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Niels Jessen Ho-Jin Koh Clifford D. Folmes Cory Wagg Nobuharu Fujii Bo Løfgren Cordula M. Wolf Charles I. Berul Michael F. Hirshman Gary D. Lopaschuk Laurie J. Goodyear 《生物化学与生物物理学报:疾病的分子基础》2010,1802(7-8):593-600
Energy deprivation in the myocardium is associated with impaired heart function and increased morbidity. LKB1 is a kinase that is required for activation of AMP-activated protein kinase (AMPK) as well as 13 AMPK-related protein kinases. AMPK stimulates ATP production during ischemia and prevents post-ischemic dysfunction. We used the Cre–Lox system to generate mice where LKB1 was selectively knocked out in cardiomyocytes and muscle cells (LKB1-KO) to assess the role of LKB1 on cardiac function in these mice.Heart rates of LKB1-KO mice were reduced and ventricle diameter was increased. Ex vivo, cardiac function was impaired during aerobic perfusion of isolated working hearts, and recovery of function after ischemia was reduced. Although oxidative metabolism and mitochondrial function were normal, the AMP/ATP ratio was increased in LKB1-KO hearts. This was associated with a complete ablation of AMPKα2 activity, and a stimulation of signaling through the mammalian target of rapamycin. Our results establish a critical role for LKB1 for normal cardiac function under both aerobic conditions and during recovery after ischemia. Ablation of LKB1 leads to a decreased cardiac efficiency despite normal mitochondrial oxidative metabolism. 相似文献
884.
HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes
Matt J. Barter Leon Pybus Gary J. Litherland Andrew D. Rowan Ian M. Clark Dylan R. Edwards Tim E. Cawston David A. Young 《Matrix biology》2010,29(7):602-612
Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-β signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-β-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-β, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-β induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-β induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-β-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-β-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-β. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-β and for the subsequent gene induction dependent on these signalling pathways. 相似文献
885.
Helene M. Langevin Kirsten N. Storch Robert R. Snapp Nicole A. Bouffard Gary J. Badger Alan K. Howe Douglas J. Taatjes 《Histochemistry and cell biology》2010,133(4):405-415
Studies in cultured cells have shown that nuclear shape is an important factor influencing nuclear function, and that mechanical
forces applied to the cell can directly affect nuclear shape. In a previous study, we demonstrated that stretching of whole
mouse subcutaneous tissue causes dynamic cytoskeletal remodeling with perinuclear redistribution of α-actin in fibroblasts
within the tissue. We have further shown that the nuclei of these fibroblasts have deep invaginations containing α-actin.
In the current study, we hypothesized that tissue stretch would cause nuclear remodeling with a reduced amount of nuclear
invagination, measurable as a change in nuclear concavity. Subcutaneous areolar connective tissue samples were excised from
28 mice and randomized to either tissue stretch or no stretch for 30 min, then examined with histochemistry and confocal microscopy.
In stretched tissue (vs. non-stretched), fibroblast nuclei had a larger cross-sectional area (P < 0.001), smaller thickness (P < 0.03) in the plane of the tissue, and smaller relative concavity (P < 0.005) indicating an increase in nuclear convexity. The stretch-induced loss of invaginations may have important influences
on gene expression, RNA trafficking and/or cell differentiation. 相似文献
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Nilantha Sirisoma Azra Pervin Hong Zhang Songchun Jiang J. Adam Willardsen Mark B. Anderson Gary Mather Christopher M. Pleiman Shailaja Kasibhatla Ben Tseng John Drewe Sui Xiong Cai 《Bioorganic & medicinal chemistry letters》2010,20(7):2330-2334
As a continuation of our efforts to discover and develop apoptosis inducing N-methyl-4-(4-methoxyanilino)quinazolines as novel anticancer agents, we explored substitution at the 5-, 6-, 7-positions of the quinazoline and replacement of the quinazoline by other nitrogen-containing heterocycles. A small group at the 5-position was found to be well tolerated. At the 6-position a small group like an amino was preferred. Substitution at the 7-position was tolerated much less than at the 6-position. Replacing the carbon at the 8-position or both the 5- and 8-positions with nitrogen led to about 10-fold reductions in potency. Replacement of the quinazoline ring with a quinoline, a benzo[d][1,2,3]triazine, or an isoquinoline ring showed that the nitrogen at the 1-position is important for activity, while the carbon at the 2-position can be replaced by a nitrogen and the nitrogen at the 3-position can be replaced by a carbon. Through the SAR study, several 5- or 6-substituted analogs, such as 2a and 2c, were found to have potencies approaching that of lead compound N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1g, EP128495, MPC-6827, Azixa®). 相似文献
889.
Gary Tresadern Jose María Cid Gregor J. Macdonald Juan Antonio Vega Ana Isabel de Lucas Aránzazu García Encarnación Matesanz María Lourdes Linares Daniel Oehlrich Hilde Lavreysen Ilse Biesmans Andrés A. Trabanco 《Bioorganic & medicinal chemistry letters》2010,20(1):175-179
Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies. 相似文献
890.
Jianming Bao Huagang Lu Gregori J. Morriello Emma J. Carlson Alan Wheeldon Gary G. Chicchi Marc M. Kurtz Kwei-Lan C. Tsao Song Zheng Xinchun Tong Sander G. Mills Robert J. DeVita 《Bioorganic & medicinal chemistry letters》2010,20(7):2354-2358
A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK1 receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK1 binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P450 inhibition and hPXR induction profiles. 相似文献