全文获取类型
收费全文 | 6087篇 |
免费 | 582篇 |
国内免费 | 650篇 |
专业分类
7319篇 |
出版年
2024年 | 23篇 |
2023年 | 93篇 |
2022年 | 236篇 |
2021年 | 336篇 |
2020年 | 239篇 |
2019年 | 291篇 |
2018年 | 290篇 |
2017年 | 226篇 |
2016年 | 275篇 |
2015年 | 409篇 |
2014年 | 457篇 |
2013年 | 455篇 |
2012年 | 594篇 |
2011年 | 506篇 |
2010年 | 308篇 |
2009年 | 311篇 |
2008年 | 304篇 |
2007年 | 277篇 |
2006年 | 211篇 |
2005年 | 224篇 |
2004年 | 227篇 |
2003年 | 180篇 |
2002年 | 152篇 |
2001年 | 119篇 |
2000年 | 96篇 |
1999年 | 81篇 |
1998年 | 68篇 |
1997年 | 54篇 |
1996年 | 39篇 |
1995年 | 29篇 |
1994年 | 36篇 |
1993年 | 29篇 |
1992年 | 39篇 |
1991年 | 34篇 |
1990年 | 15篇 |
1989年 | 13篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 10篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 1篇 |
排序方式: 共有7319条查询结果,搜索用时 15 毫秒
981.
Wang SX Ju HQ Liu KS Zhang JX Wang X Xiang YF Wang R Liu JY Liu QY Xia M Xing GW Liu Z Wang YF 《Bioscience, biotechnology, and biochemistry》2011,75(8):1540-1545
SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins. 相似文献
982.
In order to develop an eco-friendly polymer, a novel super-absorbent polymer was prepared by graft copolymerization of acrylic acid (AA), acrylic amide (AM) and dimethyl diallyl ammonium chloride (DMDAAC) onto the pretreatment wheat straw (PTWS). The molecular structure of the super-absorbent was confirmed by FTIR. The factors that can influence absorbencies of the super-absorbent resin (SAR) were investigated, such as weight ratio between the monomers, the ratio of PTWS to monomers, the amount of initiator and cross-linker, temperature reaction time and neutralization degree of AA. The SAR has the water absorbency of 133.76 g/g in distilled water and 33.83 g/g in 0.9 wt.% NaCl solution. 相似文献
983.
Ju HQ Xiang YF Xin BJ Pei Y Lu JX Wang QL Xia M Qian CW Ren Z Wang SY Wang YF Xing GW 《Bioorganic & medicinal chemistry letters》2011,21(6):1675-1677
In this study, a novel Hsp90 inhibitor BJ-B11, was synthesized and evaluated for in vitro antiviral activity against several viruses. Possible anti-HSV-1 mechanisms were also investigated. BJ-B11 displayed no antiviral activity against coxsackievirus B3 (CVB3), human respiratory syncytial virus (RSV) and influenza virus (H1N1), but exhibited potent anti-HSV-1 and HSV-2 activity with EC50 values of 0.42 ± 0.18 μM and 0.60 ± 0.21 μM, respectively. Additionally, the inhibitory effects of BJ-B11 against HSV-1 were likely to be introduced at early stage of infection. Our results indicate that BJ-B11 with alternative mechanisms of action is potent as an anti-HSV clinical trial candidate. 相似文献
984.
In stem cell niches, the spatial extent of growth factor signaling needs to be tightly controlled. A new study on the Drosophila testicular germline stem cell niche has revealed that BMP signaling is locally activated through linkage to adherens junctions. 相似文献
985.
986.
