10篇 |
1974年 | 9篇 |
1973年 | 11篇 |
1972年 | 6篇 |
1971年 | 7篇 |
1970年 | 11篇 |
排序方式: 共有1070条查询结果,搜索用时 15 毫秒
1.
Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease. 相似文献
2.
3.
4.
5.
J. Telser H. -I. Lee E. T. Smith H. Huang P. Brereton M. W. W. Adams R. C. Conover M. K. Johnson B. M. Hoffman 《Applied magnetic resonance》1998,14(2-3):305-321
The hyperthermophilic archaeonPyrococcus furiosus contains a four-Fe ferredoxin (Pf- Fd) that differs from most other 4Fe-Fd’s in that its [Fe4S4] cluster is anchored to protein by only three cysteinyl residues.Pf- Fd also is of interest because in its reduced form, [Fe4S4]+, the cluster exhibits bothS = 1/2 andS = 3/2 spin states. Addition of excess cyanide ion converts the cluster exclusively to anS = 1/2 state (g1 = 2.09, g2 = 1.95, g3 = 1.92), however dialysis restores the EPR signal of native reduced protein indicating that the cluster is not irreversibly altered by cyanide. Both the native protein and protein in the presence of excess cyanide ion (Pf- Fd 4Fe-CN) were investigated here using the techniques of electron paramagnetic resonance (EPR) and electron-nuclear double resonance (ENDOR) spectroscopy. In particular,Pf- Fd 4Fe-CN was investigated using13CN? and C15N? ligands.13C and15N ENDOR indicated that a single cyanide ion bound directly, with the cluster showing an unusually small contact interaction (aiso(13C)~ ?3 MHz, aiso(15N) ~ 0). This is in contrast to cyanide bound to monomeric low-spin Fe(III)-containing proteins such as transferrin and myoglobin, for which the13C hyperfine coupling has a large isotropic component (aiso(13C) ≈ ?30 MHz). This small contact interaction is not due to low spin density of Fe, as57Fe ENDOR of the singly and triply labeledPf- Fd 4FeCN isotopologs, [57FeFe3S4]+ and [Fe57Fe3S4]+, show hyperfine coupling characteristic for [Fe4S4]+ clusters, particularly for the Fe to which cyanide binds. Thus, the low spin density on13C is not due to low spin density on the Fe ion to which it binds. Further theoretical work is needed to explain the contrast between the strong electronic effect of cyanide ion binding with the low spin density on the ligand. 相似文献
6.
7.
8.
9.
10.
Grosnick D Wright SC Bolton RD Cooper MD Frank JS Hallin AL Heusi PA Hoffman CM Hogan GE Mariam FG Matis HS Mischke RE Piilonen LE Sandberg VD Sanders GH Sennhauser U Werbeck R Williams RA Wilson SL Hofstadter R Hughes EB Ritter MW Highland VL McDonough J 《Physical review letters》1986,57(26):3241-3244