全文获取类型
收费全文 | 3024篇 |
免费 | 163篇 |
国内免费 | 3篇 |
出版年
2023年 | 8篇 |
2022年 | 16篇 |
2021年 | 32篇 |
2020年 | 34篇 |
2019年 | 32篇 |
2018年 | 64篇 |
2017年 | 61篇 |
2016年 | 87篇 |
2015年 | 127篇 |
2014年 | 142篇 |
2013年 | 183篇 |
2012年 | 209篇 |
2011年 | 212篇 |
2010年 | 136篇 |
2009年 | 121篇 |
2008年 | 196篇 |
2007年 | 222篇 |
2006年 | 181篇 |
2005年 | 178篇 |
2004年 | 194篇 |
2003年 | 187篇 |
2002年 | 163篇 |
2001年 | 32篇 |
2000年 | 20篇 |
1999年 | 24篇 |
1998年 | 34篇 |
1997年 | 23篇 |
1996年 | 20篇 |
1995年 | 11篇 |
1994年 | 11篇 |
1993年 | 13篇 |
1992年 | 15篇 |
1991年 | 7篇 |
1990年 | 12篇 |
1989年 | 11篇 |
1988年 | 9篇 |
1987年 | 10篇 |
1985年 | 16篇 |
1984年 | 11篇 |
1983年 | 9篇 |
1982年 | 16篇 |
1981年 | 10篇 |
1980年 | 9篇 |
1979年 | 8篇 |
1977年 | 19篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1973年 | 7篇 |
1970年 | 6篇 |
1967年 | 4篇 |
排序方式: 共有3190条查询结果,搜索用时 15 毫秒
991.
992.
Patrycja Kosza?ka Monika Go?uńska Aleksandra Urban Grzegorz Stasi?oj? Marcin Stanis?awowski Marceli Majewski Andrzej C. Sk?adanowski Jacek Bigda 《PloS one》2016,11(3)
CD73 (ecto-5''-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine α,β-methylene 5’-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in recently proposed anti-CD73 cancer therapy. 相似文献
993.
This is the first report on the ultrastructural pattern of distribution of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in endothelial cells, using the rabbit aorta, and its colocalization with the neuronal isoform (type I) of nitric oxide synthase. About 30% of the endothelial cells showed a positive reaction for NADPH-d compared to about 6% for nitric oxide synthase immunoreactivity. Simultaneous double histochemical-immunocytochemical labelling procedures indicate that all of the cells displaying nitric oxide synthase-positive reactivity also contained NADPH-d; the remainder of NADPH-d-positive endothelial cells were negative for this isoform of nitric oxide synthase. Nitric oxide synthase-immunogold labelling was mostly associated with free ribosomes, while NADPH-d activity was distributed largely in patches in the cytoplasm and in association with the cell membrane. 相似文献
994.
995.
Jadwiga Pietkiewicz Andrzej Gamian Magdalena Staniszewska Regina Danielewicz 《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):356-364
Methylglyoxal (MG) was studied as an inhibitor and effective glycating factor of human muscle-specific enolase. The inhibition was carried out by the use of a preincubation procedure in the absence of substrate. Experiments were performed in anionic and cationic buffers and showed that inhibition of enolase by methylglyoxal and formation of enolase-derived glycation products arose more effectively in slight alkaline conditions and in the presence of inorganic phosphate. Incubation of 15 micromolar solutions of the enzyme with 2 mM, 3.1 mM and 4.34 mM MG in 100 mM phosphate buffer pH 7.4 for 3 h caused the loss a 32%, 55% and 82% of initial specific activity, respectively. The effect of MG on catalytic properties of enolase was investigated. The enzyme changed the KM value for glycolytic substrate 2-phospho-D-glycerate (2-PGA) from 0.2 mM for native enzyme to 0.66 mM in the presence of MG. The affinity of enolase for gluconeogenic substrate phosphoenolpyruvate altered after preincubation with MG in the same manner, but less intensively. MG has no effect on Vmax and optimal pH values. Incubation of enolase with MG for 0-48 h generated high molecular weight protein derivatives. Advanced glycation end products (AGEs) were resistant to proteolytic degradation by trypsin. Magnesium ions enhanced the enzyme inactivation by MG and facilitated AGEs formation. However, the protection for this inhibition in the presence of 2-PGA as glycolytic substrate was observed and AGEs were less effectively formed under these conditions. 相似文献
996.
Agnieszka Szamborska-Gbur Grzegorz Rymarczyk Marek Or?owski Tomasz Kuzynowski Micha? Jakób Agnieszka Dziedzic-Letka Andrzej Górecki Piotr Dobryszycki Andrzej O?yhar 《PloS one》2014,9(1)
The heterodimer of the ecdysone receptor (EcR) and ultraspiracle (Usp), members of the nuclear receptors superfamily, regulates gene expression associated with molting and metamorphosis in insects. The DNA binding domains (DBDs) of the Usp and EcR play an important role in their DNA-dependent heterodimerization. Analysis of the crystal structure of the UspDBD/EcRDBD heterocomplex from Drosophila melanogaster on the hsp27 gene response element, suggested an appreciable similarity between both DBDs. However, the chemical denaturation experiments showed a categorically lower stability for the EcRDBD in contrast to the UspDBD. The aim of our study was an elucidation of the molecular basis of this intriguing instability. Toward this end, we mapped the EcRDBD amino acid sequence positions which have an impact on the stability of the EcRDBD. The computational protein design and in vitro analyses of the EcRDBD mutants indicate that non-conserved residues within the α-helix 2, forming the EcRDBD hydrophobic core, represent a specific structural element that contributes to instability. In particular, the L58 appears to be a key residue which differentiates the hydrophobic cores of UspDBD and EcRDBD and is the main reason for the low stability of the EcRDBD. Our results might serve as a benchmark for further studies of the intricate nature of the EcR molecule. 相似文献
997.
Janeczko Anna Biesaga-Kościelniak Jolanta Dziurka Michał Filek Maria Hura Katarzyna Jurczyk Barbara Kula Monika Oklestkova Jana Novak Ondrej Rudolphi-Skórska Elżbieta Skoczowski Andrzej 《Journal of Plant Growth Regulation》2020,39(1):507-507
Journal of Plant Growth Regulation - The original version of this article unfortunately contained an error in Dr. Andrzej Skoczowski’s affiliation. The author would like to correct the error... 相似文献
998.
This article presents results of continuous multistage aqueous two‐phase extraction of an immunoglobulin G1 from cell supernatant in a mixer‐settler unit. An aqueous two‐phase system consisting of polyethylene glycol 2000, phosphate salt, and water was applied without and with sodium chloride (NaCl). Influences of different parameters such as throughput, phase ratio, and stage number on the extraction performance were analyzed. For systems without NaCl, the extraction was carried out as a washing step. An increase of stage number from one to five stages enabled to increase the immunoglobulin G1 purity from 11.8 to 32.6% at a yield of nearly 90%. Furthermore, a reduction of product phase volume due to a higher phase ratio led to an increase of purity from 20.8 to 29.6% in a three‐stage countercurrent extraction. For experiments with NaCl moderate partitioning conditions were adjusted by adding 8 wt% NaCl. In that case, the extraction was carried out as a stripping step. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:925–936, 2015 相似文献
999.
Miroslaw Janczura Grazyna Bochenek Roman Nowobilski Jerzy Dropinski Katarzyna Kotula-Horowitz Bartosz Laskowicz Andrzej Stanisz Jacek Lelakowski Teresa Domagala 《PloS one》2015,10(8)