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41.
Guthikonda RN Shah SK Pacholok SG Humes JL Mumford RA Grant SK Chabin RM Green BG Tsou N Ball R Fletcher DS Luell S Euan MacIntyre D Maccoss M 《Bioorganic & medicinal chemistry letters》2005,15(8):1997-2001
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing. 相似文献
42.
Teall M Oakley P Harrison T Shaw D Kay E Elliott J Gerhard U Castro JL Shearman M Ball RG Tsou NN 《Bioorganic & medicinal chemistry letters》2005,15(10):2685-2688
The development of a novel series of 4-aryl, 4-phenylsulfonyl cyclohexananone-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described. 相似文献
43.
Embrey MW Wai JS Funk TW Homnick CF Perlow DS Young SD Vacca JP Hazuda DJ Felock PJ Stillmock KA Witmer MV Moyer G Schleif WA Gabryelski LJ Jin L Chen IW Ellis JD Wong BK Lin JH Leonard YM Tsou NN Zhuang L 《Bioorganic & medicinal chemistry letters》2005,15(20):4550-4554
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs. 相似文献
44.
Black WC Bayly CI Davis DE Desmarais S Falgueyret JP Léger S Li CS Massé F McKay DJ Palmer JT Percival MD Robichaud J Tsou N Zamboni R 《Bioorganic & medicinal chemistry letters》2005,15(21):4741-4744
The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins. 相似文献
45.
Huang HD Lee TY Wu LC Lin FM Juan HF Horng JT Tsou AP 《Journal of proteome research》2005,4(3):690-697
Protein identification is important in proteomics. Proteomic analyses based on mass spectra (MS) constitute innovative ways to identify the components of protein complexes. Instruments can obtain the mass spectrum to an accuracy of 0.01 Da or better, but identification errors are inevitable. This study shows a novel tool, MultiProtIdent, which can identify proteins using additional information about protein-protein interactions and protein functional associations. Both single and multiple Peptide Mass Fingerprints (PMFs) are input to MultiProtIdent, which matches the PMFs to a theoretical peptide mass database. The relationships or interactions among proteins are considered to reduce false positives in PMF matching. Experiments to identify protein complexes reveal that MultiProtIdent is highly promising. The website associated with this study is http://dbms104.csie.ncu.edu.tw/. 相似文献
46.
Miyayama T Tsou PS Fung SM Fung HL 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2006,835(1-2):21-26
We have developed a liquid chromatographic-mass spectrometric method for the simultaneous determination of nitroglycerin (NTG) and its active metabolites, glyceryl 1,2-dinitrate (1,2-GDN) and glyceryl 1,3-dinitrate (1,3-GDN), for metabolism studies in cell cultures. 1,2,4-Butanetriol-1,4-dinitrate was chosen as an internal standard. Using a linear gradient of water/methanol containing 0.025 mM NH(4)Cl, the compounds were eluted within 12.5 min on an Allure Aqueous C(18) column (100 mm x 2.1 mm). Detection and quantification was achieved with multiple reaction monitoring in the negative ion mode. Intra- and inter-day variabilities for simultaneous determination of the three nitrates were below 10 and 18%, respectively, over a range of NTG and GDN concentrations of 0.5-15 ng/ml. The lower limit of quantification was found to be about 0.01 ng on column. Application of this method was illustrated through in vitro metabolism studies of NTG in culture media bathing LLC-PK1 cells and human vascular smooth muscle cells (HA-VSMC) at 37 degrees C. The degradation half-life of NTG was found to be 4.5 +/- 0.4 h and 39.2 +/- 0.02 h, respectively, for LLC-PK1 cells versus HA-VSMC. At 5 h, the 1,2-GDN versus 1,3-GDN metabolite distribution ratio in the bathing medium was found to be 1.5 +/- 0.1 and 0.2 +/- 0.02 for LLC-PK1 and HA-VSMC cells, respectively. With this method, the degradation half-life of NTG in rat plasma at 37 degrees C was shown to be 26.8 +/- 1.8 min, consistent with previous values obtained using gas chromatography. 相似文献
47.
Fechner-Benham subjective color is widely believed to be governed by local interactions in early (probably retinal) mechanisms. Here we report three lines of phenomenological evidence that suggest otherwise: subjective colors seen in spatially extended stimuli (a) are dependent on global aspects of the stimuli; (b) can become multistable in position; and (c) even after being stabilized do not support the creation of McCollough's colored after-effects--a cortically based phenomenon generally thought to be more central than Fechner-Benham color. These phenomena suggest a central locus that controls perception of subjective color, characterized by pattern dependent interactions among cortical mechanisms that draw their inputs from peripheral units. 相似文献
48.
Hsu CC Lee YC Yeh SH Chen CH Wu CC Wang TY Chen YN Hung LY Liu YW Chen HK Hsiao YT Wang WS Tsou JH Tsou YH Wu MH Chang WC Lin DY 《The Journal of biological chemistry》2012,287(27):22533-22548
The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties. 相似文献
49.
Chang ML Yeh HC Tsou YK Wang CJ Cheng HY Sung CM Ho YP Chen TH Yeh CT 《Obesity (Silver Spring, Md.)》2012,20(7):1474-1480
Obesity-related hepatic steatosis is commonly associated with central fat accumulation and alterations in adipocytokine secretion; however, the connection between nonobese hepatic steatosis and adipocytokines remains unclear. We aim to investigate this connection using an animal model of conditional hepatitis C virus (HCV) core-transgenic mice. Double transgenic mice (DTM) with doxycycline (dox)-regulated hepatic overexpression of the HCV core protein were fed standard rodent chow ad libitum following 1 month of a dox-rich diet. The mice exhibited nonobese hepatic steatosis at 2 months of age. The levels of leptin and adiponectin were assessed in 2-month-old DTM (i.e., HCV core-tetracycline transactivator (tTA)) and single transgenic mice (STM; i.e., tTA). The total fat mass and the body fat distribution of the mice were evaluated using dual-energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI). Microarray analyses and quantitative real-time PCR were conducted using RNA obtained from the visceral fat of paired DTM and STM. Adiponectin was administered intraperitoneally to the 2-month-old DTM. No significant differences of the various fat components were noted between the DTM and STM. Leptin mRNA was downregulated in the visceral fat of DTM (P = 0.011), and serum adiponectin protein levels were reduced in the DTM compared with those in the STM (P = 0.035). Adiponectin treatment also significantly ameliorated hepatic steatosis in the DTM compared to the controls (P = 0.024). In conclusion, HCV core-induced nonobese hepatic steatosis is associated with downregulation of the leptin gene in visceral fat and concurrent hypoadiponectinemia; however, these effects may be ameliorated by adiponectin treatment. 相似文献
50.
Polarized cortical cues are known to guide spindle movements to dictate division axis and cleavage site during asymmetric cell division. In a recent issue of Nature Cell Biology, Kiyomitsu and Cheeseman (2012) report two novel spindle-intrinsic signals that regulate spindle orientation and position in symmetrically dividing human cells. 相似文献