全文获取类型
收费全文 | 1441篇 |
免费 | 200篇 |
出版年
2021年 | 20篇 |
2020年 | 12篇 |
2018年 | 16篇 |
2016年 | 23篇 |
2015年 | 43篇 |
2014年 | 54篇 |
2013年 | 65篇 |
2012年 | 75篇 |
2011年 | 81篇 |
2010年 | 49篇 |
2009年 | 46篇 |
2008年 | 61篇 |
2007年 | 61篇 |
2006年 | 53篇 |
2005年 | 61篇 |
2004年 | 62篇 |
2003年 | 53篇 |
2002年 | 63篇 |
2001年 | 14篇 |
2000年 | 16篇 |
1999年 | 18篇 |
1998年 | 27篇 |
1997年 | 19篇 |
1996年 | 13篇 |
1995年 | 14篇 |
1994年 | 19篇 |
1992年 | 16篇 |
1991年 | 19篇 |
1990年 | 12篇 |
1989年 | 15篇 |
1988年 | 16篇 |
1987年 | 16篇 |
1986年 | 13篇 |
1984年 | 12篇 |
1983年 | 18篇 |
1982年 | 17篇 |
1981年 | 25篇 |
1980年 | 19篇 |
1978年 | 12篇 |
1977年 | 15篇 |
1976年 | 17篇 |
1974年 | 15篇 |
1973年 | 16篇 |
1971年 | 14篇 |
1970年 | 13篇 |
1969年 | 15篇 |
1968年 | 18篇 |
1967年 | 12篇 |
1964年 | 16篇 |
1963年 | 15篇 |
排序方式: 共有1641条查询结果,搜索用时 78 毫秒
131.
132.
Stringer AM Gibson RJ Logan RM Bowen JM Yeoh AS Burns J Keefe DM 《Experimental biology and medicine (Maywood, N.J.)》2007,232(1):96-106
The microflora of the gastrointestinal tract (GIT) are a complex ecosystem, performing a number of beneficial functions. Irinotecan causes both early and late diarrhea, the latter possibly caused, in part, by changes in the microflora of the GIT. Female DA rats were given atropine subcutaneously, prior to a single 200 mg/kg intraperitoneal dose of irinotecan. Animals were monitored for diarrhea and killed at 30 and 60 mins, 2, 6, 12, 24, 48, and 72 hrs after chemotherapy administration. Control rats received no treatment. Fecal samples and stomach, jejunum, and colon samples were collected and stored at -70 degrees C until required. Standard microbiological culture techniques were used to grow and isolate the flora. Biochemical tests were used to identify the bacteria. The level of growth was noted for relative comparison between time points and graded accordingly. Early diarrhea was observed in the rats from 2-6 hrs after treatment, after which time the diarrhea resolved. Late onset diarrhea was apparent 72 hrs after treatment. Changes were seen in the flora of the stomach, jejunum, colon and feces. The majority of microflora changes were seen 6, 12, and 24 hrs after treatment, with a relative increase or decrease in the presence of bacteria in comparison with control rats. In some rats bacteria were not observed at all time points, and different bacteria not seen in control animals were identified in rats treated with irinotecan. These changes were observed up to 72 hrs after treatment. In conclusion, irinotecan treatment causes changes in the flora of the stomach, jejunum, colon, and feces of rats and is associated with the development of diarrhea. These changes in flora may have systemic effects and in particular may contribute to the development of chemotherapy-induced mucositis. 相似文献
133.
The key role of coenzyme Q (ubiquinone or Q) is in mitochondrial and prokaryotic energetics. Less well investigated is the basis for its presence in eukaryotic membrane locations other than mitochondria and in plasma where both antioxidant and potentially more targeted roles are indicated. Included in the latter is that of a lipid-soluble electron transfer intermediate that serves as the transmembrane component of plasma membrane and Golgi apparatus electron transport, which regulates cytosolic NAD(+) /NADH ratios and is involved in vectorial membrane displacements and in the regulation of cell growth. Important protective effects on circulating lipoproteins and in the prevention of coronary artery disease ensue not only from the antioxidant role of CoQ(10) but also from its ability to directly block protein oxidation and superoxide generation of the TM-9 family of membrane proteins known as age-related NADH oxidase or arNOX (ENOX3) and their shed forms that appear after age 30 and some of which associate specifically with low-density lipoprotein particles to catalyze protein oxidation and crosslinking. 相似文献
134.
Xu L Zhang L Jones R Bryant C Boddeker N Mabery E Bahador G Watson J Clough J Arimilli M Gillette W Colagiovanni D Wang K Gibbs C Kim CU 《Bioorganic & medicinal chemistry letters》2011,21(6):1670-1674
There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified. 相似文献
135.
