全文获取类型
收费全文 | 1763篇 |
免费 | 106篇 |
国内免费 | 1篇 |
出版年
2021年 | 12篇 |
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 10篇 |
2017年 | 14篇 |
2016年 | 32篇 |
2015年 | 45篇 |
2014年 | 49篇 |
2013年 | 106篇 |
2012年 | 96篇 |
2011年 | 123篇 |
2010年 | 80篇 |
2009年 | 81篇 |
2008年 | 98篇 |
2007年 | 108篇 |
2006年 | 103篇 |
2005年 | 107篇 |
2004年 | 109篇 |
2003年 | 102篇 |
2002年 | 109篇 |
2001年 | 29篇 |
2000年 | 21篇 |
1999年 | 25篇 |
1998年 | 23篇 |
1997年 | 28篇 |
1996年 | 19篇 |
1995年 | 29篇 |
1994年 | 22篇 |
1993年 | 33篇 |
1992年 | 29篇 |
1991年 | 24篇 |
1990年 | 11篇 |
1989年 | 14篇 |
1988年 | 14篇 |
1987年 | 13篇 |
1986年 | 12篇 |
1985年 | 14篇 |
1984年 | 17篇 |
1983年 | 7篇 |
1982年 | 10篇 |
1981年 | 8篇 |
1980年 | 10篇 |
1979年 | 5篇 |
1978年 | 9篇 |
1977年 | 8篇 |
1976年 | 8篇 |
1975年 | 9篇 |
1974年 | 4篇 |
1973年 | 8篇 |
1964年 | 2篇 |
排序方式: 共有1870条查询结果,搜索用时 296 毫秒
61.
Michel Camplo Philippe Faury Anne-Sophie Charvet Florence Lederer Jean-Claude Chermann Jean-Louis Kraus 《Nucleosides, nucleotides & nucleic acids》2013,32(6):631-641
Abstract The synthesis of a new analogue of 2′,3′-dideoxy-3′-thiacytidine 9 covalently linked to an N-formyl methionyl leucyl phenylalanine peptide is described. This new prodrug analogue has been tested on the one hand as activator of human polymorphonuclear leukocytes (an EC50 value of 1.8 10?5 M was determined from dose-response curve for superoxide production) and on the other hand as inhibitor of the syncitium formation caused by HIV-1 in MT4-cells (IC50 = 8.0± 0.8 μM). In so far as this new prodrug possesses these two biological properties, it represents a useful “chemical-head” capable of targeting specific receptors located on leukocytes membranes. 相似文献
62.
Abdesslem Faraj M. Abdelaziz El Alaoui Geraldine Pavia Gilles Gosselin Jean-Louis Imbach Raymond F. Schinazi 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):1287-1290
Abstract Several β-L-3′-substituted-3′-deoxythymidine were stereospecifically synthesized. None of these analogs inhibited HIV-1 nor HBV replication in vitro suggesting that these β-L-pyrimidine derivatives may not be efficiently phosphorylated inside the cells. 相似文献
63.
Julian Bertrand Bertrand Liagre Lamia Ghezali Jean-Louis Beneytout David Yannick Leger 《Apoptosis : an international journal on programmed cell death》2013,18(7):836-850
Cyclooxygenase-2 (COX-2) has been found to be highly expressed in many types of cancers and to contribute to tumorigenesis via the inhibition of apoptosis, increased angiogenesis and invasiveness. In hematological malignancies, COX-2 expression was found to correlate with poor patient prognosis. However, the exact role of COX-2 expression in these malignancies, and particularly in erythroleukemias, remains unclear. The aim of this work was to describe and understand the relationships between COX-2 expression and apoptosis rate in erythroleukemia cells after apoptosis induction by several anticancer agents. We used three different erythroleukemia cell lines in which COX-2 expression was modulated by transfection with either COX-2 siRNA or COX-2 cDNA. These cellular models were then treated with apoptosis inducers and apoptosis onset and intensity was followed. Cell signalling was evaluated in unstimulated transfected cells or after apoptosis induction. We found that COX-2 inhibition rendered erythroleukemia cells more sensitive to apoptosis induction and that in cells overexpressing COX-2 apoptosis induction was reduced. We demonstrated that COX-2 inhibition decreased the pro-survival Akt signalling and activated the negative regulator of Akt signalling, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Conversely, in COX-2 overexpressing cells, Akt signalling was activated and PTEN was inhibited. In these last cells, inhibition of casein kinase 2 or Akt signalling restored sensitivity to apoptotic agents. Our findings highlighted that COX-2 can positively regulate Akt signalling mostly through PTEN inhibition, partly via casein kinase 2 activation, and enhances survival of erythroleukemia cells exposed to anticancer agents. 相似文献
64.
