全文获取类型
收费全文 | 1747篇 |
免费 | 111篇 |
国内免费 | 2篇 |
出版年
2023年 | 6篇 |
2022年 | 6篇 |
2021年 | 28篇 |
2019年 | 18篇 |
2018年 | 34篇 |
2017年 | 23篇 |
2016年 | 29篇 |
2015年 | 50篇 |
2014年 | 52篇 |
2013年 | 99篇 |
2012年 | 87篇 |
2011年 | 95篇 |
2010年 | 46篇 |
2009年 | 67篇 |
2008年 | 104篇 |
2007年 | 102篇 |
2006年 | 77篇 |
2005年 | 90篇 |
2004年 | 82篇 |
2003年 | 93篇 |
2002年 | 85篇 |
2001年 | 47篇 |
2000年 | 50篇 |
1999年 | 49篇 |
1998年 | 20篇 |
1997年 | 19篇 |
1996年 | 12篇 |
1995年 | 21篇 |
1994年 | 13篇 |
1993年 | 12篇 |
1992年 | 31篇 |
1991年 | 36篇 |
1990年 | 33篇 |
1989年 | 36篇 |
1988年 | 21篇 |
1987年 | 21篇 |
1986年 | 18篇 |
1985年 | 19篇 |
1984年 | 11篇 |
1983年 | 11篇 |
1982年 | 7篇 |
1978年 | 5篇 |
1977年 | 7篇 |
1976年 | 9篇 |
1975年 | 7篇 |
1974年 | 10篇 |
1973年 | 12篇 |
1972年 | 6篇 |
1971年 | 8篇 |
1967年 | 7篇 |
排序方式: 共有1860条查询结果,搜索用时 15 毫秒
171.
Koseki M Hirano K Masuda D Ikegami C Tanaka M Ota A Sandoval JC Nakagawa-Toyama Y Sato SB Kobayashi T Shimada Y Ohno-Iwashita Y Matsuura F Shimomura I Yamashita S 《Journal of lipid research》2007,48(2):299-306
Lipid rafts on the cell surface are believed to be very important as platforms for various cellular functions. The aim of this study was to know whether defective lipid efflux may influence lipid rafts on the cell surface and their related cellular functions. We investigated macrophages with defective lipid efflux from ATP binding cassette transporter A1-deficient (Abca1-KO) mice. Lipid rafts were evaluated by the following two novel probes: a biotinylated and protease (subtilisin Carlsberg)-nicked derivative of theta-toxin and a fluorescein ester of polyethylene glycol-derived cholesterol. Lipid rafts in Abca1-KO macrophages were increased, as demonstrated by both probes. Moreover, activities of nuclear factor kappaB, mRNA and intracellular distribution, and secretion of tumor necrosis factor-alpha (TNF-alpha) were examined after stimulation by lipopolysaccharides (LPSs). LPS-induced responses of the activation of nuclear factor kappaB and TNF-alpha were more prompt and accelerated in the Abca1-KO macrophages compared with wild-type macrophages. Modification of lipid rafts by cyclodextrin and nystatin corrected the abnormal response, suggesting an association between the increased lipid rafts and abnormal TNF-alpha secretion. We report here that Abca1-KO macrophages with defective lipid efflux exhibited increased lipid rafts on the cell surface and accelerated TNF-alpha secretion. 相似文献
172.
