全文获取类型
收费全文 | 1358篇 |
免费 | 117篇 |
出版年
2023年 | 8篇 |
2022年 | 18篇 |
2021年 | 27篇 |
2020年 | 20篇 |
2019年 | 23篇 |
2018年 | 23篇 |
2017年 | 21篇 |
2016年 | 37篇 |
2015年 | 80篇 |
2014年 | 87篇 |
2013年 | 97篇 |
2012年 | 150篇 |
2011年 | 119篇 |
2010年 | 112篇 |
2009年 | 82篇 |
2008年 | 84篇 |
2007年 | 94篇 |
2006年 | 90篇 |
2005年 | 70篇 |
2004年 | 72篇 |
2003年 | 57篇 |
2002年 | 60篇 |
2001年 | 7篇 |
2000年 | 3篇 |
1999年 | 8篇 |
1998年 | 9篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1982年 | 1篇 |
1980年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有1475条查询结果,搜索用时 15 毫秒
91.
Annabelle Fernandez Delphine Lechardeur Aurélie Derré-Bobillot Elisabeth Couvé Philippe Gaudu Alexandra Gruss 《PLoS pathogens》2010,6(4)
Streptococcus agalactiae is a major neonatal pathogen whose infectious route involves septicemia. This pathogen does not synthesize heme, but scavenges it from blood to activate a respiration metabolism, which increases bacterial cell density and is required for full virulence. Factors that regulate heme pools in S. agalactiae are unknown. Here we report that one main strategy of heme and protoporphyrin IX (PPIX) homeostasis in S. agalactiae is based on a regulated system of efflux using two newly characterized operons, gbs1753 gbs1752 (called pefA pefB), and gbs1402 gbs1401 gbs1400 (called pefR pefC pefD), where pef stands for ‘porphyrin-regulated efflux’. In vitro and in vivo data show that PefR, a MarR-superfamily protein, is a repressor of both operons. Heme or PPIX both alleviate PefR-mediated repression. We show that bacteria inactivated for both Pef efflux systems display accrued sensitivity to these porphyrins, and give evidence that they accumulate intracellularly. The ΔpefR mutant, in which both pef operons are up-regulated, is defective for heme-dependent respiration, and attenuated for virulence. We conclude that this new efflux regulon controls intracellular heme and PPIX availability in S. agalactiae, and is needed for its capacity to undergo respiration metabolism, and to infect the host. 相似文献
92.
93.
Delphine Benaitreau Esther Dos Santos Marie-Christine Leneveu Philippe De Mazancourt René Pecquery Marie-Noëlle Dieudonné 《Reproductive biology and endocrinology : RB&E》2010,8(1):128
Background
In human pregnancy, a correct placentation depends on trophoblast proliferation, differentiation, migration and invasion. These processes are highly regulated by placental hormones, growth factors and cytokines. Recently, we have shown that adiponectin, an adipokine, has anti-proliferative effects on trophoblastic cells. Here, we complete this study by demonstrating that adiponectin modulates BeWo and human villous cytotrophoblast cell differentiation. 相似文献94.
Clémentine Thabuis Frédéric Destaillats Jean-François Landrier Delphine Tissot-Favre Jean-Charles Martin 《The Journal of nutritional biochemistry》2010,21(10):922-928
Oleoylethanolamide (OEA) has been previously reported to regulate food intake and body weight gain when administered intraperitoneally. Nevertheless, little information is available with regard to oral administration. To assess whether oral OEA can also exert a similar effect on body fat, we fed C3H mice a high-fat diet supplemented with either 10 or 100 mg/kg body weight OEA for 4 weeks. OEA supplementation significantly lowered food intake over the 4 weeks and decreased adipose tissue mass. Plasma triglyceride levels were also significantly decreased by OEA treatment. In order to identify the potential molecular targets of OEA action, we screened the expression levels of 44 genes related to body fat mass and food intake in peripheral tissues. Adipose tissue fatty acid amide hydrolase (FAAH), intestinal fatty acid transporter/cluster of differentiation 36 and the OEA receptor G-protein-coupled receptor 119 (GPR119) were among the most OEA-responsive genes. They were also associated with reduced body fat pads regardless of the dose. Adipose FAAH was found to be primarily associated with a decrease in food intake. Our data suggest that the anti-obesity activity of OEA partially relies on modulation of the FAAH pathway in adipose tissue. Another mechanism might involve modulation of the newly discovered GPR119 OEA signaling pathway in the proximal intestine. In conclusion, our study indicates that oral administration of OEA can effectively decrease obesity in the mouse model and that modulation of the endocannabinoid fatty acid ethanolamide pathway seems to play an important role both in adipose tissue and in small intestine. 相似文献
95.
96.
97.
