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1.
Shuichi Nagashima Hiroaki Yagyu Ryuichi Tozawa Fumiko Tazoe Manabu Takahashi Tetsuya Kitamine Daisuke Yamamuro Kent Sakai Motohiro Sekiya Hiroaki Okazaki Jun-ichi Osuga Akira Honda Shun Ishibashi 《Journal of lipid research》2015,56(5):998-1005
Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. 相似文献
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骨形成蛋白-9(BMP-9)是从胚胎鼠的肝脏c DNA文库中克隆得到的新型细胞因子,属于转化生长因子β超家族的成员,由肝脏非实质细胞合成分泌,在体内以类激素的形式发挥广泛的生物学作用。BMP-9不仅具有强烈的骨诱导活性,促进成骨细胞分化,还可通过调控糖代谢过程中关键酶的表达、促进胰岛素合成及分泌、增加胰岛素敏感性等方式调节体内葡萄糖平衡。本文主要对BMP-9与骨代谢及糖代谢的关系进行综述,为深入认识糖尿病、代谢性骨病及糖尿病性骨质疏松的发生机理提供理论依据,为糖尿病和骨骼疾病的防治提供新的思路。 相似文献
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Eric J. Camire John D. Grossman Grace J. Thole Nicholas M. Fleischman Deborah L. Perlstein 《The Journal of biological chemistry》2015,290(39):23793-23802
Nbp35 and Cfd1 are prototypical members of the MRP/Nbp35 class of iron-sulfur (FeS) cluster scaffolds that function to assemble nascent FeS clusters for transfer to FeS-requiring enzymes. Both proteins contain a conserved NTPase domain that genetic studies have demonstrated is essential for their cluster assembly activity inside the cell. It was recently reported that these proteins possess no or very low nucleotide hydrolysis activity in vitro, and thus the role of the NTPase domain in cluster biogenesis has remained uncertain. We have reexamined the NTPase activity of Nbp35, Cfd1, and their complex. Using in vitro assays and site-directed mutagenesis, we demonstrate that the Nbp35 homodimer and the Nbp35-Cfd1 heterodimer are ATPases, whereas the Cfd1 homodimer exhibited no or very low ATPase activity. We ruled out the possibility that the observed ATP hydrolysis activity might result from a contaminating ATPase by showing that mutation of key active site residues reduced activity to background levels. Finally, we demonstrate that the fluorescent ATP analog 2′/3′-O-(N′-methylanthraniloyl)-ATP (mantATP) binds stoichiometrically to Nbp35 with a KD = 15.6 μm and that an Nbp35 mutant deficient in ATP hydrolysis activity also displays an increased KD for mantATP. Together, our results demonstrate that the cytosolic iron-sulfur cluster assembly scaffold is an ATPase and pave the way for interrogating the role of nucleotide hydrolysis in cluster biogenesis by this large family of cluster scaffolding proteins found across all domains of life. 相似文献
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The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer. 相似文献
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Manuele Rebsamen 《Autophagy》2016,12(6):1061-1062
The mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) acts as a crucial regulator of cellular metabolism by integrating growth factor presence, energy and nutrient availability to coordinate anabolic and catabolic processes, and controls cell growth and proliferation. Amino acids are critical for MTORC1 activation, but the molecular mechanisms involved in sensing their presence are just beginning to be understood. We recently reported that the previously uncharacterized amino acid transporter SLC38A9 is a member of the lysosomal sensing machinery that signals amino acid availability to MTORC1. SLC38A9 is the first component of this complex shown to physically engage amino acids, suggesting a role at the core of the amino acid-sensing mechanism. 相似文献
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磨盘山天然次生林凋落物数量及动态 总被引:2,自引:0,他引:2
以磨盘山5.76hm2天然次生林群落固定监测样地为平台,均匀布设144个凋落物收集器,于2006年每月末(4—11月)连续收集其凋落物,用以分析群落尺度上的凋落物产量、组成及时空变化。结果表明,天然次生林年凋落量为3039.6 kg/hm2,以凋落叶(2499.2 kg/hm2)所占的比例最大,占年凋落量的82.22%,而凋落枝仅占年凋落量的9.92%,花果皮等所占比例更小,占总量的5%以下。1a内,凋落物收集器内共收集到42种树木的凋落叶,占样地内树种总数(46种)的91.30%,其中花曲柳(Fraxinus rhynchophylla)、核桃楸(Juglans mandshurica)和蒙古栎(Quercus mongolica)3个树种的凋落叶占落叶总量的82.97%,为叶凋落量的主要来源。不同收集器之间凋落量存在较大差异,99个收集器的年凋落量在200—400 g,2个收集器超过600 g;单个收集器全年最多可收集到19种树种的凋落叶,收集到凋落叶种数12种的收集器最多(29个)。凋落量月动态呈单峰型,69.78%的凋落量产生于9—10月份,叶凋落量月动态与凋落总量变化相同。落叶以秋季为主,但树种间叶凋落节律存在差异,其中核桃楸叶的凋落高峰集中在8—9月,花曲柳和春榆(Ulmus japonica)集中在9—10月,色木槭(Acer mono)为10月,蒙古栎叶为10—11月。 相似文献
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Sodium Fluoride Mimics the Effect of Prostaglandin E2 on Catecholamine Release from Bovine Adrenal Chromaffin Cells 总被引:1,自引:1,他引:0
Seiji Ito† Manabu Negishi Noriko Mochizuki-Oda Hiromitsu Yokohama† Osamu Hayaishi† 《Journal of neurochemistry》1991,56(1):44-51
We have reported recently that prostaglandin E2 (PGE2) stimulated phosphoinositide metabolism in bovine adrenal chromaffin cells and that PGE2 and ouabain, an inhibitor of Na+, K(+)-ATPase, synergistically induced a gradual secretion of catecholamines from the cells. Here we examined the involvement of a GTP-binding protein(s) in PGE receptor-induced responses by using NaF. In the presence of Ca2+ in the medium, NaF stimulated the formation of all three inositol phosphates, i.e., inositol monophosphate, bisphosphate, and trisphosphate, linearly over 30 min in a dose-dependent manner (15-30 mM). This effect on phosphoinositide metabolism was accompanied by an increase in cytosolic free Ca2+. NaF also induced catecholamine release from chromaffin cells, and the dependency of stimulation of the release on NaF concentration was well correlated with those of NaF-enhanced inositol phosphate formation and increase in cytosolic free Ca2+. Although the effect of NaF on PGE2-induced catecholamine release in the presence of ouabain was additive at concentrations below 20 mM, there was no additive effect at 25 mM NaF. Furthermore, the time course of catecholamine release stimulated by 20 mM NaF in the presence of ouabain was quite similar to that by 1 microM PGE2, and both stimulations were markedly inhibited by amiloride, with half-maximal inhibition at 10 microM. Pretreatment of the cells with pertussis toxin did not prevent, but rather enhanced, PGE2-induced catecholamine release over the range of concentrations examined. These results demonstrate that NaF mimics the effect of PGE2 on catecholamine release from chromaffin cells and suggest that PGE2-evoked catecholamine release may be mediated by the stimulation of phosphoinositide metabolism through a putative GTP-binding protein insensitive to pertussis toxin. 相似文献