全文获取类型
收费全文 | 945篇 |
免费 | 59篇 |
出版年
2021年 | 15篇 |
2020年 | 9篇 |
2019年 | 16篇 |
2018年 | 18篇 |
2017年 | 10篇 |
2016年 | 24篇 |
2015年 | 41篇 |
2014年 | 47篇 |
2013年 | 61篇 |
2012年 | 78篇 |
2011年 | 61篇 |
2010年 | 22篇 |
2009年 | 37篇 |
2008年 | 45篇 |
2007年 | 55篇 |
2006年 | 51篇 |
2005年 | 28篇 |
2004年 | 44篇 |
2003年 | 33篇 |
2002年 | 36篇 |
2001年 | 19篇 |
2000年 | 24篇 |
1999年 | 17篇 |
1998年 | 14篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 4篇 |
1994年 | 8篇 |
1993年 | 6篇 |
1992年 | 9篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 11篇 |
1988年 | 6篇 |
1987年 | 8篇 |
1985年 | 6篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 6篇 |
1981年 | 9篇 |
1980年 | 6篇 |
1979年 | 11篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1975年 | 7篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1969年 | 7篇 |
1968年 | 5篇 |
1967年 | 4篇 |
排序方式: 共有1004条查询结果,搜索用时 31 毫秒
71.
Filomeni G Cerchiaro G Da Costa Ferreira AM De Martino A Pedersen JZ Rotilio G Ciriolo MR 《The Journal of biological chemistry》2007,282(16):12010-12021
We characterized the pro-apoptotic activity of two new synthesized isatin-Schiff base copper(II) complexes, obtained from isatin and 1,3-diaminopropane or 2-(2-aminoethyl)pyridine: (Cu(isapn)) and (Cu(isaepy)(2)), respectively. We demonstrated that these compounds trigger apoptosis via the mitochondrial pathway. The early induction of the p53/p21 system indicates a role for p53 in cell death, however, experiments carried out with small interfering RNA against p53, or with cells lacking p53, support that a p53-independent mechanism can also occur. The extent of apoptosis mirrors the kinetics of intracellular copper uptake. Particularly, Cu(isaepy)(2) enters the cells more efficiently and specifically damages nuclei and mitochondria, as evidenced by atomic absorption analysis of copper content and by the extent of nuclear and mitochondrial integrity. Conversely, Cu(isapn), although less permeable, induces a wide-spread oxidative stress, as demonstrated by analyses of reactive oxygen species concentration, and oxidation of proteins and lipids. The increase of the antioxidant defense, through the overexpression of Cu,Zn-SOD, partially counteracts cell death; whereas retinoic acid-mediated differentiation completely rescues cells from apoptosis induced by both compounds. The activation of JNK- and Akt-mediated phosphorylative pathways has been found to be not functional for apoptosis induction. On the contrary, apoptosis significantly decreased when the analogous zinc complex was used or when Cu(isaepy)(2) was incubated in the presence of a copper chelator. Altogether, our data provide evidence for a dual role of these copper(II) complexes: they are able to vehicle copper into the cell, thus producing reactive oxygen species, and could behave as delocalized lipophilic cation-like molecules, thus specifically targeting organelles. 相似文献
72.
73.
Musayev FN di Salvo ML Ko TP Gandhi AK Goswami A Schirch V Safo MK 《Protein science : a publication of the Protein Society》2007,16(10):2184-2194
Pyridoxal kinase catalyzes the transfer of a phosphate group from ATP to the 5' alcohol of pyridoxine, pyridoxamine, and pyridoxal. In this work, kinetic studies were conducted to examine monovalent cation dependence of human pyridoxal kinase kinetic parameters. The results show that hPLK affinity for ATP and PL is increased manyfold in the presence of K(+) when compared to Na(+); however, the maximal activity of the Na(+) form of the enzyme is more than double the activity in the presence of K(+). Other monovalent cations, Li(+), Cs(+), and Rb(+) do not show significant activity. We have determined the crystal structure of hPLK in the unliganded form, and in complex with MgATP to 2.0 and 2.2 A resolution, respectively. Overall, the two structures show similar open conformation, and likely represent the catalytically idle state. The crystal structure of the MgATP complex also reveals Mg(2+) and Na(+) acting in tandem to anchor the ATP at the active site. Interestingly, the active site of hPLK acts as a sink to bind several molecules of MPD. The features of monovalent and divalent metal cation binding, active site structure, and vitamin B6 specificity are discussed in terms of the kinetic and structural studies, and are compared with those of the sheep and Escherichia coli enzymes. 相似文献
74.
D'Onofrio J Petraccone L Erra E Martino L Fabio GD Napoli LD Giancola C Montesarchio D 《Bioconjugate chemistry》2007,18(4):1194-1204
Oligodeoxyribonucleotides of sequence d(5'TGGGAG3') carrying bulky aromatic groups at the 5' end were found to exhibit potent anti-HIV activity [Hotoda, H., et al. (1998) J. Med. Chem. 41, 3655-3663 and references therein]. Structure-activity relationship investigations indicated that G-quadruplex formation, as well as the presence of large aromatic substituents at the 5'-end, were both essential for their antiviral activity. In this work, we synthesized some representative examples of the anti-HIV active Hotoda's 6-mers and analyzed the resulting G-quadruplexes by CD, DSC, and molecular modeling studies, in comparison with the unmodified oligonucleotide. In the case of the sequence carrying the 3,4-dibenzyloxybenzyl (DBB) group, identified as the best candidate for further drug optimization, we developed an alternative protocol to synthesize the 5'-DBB-thymidine phosphoramidite building block in higher yields. The thermodynamic and kinetic parameters for the association/dissociation processes of the 5'-conjugated quadruplexes, determined with respect to the unmodified one, were discussed in light of the molecular modeling studies. The aromatic groups at the 5' position of d(5'TGGGAG3') dramatically enhance both the equilibrium and the rate of formation of the quadruplex complexes. The overall stability of the investigated quadruplexes was found to correlate with the reported IC50 values, thus furnishing quantitative evidence for the hypothesis that the G-quadruplex structures are the ultimate active species, effectively responsible for the biological activity. 相似文献
75.