Vincent D Ergül A Bohlman MC Tattersall EA Tillett RL Wheatley MD Woolsey R Quilici DR Joets J Schlauch K Schooley DA Cushman JC Cramer GR 《Journal of experimental botany》2007,58(7):1873-1892
The impact of water deficit and salt stress on two important wine grape cultivars, Chardonnay and Cabernet Sauvignon, was investigated. Plants were exposed to increasing salinity and water deficit stress over a 16 d time period. Measurements of stem water potentials, and shoot and leaf lengths indicated that Chardonnay was more tolerant to these stresses than Cabernet Sauvignon. Shoot tips were harvested every 8 d for proteomic analysis using a trichloroacetic acid/acetone extraction protocol and two-dimensional gel electrophoresis. Proteins were stained with Coomassie Brilliant Blue, quantified, and then 191 unique proteins were identified using matrix-assisted laser desorption ionization time of flight/time of flight mass spectrometry. Peptide sequences were matched against both the NCBI nr and TIGR Vitis expressed sequence tag (EST) databases that had been implemented with all public Vitis sequences. Approximately 44% of the protein isoforms could be identified. Analysis of variance indicated that varietal difference was the main source of protein expression variation (40%). In stressed plants, reduction of the amount of proteins involved with photosynthesis, protein synthesis, and protein destination was correlated with the inhibition of shoot elongation. Many of the proteins up-regulated in Chardonnay were of unclassified or of unknown function, whereas proteins specifically up-regulated in Cabernet Sauvignon were involved in protein metabolism. 相似文献
98.
Proteome analysis of grape skins during ripening 总被引:3,自引:0,他引:3
Deytieux C Geny L Lapaillerie D Claverol S Bonneu M Donèche B 《Journal of experimental botany》2007,58(7):1851-1862
The characterization of proteins isolated from skin tissue is apparently an essential parameter for understanding grape ripening as this tissue contains the key compounds for wine quality. It has been particularly difficult to extract proteins from skins for analysis by two-dimensional electrophoresis gels and, therefore, a protocol for this purpose has been adapted. The focus was on the evolution of the proteome profile of grape skin during maturation. Proteome maps obtained at three stages of ripening were compared to assess the extent to which protein distribution differs in grape skin during ripening. The comparative analysis shows that numerous soluble skin proteins evolve during ripening and reveal specific distributions at different stages. Proteins involved in photosynthesis, carbohydrate metabolisms, and stress response are identified as being over-expressed at the beginning of colour-change. The end of colour-change is characterized by the over-expression of proteins involved in anthocyanin synthesis and, at harvest, the dominant proteins are involved in defence mechanisms. In particular, increases in the abundance of different chitinase and beta-1,3-glucanase isoforms were found as the berry ripens. This observation can be correlated with the increase of the activities of both of these enzymes during skin ripening. The differences observed in proteome maps clearly show that significant metabolic changes occur in grape skin during this crucial phase of ripening. This comparative analysis provides more detailed characterization of the fruit ripening process. 相似文献
99.
Botia B Basille M Allais A Raoult E Falluel-Morel A Galas L Jolivel V Wurtz O Komuro H Fournier A Vaudry H Burel D Gonzalez BJ Vaudry D 《Peptides》2007,28(9):1746-1752
In the rodent cerebellum, PACAP is expressed by Purkinje neurons and PAC1 receptors are present on granule cells during both the development period and in adulthood. Treatment of granule neurons with PACAP inhibits proliferation, slows migration, promotes survival and induces differentiation. PACAP also protects cerebellar granule cells against the deleterious effects of neurotoxic agents. Most of the neurotrophic effects of PACAP are mediated through the cAMP/PKA signaling pathway and often involve the ERK MAPkinase. Caspase-3 is one of the key enzymes implicated in the neuroprotective action of PACAP but PACAP also inhibits caspase-9 activity and increases Bcl-2 expression. PACAP and functional PAC1 receptors are expressed in the monkey and human cerebellar cortex with a pattern of expression very similar to that described in rodents, suggesting that PACAP could also exert neurodevelopmental and neuroprotective functions in the cerebellum of primates including human. 相似文献
100.
HP1alpha guides neuronal fate by timing E2F-targeted genes silencing during terminal differentiation 总被引:3,自引:0,他引:3 下载免费PDF全文
Panteleeva I Boutillier S See V Spiller DG Rouaux C Almouzni G Bailly D Maison C Lai HC Loeffler JP Boutillier AL 《The EMBO journal》2007,26(15):3616-3628
A critical step of neuronal terminal differentiation is the permanent withdrawal from the cell cycle that requires the silencing of genes that drive mitosis. Here, we describe that the alpha isoform of the heterochromatin protein 1 (HP1) protein family exerts such silencing on several E2F-targeted genes. Among the different isoforms, HP1alpha levels progressively increase throughout differentiation and take over HP1gamma binding on E2F sites in mature neurons. When overexpressed, only HP1alpha is able to ensure a timed repression of E2F genes. Specific inhibition of HP1alpha expression drives neuronal progenitors either towards death or cell cycle progression, yet preventing the expression of the neuronal marker microtubule-associated protein 2. Furthermore, we provide evidence that this mechanism occurs in cerebellar granule neurons in vivo, during the postnatal development of the cerebellum. Finally, our results suggest that E2F-targeted genes are packaged into higher-order chromatin structures in mature neurons relative to neuroblasts, likely reflecting a transition from a 'repressed' versus 'silenced' status of these genes. Together, these data present new epigenetic regulations orchestrated by HP1 isoforms, critical for permanent cell cycle exit during neuronal differentiation. 相似文献