全文获取类型
收费全文 | 6162篇 |
免费 | 540篇 |
国内免费 | 339篇 |
专业分类
7041篇 |
出版年
2024年 | 18篇 |
2023年 | 207篇 |
2022年 | 295篇 |
2021年 | 329篇 |
2020年 | 298篇 |
2019年 | 359篇 |
2018年 | 338篇 |
2017年 | 278篇 |
2016年 | 224篇 |
2015年 | 238篇 |
2014年 | 363篇 |
2013年 | 398篇 |
2012年 | 255篇 |
2011年 | 359篇 |
2010年 | 240篇 |
2009年 | 259篇 |
2008年 | 287篇 |
2007年 | 269篇 |
2006年 | 245篇 |
2005年 | 223篇 |
2004年 | 201篇 |
2003年 | 189篇 |
2002年 | 135篇 |
2001年 | 78篇 |
2000年 | 91篇 |
1999年 | 70篇 |
1998年 | 54篇 |
1997年 | 55篇 |
1996年 | 37篇 |
1995年 | 34篇 |
1994年 | 35篇 |
1993年 | 29篇 |
1992年 | 19篇 |
1991年 | 19篇 |
1989年 | 13篇 |
1988年 | 12篇 |
1987年 | 26篇 |
1986年 | 17篇 |
1985年 | 35篇 |
1984年 | 53篇 |
1983年 | 49篇 |
1982年 | 45篇 |
1981年 | 46篇 |
1980年 | 32篇 |
1979年 | 36篇 |
1978年 | 43篇 |
1977年 | 27篇 |
1976年 | 14篇 |
1975年 | 18篇 |
1974年 | 22篇 |
排序方式: 共有7041条查询结果,搜索用时 15 毫秒
51.
Abstract: A synthetic peptide corresponding to residues 226–240 (E9 peptide) of human τ, which contains an Lys-Ser-Pro motif, was used to raise a polyclonal antibody. The antibody, E9, was 10-fold less reactive with phospho-E9 peptide than with native E9 peptide. E9 antibody was used to study the extent of phosphorylation in a modified form of τ (PHF-τ) that is found in Alzheimer's disease brain and is incorporated into paired helical filaments (PHFs). E9 immunolabeled Alzheimer's disease neurofibrillary tangles and abnormal neurites in brain sections intensely, with increased immunoreactivity detected after pretreatment of sections with phosphatase. On immunoblots and ELISA, E9 reacted with PHF-τ and recombinant human τ but not with the high and middle molecular weight neurofilament proteins. Phosphatase treatment of PHF-τ improved the E9 immunoreactivity by 30–50%. Dephosphorylated high but not middle molecular weight neurofilament protein became reactive with E9. These results indicate that <50% of the PHF-T is phosphorylated in the subregion corresponding to residues 226–240 of τ and suggest that the phosphorylation of this region may not be essential for PHF formation. 相似文献
52.
A. Herchuelz P. Lebrun A. Carpinelli N. Thonnart A. Sener W.J. Malaisse 《生物化学与生物物理学报:生物膜》1981,640(1):16-30
The effects of quinine and 9-aminoacridine, two blockers of potassium conductance in islet cells, on 45Ca efflux and insulin release from perifused islets were investigated in order to elucidate the mechanisms by which glucose initially reduces 45Ca efflux and later stimulates calcium inflow in islet cells. In the absence of glucose, 100 μM quinine stimulated 45Ca net uptake, 45Ca outflow rate and insulin release. Quinine also dramatically enhanced the cationic and the secretory response to intermediate concentrations of glucose, but had little effect on 45Ca net uptake, 45Ca fractional outflow rate and insulin release at a high glucose concentration (16.7 mM). The ability of quinine to stimulate 45Ca efflux depended on the presence of extracellular calcium, suggesting that it reflects a stimulation of calcium entry in the islet cells. In the absence of extracellular calcium, quinine provoked a sustained decrease in 45Ca efflux. Such an inhibitory effect was not additive to that of glucose, and was reduced at low extracellular Na+ concentration. At a low concentration (5 μM), quinine, although reducing 86Rb efflux from the islets to the same extent as a non-insulinotropic glucose concentration (4.4 mM), failed to inhibit 45Ca efflux. In the presence of extracellular calcium, 9-aminoacridine produced an important but transient increase in 45Ca outflow rate and insulin release from islets perifused in the absence of glucose. In the absence of extracellular calcium, 9-aminoacridine, however, failed to reduced 45Ca efflux from perifused islets. It is concluded that quinine, by reducing K+ conductance, reproduces the effect of glucose to activate voltage-sensitive calcium channels and to stimulate the entry of calcium into the B-cell. However, the glucose-induced inhibition of calcium outflow rate, which may also participate in the intracellular accumulation of calcium, does not appear to be mediated by changes in K+ conductance. 相似文献
53.
