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排序方式: 共有355条查询结果,搜索用时 171 毫秒
171.
Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease 总被引:3,自引:0,他引:3
Recent studies of postmortem brains from Alzheimer's disease (AD) patients and transgenic mouse models of AD suggest that oxidative damage, induced by amyloid beta (Abeta), is associated with mitochondria early in AD progression. Abeta and amyloid-precursor protein are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron-transport chain, increase reactive oxygen species production, cause mitochondrial damage and prevent neurons from functioning normally. Furthermore, accumulation of Abeta at synaptic terminals might contribute to synaptic damage and cognitive decline in patients with AD. Here, we describe recent studies regarding the roles of Abeta and mitochondrial function in AD progression and particularly in synaptic damage and cognitive decline. 相似文献
172.
The RNA-dependent protein kinase (PKR) is regulated by the binding of double-stranded RNA (dsRNA) or single-stranded RNAs with extensive duplex secondary structure. PKR has an RNA binding domain (RBD) composed of two copies of the dsRNA binding motif (dsRBM). The dsRBM is an alpha-beta-beta-beta-alpha structure present in a number of proteins that bind RNA, and the selectivity demonstrated by these proteins is currently not well understood. We have used affinity cleavage to study the binding of PKR's RBD to RNA. In this study, we site-specifically modified the first dsRBM of PKR's RBD at two different amino acid positions with the hydroxyl radical generator EDTA.Fe. Cleavage by these proteins of a synthetic stem-loop ligand of PKR indicates that PKR's dsRBMI binds the RNA in a preferred orientation, placing the loop between strands beta1 and beta2 near the single-stranded RNA loop. Additional cleavage experiments demonstrated that defects in the RNA stem, such as an A bulge and two GA mismatches, do not dictate dsRBMI's binding orientation preference. Cleavage of VA(I) RNA, an adenoviral RNA inhibitor of PKR, indicates that dsRBMI is bound near the loop of the apical stem of this RNA in the same orientation as observed with the synthetic stem-loop RNA ligands. This work, along with an NMR study of the binding of a dsRBM derived from the Drosophila protein Staufen, indicates that dsRBMs can bind stem-loop RNAs in distinct ways. In addition, the successful application of the affinity cleavage technique to localizing dsRBMI of PKR on stem-loop RNAs and defining its orientation suggests this approach could be applied to dsRBMs found in other proteins. 相似文献
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174.
Barberi T Klivenyi P Calingasan NY Lee H Kawamata H Loonam K Perrier AL Bruses J Rubio ME Topf N Tabar V Harrison NL Beal MF Moore MA Studer L 《Nature biotechnology》2003,21(10):1200-1207
Existing protocols for the neural differentiation of mouse embryonic stem (ES) cells require extended in vitro culture, yield variable differentiation results or are limited to the generation of selected neural subtypes. Here we provide a set of coculture conditions that allows rapid and efficient derivation of most central nervous system phenotypes. The fate of both fertilization- and nuclear transfer-derived ES (ntES) cells was directed selectively into neural stem cells, astrocytes, oligodendrocytes or neurons. Specific differentiation into gamma-aminobutyric acid (GABA), dopamine, serotonin or motor neurons was achieved by defining conditions to induce forebrain, midbrain, hindbrain and spinal cord identity. Neuronal function of ES cell-derived dopaminergic neurons was shown in vitro by electron microscopy, measurement of neurotransmitter release and intracellular recording. Furthermore, transplantation of ES and ntES cell-derived dopaminergic neurons corrected the phenotype of a mouse model of Parkinson disease, demonstrating an in vivo application of therapeutic cloning in neural disease. 相似文献
175.
Burchmore RJ Wallace LJ Candlish D Al-Salabi MI Beal PR Barrett MP Baldwin SA de Koning HP 《The Journal of biological chemistry》2003,278(26):23502-23507
While multiple nucleoside transporters, some of which can also transport nucleobases, have been cloned in recent years from many different organisms, no sequence information is available for the high affinity, nucleobase-selective transporters of metazoa, parazoa, or protozoa. We have identified a gene, TbNBT1, from Trypanosoma brucei brucei that encodes a 435-residue protein of the equilibrative nucleoside transporter superfamily. The gene was expressed in both the procyclic and bloodstream forms of the organism. Expression of TbNBT1 in a Saccharomyces cerevisiae strain lacking an endogenous purine transporter allowed growth on adenine as sole purine source and introduced a high affinity transport activity for adenine and hypoxanthine, with Km values of 2.1 +/- 0.6 and 0.66 +/- 0.22 microm, respectively, as well as high affinity for xanthine, guanine, guanosine, and allopurinol and moderate affinity for inosine. A transporter with an indistinguishable kinetic profile was identified in T. b. brucei procyclics and designated H4. RNA interference of TbNBT1 in procyclics reduced cognate mRNA levels by approximately 80% and H4 transport activity by approximately 90%. Expression of TbNBT1 in Xenopus oocytes further confirmed that this gene encodes the first high affinity nucleobase transporter from protozoa or animals to be identified at the molecular level. 相似文献
176.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a "double PCR and digestion" technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords. 相似文献
177.