Kun Jia Jean-Louis Bijeon Pierre-Michel Adam Rodica Elena Ionescu 《Plasmonics (Norwell, Mass.)》2013,8(1):143-151
The present work is reporting on the fabrication of localized surface plasmonic resonant (LSPR) gold nano-structures on glass substrate by using different high annealing temperatures (500 °C, 550 °C, 600 °C) of initially created semi-continue gold films (2 nm and 5 nm) by the electron beam evaporation technique. Interestingly, well-defined gold nano-structures were also obtained from continuous 8 nm evaporated gold film - known as the value above gold percolated thickness - once exposed to high temperatures. The surface morphology and plasmonic spectroscopy of “annealed” nano-structures were controlled by key experimental parameters such as evaporated film thickness and annealing temperature. By using scanning electron microscopy (SEM) characterization of annealed surface it was noticed that the size and inter-particle distance between nano-structures were highly dependent on the evaporated thin film thickness, while the nanoparticle shape evolution was mainly affected by the employed annealing temperature. Due to the well-controlled morphology of gold nano-particles, prominent and stable LSPR spectra were observed with good plasmon resonance tunability from 546 nm to 780 nm that recommend the developed protocol as a robust alternative to fabricate large scale LSPR surface. An example of a LSPR-immunosensor is reported. Thus, the monoclonal anti-atrazine antibodies immobilizion on the “annealed” gold nano-structures, as well as the specific antigen (atrazine) recognition were monitored as variations of the resonance wavelength shifts and optical density changes in the extinction measurements. 相似文献
65.
Gene diversity and allelic diversity are both recognized as useful criteria for establishing priorities of conservation. Similarly to gene diversity partitioning, based on variation of gene frequencies both within and between subpopulations, allelic diversity can be partitioned using variation in allele numbers. Allelic diversity components have to meet a number of desirable properties, among which orthogonality (i.e. independence of the within-subpopulation and between-subpopulation components), and concavity (i.e. no within-subpopulation diversity larger than total diversity). In this note it is shown how the partitioning recommended in species diversity studies should be transposed to allelic diversity. Attention is drawn to some methods of allelic diversity partitioning currently proposed, essentially the widely used rarefaction method of Petit et al. (Conserv Biol 12:844–855, 1998) and a more recently proposed method by Caballero and Rodriguez-Ramilo (Conserv Genet 11:2219–2229, 2010). Their contrasting properties and the potentially contrasting conclusions to be expected from their application in conservation are emphasized. Some simple examples are used to show how an improper measure of allelic diversity may lead to misleading conclusions when defining priorities of conservation. 相似文献
66.
67.
