全文获取类型
收费全文 | 129012篇 |
免费 | 2735篇 |
国内免费 | 826篇 |
出版年
2023年 | 194篇 |
2022年 | 188篇 |
2021年 | 878篇 |
2020年 | 518篇 |
2019年 | 674篇 |
2018年 | 12527篇 |
2017年 | 11193篇 |
2016年 | 8609篇 |
2015年 | 2560篇 |
2014年 | 2401篇 |
2013年 | 3201篇 |
2012年 | 7462篇 |
2011年 | 15693篇 |
2010年 | 13710篇 |
2009年 | 9736篇 |
2008年 | 11922篇 |
2007年 | 13427篇 |
2006年 | 2295篇 |
2005年 | 2341篇 |
2004年 | 2680篇 |
2003年 | 2672篇 |
2002年 | 2273篇 |
2001年 | 556篇 |
2000年 | 365篇 |
1999年 | 319篇 |
1998年 | 385篇 |
1997年 | 274篇 |
1996年 | 232篇 |
1995年 | 229篇 |
1994年 | 230篇 |
1993年 | 247篇 |
1992年 | 154篇 |
1991年 | 180篇 |
1990年 | 153篇 |
1989年 | 115篇 |
1988年 | 116篇 |
1987年 | 103篇 |
1986年 | 69篇 |
1985年 | 95篇 |
1984年 | 102篇 |
1983年 | 88篇 |
1982年 | 85篇 |
1981年 | 80篇 |
1980年 | 80篇 |
1979年 | 72篇 |
1977年 | 50篇 |
1975年 | 43篇 |
1973年 | 42篇 |
1972年 | 277篇 |
1971年 | 299篇 |
排序方式: 共有10000条查询结果,搜索用时 109 毫秒
991.
Karolina Pulka Marta Slupska Anna Puszko Maria Misiak Marcin Wilczek Wiktor Kozminski Aleksandra Misicka 《Journal of peptide science》2013,19(7):433-440
The Pictet–Spengler (PS) reaction was performed with various types of substrates: H‐Trp‐OMe and dipeptides with N‐terminal Trp as arylethylamine components and Z‐protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C‐terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters of Trp and dipeptides. On the contrary, the selectivity of the PS reaction with peptidoaldehydes with L configuration of the C‐terminus residue is totally different from that obtained with simple L‐amino aldehydes. It allows us to obtain cis stereoisomers, which cannot be isolated from the reaction with amino aldehydes. But the utility of the peptidoaldehydes as substrates for the PS reaction is reduced by the side formation of enamides which decrease the yield of cyclization. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
992.
Inderpreet Sur Maria Ulvmar Roger Jungedal Rune Toftgård 《Journal of receptor and signal transduction research》2013,33(1):44-51
A skin-specific block in NF-κB signaling leads to hyperproliferation of the keratinocytes, inflammation, and spontaneous development of squamous cell carcinoma (SCC). Here we show that an inhibition of NF-κB signaling in keratinocytes, via the expression of the super-repressor/ degradation-resistant form of the IκBα protein (IκBαDN), interferes with the growth arrest induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). The IκBαDN cells are able to overcome the TPA-induced cell cycle block. Although SCC development as well as hyperproliferation due to IκBαDN expression in keratinocytes is known to require TNFR1 signaling, the effect of IκBαDN on phorbol ester signaling is downstream/independent of TNFR1. These data thus identify an interaction between IκBαDN and the tumor promoter TPA in the growth regulation of keratinocytes. The proposed mechanism is also likely to be significant in the process of cancer development due to NF-κB inhibition. 相似文献
993.
Joana A. Loureiro Sandra Rocha Maria do Carmo Pereira 《Journal of peptide science》2013,19(9):581-587
The amyloid β‐peptide with a sequence of 42 amino acids is the major constituent of extracellular amyloid deposits in Alzheimer's disease plaques. The control of the peptide self‐assembly is difficult to achieve because the process is fast and is affected by many variables. In this paper, we describe the effect of different charged and non‐charged surfactants on Aβ(1‐42) fibrillation to define common alternate aggregation pathways. The characterization of the peptide‐surfactant interactions by ultra‐structural analysis, thioflavin T assay and secondary structure analysis, suggested that charged surfactants interact with Aβ(1‐42) through electrostatic interactions. Charged micelles slow down the aggregation process and stabilize the peptide in the oligomeric state, whereas non‐charged surfactants promote the Aβ(1‐42) fibril formation. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
994.