Regulation of glial development by cystatin C 总被引:1,自引:0,他引:1
Hasegawa A Naruse M Hitoshi S Iwasaki Y Takebayashi H Ikenaka K 《Journal of neurochemistry》2007,100(1):12-22
Cystatin C (CysC) is an endogenous cysteine proteases inhibitor produced by mature astrocytes in the adult brain. Previously we isolated CysC as a factor activating the glial fibrillary acidic protein (GFAP) promoter, and showed that CysC is expressed in astrocyte progenitors during development. Here we show that protease inhibitor activity increased daily in conditioned medium, and that this activity was mainly a result of CysC released from primary cultured cells. Human CysC added to the culture medium of primary brain cells increased the number of GFAP-positive and nestin-positive cells. Human CysC also increased the number of neurospheres formed from embryonic brain, and thus it increases the number of neural stem/precursor cells in a manner similar to glycosylated rat CysC. The addition of a neutralizing antibody, on the other hand, greatly decreased the number of GFAP and glutamate aspartate transporter (GLAST)-positive astrocytes. This decrease was reversed by the addition of CysC but not by another cysteine protease inhibitor. Thus, the promotion of astrocyte development by CysC appears to be independent of its protease inhibitor activity. The antibody increased the number of oligodendrocytes and their precursors. Therefore, CysC modifies glial development in addition to its activity against neural stem/precursor cells. 相似文献
173.
The stationary phase survival protein SurE is a metal ion-dependent phosphatase distributed among eubacteria, archaea, and eukaryotes. In Escherichia coli, SurE has activities as nucleotidase and exopolyphosphatase, and is thought to be involved in stress response. However, its physiological role and reaction mechanism are unclear. We report here the crystal structures of the tetramer of SurE from Thermus thermophilus HB8 (TtSurE) both alone and crystallized with Mn(2+) and substrate AMP. In the presence of Mn(2+) and AMP, differences between the protomers were observed in the active site and in the loop located near the active site; AMP-bound active sites with the loops in a novel open conformation were found in the two protomers, and AMP-free active sites with the loops in a conventional closed conformation were found in the other two protomers. The two loops in the open conformation are entwined with each other, and this entwining is suggested to be required for enzymatic activity by site-directed mutagenesis. TtSurE exists as an equilibrium mixture of dimer and tetramer in solution. The loop-entwined structure indicates that SurE acts as a tetramer. The structural features and the absence of negative cooperativity imply the half-of-the-sites reactivity mechanism resulting from a pre-existing tendency toward structural asymmetry. 相似文献
174.
175.
Hayashi Y Okino N Kakuta Y Shikanai T Tani M Narimatsu H Ito M 《The Journal of biological chemistry》2007,282(42):30889-30900
Using C6-NBD-glucosylceramide (GlcCer) as a substrate, we detected the activity of a conduritol B epoxide-insensitive neutral glycosylceramidase in cytosolic fractions of zebrafish embryos, mouse and rat brains, and human fibroblasts. The candidates for the enzyme were assigned to the Klotho (KL), whose family members share a beta-glucosidase-like domain but whose natural substrates are unknown. Among this family, only the KL-related protein (KLrP) is capable of degrading C6-NBD-GlcCer when expressed in CHOP cells, in which Myc-tagged KLrP was exclusively distributed in the cytosol. In addition, knockdown of the endogenous KLrP by small interfering RNA increased the cellular level of GlcCer. The purified recombinant KLrP hydrolyzed 4-methylumbelliferyl-glucose, C6-NBD-GlcCer, and authentic GlcCer at pH 6.0. The enzyme also hydrolyzed the corresponding galactosyl derivatives, but each k(cat)/Km was much lower than that for glucosyl derivatives. The x-ray structure of KLrP at 1.6A resolution revealed that KLrP is a (beta/alpha)8 TIM barrel, in which Glu(165) and Glu(373) at the carboxyl termini of beta-strands 4 and 7 could function as an acid/base catalyst and nucleophile, respectively. The substrate-binding cleft of the enzyme was occupied with palmitic acid and oleic acid when the recombinant protein was crystallized in a complex with glucose. GlcCer was found to fit well the cleft of the crystal structure of KLrP. Collectively, KLrP was identified as a cytosolic neutral glycosylceramidase that could be involved in a novel nonlysosomal catabolic pathway of GlcCer. 相似文献
176.
177.
178.