蛋白酪氨酸磷酸酶SHP-2在乳腺癌细胞移动及粘附中的作用 总被引:2,自引:0,他引:2
探讨蛋白酪氨酸磷酸酶SHP 2在乳腺癌细胞MCF 7的移动及粘附中的作用 .利用基因重组技术分别将野生型SHP 2与突变型SHP 2与绿色荧光蛋白GFP的基因片段构成重组质粒 (SHP 2 GFP、SHP 2C >S GFP) .脂质体转染法分别转入MCF 7中 ,表达成功后筛选并建立SHP 2 GFP和SHP 2C >S GFP细胞株 .荧光显微镜观察细胞移动情况 ,免疫印迹法检测粘附分子E 钙粘蛋白和金属蛋白酶MMP 1及MMP 9的表达 .实验后建立SHP 2 GFP及SHP 2C >S GFP细胞株 ,同时观察到SHP 2C >S GFP细胞的形态发生明显改变 :从梭形状态变成圆形状态 .荧光显微镜发现 ,MCF 7细胞和SHP 2 GFP、SHP 2C >S GFP转染的细胞在 3h、6h、9h的移动情况分别是MCF 7为 10 %、2 3%、5 4% ,SHP 2 GFP为 15 %、4 9%、98% ,SHP 2C >S GFP为 4 %、11%、30 % .免疫印迹结果表明 ,SHP 2C >S GFP细胞的E 钙粘蛋白表达比SHP 2 GFP细胞明显升高 (P <0 0 5 ) .MMP 1及MMP 9的表达量在SHP 2 GFP细胞中有所增强 (P <0 0 5 ) .实验表明 ,SHP 2可能通过调节粘附分子和基质金属磷酸酶而在细胞移动、粘附中发挥重要作用 相似文献
54.
Stephanie Brunet Nassim Shahrzad Djenann Saint‐Dic Hartley Dutczak Michael Sacher 《Traffic (Copenhagen, Denmark)》2013,14(10):1091-1104
TRAPP is a multisubunit complex that functions in membrane traffic. Mutations in the mammalian TRAPP protein C2 are linked to the skeletal disorder spondyloepiphyseal dysplasia tarda (SEDT) that is thought to arise from an inability to secrete procollagen from the endoplasmic reticulum. Here, we show that C2 binds to the SNARE protein Syntaxin 5 and this interaction is weakened by an SEDT‐causing missense mutation (D47Y). Interestingly, the equivalent mutation (D46Y) in the yeast C2 homolog Trs20p does not block anterograde traffic but did affect endocytosis. The trs20D46Y mutation interfered with the interaction between Trs20p and Trs85p (TRAPP III‐specific subunit), Trs120p and Trs130p (TRAPP II‐specific subunits). Size exclusion chromatography suggested that this yeast mutation destabilized the TRAPP III complex that is involved in autophagy. We further show that this mutation blocks both the selective cytosol‐to‐vacuole (cvt) pathway as well as non‐selective autophagy. We demonstrate that the apparent molecular size of the TRAPP III complex is dependent upon membranes, and that the presence of TRAPP III is dependent upon Atg9p. Finally, we demonstrate that lipidated Bet3p is enriched in TRAPP III and that lipidation increases the efficiency of autophagy. Our study suggests that Trs20p acts as an adaptor for Trs85p and Trs120p and reveals complexities in TRAPP III assembly and function. The implications of C2D47Y in SEDT are discussed . 相似文献
55.
Lin Xu Qi Liu Min Qing Xin-Shen Yao Zhen-Ke Wen 《Biochemical and biophysical research communications》2009,382(3):571-824
Accumulating data suggested that CXCR4/SDF-1 pathway may play an important role in the metastasis of tumor. We previously demonstrated that CpG ODN could enhance the metastasis of human lung cancer cell via TLR9. Here we further evaluated the possible role of CXCR4/SDF-1 pathway in the enhanced metastasis of human lung cancer 95D cells induced by CpG ODN. Our data showed down-regulation of CXCR4 expression using siRNA against CXCR4 could significantly reduce the enhanced metastasis of 95D cells induced by CpG ODN both in vitro and in vivo. These results suggested that TLR9 agonist might promote the metastasis of human lung cancer cells via CXCR4/SDF-1 pathway. 相似文献
56.
