全文获取类型
收费全文 | 1300篇 |
免费 | 98篇 |
国内免费 | 1篇 |
出版年
2023年 | 7篇 |
2022年 | 12篇 |
2021年 | 53篇 |
2020年 | 20篇 |
2019年 | 36篇 |
2018年 | 31篇 |
2017年 | 22篇 |
2016年 | 39篇 |
2015年 | 71篇 |
2014年 | 74篇 |
2013年 | 85篇 |
2012年 | 112篇 |
2011年 | 108篇 |
2010年 | 76篇 |
2009年 | 62篇 |
2008年 | 81篇 |
2007年 | 73篇 |
2006年 | 64篇 |
2005年 | 73篇 |
2004年 | 48篇 |
2003年 | 56篇 |
2002年 | 58篇 |
2001年 | 6篇 |
2000年 | 9篇 |
1999年 | 15篇 |
1998年 | 12篇 |
1997年 | 10篇 |
1996年 | 2篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 8篇 |
1992年 | 7篇 |
1991年 | 10篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 7篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1970年 | 1篇 |
1963年 | 1篇 |
1933年 | 1篇 |
排序方式: 共有1399条查询结果,搜索用时 31 毫秒
991.
Pablo Sánchez-Aguilera Alexis Diaz-Vegas Cristián Campos Oscar Quinteros-Waltemath Hugo Cerda-Kohler Genaro Barrientos Ariel Contreras-Ferrat Paola Llanos 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(12):1469-1477
The ATP-binding cassette transporter A1 (ABCA1) promotes cellular cholesterol efflux, leading to cholesterol binding to the extracellular lipid-free apolipoprotein A-I. ABCA1 regulates lipid content, glucose tolerance and insulin sensitivity in adipose tissue. In skeletal muscle, most GLUT4-mediated glucose transport occurs in the transverse tubule, a system composed by specialized cholesterol-enriched invaginations of the plasma membrane. We have reported that insulin resistant mice have higher cholesterol levels in transverse tubule from adult skeletal muscle. These high levels correlate with decreased GLUT4 trafficking and glucose uptake; however, the role of ABCA1 on skeletal muscle insulin-dependent glucose metabolism remains largely unexplored. Here, we evaluated the functional role of the ABCA1 on insulin-dependent signaling pathways, glucose uptake and cellular cholesterol content in adult skeletal muscle. Male mice were fed for 8?weeks with normal chow diet (NCD) or high fat diet (HFD). Compared to NCD-fed mice, ABCA1 mRNA levels and protein content were lower in muscle homogenates from HFD-fed mice. In Flexor digitorum brevis muscle from NCD-fed mice, shABCA1-RFP in vivo electroporation resulted in 65% reduction of ABCA1 protein content, 1.6-fold increased fiber cholesterol levels, 74% reduction in insulin-dependent Akt (Ser473) phosphorylation, total suppression of insulin-dependent GLUT4 translocation and decreased 2-NBDG uptake compared to fibers electroporated with the scrambled plasmid. Pre-incubation with methyl-β cyclodextrin reestablished both GLUT4 translocation and 2-NBDG transport. Based on the present results, we suggest that decreased ABCA1 contributes to the anomalous cholesterol accumulation and decreased glucose transport displayed by skeletal muscle membranes in the insulin resistant condition. 相似文献
992.
Melanie?Morris Ariel?Shaw Madison?Lambert Haley?Halperin?Perry Eve?Lowenstein David?Valenzuela Norma?Andrea?Velazquez-UlloaEmail authorView authors OrcID profile 《BMC developmental biology》2018,18(1):13
Background
Pregnant women may be exposed to nicotine if they smoke or use tobacco products, nicotine replacement therapy, or via e-cigarettes. Prenatal nicotine exposure has been shown to have deleterious effects on the nervous system in mammals including changes in brain size and in the dopaminergic system. The genetic and molecular mechanisms for these changes are not well understood. A Drosophila melanogaster model for these effects of nicotine exposure could contribute to faster identification of genes and molecular pathways underlying these effects. The purpose of this study was to determine if developmental nicotine exposure affects the nervous system of Drosophila melanogaster, focusing on changes to brain size and the dopaminergic system at two developmental stages.Results
We reared flies on control or nicotine food from egg to 3rd instar larvae or from egg to adult and determined effectiveness of the nicotine treatment. We used immunohistochemistry to visualize the whole brain and dopaminergic neurons, using tyrosine hydroxylase as the marker. We measured brain area, tyrosine hydroxylase fluorescence, and counted the number of dopaminergic neurons in brain clusters.We detected an increase in larval brain hemisphere area, a decrease in tyrosine hydroxylase fluorescence in adult central brains, and a decrease in the number of neurons in the PPM3 adult dopaminergic cluster. We tested involvement of Dα7, one of the nicotinic acetylcholine receptor subunits, and found it was involved in eclosion, as previously described, but not involved in brain size.Conclusions
We conclude that developmental nicotine exposure in Drosophila melanogaster affects brain size and the dopaminergic system. Prenatal nicotine exposure in mammals has also been shown to have effects on brain size and in the dopaminergic system. This study further establishes Drosophila melanogaster as model organism to study the effects of developmental nicotine exposure. The genetic and molecular tools available for Drosophila research will allow elucidation of the mechanisms underlying the effects of nicotine exposure during development.993.
