全文获取类型
收费全文 | 140篇 |
免费 | 5篇 |
出版年
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 6篇 |
2019年 | 6篇 |
2018年 | 1篇 |
2017年 | 1篇 |
2016年 | 4篇 |
2015年 | 8篇 |
2014年 | 8篇 |
2013年 | 11篇 |
2012年 | 4篇 |
2011年 | 13篇 |
2010年 | 15篇 |
2009年 | 9篇 |
2008年 | 9篇 |
2007年 | 6篇 |
2006年 | 3篇 |
2005年 | 3篇 |
2004年 | 6篇 |
2003年 | 2篇 |
2002年 | 1篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1989年 | 1篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1978年 | 1篇 |
排序方式: 共有145条查询结果,搜索用时 31 毫秒
61.
Background
Animal models of human diseases are essential as they allow analysis of the disease process at the cellular level and can advance therapeutics by serving as a tool for drug screening and target validation. Here we report the development of a complete genetic model of spinal muscular atrophy (SMA) in the vertebrate zebrafish to complement existing zebrafish, mouse, and invertebrate models and show its utility for testing compounds that alter SMN2 splicing.Results
The human motoneuron disease SMA is caused by low levels, as opposed to a complete absence, of the survival motor neuron protein (SMN). To generate a true model of SMA in zebrafish, we have generated a transgenic zebrafish expressing the human SMN2 gene (hSMN2), which produces only a low amount of full-length SMN, and crossed this onto the smn -/- background. We show that human SMN2 is spliced in zebrafish as it is in humans and makes low levels of SMN protein. Moreover, we show that an antisense oligonucleotide that enhances correct hSMN2 splicing increases full-length hSMN RNA in this model. When we placed this transgene on the smn mutant background it rescued the neuromuscular presynaptic SV2 defect that occurs in smn mutants and increased their survival.Conclusions
We have generated a transgenic fish carrying the human hSMN2 gene. This gene is spliced in fish as it is in humans and mice suggesting a conserved splicing mechanism in these vertebrates. Moreover, antisense targeting of an intronic splicing silencer site increased the amount of full length SMN generated from this transgene. Having this transgene on the smn mutant fish rescued the presynaptic defect and increased survival. This model of zebrafish SMA has all of the components of human SMA and can thus be used to understand motoneuron dysfunction in SMA, can be used as an vivo test for drugs or antisense approaches that increase full-length SMN, and can be developed for drug screening. 相似文献62.
Lalitha Venkatramani Eric S Johnson Gundurao Kolavi Gillian M Air Wayne J Brouillette Blaine HM Mooers 《BMC structural biology》2012,12(1):1-11
Background
The quaternary structure of eukaryotic NADH:ubiquinone oxidoreductase (complex I), the largest complex of the oxidative phosphorylation, is still mostly unresolved. Furthermore, it is unknown where transiently bound assembly factors interact with complex I. We therefore asked whether the evolution of complex I contains information about its 3D topology and the binding positions of its assembly factors. We approached these questions by correlating the evolutionary rates of eukaryotic complex I subunits using the mirror-tree method and mapping the results into a 3D representation by multidimensional scaling.Results
More than 60% of the evolutionary correlation among the conserved seven subunits of the complex I matrix arm can be explained by the physical distance between the subunits. The three-dimensional evolutionary model of the eukaryotic conserved matrix arm has a striking similarity to the matrix arm quaternary structure in the bacterium Thermus thermophilus (rmsd=19 ?) and supports the previous finding that in eukaryotes the N-module is turned relative to the Q-module when compared to bacteria. By contrast, the evolutionary rates contained little information about the structure of the membrane arm. A large evolutionary model of 45 subunits and assembly factors allows to predict subunit positions and interactions (rmsd = 52.6 ?). The model supports an interaction of NDUFAF3, C8orf38 and C2orf56 during the assembly of the proximal matrix arm and the membrane arm. The model further suggests a tight relationship between the assembly factor NUBPL and NDUFA2, which both have been linked to iron-sulfur cluster assembly, as well as between NDUFA12 and its paralog, the assembly factor NDUFAF2.Conclusions
The physical distance between subunits of complex I is a major correlate of the rate of protein evolution in the complex I matrix arm and is sufficient to infer parts of the complex??s structure with high accuracy. The resulting evolutionary model predicts the positions of a number of subunits and assembly factors. 相似文献63.
Ischemia–reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of
cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been
clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced
apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia),
and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared
with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases
(AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min),
and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic
Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared
with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced
caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was
more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion,
single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced
apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation
procedures. 相似文献
64.
65.
66.
67.
Two wheat (Triticum aestivum L.) cultivars, Sids 1 and Giza 168, were grown under non-saline or saline conditions (4.7 and 9.4 dS m?1) and were sprayed with 0.00, 0.05 and 0.10 mg l?1 24-epibrassinolide (EBL). Salt stress markedly decreased plant productivity and N, P, and K uptake, particularly in Giza 168. A follow-up treatment with 0.1 mg l?1 EBL detoxified the stress generated by salinity and considerably improved the above parameters, especially in Sids 1. Organic solutes (soluble sugars, free amino acids, proline and glycinebetaine), antioxidative enzymes (superoxide dismutase, peroxidase, catalase and glutathione reductase), antioxidant molecules (glutathione and ascorbate) and Ca and Mg levels were increased under saline condition, and these increases proved to be more significant in salt-stressed plants sprayed with EBL, particularly at 0.1 mg l?1 EBL with Sids 1. Sodium concentration, lipid peroxidation, hydrogen peroxide content and electrolyte leakage were increased under salt stress and significantly decreased when 0.1 mg l?1 EBL was sprayed. Clearly, EBL alleviates salt-induced inhibition of productivity by altering the physiological and biochemical properties of the plant. 相似文献
68.
69.
70.
Nick A Guldemond Pieter Leffers Geert HIM Walenkamp Nicolaas C Schaper Antal P Sanders Fred HM Nieman Lodewijk W van Rhijn 《BMC endocrine disorders》2008,8(1):1-14