Hansel Gómez Mae Chappé Pedro A Valiente Tirso Pons María de Los Angeles Chávez Jean-Louis Charli Isel Pascual 《Journal of biosciences》2013,38(3):461-469
Dipeptidyl peptidase IV (DPP-IV) is an ectopeptidase with many roles, and a target of therapies for different pathologies. Zinc and calcium produce mixed inhibition of porcine DPP-IV activity. To investigate whether these results may be generalized to mammalian DPP-IV orthologues, we purified the intact membrane-bound form from rat kidney. Rat DPP-IV hydrolysed Gly-Pro-p-nitroanilide with an average Vmax of 0.86±0.01 μmol min–1mL–1 and KM of 76±6 μM. The enzyme was inhibited by the DPP-IV family inhibitor l-threo-Ile-thiazolidide (Ki=64.0±0.53 nM), competitively inhibited by bacitracin (Ki=0.16±0.01 mM) and bestatin (Ki=0.23±0.02 mM), and irreversibly inhibited by TLCK (IC50 value of 1.20±0.11 mM). The enzyme was also inhibited by divalent ions like Zn2+ and Ca2+, for which a mixed inhibition mechanism was observed (Ki values of the competitive component: 0.15±0.01 mM and 50.0±1.05 mM, respectively). According to bioinformatic tools, Ca2+ ions preferentially bound to the β-propeller domain of the rat and human enzymes, while Zn2+ ions to the α-β hydrolase domain; the binding sites were essentially the same that were previously reported for the porcine DPP-IV. These data suggest that the cationic susceptibility of mammalian DPP-IV orthologues involves conserved mechanisms. 相似文献
68.
Sabiha Abekhoukh Chris Planque Clémentine Ripoll Paulina Urbaniak Jean-Louis Paul Jean-Maurice Delabar Nathalie Janel 《Molecular neurobiology》2013,47(1):105-116
Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal-regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. 相似文献
69.
Hélène Valladas Norbert Mercier Israel Hershkovitz Yossi Zaidner Alexander Tsatskin Reuven Yeshurun Laurence Vialettes Jean-Louis Joron Jean-Louis Reyss Mina Weinstein-Evron 《Journal of human evolution》2013
The transition from the Lower to the Middle Paleolithic in the Levant is a crucial event in human evolution, since it may involve the arrival of a new human population. In the current study, we present thermoluminescence (TL) dates obtained from 32 burnt flints retrieved from the late Lower Paleolithic (Acheulo-Yabrudian) and Early Middle Paleolithic (Mousterian) layers of Misliya Cave, Mount Carmel, Israel. Early Middle Paleolithic industries rich in Levallois and laminar products were assigned mean ages ranging from ∼250 to ∼160 ka (thousands of years ago), suggesting a production of this industry during MIS 7 and the early part of MIS 6. The mean ages obtained for the samples associated with the Acheulo-Yabrudian (strengthened by an isochron analysis) indicate a production of this cultural complex ∼250 ka ago, at the end of MIS 8. According to the Misliya TL dates, the transition from the Lower to the Middle Paleolithic in the site took place at the limit MIS 8/7 or during the early part of MIS 7. The dates, together with the pronounced differences in lithic technology strongly suggest the arrival of a new population during this period. 相似文献
70.
Sabina Gerber Christian Lizak Ga?lle Michaud Monika Bucher Tamis Darbre Markus Aebi Jean-Louis Reymond Kaspar P. Locher 《The Journal of biological chemistry》2013,288(13):8849-8861
N-Linked glycosylation is an essential post-translational protein modification in the eukaryotic cell. The initial transfer of an oligosaccharide from a lipid carrier onto asparagine residues within a consensus sequon is catalyzed by oligosaccharyltransferase (OST). The first X-ray structure of a complete bacterial OST enzyme, Campylobacter lari PglB, was recently determined. To understand the mechanism of PglB, we have quantified sequon binding and glycosylation turnover in vitro using purified enzyme and fluorescently labeled, synthetic peptide substrates. Using fluorescence anisotropy, we determined a dissociation constant of 1.0 μm and a strict requirement for divalent metal ions for consensus (DQNAT) sequon binding. Using in-gel fluorescence detection, we quantified exceedingly low glycosylation rates that remained undetected using in vivo assays. We found that an alanine in the −2 sequon position, converting the bacterial sequon to a eukaryotic one, resulted in strongly lowered sequon binding, with in vitro turnover reduced 50,000-fold. A threonine is preferred over serine in the +2 sequon position, reflected by a 4-fold higher affinity and a 1.2-fold higher glycosylation rate. The interaction of the +2 sequon position with PglB is modulated by isoleucine 572. Our study demonstrates an intricate interplay of peptide and metal binding as the first step of protein N-glycosylation. 相似文献