Gao P Wei JM Li PY Zhang CJ Jian WC Zhang YH Xing AY Zhou GY 《Journal of cellular and molecular medicine》2011,15(10):2130-2138
Specific inhibition of P-glycoprotein (Pgp) expression, which is encoded by multidrug resistance gene-1 (MDR1), is considered a well-respected strategy to overcome multidrug resistance (MDR). Deoxyribozymes (DRz) are catalytic nucleic acids that could cleave a target RNA in sequence-specific manner. However, it is difficult to select an effective target site for DRz in living cells. In this study, target sites of DRz were screened according to MDR1 mRNA secondary structure by RNA structure analysis software. Twelve target sites on the surface of MDR1 mRNA were selected. Accordingly, 12 DRzs were synthesized and their suppression effect on the MDR phenotype in breast cancer cells was confirmed. The results showed that 4 (DRz 2, 3, 4, 9) of the 12 DRzs could, in a dose-dependent response, significantly suppress MDR1 mRNA expression and restore chemosensitivity in breast cancer cells with MDR phenotype. This was especially true of DRz 3, which targets the 141 site purine-pyrimidine dinucleotide. Compared with antisense oligonucleotide or anti-miR-27a inhibitor, DRz 3 was more efficient in suppressing MDR1 mRNA and Pgp protein expression or inhibiting Pgp function. The chemosensitivity assay also proved DRz 3 to be the best one to reverse the MDR phenotype. The present study suggests that screening targets of DRzs according to MDR1 mRNA secondary structure could be a useful method to obtain workable ones. We provide evidence that DRzs (DRz 2, 3, 4, 9) are highly efficient at reversing the MDR phenotype in breast carcinoma cells and restoring chemosensitivity. 相似文献
987.
Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes. 相似文献
988.
To bring cryo electron microscopy (cryoEM) of large biological complexes to atomic resolution, several factors--in both cryoEM image acquisition and 3D reconstruction--that may be neglected at low resolution become significantly limiting. Here we present thorough analyses of four limiting factors: (a) electron-beam tilt, (b) inaccurate determination of defocus values, (c) focus gradient through particles, and (d) particularly for large particles, dynamic (multiple) scattering of electrons. We also propose strategies to cope with these factors: (a) the divergence and direction tilt components of electron-beam tilt could be reduced by maintaining parallel illumination and by using a coma-free alignment procedure, respectively. Moreover, the effect of all beam tilt components, including spiral tilt, could be eliminated by use of a spherical aberration corrector. (b) More accurate measurement of defocus value could be obtained by imaging areas adjacent to the target area at high electron dose and by measuring the image shift induced by tilting the electron beam. (c) Each known Fourier coefficient in the Fourier transform of a cryoEM image is the sum of two Fourier coefficients of the 3D structure, one on each of two curved 'characteristic surfaces' in 3D Fourier space. We describe a simple model-based iterative method that could recover these two Fourier coefficients on the two characteristic surfaces. (d) The effect of dynamic scattering could be corrected by deconvolution of a transfer function. These analyses and our proposed strategies offer useful guidance for future experimental designs targeting atomic resolution cryoEM reconstruction. 相似文献
989.
Wang YY Wen ZH Duan JH Zhu JL Wang WT Dong H Li HM Gao GD Xing JL Hu SJ 《Neuro-Signals》2011,19(1):54-62
Noise can play a constructive role in the detection of weak signals in various kinds of peripheral receptors and neurons. What the mechanism underlying the effect of noise is remains unclear. Here, the perforated patch-clamp technique was used on isolated cells from chronic compression of the dorsal root ganglion (DRG) model. Our data provided new insight indicating that, under conditions without external signals, noise can enhance subthreshold oscillations, which was observed in a certain type of neurons with high-frequency (20-100 Hz) intrinsic resonance from injured DRG neurons. The occurrence of subthreshold oscillation considerably decreased the threshold potential for generating repetitive firing. The above effects of noise can be abolished by blocking the persistent sodium current (I(Na, P)). Utilizing a mathematical neuron model we further simulated the effect of noise on subthreshold oscillation and firing, and also found that noise can enhance the electrical activity through autonomous stochastic resonance. Accordingly, we propose a new concept of the effects of noise on neural intrinsic activity, which suggests that noise may be an important factor for modulating the excitability of neurons and generation of chronic pain signals. 相似文献
990.