Jackson RW LaPorte MG Herbertz T Draper TL Gaboury JA Rippin SR Patel R Chunduru SK Benetatos CA Young DC Burns CJ Condon SM 《Bioorganic & medicinal chemistry letters》2011,21(11):3227-3231
We describe the structure-activity relationship of the C7-position of pyrano[3,4-b]indole-based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compounds 13 and 14. 相似文献
136.
Sun X Qiu J Strong SA Green LS Wasley JW Colagiovanni DB Mutka SC Blonder JP Stout AM Richards JP Chun L Rosenthal GJ 《Bioorganic & medicinal chemistry letters》2011,21(12):3671-3675
S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach. 相似文献
137.
Zheng YZ Boscher C Inder KL Fairbank M Loo D Hill MM Nabi IR Foster LJ 《Molecular & cellular proteomics : MCP》2011,10(10):M110.007146
Caveolae, a class of cholesterol-rich lipid rafts, are smooth invaginations of the plasma membrane whose formation in nonmuscle cells requires caveolin-1 (Cav1). The recent demonstration that Cav1-associated cavin proteins, in particular PTRF/cavin-1, are also required for caveolae formation supports a functional role for Cav1 independently of caveolae. In tumor cells deficient for Golgi β-1,6N-acetylglucosaminyltransferase V (Mgat5), reduced Cav1 expression is associated not with caveolae but with oligomerized Cav1 domains, or scaffolds, that functionally regulate receptor signaling and raft-dependent endocytosis. Using subdiffraction-limit microscopy, we show that Cav1 scaffolds are homogenous subdiffraction-limit sized structures whose size distribution differs from that of Cav1 in caveolae expressing cells. These cell lines displaying differing Cav1/caveolae phenotypes are effective tools for probing the structure and composition of caveolae. Using stable isotope labeling by amino acids in cell culture, we are able to quantitatively distinguish the composition of caveolae from the background of detergent-resistant membrane proteins and show that the presence of caveolae enriches the protein composition of detergent-resistant membrane, including the recruitment of multiple heterotrimeric G-protein subunits. These data were further supported by analysis of immuno-isolated Cav1 domains and of methyl-β-cyclodextrin-disrupted detergent-resistant membrane. Our data show that loss of caveolae results in a dramatic change to the membrane raft proteome and that this change is independent of Cav1 expression. The proteomics data, in combination with subdiffraction-limit microscopy, indicates that noncaveolar Cav1 domains, or scaffolds are structurally and functionally distinct from caveolae and differentially impact on the molecular composition of lipid rafts. 相似文献
138.
139.
Eschelbach JW Zhuomei D Grady B Goetzinger W 《Journal of biomolecular screening》2011,16(9):1112-1118
Many compound collections are stored under the same temperature conditions, which can limit flexibility by increasing the processing time required for high-demand compounds. In this study, the authors wanted to evaluate the impact of a hybrid-storage approach where high-demand compounds are stored for a shortened time period at room temperature to expedite processing operations. The use of a Covaris adaptive-focused acoustics platform was also characterized as a potential enhancement or alternative to storage at elevated temperatures. This study evaluated the impact of temperature, exposure, and solubilization on overall compound quality for short-term storage. A small library of 25 representative compounds was evaluated over an 18-week period to monitor the change in purity and concentration by high-performance liquid chromatography with ultraviolet detection. The authors concluded that temperature had a significant impact on compound concentration, and the effects due to exposure cycles were minimal. A storage time of 12 weeks at room temperature resulted in minimal compound loss, but storage times beyond this would be unacceptable because of a >20% decrease in concentration. Finally, the acoustic solubilization protocol also increased the number of compounds at the target concentration with no impact on overall purity, leading to a potential for increased storage times at frozen temperatures. 相似文献
140.
Wan L Zou W Gao D Inuzuka H Fukushima H Berg AH Drapp R Shaik S Hu D Lester C Eguren M Malumbres M Glimcher LH Wei W 《Molecular cell》2011,44(5):721-733
The APC/Cdh1 E3 ubiquitin ligase plays an essential role in both mitotic exit and G1/S transition by targeting key cell-cycle regulators for destruction. There is mounting evidence indicating that Cdh1 has other functions in addition to cell-cycle regulation. However, it remains unclear whether these additional functions depend on its E3 ligase activity. Here, we report that Cdh1, but not Cdc20, promotes the E3 ligase activity of Smurf1. This is mediated by disruption of an autoinhibitory Smurf1 homodimer and is independent of APC/Cdh1 E3 ligase activity. As a result, depletion of Cdh1 leads to reduced Smurf1 activity and subsequent activation of multiple downstream targets, including the MEKK2 signaling pathway, inducing osteoblast differentiation. Our studies uncover a cell-cycle-independent function of Cdh1, establishing Cdh1 as an upstream component that governs Smurf1 activity. They further suggest that modulation of Cdh1 is a potential therapeutic option for treatment of osteoporosis. 相似文献