Bontempo P Mita L Miceli M Doto A Nebbioso A De Bellis F Conte M Minichiello A Manzo F Carafa V Basile A Rigano D Sorbo S Castaldo Cobianchi R Schiavone EM Ferrara F De Simone M Vietri M Cioffi M Sica V Bresciani F de Lera AR Altucci L Molinari AM 《The international journal of biochemistry & cell biology》2007,39(10):1902-1914
Curative properties of some medicinal plants such as the Feijoa sellowiana Bert. (Myrtaceae), have been often claimed, although the corresponding molecular mechanism(s) remain elusive. We report here that the Feijoa acetonic extract exerts anti-cancer activities on solid and hematological cancer cells. Feijoa extract did not show toxic effects on normal myeloid progenitors thus displaying a tumor-selective activity. In the Feijoa acetonic extract, fractionation and subsequent purification and analyses identified Flavone as the active component. Flavone induces apoptosis which is accompanied by caspase activation and p16, p21 and TRAIL over-expression in human myeloid leukemia cells. Use of ex vivo myeloid leukemia patients blasts confirms that both the full acetonic Feijoa extract and its derived Flavone are able to induce apoptosis. In both cell lines and myeloid leukemia patients blasts the apoptotic activity of Feijoa extract and Flavone is accompanied by increase of histone and non-histone acetylation levels and by HDAC inhibition. Our findings show for the first time that the Feijoa apoptotic active principle is the Flavone and that this activity correlates with the induction of HDAC inhibition, supporting the hypothesis of its epigenetic pro-apoptotic regulation in cancer systems. 相似文献
76.
Rigano LA Siciliano F Enrique R Sendín L Filippone P Torres PS Qüesta J Dow JM Castagnaro AP Vojnov AA Marano MR 《Molecular plant-microbe interactions : MPMI》2007,20(10):1222-1230
The phytopathogenic bacterium Xanthomonas axonopodis pv. citri is responsible for the canker disease affecting citrus plants throughout the world. Here, we have evaluated the role of bacterial attachment and biofilm formation in leaf colonization during canker development on lemon leaves. Crystal violet staining and confocal laser scanning microscopy analysis of X. axonopodis pv. citri strains expressing the green fluorescent protein were used to evaluate attachment and biofilm formation on abiotic and biotic (leaf) surfaces. Wild-type X. axonopodis pv. citri attached to and formed a complex, structured biofilm on glass in minimal medium containing glucose. Similar attachment and structured biofilm formation also were seen on lemon leaves. An X. axonopodis pv. citri gumB mutant strain, defective in production of the extracellular polysaccharide xanthan, did not form a structured biofilm on either abiotic or biotic surfaces. In addition, the X. axonopodis pv. citri gumB showed reduced growth and survival on leaf surfaces and reduced disease symptoms. These findings suggest an important role for formation of biofilms in the epiphytic survival of X. axonopodis pv. citri prior to development of canker disease. 相似文献
77.
Redko F Clavin ML Weber D Ranea F Anke T Martino V 《Zeitschrift für Naturforschung. C, Journal of biosciences》2007,62(3-4):164-168
The isoflavonoids coumestrol, genistein and daidzein have been isolated and identified by bioassay-guided fractionation from the acetone extract of Erythrina crista galli young twigs infected with Phomopsis sp. These compounds showed antimicrobial activity against Bacillus brevis (MIC values 16.3, 64.8 and 137.8 microM, respectively). This is the first time that coumestrol, besides lutein and n-nonacosane, are reported in this species. 相似文献
78.
Meister J Weber D Martino V Sterner O Anke T 《Zeitschrift für Naturforschung. C, Journal of biosciences》2007,62(1-2):11-15
The medicinal plant Eupatorium arnottianum can be found in the Northeast and center of Argentina and the South of Bolivia. From plant material collected in Argentina an endophytic Phomopsis was isolated. The fungus was identified by microscopic features and analysis of its ITS sequence. Cultures yielded, besides mellein and nectriapyrone, a novel depsidone derivative for which we propose the name phomopsidone (1). The structure of 1 was determined from its spectroscopic data. 相似文献
79.
Eloise Mastrangelo Patrice Vachette Federica Cossu Francesca Malvezzi Martino Bolognesi Mario Milani 《Biophysical journal》2015,108(3):714-723
Smac-DIABLO in its mature form (20.8 kDa) binds to baculoviral IAP repeat (BIR) domains of inhibitor of apoptosis proteins (IAPs) releasing their inhibitory effects on caspases, thus promoting cell death. Despite its apparent molecular mass (∼100 kDa), Smac-DIABLO was held to be a dimer in solution, simultaneously targeting two distinct BIR domains. We report an extensive biophysical characterization of the protein alone and in complex with the X-linked IAP (XIAP)-BIR2-BIR3 domains. Our data show that Smac-DIABLO adopts a tetrameric assembly in solution and that the tetramer is able to bind two BIR2-BIR3 pairs of domains. Our small-angle x-ray scattering-based tetrameric model of Smac-DIABLO/BIR2-BIR3 highlights some conformational freedom of the complex that may be related to optimization of IAPs binding. 相似文献