Gustavo D. Campagnaro Janaína de Freitas Nascimento Richard B.M. Girard Ariel M. Silber Harry P. de Koning 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(12):2750-2763
Background
Trypanosoma cruzi, the causative agent of Chagas' disease is unable to synthesise its own purines and relies on salvage from the host. In other protozoa, purine uptake has been shown to be mediated by Equilibrative Nucleoside Transporters (ENTs).Methods
To investigate the functionality of T. cruzi-encoded ENT transporters, its four putative ENT genes (TcrNB1, TcrNB2, TcrNT1 and TcrNT2) were cloned and expressed in genetically adapted Trypanosoma brucei procyclic cells from which the nucleobase transporter locus was deleted.Results
TcrNB1 displayed very high affinity for hypoxanthine (Km 93.8?±?4.7?nM for) and guanine, and moderate affinity for adenine. TcrNT1 was found to be a high-affinity guanosine/inosine transporter (inosine Km is 1.0?±?0.03?μM; guanosine Ki is 0.92?±?0.2?μM). TcrNT2 encoded a high-affinity thymidine transporter (Km?=?223.5?±?7.1?nM) with a clear preference for 2’-deoxypyrimidines. TcrNB2, whose activity could not be determined in our system, could be a low-affinity purine nucleobase transporter, given its sequence and predicted structural similarities to Leishmania major NT4. All 4 transporter genes were highly expressed in the amastigote forms, with much lower expression in the non-dividing stages.Conclusions
The data appear to show that, surprisingly, T. cruzi has a preference for oxopurines over aminopurines and efficiently transports 2′-deoxypyrimidines. The T. cruzi ENTs display exceptionally high substrate affinity as an adaptation to their intracellular localisation.General significance
This study reports the first cloning of T. cruzi purine and pyrimidine transporters, including the first gene encoding a pyrimidine-selective protozoan transporter. 相似文献994.
Chester Meyers Akira Arimura Ariel Gordin R. Fernandez-Durango David H. Coy Andrew V. Schally Jacques Drouin Louise Ferland Michele Beaulieu Fernand Labrie 《Biochemical and biophysical research communications》1977,74(2):630-636
Three analogs of somatostatin, [-Cys14] -, [Ala2, -Cys14] - and [-Trp8, -Cys14] - somatostatin, were synthesized by the solid phase method, characterized by several means, and tested for their effects on the release of insulin, glucagon, and growth hormone. The peptides sharply suppressed the release of growth hormone and glucagon , but had less effect on insulin secretion . These analogs, particularly [-Trp8, -Cys14] - somatostatin, could possibly be useful for the treatment of diabetes mellitus. 相似文献
995.
996.
Ovulation is a complex process initiated by the surge of the pituitary luteinizing hormone (LH) that provokes the expression of specific genes. We report herein the isolation and characterization of an ovulation-associated, ovary-specific novel isoform of epoxide hydrolase 2 (Ephx2), Ephx2C. This variant is exclusively expressed in the granulosa cells of preovulatory mouse ovarian follicles. The LH-induced expression of Ephx2C is mediated by the protein kinase A and partially by the protein kinase C signaling pathways. The involvement of p38 kinase has also been demonstrated. 相似文献
997.