Beal AM 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2002,172(5):399-407
Intracarotid infusions of l-phenylephrine at 1.0 nmol.kg(-1).min(-1) or(.)10 nmol.kg(-1).min(-1) were accompanied by increases in salivary protein, urea, magnesium and bicarbonate, and by decreases in osmolality, hydrogen ion activity, sodium, potassium and chloride relative to cholinergically stimulated saliva. Intravenous infusions of phenylephrine at the same dose rates had much less effect on salivary composition with the differences between the routes of administration being greatest for the higher dose rate. Propranolol administered with phenylephrine via the carotid artery, at an antagonist:agonist ratio of 10:1, was much more effective in blocking the phenylephrine-induced changes in salivary composition than equimolar infusion of phentolamine with phenylephrine. Simultaneous intracarotid infusions of either a beta(1)-antagonist (CGP20712A) or a beta(2)-antagonist (ICI118551) with phenylephrine showed that ICI118551 was more potent than CGP20712A at preventing the changes in salivary composition associated with phenylephrine administration. It was concluded that alpha(1)-adrenoreceptors were not present in functionally significant numbers in the gland and that the effect of phenylephrine on the kangaroo mandibular was mediated by beta-adrenoreceptors predominantly of the beta(2)-subtype. As the phenylephrine dose rates in the kangaroos were comparable with those used to determine alpha-adrenergic responses of eutherian salivary glands and as both propranolol and phentolamine appeared to have minor beta-sympathomimetic activity, at least one subtype of beta-adrenoreceptors in macropods may not be identical to its eutherian counterpart. 相似文献
178.
The binding site of the RNA-dependent protein kinase (PKR) on EBER1 RNA from Epstein-Barr virus
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The RNA-dependent protein kinase (PKR) is an interferon-induced, RNA-activated enzyme that phosphorylates the eukaryotic initiation factor 2α, rendering the translation machinery inactive. Viruses have developed strategies for preventing the action of PKR, one of which is the production of small RNAs that inhibit the enzyme. Epstein–Barr virus (EBV) encodes EBER1, a 167 nucleotide non-coding RNA that is constitutively expressed by the EBV-infected cells. EBER1 binds PKR in vitro and has been shown to prevent inhibition of translation by PKR in vitro. We used affinity cleavage by the EDTA·Fe-modified double-stranded RNA-binding domain (dsRBD) of PKR to show that stem–loop IV (nucleotides 87–123) of EBER1 makes specific contacts with the dsRBD. To further demonstrate the specificity of this interaction, we generated a deletion mutant of EBER1, comprising only stem–loop IV (mEBER1). Cleavage patterns produced on mEBER1 by the bound dsRBD were remarkably similar to those found on full-length EBER1. Using cleavage data from two different dsRBD mutants, we present a model of the interaction of PKR dsRBD and mEBER1. 相似文献
179.
Triantafyllou MS Techet AH Zhu Q Beal DN Hover FS Yue DK 《Integrative and comparative biology》2002,42(5):1026-1031
Vorticity control is employed by marine animals to enhance performancein maneuvering and propulsion. Studies on fish-like robots andexperimental apparatus modelling rigid and flexible fins providesome of the basic mechanisms employed for controlling vorticity. 相似文献
180.
Vives-Bauza C Andreu AL Manfredi G Beal MF Janetzky B Gruenewald TH Lin MT 《Biochemical and biophysical research communications》2002,290(5):1593-1601
The pathogenesis of Parkinson's disease (PD) is largely unknown. Indirect evidence suggests that mutations in mitochondrial DNA (mtDNA) might play a role, but previous studies have not consistently associated any specific mutations with PD. However, these studies have generally been confined to limited areas of the mitochondrial genome. We therefore sequenced the entire mitochondrial genome from substantia nigra of 8 PD and 9 control subjects. Several sequence variants were distributed differently between PD and control subjects, but all were previously reported polymorphisms. Several secondary LHON mutations were found, as well as a number of novel missense mutations, but all were rare and did not differ between PD and control subjects. Finally, PD and control subjects did not differ in the total number of all mutations, nor the total number of missense mutations. Thus, mtDNA involvement in PD, if any, is likely to be complex and should be reconsidered carefully. 相似文献