全文获取类型
收费全文 | 386篇 |
免费 | 17篇 |
出版年
2021年 | 2篇 |
2017年 | 6篇 |
2016年 | 6篇 |
2015年 | 7篇 |
2014年 | 11篇 |
2013年 | 13篇 |
2012年 | 16篇 |
2011年 | 15篇 |
2010年 | 13篇 |
2009年 | 10篇 |
2008年 | 14篇 |
2007年 | 18篇 |
2006年 | 16篇 |
2005年 | 9篇 |
2004年 | 18篇 |
2003年 | 12篇 |
2002年 | 23篇 |
2001年 | 14篇 |
2000年 | 23篇 |
1999年 | 18篇 |
1998年 | 6篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1995年 | 4篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 12篇 |
1988年 | 9篇 |
1987年 | 7篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1979年 | 2篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 4篇 |
1969年 | 4篇 |
1967年 | 2篇 |
1966年 | 1篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1962年 | 2篇 |
1959年 | 1篇 |
排序方式: 共有403条查询结果,搜索用时 31 毫秒
151.
Asaki T Hamamoto T Sugiyama Y Kuwano K Kuwabara K Niwa T 《Bioorganic & medicinal chemistry letters》2007,17(23):6588-6592
A series of prostacyclin receptor agonists was prepared by modifying the central heteroaromatic ring of lead compound 2, and a docking study was performed to investigate their structure-activity relationships by using a homology-modeled structure of the prostacyclin receptor. Compound 2 and its derivatives could be docked to the prostacyclin receptor in two ways depending on the position of the nitrogen atom within the heteroaromatic ring. Furthermore, hydrogen bonding between the nitrogen atom in the heteroaromatic ring and the hydroxyl group of Ser20 or Tyr75 of the receptor appears to be important for the potent expression of biological activity. 相似文献
152.
Tanaka R Rubio A Harn NK Gernert D Grese TA Eishima J Hara M Yoda N Ohashi R Kuwabara T Soga S Akinaga S Nara S Kanda Y 《Bioorganic & medicinal chemistry》2007,15(3):1363-1382
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described. 相似文献
153.
Asaki T Hamamoto T Sugiyama Y Kuwano K Kuwabara K 《Bioorganic & medicinal chemistry》2007,15(21):6692-6704
To develop nonprostanoid prostacyclin receptor agonists with a high degree of metabolic resistance and an extended duration of action, a novel series of diphenylpyrazine derivatives was synthesized and evaluated for their inhibition of ADP-induced human platelet aggregation. Structure-activity relationship studies on the side chain containing the carboxylic acid moiety of the lead compound 5c showed that the length of the linker and the presence of the concatenating nitrogen atom adjacent to the pyrazine ring are critical for the antiaggregatory activity. This study led to the discovery of 2-amino-5,6-diphenylpyrazine derivatives 8c, 15a, and 15b, which showed potent inhibition of platelet aggregation with IC(50) values of 0.2 microM. Among these compounds, 15b is an orally available and long-lasting prostacyclin receptor agonist which is promising for the treatment of various vascular diseases. 相似文献
154.
Kanie K Narita Y Zhao Y Kuwabara F Satake M Honda S Kaneko H Yoshioka T Okochi M Honda H Kato R 《Biotechnology and bioengineering》2012,109(7):1808-1816
Controlling the balance of endothelial cells (ECs) and smooth muscle cells (SMCs) in blood vessels is critically important to minimize the risk associated with vascular implants. Extracellular matrix (ECM) plays a key role in controlling the cellular balance, suggesting a promising source of cell-selective peptides. To obtain EC- or SMC-selective peptides, we start by highlighting sequence differences found among ECM molecules as enriched targets for cell-selective peptides. We explored the EC- or SMC-selective performance of tripeptides that are specifically enriched only in collagen type IV, but not in types I, II, III, and V. Collagen type IV was chosen since it is the major ECM in the basement membrane of blood vessels, which separates ECs and SMCs. Among 114 collagen type IV-derived tripeptides pre-screened from in silico analysis, 22 peptides (19%) were found to promote cell-selective adhesion, as determined by peptide array. One of the best performing EC-selective peptides (Cys-Ala-Gly (CAG)) was mixed into an electrospun fine-fiber, a vascular graft material, for practical application. Compared to unmodified fiber, the CAG containing fiber surface was found to enhance adhesion of ECs (+190%) while limiting SMCs (-20%). These results are not only consistent with the hypothesis of ECM as a source of cell selective peptides, but also suggest a new genre of EC- or SMC-selective peptides for tissue engineering applications. Collectively, these findings favorably support the screening approach used to discover new peptides for these purposes. 相似文献
155.