Turbellarians, which typically feed on bacteria, algae, rotifers, oligochaetes, dipteran larvae, microcrustaceans, and other organisms, are abundant in diverse types of wetlands. Despite their importance, abundance, and species richness in freshwater environments, turbellarians are seldom considered in studies on biodiversity. We analyzed the structure of turbellarian communities in shore areas of three categories of permanent wetlands classified according to their perimeter as small, intermediate, and large during an annual cycle. In total, 1847 turbellarians were collected representing 42 species and 15 genera, from the orders Catenulida, Macrostomida, Lecithoepitheliata, Rhabdocoela, and Tricladida. Sixteen species were common to the three categories of wetlands, whereas nineteen species were unique to a particular category. Species composition varied among wetlands of different sizes; small, intermediate, and large wetlands had different dominant species. We found seasonal differences in community composition over the year, but no significant differences in mean values of observed species richness among wetlands with different sizes and among seasonal samples. The estimated species richness was, however, higher in the small wetlands, followed by the large and intermediate wetlands. In the summer, abundance was significantly lower in the small water bodies than in the intermediate and large bodies of water. Our results reinforce the need for conservation of wetlands of different sizes. 相似文献
995.
Giuseppe Battistoni Fabrizio Cappucci Nicola Bertolino Maria Grazia Brambilla Hae Song Mainardi Alberto Torresin 《Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)》2013,29(6):656-661
The purpose of this work is to investigate the capability of the FLUKA Monte Carlo (MC) code to simulate the Elekta Leksell Gamma Knife Perfexion (LGK-PFX) and reproduce the Treatment Planning System (TPS) Leksell GammaPlan version 8.2 (LGP) dose calculations for the case of a water equivalent phantom target. Thanks to the collaboration with Elekta Instruments AB, the collimation system geometry, the source positions and all the involved material have been simulated in detail. The relative linear dose distribution along the three coordinate axes, for each collimator size, and the Relative Output Factors (ROF) have been investigated. The simulation has been validated comparing simulated linear dose profiles with measurements performed with EBT radiochromic films. The acceptance criterion between experimental data and FLUKA results is based on the gamma index (GI) method. The FLUKA MC calculation for the ROF provided the values of 0.920 for the 8 mm collimators and 0.800 for the 4 mm collimators. These values are in good agreement with the Elekta reference data of 0.924 and 0.805 respectively. The percentage difference between calculated and reference values for the ROF is under 1% and within the FLUKA uncertainty. Also the simulated relative dose profiles show a good agreement with the LGP calculation expressed by means of the gamma index method. This established accuracy proves that FLUKA is a suitable and powerful tool in order to reproduce successfully the LGP calculations for the homogeneous media. 相似文献
996.
Monalessa Fábia Pereira Carolina Maria de Araújo dos Santos Elza Fernandes de Araújo Marisa Vieira de Queiroz Denise Mara Soares Bazzolli 《Journal of microbiology (Seoul, Korea)》2013,51(1):70-81
Fungi of the Colletotrichum genus are among the most prominent phytopathogens that cause diseases with a considerable economic impact, such as anthracnose. The hemibiotrophic fungus Colletotrichum lindemuthianum (teleomorph Glomerella cingulata f. sp. phaseoli) is the causal agent of the anthracnose of the common bean; and similarly to other phytopathogens, it uses multiple strategies to gain access to different carbon sources from its host. In this study, we examine mfs1, a newly identified C. lindemuthianum hexose transporter. The mfs1 gene is expressed only during the necrotrophic phase of the fungus’ interaction within the plant and allows it to utilize the available sugars during this phase. The deletion of mfs1 gene resulted in differential growth of the fungus in a medium that contained glucose, mannose or fructose as the only carbon source. This study is the first to describe a hexose transporter in the hemibiotrophic pathogen C. lindemuthianum and to demonstrate the central role of this protein in capturing carbon sources during the necrotrophic development of the plant/pathogen interaction. 相似文献
997.
Lorena Souza e Silva Aline Mayrink de Miranda Cíntia Lopes de Brito Magalhães Rinaldo Cardoso dos Santos Maria Lúcia Pedrosa Marcelo Eustáquio Silva 《Journal of physiology and biochemistry》2013,69(4):811-820
The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of beta-carotene by examining its effects on the serum lipid profile, fecal cholesterol excretion, and gene expression of the major receptors, enzymes, and transporters involved in cholesterol metabolism. Female Fischer rats were divided into three groups and were fed either a control or a hypercholesterolemic diet supplemented or not supplemented with 0.2 % beta-carotene. After 6 weeks of feeding, blood, livers, and feces were collected for analysis, and quantitative real-time polymerase chain reaction (qRT-PCR) was performed. Dietary supplementation with 0.2 % beta-carotene decreased serum total cholesterol, non-HDL cholesterol, the atherogenic index, and hepatic total lipid and cholesterol contents. These changes were accompanied by an increase in the total lipid and cholesterol contents excreted in the feces. The qRT-PCR analyses demonstrated that the hypercholesterolemic diet promoted a decrease in the gene expression of sterol regulatory element-binding protein 2, 3-hydroxy-3-methylglutaryl CoA reductase, and low-density lipoprotein receptor and an increase in the gene expression of peroxisome proliferator-activated receptor α and cholesterol-7a-hydroxylase. The expression of these genes and gene expression of ATP-binding cassette subfamily G transporters 5and 8 were unaffected by beta-carotene supplementation. In conclusion, the decrease in serum cholesterol and the elevation of fecal cholesterol obtained following beta-carotene administration indicate that this substance may decrease cholesterol absorption in the intestine and increase cholesterol excretion into the feces without a direct effect on the expression of cholesterol metabolism genes. 相似文献
998.
