全文获取类型
收费全文 | 11363篇 |
免费 | 934篇 |
国内免费 | 1084篇 |
出版年
2024年 | 23篇 |
2023年 | 173篇 |
2022年 | 216篇 |
2021年 | 655篇 |
2020年 | 471篇 |
2019年 | 537篇 |
2018年 | 515篇 |
2017年 | 340篇 |
2016年 | 490篇 |
2015年 | 757篇 |
2014年 | 864篇 |
2013年 | 924篇 |
2012年 | 1045篇 |
2011年 | 913篇 |
2010年 | 605篇 |
2009年 | 489篇 |
2008年 | 612篇 |
2007年 | 549篇 |
2006年 | 480篇 |
2005年 | 394篇 |
2004年 | 337篇 |
2003年 | 301篇 |
2002年 | 237篇 |
2001年 | 186篇 |
2000年 | 155篇 |
1999年 | 183篇 |
1998年 | 97篇 |
1997年 | 86篇 |
1996年 | 88篇 |
1995年 | 83篇 |
1994年 | 100篇 |
1993年 | 51篇 |
1992年 | 54篇 |
1991年 | 74篇 |
1990年 | 45篇 |
1989年 | 49篇 |
1988年 | 32篇 |
1987年 | 26篇 |
1986年 | 34篇 |
1985年 | 25篇 |
1984年 | 16篇 |
1983年 | 12篇 |
1982年 | 10篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1978年 | 4篇 |
1973年 | 4篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 265 毫秒
961.
Zhengfeng Fang Kang Yao Xiaoling Zhang Shengjun Zhao Zhihong Sun Gang Tian Bing Yu Yan Lin Biquan Zhu Gang Jia Keying Zhang Daiwen Chen De Wu 《Amino acids》2010,39(3):633-640
Sulfur amino acids (SAA), particularly methionine and cysteine, are critical for the gut to maintain its functions including the digestion, absorption and metabolism of nutrients, the immune surveillance of the intestinal epithelial layer and regulation of the mucosal response to foreign antigens. However, the metabolism of SAA in the gut, specifically the transmethylation of methionine, will result in a net release of homocysteine, which is shown to be associated with cardiovascular disease and stroke. Furthermore, the extensive catabolism of dietary methionine by the intestine or by luminal microbes may result in a decrease in nutritional efficiency. Therefore, the regulation of SAA metabolism in the gut is not only nutritionally relevant, but also relevant to the overall health and well-being. The superiority of dl-2-hydroxy-4-methylthiobutyrate to dl-methionine in decreasing homocysteine production, alleviating stress responses, and reducing the first-pass intestinal metabolism of dietary methionine may provide a promising implication for nutritional strategies to manipulate SAA metabolism and thus to improve the nutrition and health status of animals and perhaps humans. 相似文献
962.
Youyi Peng Qiang Zhang Gretchen L. Snyder Hongwen Zhu Wei Yao John Tomesch Roger L. Papke James P. O’Callaghan William J. Welsh Lawrence P. Wennogle 《Bioorganic & medicinal chemistry letters》2010,20(16):4825-4830
Two distinct families of small molecules were discovered as novel α7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal α7 subtype over other nAChRs and good brain penetration. Neuroprotection was demonstrated by representative compounds 7i and 8 in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP). These novel nAChR antagonists have potential use as antidote for organophosphorus nerve agent intoxication. 相似文献
963.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
964.
Wang YE Park A Lake M Pentecost M Torres B Yun TE Wolf MC Holbrook MR Freiberg AN Lee B 《PLoS pathogens》2010,6(11):e1001186
Paramyxoviruses are known to replicate in the cytoplasm and bud from the plasma membrane. Matrix is the major structural protein in paramyxoviruses that mediates viral assembly and budding. Curiously, the matrix proteins of a few paramyxoviruses have been found in the nucleus, although the biological function associated with this nuclear localization remains obscure. We report here that the nuclear-cytoplasmic trafficking of the Nipah virus matrix (NiV-M) protein and associated post-translational modification play a critical role in matrix-mediated virus budding. Nipah virus (NiV) is a highly pathogenic emerging paramyxovirus that causes fatal encephalitis in humans, and is classified as a Biosafety Level 4 (BSL4) pathogen. During live NiV infection, NiV-M was first detected in the nucleus at early stages of infection before subsequent localization to the cytoplasm and the plasma membrane. Mutations in the putative bipartite nuclear localization signal (NLS) and the leucine-rich nuclear export signal (NES) found in NiV-M impaired its nuclear-cytoplasmic trafficking and also abolished NiV-M budding. A highly conserved lysine residue in the NLS served dual functions: its positive charge was important for mediating nuclear import, and it was also a potential site for monoubiquitination which regulates nuclear export of the protein. Concordantly, overexpression of ubiquitin enhanced NiV-M budding whereas depletion of free ubiquitin in the cell (via proteasome inhibitors) resulted in nuclear retention of NiV-M and blocked viral budding. Live Nipah virus budding was exquisitely sensitive to proteasome inhibitors: bortezomib, an FDA-approved proteasome inhibitor for treating multiple myeloma, reduced viral titers with an IC(50) of 2.7 nM, which is 100-fold less than the peak plasma concentration that can be achieved in humans. This opens up the possibility of using an "off-the-shelf" therapeutic against acute NiV infection. 相似文献
965.