Kuwabara C Wang D Kasuga J Fukushi Y Arakawa K Koyama T Inada T Fujikawa S 《Cryobiology》2012,64(3):279-285
In this study, we examined the effects on freezing of 26 kinds of flavonoid compounds, which were randomly selected as compounds with structures similar to those of flavonoid compounds existing in deep supercooling xylem parenchyma cells (XPCs) in trees, in solutions containing different kinds of ice nucleators, including the ice nucleation bacterium (INB) Erwinia ananas, INB Xanthomonas campestris, silver iodide, phloroglucinol and unidentified airborne impurities in buffered Milli-Q water (BMQW). Cumulative freezing spectra were obtained in each solution by cooling 2 μL droplets at 0.2 °C/min by a droplet freezing assay. Freezing temperature of 50% droplets (FT(50)) was obtained from each spectra in a separate analysis with more than 20 droplets and mean FT(50) were obtained from more than five separate analyses using more than 100 droplets in total in each flavonoid. Supercooling-promoting activities (SCA) or ice nucleation-enhancing activities (INA) of these flavonoids were determined by the difference in FT(50) between control solutions without flavonoids and experimental solutions with flavonoids. In mean values, most of the compounds examined exhibited SCA in solutions containing the INB E. ananas, INB X. campestris, silver iodide, and phloroglucinol although the magnitudes of their activities were different depending on the ice nucleator. In solutions containing the INB E. ananas, 10 compounds exhibited SCAs with significant differences (p<0.05) in the range of 1.4-4.2 °C. In solutions containing silver iodide, 23 compounds exhibited SCAs with significant differences in the range of 2.0-7.1 °C. In solutions containing phloroglucinol, six compounds exhibited SCAs with significant differences in the range of 2.4-3.5 °C. In solutions containing the INB X. campestris, only three compounds exhibited SCAs with significant differences in the range of 0.9-2.3 °C. In solutions containing unidentified airborne impurities (BMQW alone), on the other hand, many compounds exhibited INA rather than SCA. In mean values, only four compounds exhibited SCAs in the range of 2.4-3.2 °C (no compounds with significant difference at p<0.05), whereas 21 compounds exhibited INAs in the range of 0.1-12.3 °C (eight compounds with significant difference). It was also shown by an emulsion freezing assay that most flavonoid glycosides examined did not affect homogeneous ice nucleation temperatures, except for a few compounds that become ice nucleators in BMQW alone. These results suggest that most flavonoid compounds affect freezing temperatures by interaction with unidentified ice nucleators in BMQW as examined by a droplet freezing assay. The results of our previous and present studies indicate that flavonoid compounds have very complex effects to regulate freezing of water. 相似文献
156.
Vallin E Gallagher J Granger L Martin E Belougne J Maurizio J Duverger Y Scaglione S Borrel C Cortier E Abouzid K Carre-Pierrat M Gieseler K Ségalat L Kuwabara PE Ewbank JJ 《PloS one》2012,7(2):e30482
Methods that use homologous recombination to engineer the genome of C. elegans commonly use strains carrying specific insertions of the heterologous transposon Mos1. A large collection of known Mos1 insertion alleles would therefore be of general interest to the C. elegans research community. We describe here the optimization of a semi-automated methodology for the construction of a substantial collection of Mos1 insertion mutant strains. At peak production, more than 5,000 strains were generated per month. These strains were then subject to molecular analysis, and more than 13,300 Mos1 insertions characterized. In addition to targeting directly more than 4,700 genes, these alleles represent the potential starting point for the engineered deletion of essentially all C. elegans genes and the modification of more than 40% of them. This collection of mutants, generated under the auspices of the European NEMAGENETAG consortium, is publicly available and represents an important research resource. 相似文献
157.
