全文获取类型
收费全文 | 725篇 |
免费 | 27篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 16篇 |
2020年 | 5篇 |
2019年 | 4篇 |
2018年 | 3篇 |
2017年 | 8篇 |
2016年 | 13篇 |
2015年 | 35篇 |
2014年 | 25篇 |
2013年 | 55篇 |
2012年 | 61篇 |
2011年 | 59篇 |
2010年 | 25篇 |
2009年 | 33篇 |
2008年 | 53篇 |
2007年 | 47篇 |
2006年 | 39篇 |
2005年 | 36篇 |
2004年 | 45篇 |
2003年 | 38篇 |
2002年 | 31篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 11篇 |
1998年 | 5篇 |
1997年 | 6篇 |
1996年 | 10篇 |
1995年 | 3篇 |
1994年 | 5篇 |
1993年 | 8篇 |
1992年 | 8篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1976年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有752条查询结果,搜索用时 203 毫秒
101.
Sivan Vadakkadath Meethal Miguel J Gallego Ryan J Haasl Stephen J Petras III Jean-Yves Sgro Craig S Atwood 《BMC evolutionary biology》2006,6(1):103-17
Background
The Caenorhabditis elegans genome is known to code for at least 1149 G protein-coupled receptors (GPCRs), but the GPCR(s) critical to the regulation of reproduction in this nematode are not yet known. This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR) exist in C. elegans. 相似文献102.
Raoul M Patigny D Fabis F Dauphin F Rault S Sapi J Laronze JY 《Journal of enzyme inhibition and medicinal chemistry》2006,21(3):251-260
Several new 2-vinyl-Nb,Nb-dimethyltryptamines were prepared using Fischer indole synthesis followed by simple functional group transformations and evaluated on 5-HT4, 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. It was found that 2-vinyl substitution conferred a potent and selective 5-HT6 binding activity to these molecules which could be enhanced by Na-arylsulfonyl substituents. 相似文献
103.
Savalle M Gillaizeau F Maruani G Puymirat E Bellenfant F Houillier P Fagon JY Faisy C 《American journal of physiology. Endocrinology and metabolism》2012,303(3):E389-E396
Critical illness affects body composition profoundly, especially body cell mass (BCM). BCM loss reflects lean tissue wasting and could be a nutritional marker in critically ill patients. However, BCM assessment with usual isotopic or tracer methods is impractical in intensive care units (ICUs). We aimed to modelize the BCM of critically ill patients using variables available at bedside. Fat-free mass (FFM), bone mineral (Mo), and extracellular water (ECW) of 49 critically ill patients were measured prospectively by dual-energy X-ray absorptiometry and multifrequency bioimpedance. BCM was estimated according to the four-compartment cellular level: BCM = FFM - (ECW/0.98) - (0.73 × Mo). Variables that might influence the BCM were assessed, and multivariable analysis using fractional polynomials was conducted to determine the relations between BCM and these data. Bootstrap resampling was then used to estimate the most stable model predicting BCM. BCM was 22.7 ± 5.4 kg. The most frequent model included height (cm), leg circumference (cm), weight shift (Δ) between ICU admission and body composition assessment (kg), and trunk length (cm) as a linear function: BCM (kg) = 0.266 × height + 0.287 × leg circumference + 0.305 × Δweight - 0.406 × trunk length - 13.52. The fraction of variance explained by this model (adjusted r(2)) was 46%. Including bioelectrical impedance analysis variables in the model did not improve BCM prediction. In summary, our results suggest that BCM can be estimated at bedside, with an error lower than ±20% in 90% subjects, on the basis of static (height, trunk length), less stable (leg circumference), and dynamic biometric variables (Δweight) for critically ill patients. 相似文献
104.