Yuanwei Jia Haitang Xie Guangji Wang Jianguo Sun Wei Wang Huang Qing Xuan Wang Hao Yang Meijuan Xu Yi Gu Chen Yao Jie Shen 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(9-10):791-797
A simple liquid chromatography electrospray ionization mass spectrometry (LC–ESI–MS) method with highly improved sensitivities for the determination of helicid in rat bile, urine, feces and most tissues was developed. The tissues and feces were firstly homogenized mechanically using deionized water as the media. Bile, urine, tissues and feces homogenates were extracted by liquid–liquid extraction with n-butyl alcohol for sample preparation. The subsequent analysis procedures were performed on a Shimadzu LCMS2010A system (electrospray ionization single quadrupole mass analyzer). A Luna C18 column (150 mm × 2.00 mm, 5 μm) was used as the analytical column, while a mixture of acetonitrile and ammonium chloride water solution was used as the mobile phase. The proportions of mobile phase were changed timely according to gradient programs. Chlorinated adducts of molecular ions [M+Cl]? at m/z 319.00 and 363.05 were used to quantify helicid and bergeninum (internal standard), respectively. The method was validated to be accurate, precise and rugged with good linearity. The proposed method was successfully applied to the preclinical tissue distribution and excretion studies of helicid in rats. 相似文献
966.
Chang Cheng Shaorong Liu Deqing Xiao John Hollembaek Lili Yao Jing Lin Steven Hansel 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(28):2831-2838
Simple, sensitive and robust liquid chromatography–tandem mass spectrometer (LC–MS/MS) methods were developed and validated for the determination of lipopeptide polymyxins and glycopeptide vancomycin in rat plasma. The effect of trichloroacetic acid (TCA) concentration on sample recoveries (peak area of sample recovered from plasma/peak area of sample from neat solvent solutions) was studied and an optimized concentration of 30% TCA were determined that gives the best sample recovery for the peptides from rat plasma. The effect of the TCA concentration on the chromatographic behavior of peptides was studied on a Phenomenex Jupiter C18 5 μ 300 Å 50 mm × 2 mm column using a mobile phase with a pH of 2.8. Other than protein precipitation, TCA also acted as ion pairing reagent and was only present in the samples but not in the mobile phases. The data demonstrated that by increasing the TCA concentration, the analyte retention and sensitivity were improved. The absence of TCA in mobile phase helped to reduce the ion source contamination and to achieve good reproducibility. The plasma method was linearly calibrated from 5 to 5000 ng/mL for polymyxins with precisions to be of 2.3–10.8%, and accuracies to be 91.7–107.4% for polymyxin B1, B2, E1, E2, respectively. For vancomycin the calibration is from 1 to 5000 ng/mL with precisions to be of 7.8–10.3 and accuracies to be 96.2–102.0%. The LLOQs corresponding with a coefficient of variation less than 20% were 7.5, 18.1, 7.3, 5.0 and 1.0 ng/mL for polymyxin B1, B2, E1, E2 and vancomycin, respectively. 相似文献
967.