Expression of 3-Ketoacyl-Acyl Carrier Protein Reductase (fabG) Genes Enhances Production of Polyhydroxyalkanoate Copolymer from Glucose in Recombinant Escherichia coli JM109 下载免费PDF全文
Christopher T. Nomura Kazunori Taguchi Zhihua Gan Kazuhiro Kuwabara Tomoyo Tanaka Kazuma Takase Yoshiharu Doi 《Applied microbiology》2005,71(8):4297-4306
Polyhydroxyalkanoates (PHAs) are biologically produced polyesters that have potential application as biodegradable plastics. Especially important are the short-chain-length-medium-chain-length (SCL-MCL) PHA copolymers, which have properties ranging from thermoplastic to elastomeric, depending on the ratio of SCL to MCL monomers incorporated into the copolymer. Because of the potential wide range of applications for SCL-MCL PHA copolymers, it is important to develop and characterize metabolic pathways for SCL-MCL PHA production. In previous studies, coexpression of PHA synthase genes and the 3-ketoacyl-acyl carrier protein reductase gene (fabG) in recombinant Escherichia coli has been shown to enhance PHA production from related carbon sources such as fatty acids. In this study, a new fabG gene from Pseudomonas sp. 61-3 was cloned and its gene product characterized. Results indicate that the Pseudomonas sp. 61-3 and E. coli FabG proteins have different substrate specificities in vitro. The current study also presents the first evidence that coexpression of fabG genes from either E. coli or Pseudomonas sp. 61-3 with fabH(F87T) and PHA synthase genes can enhance the production of SCL-MCL PHA copolymers from nonrelated carbon sources. Differences in the substrate specificities of the FabG proteins were reflected in the monomer composition of the polymers produced by recombinant E. coli. SCL-MCL PHA copolymer isolated from a recombinant E. coli strain had improved physical properties compared to the SCL homopolymer poly-3-hydroxybutyrate. This study defines a pathway to produce SCL-MCL PHA copolymer from the fatty acid biosynthesis that may impact on PHA production in recombinant organisms. 相似文献
158.
Watanabe Y Hiraoka W Shimoyama Y Horiuchi M Kuwabara M Inanami O 《Biochemical and biophysical research communications》2008,366(1):244-249
We examined the influence of D177N (D178N in humans) mutation on the conformational stability of the S2 region of moPrPC with varying pHs by using the SDSL-ESR technique. The ESR spectrum of D177N at pH 7.5 was narrower than that of Y161R1, referred to as WT∗. The ESR spectrum of D177N did not change when pH in the solution decreased to pH 4.0. Our results suggested that the disappearance of a salt bridge (D177-R163) induced the increase in the instability of S2 region. Moreover, the line shape of the ESR spectrum obtained from H176S neighboring the salt bridge linked to the S2 region was similar to D177N. These results indicate that the protonation of H176 is strongly associated with the stability of S2 region. These findings are important for understanding the mechanism by which the disruption of the salt bridge in the S2 region forms the pathogenic PrPSc structure in hereditary prion disease. 相似文献
159.
Mori S Wu CY Yamaji S Saegusa J Shi B Ma Z Kuwabara Y Lam KS Isseroff RR Takada YK Takada Y 《The Journal of biological chemistry》2008,283(26):18066-18075
Integrins play a role in fibroblast growth factor (FGF) signaling through cross-talk with FGF receptors (FGFRs), but the mechanism underlying the cross-talk is unknown. We discovered that FGF1 directly bound to soluble and cell-surface integrin alphavbeta3 (K(D) about 1 microm). Antagonists to alphavbeta3 (monoclonal antibody 7E3 and cyclic RGDfV) blocked this interaction. alphavbeta3 was the predominant, if not the only, integrin that bound to FGF1, because FGF1 bound only weakly to several beta1 integrins tested. We presented evidence that the CYDMKTTC sequence (the specificity loop) within the ligand-binding site of beta3 plays a role in FGF1 binding. We found that the integrin-binding site of FGF1 overlaps with the heparin-binding site but is distinct from the FGFR-binding site using docking simulation and mutagenesis. We identified an FGF1 mutant (R50E) that was defective in integrin binding but still bound to heparin and FGFR. R50E was defective in inducing DNA synthesis, cell proliferation, cell migration, and chemotaxis, suggesting that the direct integrin binding to FGF1 is critical for FGF signaling. Nevertheless, R50E induced phosphorylation of FGFR1 and FRS2alpha and activation of AKT and ERK1/2. These results suggest that the defect in R50E in FGF signaling is not in the initial activation of FGF signaling pathway components, but in the later steps in FGF signaling. We propose that R50E is a useful tool to identify the role of integrins in FGF signaling. 相似文献
160.