全文获取类型
收费全文 | 2992篇 |
免费 | 228篇 |
专业分类
3220篇 |
出版年
2023年 | 19篇 |
2022年 | 49篇 |
2021年 | 98篇 |
2020年 | 51篇 |
2019年 | 71篇 |
2018年 | 94篇 |
2017年 | 79篇 |
2016年 | 115篇 |
2015年 | 174篇 |
2014年 | 224篇 |
2013年 | 248篇 |
2012年 | 317篇 |
2011年 | 268篇 |
2010年 | 163篇 |
2009年 | 143篇 |
2008年 | 146篇 |
2007年 | 158篇 |
2006年 | 129篇 |
2005年 | 114篇 |
2004年 | 103篇 |
2003年 | 85篇 |
2002年 | 76篇 |
2001年 | 18篇 |
2000年 | 12篇 |
1999年 | 22篇 |
1998年 | 13篇 |
1997年 | 11篇 |
1996年 | 7篇 |
1995年 | 4篇 |
1994年 | 10篇 |
1993年 | 16篇 |
1991年 | 11篇 |
1990年 | 5篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 6篇 |
1986年 | 8篇 |
1985年 | 9篇 |
1984年 | 5篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1980年 | 5篇 |
1972年 | 7篇 |
1970年 | 6篇 |
1969年 | 8篇 |
1968年 | 5篇 |
1967年 | 6篇 |
1966年 | 4篇 |
1951年 | 5篇 |
1950年 | 4篇 |
排序方式: 共有3220条查询结果,搜索用时 0 毫秒
21.
Federico Riu Roberta Ibba Stefano Zoroddu Simona Sestito Michele Lai Sandra Piras Luca Sanna Valentina Bordoni Luigi Bagella Antonio Carta 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):2223
Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents.Results: A novel series of 4′-fluoro-substituted ligands (5–13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability.Discussion: The 4′-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration. 相似文献
22.
The effect of melatonin treatment on intervals from calving to first postpartum estrus and ovulation was determined in Shorthorn cows which calved May 8 to June 14. Melatonin (500 mg in beef tallow) was injected subcutaneously (s.c.) into 20 cows on June 15 (4 to 38 d postpartum). Ovulation was determined from progesterone concentrations in jugular venous blood collected weekly from June to August. Mean intervals to first estrus and first ovulation were significantly longer in primiparous than in multiparous cows (85 +/- 4 vs 55 +/- 3 d and 83 +/- 4 vs 52 +/-3 d). Melatonin treatment caused a significant increase in the intervals to first postpartum estrus (68 +/- 4 vs 58 +/- 5d) and ovulation (68 +/- 4 vs 55 +/- 5 d). Mean plasma melatonin concentrations during the daytime were significantly higher in treated than in control cows one and two weeks after melatonin injection and were within the lower range of nighttime values reported previously for cows. Thus melatonin treatment raised daytime plasma concentrations of melatonin and delayed the onset of estrus and ovulation. These results support the possibility of a role of photoperiod through melatonin secretion in the onset of postpartum ovarian activity in cattle. 相似文献
23.
Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase 总被引:1,自引:0,他引:1
Tintignac LA Lagirand J Batonnet S Sirri V Leibovitch MP Leibovitch SA 《The Journal of biological chemistry》2005,280(4):2847-2856
24.
Recent discovery of 5-hydroxymethylcytosine (5hmC) in genomic DNA raises the question how this sixth base is recognized by cellular proteins. In contrast to the methyl-CpG binding domain (MBD) of MeCP2, we found that the SRA domain of Uhrf1, an essential factor in DNA maintenance methylation, binds 5hmC and 5-methylcytosine containing substrates with similar affinity. Based on the co-crystal structure, we performed molecular dynamics simulations of the SRA:DNA complex with the flipped cytosine base carrying either of these epigenetic modifications. Our data indicate that the SRA binding pocket can accommodate 5hmC and stabilizes the flipped base by hydrogen bond formation with the hydroxyl group. 相似文献
25.