Background
Certain amino acids in proteins play a critical role in determining their structural stability and function. Examples include flexible regions such as hinges which allow domain motion, and highly conserved residues on functional interfaces which allow interactions with other proteins. Detecting these regions can aid in the analysis and simulation of protein rigidity and conformational changes, and helps characterizing protein binding and docking. We present an analysis of critical residues in proteins using a combination of two complementary techniques. One method performs in-silico mutations and analyzes the protein's rigidity to infer the role of a point substitution to Glycine or Alanine. The other method uses evolutionary conservation to find functional interfaces in proteins.Results
We applied the two methods to a dataset of proteins, including biomolecules with experimentally known critical residues as determined by the free energy of unfolding. Our results show that the combination of the two methods can detect the vast majority of critical residues in tested proteins.Conclusions
Our results show that the combination of the two methods has the potential to detect more information than each method separately. Future work will provide a confidence level for the criticalness of a residue to improve the accuracy of our method and eliminate false positives. Once the combined methods are integrated into one scoring function, it can be applied to other domains such as estimating functional interfaces.999.
Background
We introduce a protein docking refinement method that accepts complexes consisting of any number of monomeric units. The method uses a scoring function based on a tight coupling between evolutionary conservation, geometry and physico-chemical interactions. Understanding the role of protein complexes in the basic biology of organisms heavily relies on the detection of protein complexes and their structures. Different computational docking methods are developed for this purpose, however, these methods are often not accurate and their results need to be further refined to improve the geometry and the energy of the resulting complexes. Also, despite the fact that complexes in nature often have more than two monomers, most docking methods focus on dimers since the computational complexity increases exponentially due to the addition of monomeric units.Results
Our results show that the refinement scheme can efficiently handle complexes with more than two monomers by biasing the results towards complexes with native interactions, filtering out false positive results. Our refined complexes have better IRMSDs with respect to the known complexes and lower energies than those initial docked structures.Conclusions
Evolutionary conservation information allows us to bias our results towards possible functional interfaces, and the probabilistic selection scheme helps us to escape local energy minima. We aim to incorporate our refinement method in a larger framework which also enables docking of multimeric complexes given only monomeric structures.1000.
Henry Ginsberg 《Cardiovascular diabetology》2013,12(Z1):S1
The term cardiometabolic disease encompasses a range of lifestyle-related conditions, including Metabolic syndrome (MetS) and type 2 diabetes (T2D), that are characterized by different combinations of cardiovascular (CV) risk factors, including dyslipidemia, abdominal obesity, hypertension, hyperglycemia/insulin resistance, and vascular inflammation. These risk factors individually and interdependently increase the risk of CV and cerebrovascular events, and represent one of the biggest health challenges worldwide today. CV diseases account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Furthermore, the risk of CV death is increased twofold to fourfold in people with T2D. Whilst the clinical management of CV disease has improved in Western Europe, the pandemic of obesity and T2D reduces the impact of these gains. This, together with the growing, aging population, means the number of CV deaths is predicted to increase from 17.1 million worldwide in 2004 to 23.6 million in 2030. The recommended treatment for MetS is lifestyle change followed by treatment for the individual risk factors. Numerous studies have shown that lowering low-density lipoprotein-cholesterol (LDL-C) levels using statins can significantly reduce CV risk in people with and without T2D or MetS. However, the risk of major vascular events in those attaining the maximum levels of LDL-C-reduction is only reduced by around one-third, which leaves substantial residual risk. Recent studies suggest that low high-density lipoprotein-cholesterol (HDL-C) (<1 .0 mmol/l; 40 mg/dl) and high triglyceride levels (≥1.7 mmol/l; 150 mg/dl) are independent risk factors for CV disease and that the relationship between HDL-C and CV risk persists even when on-treatment LDL-C levels are low (<1.7 mmol/l; 70 mg/dl). European guidelines highlight the importance of reducing residual risk by targeting these risk factors in addition to LDL-C. This is particularly important in patients with T2D and MetS because obesity and high levels of glycated hemoglobin are directly related to low levels of HDL-C and high triglyceride. Although most statins have a similar low-density lipoprotein-lowering efficacy, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects (for example, high-density lipoprotein-elevating efficacy), adverse event profiles, and drug-drug interactions. The choice of statin should therefore depend on the needs of the individual patient. The following reviews will discuss the potential benefits of pitavastatin versus other statins in the treatment of patients with dyslipidemia and MetS or T2D, focusing on its effects on HDL-C quantity and quality, its potential impact on atherosclerosis and CV risk, and its metabolic characteristics that reduce the risk of drug interactions. Recent controversies surrounding the potentially diabetogenic effects of statins will also be discussed. 相似文献