全文获取类型
收费全文 | 149篇 |
免费 | 5篇 |
国内免费 | 5篇 |
专业分类
儿科学 | 1篇 |
妇产科学 | 2篇 |
基础医学 | 53篇 |
临床医学 | 2篇 |
内科学 | 34篇 |
皮肤病学 | 2篇 |
神经病学 | 8篇 |
特种医学 | 1篇 |
综合类 | 5篇 |
预防医学 | 8篇 |
眼科学 | 5篇 |
药学 | 21篇 |
中国医学 | 2篇 |
肿瘤学 | 15篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 7篇 |
2019年 | 1篇 |
2018年 | 7篇 |
2017年 | 2篇 |
2016年 | 3篇 |
2015年 | 9篇 |
2014年 | 9篇 |
2013年 | 18篇 |
2012年 | 8篇 |
2011年 | 13篇 |
2010年 | 11篇 |
2009年 | 18篇 |
2008年 | 10篇 |
2007年 | 6篇 |
2006年 | 8篇 |
2005年 | 6篇 |
2004年 | 6篇 |
2003年 | 7篇 |
2002年 | 4篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1997年 | 1篇 |
排序方式: 共有159条查询结果,搜索用时 15 毫秒
1.
2.
In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals.The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis.We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine. 相似文献
3.
4.
Steve Rockman Dorit Becher Allison Dyson Sandra Koernig Adriana Baz Morelli Megan Barnden Sarina Camuglia Peter Soupourmas Martin Pearse Eugene Maraskovsky 《Vaccine》2014
In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years. 相似文献
5.
6.
7.
8.
Hyun Yang 《Biochemical pharmacology》2009,77(6):1105-1115
Ribotoxic stress responses lead to the expression of genes important for cellular homeostasis by modulating cell survival, proliferation and differentiation. ATF3 was investigated for its modulation of the epithelial cellular integrity in response to mucosal ribotoxic stress. ATF3 expression was up-regulated by chemical agents causing ribotoxic stress such as deoxynivalenol and anisomycin in different types of intestinal epithelial cells. Moreover, reduction of ATF3 gene expression promoted ribotoxic stress-triggered programmed cell death, implicating a protective role of ATF3 in epithelial cell survival. Mechanistically, stabilization of ATF3 messenger RNA and protein played a critical role in maintaining enhanced levels of ATF3 production in response to the ribotoxic chemical agent. For ATF3 mRNA stability, p38 specific inhibitor SB203580 was the most efficient agent for suppression, suggesting the involvement of the p38 MAP kinase in ATF3 mRNA stabilization. In addition, the p38 MAP kinase as well as its downstream mediator glycogen synthase kinase 3β (GSK3β) was involved in ATF3 protein stabilization caused by chemical ribotoxic stress in human epithelial cells. As another separate signaling cascade, double-stranded RNA (dsRNA)-activated protein kinase (PKR) was demonstrated to translationally modulate ATF3 expression and contribute to the epithelial cell survival. PKR interference caused cells to be more susceptible to cell death caused by the chemical ribotoxic stress. The results of this study showed that enhanced ATF3 production was associated with cellular defenses by maintaining the epithelial survival after ribotoxic mucosal insults. 相似文献
9.
Takashi Shimoike Sean A. McKenna Darrin A. Lindhout Joseph D. Puglisi 《Antiviral research》2009,83(3):228-237
Translation of hepatitis C virus (HCV) is initiated at an internal ribosome entry site (IRES) located at the 5′end of its RNA genome. The HCV IRES is highly structured and greater than 50% of its nucleotides form based-paired helices. We report here that the HCV IRES is an activator of PKR, an interferon-induced enzyme that participates in host cell defense against viral infection. Binding of HCV IRES RNA to PKR leads to a greatly increased (20-fold) rate and level (4.5-fold) of PKR autophosphorylation compared to previously studied dsRNA activators. We have mapped the domains in the IRES required for PKR activation to domains III–IV and demonstrate that the N-terminal double-stranded RNA binding domains of PKR bind to the IRES in a similar manner to other RNA activators. Addition of HCV IRES RNA inhibits cap-dependent translation in lysates via phosphorylation of PKR and eIF2α. However, HCV IRES-mediated translation is not inhibited by the phosphorylation of PKR and eIF2α. The results presented here suggest that hydrolysis of GTP by eIF2 is not an essential step in IRES-mediated translation. Thus, HCV can use structured RNAs to its advantage in translation, while avoiding the deleterious effects of PKR activation. 相似文献
10.
目的研究siRNA(small interfering RNA,siRNA)对宫颈癌Hela细胞中双链RNA(dsRNA)激活的蛋白激酶(protein kinase regulated by dsRNA,PKR)基因的抑制作用,观察其对dsRNA诱导的细胞凋亡的影响。方法采用RNAi技术,对宫颈癌Hela细胞PKR基因进行特异性抑制;用阳离子脂质体与化学合成的Pre-designed anti-PKR siRNA构建转染复合体,反转染Hela细胞72h后提取总蛋白,用Western blot检测PKR蛋白表达水平的变化,用流式细胞仪检测细胞的凋亡率,激酶活性检测法测定半胱氨蛋白水解酶-3(caspase-3)活性变化。结果 siRNA能降低PKR基因的蛋白表达;未转染组的Hela细胞在加入dsRNA后,细胞凋亡明显增加,caspase-3激酶活性增强(P〈0.05)。与对照组相比,转染组的Hela细胞在加入dsRNA后,细胞凋亡显著减少,caspase-3激酶活性降低(P〈0.05)。结论 siRNA可特异有效地干扰宫颈癌Hela细胞内PKR基因的表达,从而影响肿瘤细胞凋亡。dsRNA可通过激活PKR,增强caspase-3激酶活性,而促进Hela细胞的凋亡。 相似文献