This paper aims to integrate a numerical model, vegetation index, and regional evapotranspiration estimation to assess the water cycle in Zhalong wetland, China with the aid of remote sensing technologies. An interdisciplinary analysis was performed to study the eco-hydrological characteristics of the wetland ecosystem. In particular, a new solution for solving the Two-Source Energy Balance (TSEB) was developed and applied. This new solution method is based on a definition of the aerodynamic temperature in a two-layer ground surface structure. Following this new solution for TSEB, the outputs of the Surface Energy Balance Algorithm (SEBAL) may be used as the inputs for TSEB to avoid the complex calculations of the bulk boundary layer and soil surface resistance. The new solution method makes the implementation of TSEB much easier when bi-directional thermal infrared remote sensing images are not available. Daily evapotranspiration and vegetation index of the wetland were calculated from six scenes of Landsat7/ETM+ remote sensing images acquired during 2001 and 2002 in our case study. Spatial distribution of daily evapotranspiration was also provided to help realize the wetland condition. The seasonal changes of vegetation index and evapotranspiration for some typical wetland ground surfaces were analyzed and presented as well to explore the multitemporal variations of plant species holistically. Ultimately, such integrative analysis aids in understanding the general biological patterns associated with these wetland vegetation cover, while specific situations of the wetland ecosystem can be recognized. 相似文献
968.
Jinsong Hu Nana Dang Hui Yao Yu Li Hongxin Zhang Xiangmin Yang Jing Xu Huijie Bian Jinliang Xing Ping Zhu Zhinan Chen 《Journal of cellular and molecular medicine》2010,14(8):2132-2143
HAb18G/CD147, a glycoprotein of the immunoglobulin super‐family (IgSF), is a T cell activation‐associated molecule. In this report, we demonstrated that HAb18G/CD147 expression on both activated CD4+ and CD8+ T cells was up‐regulated. In vitro cross‐linking of T cells with an anti‐HAb18G/CD147 monoclonal antibody (mAb) 5A12 inhibited T cells proliferation upon T cell receptor stimulation. Such co‐stimulation inhibited T cell proliferation by down‐regulating the expression of CD25 and interleukin‐2 (IL‐2), decreased production of IL‐4 but not interferon‐γ. Laser confocal imaging analysis indicated that HAb18G/CD147 was recruited to the immunological synapse (IS) during T cell activation; triggering HAb18G/CD147 on activated T cells by anti‐HAb18G/CD147 mAb 5A12 strongly dispersed the formation of the IS. Further functional studies showed that the ligation of HAb18G/CD147 with mAb 5A12 decreased the tyrosine phosphorylation and intracellular calcium mobilization levels of T cells. Through docking antibody–antigen interactions, we demonstrated that the function of mAb 5A12 is tightly dependent on its specificity of binding to N‐terminal domain I, which plays pivotal role in the oligomerization of HAb18G/CD147. Taken together, we provide evidence that HAb18G/CD147 could act as a co‐stimulatory receptor to negatively regulate T cell activation and is functionally linked to the formation of the IS. 相似文献
969.
Feng-Ling Cui Ying-Hua Yan Qiang-Zhai Zhang Gui-Rong Qu Juan Du Xiao-Jun Yao 《Journal of molecular modeling》2010,16(2):255-262
This work was designed to study the interaction between 5-Methyluridine and human serum albumin (HSA) under simulative physiological
conditions using fluorescence spectroscopy in combination with molecular modeling technique for the first time. Static quenching
was suggested by the fluorescence measurement. The binding constants (K) were calculated according to the relevant fluorescence data at different conditions including temperature. Thermodynamic
parameter, different conditions including temperature to determine enthalpy change and entropy change, indicating the hydrophobic
force played a major role in the binding interaction between 5-Methyluridine and HSA. The experimental result was in correspondence
with molecular modeling theory. 相似文献
970.
Three new compounds, 1 – 3 , and 20 known compounds were isolated from the AcOEt and BuOH extract of edible Opuntia Milpa Alta. The petroleum ether extract was examined by GC and MS. A total of 26 compounds were identified, representing 95.6% of the total extract, phytosterol (36.03%) being the most abundant component, and polyunsaturated fatty acids (18.57%) represented the second largest group, followed by phytol (12.28%), palmitic acid, palmitate (13.54%), vitamin E (4.51%), and other compounds (7.47%). The effects of various extracts from edible Opuntia Milpa Alta (petroleum ether extract, AcOEt extract, BuOH extract, aqueous extract, H2O parts) and the positive control (received dimethylbiguanide) were tested on streptozotocin (STZ)‐induced diabetic mice. The results indicated that all the treatment groups could significantly decrease blood glucose levels in STZ‐induced diabetic mice compared to the model control group (P<0.01), except the aqueous extract group (P<0.05). Especially, the petroleum ether extract group and the positive control group showed remarkable decrease of blood glucose levels. Taken together, the results indicate that the petroleum ether extract is the major hypoglycemic part in edible Opuntia Milpa Alta, which may be developed to a potential natural hypoglycemic functional ingredient. 相似文献