全文获取类型
收费全文 | 252篇 |
免费 | 21篇 |
专业分类
273篇 |
出版年
2024年 | 3篇 |
2023年 | 3篇 |
2022年 | 8篇 |
2021年 | 12篇 |
2020年 | 6篇 |
2019年 | 9篇 |
2018年 | 7篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 12篇 |
2014年 | 17篇 |
2013年 | 16篇 |
2012年 | 18篇 |
2011年 | 18篇 |
2010年 | 12篇 |
2009年 | 5篇 |
2008年 | 9篇 |
2007年 | 14篇 |
2006年 | 11篇 |
2005年 | 13篇 |
2004年 | 6篇 |
2003年 | 12篇 |
2002年 | 12篇 |
2001年 | 5篇 |
2000年 | 1篇 |
1997年 | 1篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1993年 | 5篇 |
1992年 | 1篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1977年 | 1篇 |
排序方式: 共有273条查询结果,搜索用时 0 毫秒
61.
62.
Gauthier JY Belley M Deschênes D Fournier JF Gagné S Gareau Y Hamel M Hénault M Hyjazie H Kargman S Lavallée G Levesque JF Li L Mamane Y Mancini J Morin N Mulrooney E Robichaud J Thérien M Tranmer G Wang Z Wu J Black WC 《Bioorganic & medicinal chemistry letters》2011,21(10):2836-2839
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY14 with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y14 with a good pharmacokinetic profile. 相似文献
63.
64.
65.
66.
Fabricating drug particles for therapeutic delivery and imaging presents important challenges in the design of the particle surfaces. Drug nanoparticle surfaces are currently functionalized with site-specific targeting ligands, biocompatible polymers, or fluorophore-polymer conjugates for specific imaging. However, if these functionalizations were to be synthesized on the drug carrier in localized, nanoscale regions on the particle surface, new schemes of drug delivery could be realized. Here we describe the use of our particle lithography technique that enables the synthesis of individual colloidal carrier assemblies that can be imaged and targeted to integrin-expressing cells. We show localized adhesion specificity for cells expressing the target integrin followed by receptor-mediated endocytosis. With the addition of localized delivery by adding drug nanoparticles to a specific region on the particle surface, our colloidal carrier assemblies have the potential to target, deliver therapeutic agents to, sense, and image diseased endothelium. 相似文献
67.
Mapmodulin/leucine-rich acidic nuclear protein binds the light chain of microtubule-associated protein 1B and modulates neuritogenesis 总被引:5,自引:0,他引:5
Opal P Garcia JJ Propst F Matilla A Orr HT Zoghbi HY 《The Journal of biological chemistry》2003,278(36):34691-34699
We had previously described the leucine-rich acidic nuclear protein (LANP) as a candidate mediator of toxicity in the polyglutamine disease, spinocerebellar ataxia type 1 (SCA1). This was based on the observation that LANP binds ataxin-1, the protein involved in this disease, in a glutamine repeat-dependent manner. Furthermore, LANP is expressed abundantly in purkinje cells, the primary site of ataxin-1 pathology. Here we focused our efforts on understanding the neuronal properties of LANP. In undifferentiated neuronal cells LANP is predominantly a nuclear protein, requiring a bona fide nuclear localization signal to be imported into the nucleus. LANP translocates from the nucleus to the cytoplasm during the process of neuritogenesis, interacts with the light chain of the microtubule-associated protein 1B (MAP1B), and modulates the effects of MAP1B on neurite extension. LANP thus could play a key role in neuronal development and/or neurodegeneration by its interactions with microtubule associated proteins. 相似文献
68.
X-chromosome inactivation patterns are unbalanced and affect the phenotypic outcome in a mouse model of rett syndrome 总被引:7,自引:0,他引:7 下载免费PDF全文
Rett syndrome (RTT), a neurodevelopmental disorder affecting mostly females, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Although the majority of girls with classic RTT have a random pattern of X-chromosome inactivation (XCI), nonbalanced patterns have been observed in patients carrying mutant MECP2 and, in some cases, account for variability of phenotypic manifestations. We have generated an RTT mouse model that recapitulates all major aspects of the human disease, but we found that females exhibit a high degree of phenotypic variability beyond what is observed in human patients with similar mutations. To evaluate whether XCI influences the phenotypic outcome of Mecp2 mutation in the mouse, we studied the pattern of XCI at the single-cell level in brains of heterozygous females. We found that XCI patterns were unbalanced, favoring expression of the wild-type allele, in most mutant females. It is notable that none of the animals had nonrandom XCI favoring the mutant allele. To explore why the XCI patterns favored expression of the wild-type allele, we studied primary neuronal cultures from Mecp2-mutant mice and found selective survival of neurons in which the wild-type X chromosome was active. Quantitative analysis indicated that fewer phenotypes are observed when a large percentage of neurons have the mutant X chromosome inactivated. The study of neuronal XCI patterns in a large number of female mice carrying a mutant Mecp2 allele highlights the importance of MeCP2 for neuronal viability. These findings also raise the possibility that there are human females who carry mutant MECP2 alleles but are not recognized because their phenotypes are subdued owing to favorable XCI patterns. 相似文献
69.
Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate-putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine-evoked c-fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c-fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA-containing neurons (Dyn-SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose-dependently decreased c-fos expression in Dyn-SP+ cells. When given in a novel environment, amphetamine induced c-fos mRNA in both Dyn-SP+ and preproenkephalin mRNA-containing neurons (Enk+ cells). In this condition, D1R and non-selective NMDAR antagonists dose-dependently decreased c-fos expression in Dyn-SP+ cells, but neither D2R nor NR2B-selective NMDAR antagonists had no effect. Furthermore, amphetamine-evoked c-fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c-fos expression only in these cells. Finally, novelty-stress also induced c-fos expression in both Dyn-SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c-fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn-SP+ vs. Enk+ cells), and environmental context (home vs. novel cage). 相似文献
70.
Huda MN Chen J Morita Y Kuroda T Mizushima T Tsuchiya T 《Microbiology and immunology》2003,47(6):419-427
We cloned a DNA fragment responsible for drug resistance from chromosome of Vibrio cholerae non-O1. Nucleotide sequence analysis of this fragment revealed the presence of a single open reading frame encoding a protein consisting of 445 amino acid residues. We designated the gene as vcrM. Hydropathy analysis of the deduced amino acid sequence of VcrM suggests the presence of 12 trans-membrane segments. A dendrogram showed that VcrM is a member of the DinF-subfamily within the MATE family of multidrug efflux pumps. Expression of the cloned vcrM gene in drug-hypersensitive Escherichia coli KAM32 cells made them resistant to acriflavine, 4', 6-diamidino-2-phenylindole, Hoechst 33342, rhodamine 6G, tetraphenylphosphonium chloride (TPPCl) and ethidium bromide. Efflux of acriflavine due to VcrM was dependent on Na+ or Li+. Moreover, Na+ efflux was observed with VcrM when TPPCl was added to Na+-loaded cells. Therefore, we conclude that VcrM is a Na+/drug antiporter-type multidrug efflux pump. 相似文献