Protein N-arginine methyltransferase (PRMT)1 catalyzes arginine methylation in a variety of substrates, although the potential role of PRMT1 in insulin action has not been defined. We therefore investigated the effect of PRMT1-mediated methylation on insulin signaling and glucose uptake in skeletal L6 myotubes. Exposure of L6 myotubes to insulin rapidly induced translocation of PRMT1 and increased its catalytic activity in membrane fraction. Several proteins in the membrane fraction were arginine-methylated after insulin treatment, which were inhibited by pretreatment with an inhibitor of methyltransferase, 5′-deoxy-5′-(methylthio)adenosine (MTA), or a small interfering RNA against PRMT1 (PRMT1-siRNA). Inhibition of arginine methylation with MTA or PRMT1-siRNA diminished later phase of insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) β and IRS-1, association of IRS-1 with p85α subunit of PI3-K, and glucose uptake. Our results suggest that PRMT1-mediated methylation serves as a positive modulator of IR/IRS-1/PI3-K pathway and subsequent glucose uptake in skeletal muscle cells. 相似文献
179.
Niisato N Hasegawa I Tokuda S Taruno A Nakajima K Miyazaki H Iwasaki Y Marunaka Y 《Biochemical and biophysical research communications》2007,356(4):1050-1055
Neltenexine has been applied to human lung diseases such as chronic obstructive pulmonary disease (COPD) as a mucolytic agent. However, we have no information on the neltenexine action in bronchial epithelial cells. We studied the neltenexine action on the ion transport in human submucosal serous Calu-3 cells. Under a hyper-secreting condition caused by terbutaline (a beta2-adrenergic agonist), neltenexine diminished anion secretion by inhibiting the Cl- and HCO3- uptake via Na+/K+/2Cl- cotransporter and Na+/HCO3- cotransporter without blockade of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, and also diminished anion secretion via stimulation of Cl-/HCO3- exchanger, which facilitates the extrusion of more CFTR-permeant anion, Cl-, with the uptake of less CFTR-permeant anion, HCO3-. Thus, neltenexine reduced the hyper-secretion to keep an appropriate fluid level in the airway, providing a possibility that neltenexine can be an effective drug in airway obstructive diseases by decreasing the airway resistance under a hyper-secreting condition. 相似文献
180.
Kajiya M Hirota M Inai Y Kiyooka T Morimoto T Iwasaki T Endo K Mohri S Shimizu J Yada T Ogasawara Y Naruse K Ohe T Kajiya F 《American journal of physiology. Heart and circulatory physiology》2007,292(6):H2737-H2744
Pulmonary hypertension (PH) causes right ventricular (RV) hypertrophy and, according to the extent of pressure overload, eventual heart failure. We tested the hypothesis that the mechanical stress in PH-RV impairs the vasoreactivity of the RV coronary microvessels of different sizes with increased superoxide levels. Five-week-old male Sprague-Dawley rats were injected with monocrotaline (n=126) to induce PH or with saline as controls (n=114). After 3 wk, coronary arterioles (diameter = 30-100 microm) and small arteries (diameter = 100-200 microm) in the RV were visualized using intravital videomicroscopy. We evaluated ACh-induced vasodilation alone, in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), in the presence of tetraethylammonium (TEA) or catalase with or without L-NAME, and in the presence of SOD. The degree of suppression in vasodilation by L-NAME and TEA was used as indexes of the contributions of endothelial nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), respectively. In PH rats, ACh-induced vasodilation was significantly attenuated in both arterioles and small arteries, especially in arterioles. This decreased vasodilation was largely attributable to reduced NO-mediated vasoreactivity, whereas the EDHF-mediated vasodilation was relatively robust. The suppressive effect on arteriolar vasodilation by catalase was similar to TEA in both groups. Superoxide, as measured by lucigenin chemiluminescence, was significantly elevated in the RV tissues in PH. SOD significantly ameliorated the impairment of ACh-induced vasodilation in PH. Robust EDHF function will play a protective role in preserving coronary microvascular homeostasis in the event of NO dysfunction with increased superoxide levels. 相似文献