26.
Higgs RE Knierman MD Gelfanova V Butler JP Hale JE 《Journal of proteome research》2005,4(4):1442-1450
Pharmaceutical companies and regulatory agencies are broadly pursuing biomarkers as a means to increase the productivity of drug development. Quantifying differential levels of proteins from complex biological samples such as plasma or cerebrospinal fluid is one specific approach being used to identify markers of drug action, efficacy, toxicity, etc. We have developed a comprehensive, fully automated, and label-free approach to relative protein quantification from LC-MS/MS experiments of proteolytic protein digests including: de-noising, mass and charge state estimation, chromatographic alignment, and peptide quantification via integration of extracted ion chromatograms. Results from a variance components study of the entire method indicate that most of the variability is attributable to the LC-MS injection, with a median peptide LC-MS injection coefficient of variation of 8% on a ThermoFinnigan LTQ mass spectrometer. Spiked recovery results suggest a quantifiable range of approximately 32-fold for a sample protein. 相似文献
27.
28.
Emily L. Bruns Ian Miller Michael E. Hood Valentina Carasso Janis Antonovics 《Evolution; international journal of organic evolution》2019,73(3):497-510
In flowering plants, the evolution of females is widely hypothesized to be the first step in the evolutionary pathway to separate male and female sexes, or dioecy. Natural enemies have the potential to drive this evolution if they preferentially attack hermaphrodites over females. We studied sex‐based differences in exposure to anther‐smut (Microbotryum), a sterilizing pollinator‐transmitted disease, in Dianthus pavonius, a gynodioecious perennial herb. We found that within a heavily diseased population, females consistently had lower levels of Microbotryum spore deposition relative to hermaphrodites and that this difference was driven by rapid floral closing in females following successful pollination. We further show that this protective closing behavior is frequency dependent; females close faster when they are rare. These results indicate that anther‐smut disease is an important source of selection for females, especially since we found in a common garden experiment no evidence that females have any inherent fecundity advantages over hermaphrodites. Finally, we show that among populations, those where anther‐smut is present have a significantly higher frequency of females than those where the disease is absent. Taken together our results indicate that anther‐smut disease is likely an important biotic factor driving the evolution and maintenance of females in this gynodioecious species. 相似文献
29.
Massimo Aureli Valentina Murdica Nicoletta Loberto Maura Samarani Alessandro Prinetti Rosaria Bassi Sandro Sonnino 《Glycoconjugate journal》2014,31(6-7):449-459
The aim of radiotherapy is to eradicate cancer cells with ionizing radiation; tumor cell death following irradiation can be induced by several signaling pathways, most of which are triggered as a consequence of DNA damage, the primary and major relevant cell response to radiation. Several lines of evidence demonstrated that ceramide, a crucial sensor and/or effector of different signalling pathways promoting cell cycle arrest, death and differentiation, is directly involved in the molecular mechanisms underlying cellular response to irradiation. Most of the studies strongly support a direct relationship between ceramide accumulation and radiation-induced cell death, mainly apoptosis; for this reason, defining the contribution of the multiple metabolic pathways leading to ceramide formation and the causes of its dysregulated metabolism represent the main goal in order to elucidate the ceramide-mediated signaling in radiotherapy. In this review, we summarize the current knowledge concerning the different routes leading to ceramide accumulation in radiation-induced cell response with particular regard to the role of the enzymes involved in both ceramide neogenesis and catabolism. Emphasis is placed on sphingolipid breakdown as mechanism of ceramide generation activated following cell irradiation; the functional relevance of this pathway, and the role of glycosphingolipid glycohydrolases as direct targets of ionizing radiation are also discussed. These new findings add a further attractive point of investigation to better define the complex interplay between sphingolipid metabolism and radiation therapy. 相似文献
30.
Yuze Shang Hansen Wang Valentina Mercaldo Xiangyao Li Tao Chen Min Zhuo 《Journal of neurochemistry》2009,111(3):635-646
Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS. 相似文献