Despite recent evidence of the cancer-promoting role of adipose tissue-derived progenitor and differentiated cells, the use of lipotransfer for tissue/organ reconstruction after surgical removal of cancer is increasing worldwide. Here we discuss in a multidisciplinary fashion the preclinical data connecting obesity, adipose cells and cancer progression, as well as the clinical data concerning safety of lipotransfer procedures in cancer patients. A roadmap towards a more rationale use of lipotransfer in oncology is urgently needed and should include preclinical studies to dissect the roles of different adipose tissue-derived cells, the evaluation of drugs currently candidate to inhibit the interaction between adipose and tumor cells, and carefully designed clinical trials to investigate the safety of lipotransfer procedures in cancer patients. 相似文献
105.
Saisongkorh W El Karkouri K Patrice JY Bernard A Rolain JM Raoult D 《FEMS immunology and medical microbiology》2012,64(1):111-114
In cell culture, Rickettsia felis grows only at low temperatures (< 31 °C). Therefore, its ability to enter, survive and grow in cell lines has primarily been tested in cells derived from amphibians and arthropods, which naturally grow at low temperatures, and only infrequently in mammalian cells. We subcultured R. felis in mammalian cells for more than 10 passages using media supplemented with tryptose phosphate broth (TPB) and found that TPB is critical for optimal growth of R. felis in mammalian cells. 相似文献
106.
Balboni G Congiu C Onnis V Maresca A Scozzafava A Winum JY Maietti A Supuran CT 《Bioorganic & medicinal chemistry letters》2012,22(9):3063-3066
An inhibition study of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with flavones and aminoflavones, compounds possessing a rather similar scaffold with the coumarins, recently discovered inhibitors of this enzyme, is reported. The natural product flavone and some of its hydroxylated derivatives did not show time-dependent inhibition of the CAs, sign that they are not hydrolyzed within the enzyme active site as the (thio)coumarins and lactones. These compounds were low micromolar inhibitors of hCA I, II, IX and XII, with K(I)s in the range of 1.88-9.07 μM. A series of substituted 2-amino-3-phenyl-4H-chromen-4-ones, incorporating chloro- and methoxy substituents in various positions of the heterocycle, were then prepared and assayed as hCA I and II inhibitors, showing activity in the micromolar range. Some of these derivatives, as well as cis+trans resveratrol, were then assayed for the inhibition of all catalytically active mammalian CA isoforms, hCA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII, XIV and mCA XV (h=human, m=murine enzyme). These derivatives inhibited these CAs in the submicromolar-low micromolar range. Flavones, although not as active as the coumarins, may be considered as interesting leads for the design of non-sulfonamide CA inhibitors. 相似文献
107.
F Ferro A Ouillé TA Tran P Fontanaud P Bois D Babuty F Labarthe JY Le Guennec 《PloS one》2012,7(7):e41686
Background and purpose
In some pathological conditions carnitine concentration is high while in othersitis low.In bothcases,cardiac arrhythmiascan occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmiasthrough modulation of ionic currents. We studied the effects of acyl-CARs on hERG, KIR2.1 and Kv7.1/minKchannels (channels responsible for IKR, IK1 and IKS respectively).Experimental approach
HEK293 cells stably expressing hERG, KIR2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18∶1) fatty acids were applied intra- and extracellularly at different concentrations. Forstudies onhERG, C16 and C18∶1 free fatty acid were also used.Key results
Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of IhERG amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on KIR2.1 or Kv7.1/minK currents.Computer simulations of these effects wereconsistent with changes in action potential profile.Conclusions and applications
Extracellular LCAC tonically regulates IhERG amplitude and kineticsunder physiological conditions. This modulation maycontribute tothe changes in action potential duration thatprecede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency. 相似文献108.
