全文获取类型
收费全文 | 18677篇 |
免费 | 100篇 |
国内免费 | 87篇 |
专业分类
系统科学 | 214篇 |
丛书文集 | 121篇 |
教育与普及 | 45篇 |
理论与方法论 | 125篇 |
现状及发展 | 8135篇 |
研究方法 | 863篇 |
综合类 | 9162篇 |
自然研究 | 199篇 |
出版年
2018年 | 191篇 |
2017年 | 235篇 |
2013年 | 147篇 |
2012年 | 288篇 |
2011年 | 571篇 |
2010年 | 162篇 |
2009年 | 142篇 |
2008年 | 386篇 |
2007年 | 620篇 |
2006年 | 395篇 |
2005年 | 395篇 |
2004年 | 355篇 |
2003年 | 442篇 |
2002年 | 363篇 |
2001年 | 689篇 |
2000年 | 676篇 |
1999年 | 412篇 |
1994年 | 321篇 |
1992年 | 385篇 |
1991年 | 274篇 |
1990年 | 333篇 |
1989年 | 291篇 |
1988年 | 254篇 |
1987年 | 313篇 |
1986年 | 313篇 |
1985年 | 386篇 |
1984年 | 279篇 |
1983年 | 264篇 |
1982年 | 247篇 |
1981年 | 227篇 |
1980年 | 217篇 |
1979年 | 601篇 |
1978年 | 434篇 |
1977年 | 402篇 |
1976年 | 350篇 |
1975年 | 357篇 |
1974年 | 432篇 |
1973年 | 395篇 |
1972年 | 354篇 |
1971年 | 416篇 |
1970年 | 569篇 |
1969年 | 433篇 |
1968年 | 447篇 |
1967年 | 411篇 |
1966年 | 383篇 |
1965年 | 287篇 |
1959年 | 145篇 |
1958年 | 242篇 |
1957年 | 155篇 |
1956年 | 154篇 |
排序方式: 共有10000条查询结果,搜索用时 312 毫秒
11.
The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast 总被引:1,自引:0,他引:1
Menne TF Goyenechea B Sánchez-Puig N Wong CC Tonkin LM Ancliff PJ Brost RL Costanzo M Boone C Warren AJ 《Nature genetics》2007,39(4):486-495
The autosomal recessive disorder Shwachman-Diamond syndrome, characterized by bone marrow failure and leukemia predisposition, is caused by deficiency of the highly conserved Shwachman-Bodian-Diamond syndrome (SBDS) protein. Here, we identify the function of the yeast SBDS ortholog Sdo1, showing that it is critical for the release and recycling of the nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in 60S maturation and translational activation of ribosomes. Using genome-wide synthetic genetic array mapping, we identified multiple TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export defects and cytoplasmic mislocalization of Tif6 observed in sdo1Delta cells. Sdo1 appears to function within a pathway containing elongation factor-like 1, and together they control translational activation of ribosomes. Thus, our data link defective late 60S ribosomal subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition. 相似文献
12.
Hellgren M Strömberg P Gallego O Martras S Farrés J Persson B Parés X Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(4):498-505
The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2
(ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with
an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min−1, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities
were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup.
This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic
retinol oxidation at physiological concentrations.
Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007 相似文献
13.
14.
15.
Hermann T 《Cellular and molecular life sciences : CMLS》2007,64(14):1841-1852
Aminoglycoside antibiotics kill bacteria by binding to the ribosomal decoding site and reducing fidelity of protein synthesis.
Since the discovery of these natural products over 50 years ago, aminoglycosides have provided a mainstay of antibacterial
therapy of serious Gram-negative infections. In recent years, aminoglycosides have become important tools to study molecular
recognition of ribonucleic acid (RNA). In an ingenious exploitation of the aminoglycosides’ mechanism of action, it has been
speculated that drug-induced readthrough of premature stop codons in mutated messenger RNAs might be used to treat patients
suffering from certain heritable genetic disorders.
Received 23 January 2007; received after revision 25 February 2007; accepted 29 March 2007 相似文献
16.
17.
Komen JC Distelmaier F Koopman WJ Wanders RJ Smeitink J Willems PH 《Cellular and molecular life sciences : CMLS》2007,64(24):3271-3281
Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain
fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic
acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic
acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was
investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas
substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial
membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic
acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts.
Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007
J. C. Komen, F. Distelmaier: These authors contributed equally to this work. 相似文献
18.
Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications 总被引:2,自引:0,他引:2
Solá RJ Rodríguez-Martínez JA Griebenow K 《Cellular and molecular life sciences : CMLS》2007,64(16):2133-2152
Glycosylation constitutes one of the most important posttranslational modifications employed by biological systems to modulate
protein biophysical properties. Due to the direct biochemical and biomedical implications of achieving control over protein
stability and function by chemical means, there has been great interest in recent years towards the development of chemical
strategies for protein glycosylation. Since current knowledge about glycoprotein biophysics has been mainly derived from the
study of naturally glycosylated proteins, chemical glycosylation provides novel insights into its mechanistic understanding
by affording control over glycosylation parameters. This review presents a survey of the effects that natural and chemical
glycosylation have on the fundamental biophysical properties of proteins (structure, dynamics, stability, and function). This
is complemented by a mechanistic discussion of how glycans achieve such effects and discussion of the implications of employing
chemical glycosylation as a tool to exert control over protein biophysical properties within biochemical and biomedical applications.
Received 15 December 2006; received after revision 28 March 2007; accepted 25 April 2007 相似文献
19.
20.
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 总被引:14,自引:0,他引:14
van Heel DA Franke L Hunt KA Gwilliam R Zhernakova A Inouye M Wapenaar MC Barnardo MC Bethel G Holmes GK Feighery C Jewell D Kelleher D Kumar P Travis S Walters JR Sanders DS Howdle P Swift J Playford RJ McLaren WM Mearin ML Mulder CJ McManus R McGinnis R Cardon LR Deloukas P Wijmenga C 《Nature genetics》2007,39(7):827-829
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. 相似文献