In recent years in silico analysis of common laboratory mice has been introduced and subsequently applied, in slightly different ways, as a methodology for gene mapping. Previously we have demonstrated some limitation of the methodology due to sporadic genetic correlations across the genome. Here, we revisit the three main aspects that affect in silico analysis. First, we report on the use of marker maps: we compared our existing 20,000 SNP map to the newly released 140,000 SNP map. Second, we investigated the effect of varying strain numbers on power to map QTL. Third, we introduced a novel statistical approach: a cladistic analysis, which is well suited for mouse genetics and has increased flexibility over existing in silico approaches. We have found that in our examples of complex traits, in silico analysis by itself does fail to uniquely identify quantitative trait gene (QTG)-containing regions. However, when combined with additional information, it may significantly help to prioritize candidate genes. We therefore recommend using an integrated work flow that uses other genomic information such as linkage regions, regions of shared ancestry, and gene expression information to obtain a list of candidate genes from the genome. 相似文献
998.
Johnson S Roversi P Espina M Olive A Deane JE Birket S Field T Picking WD Blocker AJ Galyov EE Picking WL Lea SM 《The Journal of biological chemistry》2007,282(6):4035-4044
Bacteria expressing type III secretion systems (T3SS) have been responsible for the deaths of millions worldwide, acting as key virulence elements in diseases ranging from plague to typhoid fever. The T3SS is composed of a basal body, which traverses both bacterial membranes, and an external needle through which effector proteins are secreted. We report multiple crystal structures of two proteins that sit at the tip of the needle and are essential for virulence: IpaD from Shigella flexneri and BipD from Burkholderia pseudomallei. The structures reveal that the N-terminal domains of the molecules are intramolecular chaperones that prevent premature oligomerization, as well as sharing structural homology with proteins involved in eukaryotic actin rearrangement. Crystal packing has allowed us to construct a model for the tip complex that is supported by mutations designed using the structure. 相似文献
999.
Milgrom C Radeva-Petrova DR Finestone A Nyska M Mendelson S Benjuya N Simkin A Burr D 《Journal of biomechanics》2007,40(4):845-850
Stress fracture is a common musculoskeletal problem affecting athletes and soldiers. Repetitive high bone strains and strain rates are considered to be its etiology. The strain level necessary to cause fatigue failure of bone ex vivo is higher than the strains recorded in humans during vigorous physical activity. We hypothesized that during fatiguing exercises, bone strains may increase and reach levels exceeding those measured in the non-fatigued state. To test this hypothesis, we measured in vivo tibial strains, the maximum gastrocnemius isokinetic torque and ground reaction forces in four subjects before and after two fatiguing levels of exercise: a 2km run and a 30km desert march. Strains were measured using strain-gauged staples inserted percutaneously in the medial aspect of their mid-tibial diaphysis. There was a decrease in the peak gastrocnemius isokinetic torque of all four subjects' post-march as compared to pre-run (p=0.0001), indicating the presence of gastrocnemius muscle fatigue. Tension strains increased 26% post-run (p=0.002, 95 % confidence interval (CI) and 29% post-march (p=0.0002, 95% CI) as compared to the pre-run phase. Tension strain rates increased 13% post-run (p=0.001, 95% CI) and 11% post-march (p=0.009, 95% CI) and the compression strain rates increased 9% post-run (p=0.0004, 95% CI) and 17% post-march (p=0.0001, 95% CI). The fatigue state increases bone strains well above those recorded in rested individuals and may be a major factor in the stress fracture etiology. 相似文献
1000.
Van-Ham II Banihashemi B Wilson AM Jacobsen KX Czesak M Albert PR 《Journal of neurochemistry》2007,102(6):1796-1804
Although they have distinct functions, the signaling of dopamine-D(2) receptor short and long isoforms (D(2)S and D(2)L) is virtually identical. We compared inhibitory regulation of extracellular signal-regulated kinases (ERK1/2) in GH4 pituitary cells separately transfected with these isoforms. Activation of rat or human dopamine-D(2)S, muscarinic or somatostatin receptors inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation, while the D(2)L receptor failed to inhibit this response. In order to address the structural basis for the differential signaling of D(2)S and D(2)L receptors, we examined the D(2)L-SS mutant, in which a protein kinase C (PKC) pseudosubstrate site that is present in the D(2)L but not D(2)S receptor was converted to a consensus PKC site. In transfected GH4 cells, the D(2)L-SS mutant inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation almost as strongly as the D(2)S receptor. A D(2)S-triple mutant that eliminates PKC sites involved in D(2)S receptor desensitization also inhibited ERK1/2 activation. Similarly, in striatal cultures, the D(2)-selective agonist quinpirole inhibited potassium-stimulated ERK1/2 phosphorylation, indicating the presence of this pathway in neurons. In conclusion, the D(2)S and D(2)L receptors differ in inhibitory signaling to ERK1/2 due to specific residues in the D(2)L receptor alternatively spliced domain, which may account for differences in their function in vivo. 相似文献