Syed Irfan Ahmad Bukhari Alejandro Vasquez-Rifo Dominic Gagné Eric R Paquet Monique Zetka Claude Robert Jean-Yves Masson Martin J Simard 《Cell research》2012,22(6):1034-1045
The discovery of the miRNA pathway revealed a new layer of molecular control of biological processes. To uncover new functions of this gene regulatory pathway, we undertook the characterization of the two miRNA-specific Argonaute proteins in Caenorhabditis elegans, ALG-1 and ALG-2. We first observed that the loss-of-function of alg-1 and alg-2 genes resulted in reduced progeny number. An extensive analysis of the germline of these mutants revealed a reduced mitotic region, indicating fewer proliferating germ cells. We also observed an early entry into meiosis in alg-1 and alg-2 mutant animals. We detected ALG-1 and ALG-2 protein expressions in the distal tip cell (DTC), a specialized cell located at the tip of both C. elegans gonadal arms that regulates mitosis-meiosis transition. Re-establishing the expression of alg-1 specifically in the DTC of mutant animals partially rescued the observed germline defects. Further analyses also support the implication of the miRNA pathway in gametogenesis. Interestingly, we observed that disruption of five miRNAs expressed in the DTC led to similar phenotypes. Finally, gene expression analysis of alg-1 mutant gonads suggests that the miRNA pathway is involved in the regulation of different pathways important for germline proliferation and differentiation. Collectively, our data indicate that the miRNA pathway plays a crucial role in the control of germ cell biogenesis in C. elegans. 相似文献
109.
Phenotypic plasticity in response to mechanical stress: hydrodynamic performance and fitness of four aquatic plant species 总被引:1,自引:0,他引:1
Puijalon S Léna JP Rivière N Champagne JY Rostan JC Bornette G 《The New phytologist》2008,177(4):907-917
Plastic responses of plants exposed to mechanical stress can lead to modified, performance-enhancing, morphologies, sometimes accompanied by costs to reproduction. The capacity to present short-term plastic responses to current stress, the resulting performance (expected lower mechanical forces), and the costs of such responses to reproduction were tested for four aquatic plant species. Two ramets of the same genet were submitted to running vs standing water treatment. Traits describing the morphology, hydrodynamic performance and reproduction (sexual and vegetative) were measured. For one species, plastic responses led to reduced hydrodynamic forces, without apparent costs to reproduction, indicating that the plastic response could be beneficial for plant maintenance in stressful habitats. For two species, plastic responses were not associated with variations in performance and reproduction, possibly because of the low hydrodynamic forces experienced, even for morphologies produced under standing conditions. For one species, plastic responses were associated with a sharp decrease in sexual reproduction, without variations in performance, revealing the negative impact of currents over a short time scale. Species maintenance is linked to the capacity of individuals to tolerate mechanical forces. The contrasting responses to currents may be a key element for predicting community dynamics. 相似文献
110.
Kouwen TR Dubois JY Freudl R Quax WJ van Dijl JM 《Applied and environmental microbiology》2008,74(24):7536-7545
Disulfide bonds are important for the correct folding, structural integrity, and activity of many biotechnologically relevant proteins. For synthesis and subsequent secretion of these proteins in bacteria, such as the well-known "cell factory" Bacillus subtilis, it is often the correct formation of disulfide bonds that is the greatest bottleneck. Degradation of inefficiently or incorrectly oxidized proteins and the requirement for costly and time-consuming reduction and oxidation steps in the downstream processing of the proteins still are major limitations for full exploitation of B. subtilis for biopharmaceutical production. Therefore, the present study was aimed at developing a novel in vivo strategy for improved production of secreted disulfide-bond-containing proteins. Three approaches were tested: depletion of the major cytoplasmic reductase TrxA; introduction of the heterologous oxidase DsbA from Staphylococcus carnosus; and addition of redox-active compounds to the growth medium. As shown using the disulfide-bond-containing molecule Escherichia coli PhoA as a model protein, combined use of these three approaches resulted in secretion of amounts of active PhoA that were approximately 3.5-fold larger than the amounts secreted by the parental strain B. subtilis 168. Our findings indicate that Bacillus strains with improved oxidizing properties can be engineered for biotechnological production of heterologous high-value proteins containing disulfide bonds. 相似文献