Plasmacytoid dendritic cells (pDCs) represent a unique and crucial immune cell population capable of producing large amounts
of type I interferons (IFNs) in response to viral infection. The function of pDCs as the professional type I IFN-producing
cells is linked to their selective expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within
the endosomal compartments. Type I IFNs produced by pDCs not only directly inhibit viral replication but also play an essential
role in linking the innate and adaptive immune system. The aberrant activation of pDCs by self nucleic acids through TLR signaling
and the ongoing production of type I IFNs do occur in some autoimmune diseases. Therefore, pDC may serve as an attractive
target for therapeutic manipulations of the immune system to treat viral infectious diseases and autoimmune diseases. 相似文献
57.
Tadao Hashimoto Yukuo Yoshida Kunio Tagawa 《Journal of bioenergetics and biomembranes》1990,22(1):27-38
An intrinsic ATPase inhibitor inhibits the ATP-hydrolyzing activity of mitochondrial F1F0-ATPase and is released from its binding site on the enzyme upon energization of mitochondrial membranes to allow phosphorylation of ADP. The mitochondrial activity to synthesize ATP is not influenced by the absence of the inhibitor protein. The enzyme activity to hydrolyze ATP is induced by dissipation of the membrane potential in the absence of the inhibitor. Thus, the inhibitor is not responsible for oxidative phosphorylation, but acts only to inhibit ATP hydrolysis by F1F0-ATPase upon deenergization of mitochondrial membranes. The inhibitor protein forms a regulatory complex with two stabilizing factors, 9K and 15K proteins, which facilitate the binding of the inhibitor to F1F0-ATPase and stabilize the resultant inactivated enzyme. The 9K protein, having a sequence very similar to the inhibitor, binds directly to F1 in a manner similar to the inhibitor. The 15K protein binds to the F0 part and holds the inhibitor and the 9K protein on F1F0-ATPase even when one of them is detached from the F1 part. 相似文献
58.
Role of phosphorylation sites and the C2 domain in regulation of cytosolic phospholipase A2. 总被引:4,自引:0,他引:4
Cytosolic phospholipase A2 (cPLA2) mediates agonist-induced arachidonic acid release, the first step in eicosanoid production. cPLA2 is regulated by phosphorylation and by calcium, which binds to a C2 domain and induces its translocation to membrane. The functional roles of phosphorylation sites and the C2 domain of cPLA2 were investigated. In Sf9 insect cells expressing cPLA2, okadaic acid, and the calcium-mobilizing agonists A23187 and CryIC toxin induce arachidonic acid release and translocation of green fluorescent protein (GFP)-cPLA2 to the nuclear envelope. cPLA2 is phosphorylated on multiple sites in Sf9 cells; however, only S505 phosphorylation partially contributes to cPLA2 activation. Although okadaic acid does not increase calcium, mutating the calcium-binding residues D43 and D93 prevents arachidonic acid release and translocation of cPLA2, demonstrating the requirement for a functional C2 domain. However, the D93N mutant is fully functional with A23187, whereas the D43N mutant is nearly inactive. The C2 domain of cPLA2 linked to GFP translocates to the nuclear envelope with calcium-mobilizing agonists but not with okadaic acid. Consequently, the C2 domain is necessary and sufficient for translocation of cPLA2 to the nuclear envelope when calcium is increased; however, it is required but not sufficient with okadaic acid. 相似文献
59.
Three group 10 complexes containing nido-carborane diphosphine, [NiCl(PPh3){7,8-(PPh2)2-7,8-C2B9H10}] (1), [PdCl(PPh3){7,8-(PPh2)2-7,8-C2B9H10}] · 1.25CH2Cl2 (2) and [PtCl(PPh3){7,8-(PPh2)2-7,8-C2B9H10}] · 2.5CH2Cl2 (3) have been synthesized by the reactions of [M(PPh3)2Cl2] (M = Ni, Pd, Pt) with closo carborane diphosphine 1,2-(PPh2)2-1,2-C2B10H10 in ethanol. For complex 3, it could also be obtained under solvothermal condition. All three complexes were characterized by elemental analysis, FT-IR, 1H and 13C NMR spectroscopy and X-ray structure determination. Single crystal structures show that their structures are similar to each other. In each complex, the nido [7,8-(PPh2)2-7,8-C2B9H10]−, which resulted from the degradation of the initial closo ligand 1,2-(PPh2)2-1,2-C2B10H10 during the reaction process, was coordinated bidentately through the P atoms to M(II) ion, and this resulted in a stable five-membered chelating ring between the bis-diphosphine ligand and the metal. The coordination mode of the metal can be described as a slightly distorted square-planar, in which the remaining two positions were occupied by one Cl− and one PPh3 group. 相似文献
60.
Nucleolin mediated pro‐angiogenic role of Hydroxysafflor Yellow A in ischaemic cardiac dysfunction: Post‐transcriptional regulation of VEGF‐A and MMP‐9 下载免费PDF全文