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41.
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo 总被引:73,自引:0,他引:73
Walsh DM Klyubin I Fadeeva JV Cullen WK Anwyl R Wolfe MS Rowan MJ Selkoe DJ 《Nature》2002,416(6880):535-539
Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically. 相似文献
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Mutation rates differ among regions of the mammalian genome 总被引:91,自引:0,他引:91
In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock. 相似文献
44.
The magnetic field pervading our Galaxy is a crucial constituent of the interstellar medium: it mediates the dynamics of interstellar clouds, the energy density of cosmic rays, and the formation of stars. The field associated with ionized interstellar gas has been determined through observations of pulsars in our Galaxy. Radio-frequency measurements of pulse dispersion and the rotation of the plane of linear polarization, that is, Faraday rotation, yield an average value for the magnetic field of B approximately 3 microG (ref. 2). The possible detection of Faraday rotation of linearly polarized photons emitted by high-redshift quasars suggests similar magnetic fields are present in foreground galaxies with redshifts z > 1. As Faraday rotation alone, however, determines neither the magnitude nor the redshift of the magnetic field, the strength of galactic magnetic fields at redshifts z > 0 remains uncertain. Here we report a measurement of a magnetic field of B approximately 84 microG in a galaxy at z = 0.692, using the same Zeeman-splitting technique that revealed an average value of B = 6 microG in the neutral interstellar gas of our Galaxy. This is unexpected, as the leading theory of magnetic field generation, the mean-field dynamo model, predicts large-scale magnetic fields to be weaker in the past rather than stronger. 相似文献
45.
解体好氧颗粒污泥修复 总被引:3,自引:0,他引:3
考察了加入新的活性污泥使解体好氧颗粒污泥完成修复的可行性.解体好氧颗粒污泥对新加入的活性污泥进行吸附,在各种选择压力特别是水力剪切力作用下和原有颗粒污泥形成一个有机整体.大约3周时间,解体颗粒污泥被完全修复.扫描电镜观察发现,被修复后的颗粒污泥呈现非常规则的结构,微生物相十分致密.在解体颗粒污泥逐渐被修复的过程中,颗粒平均粒径仅从最初的2.8mm增至2.9mm,说明活性污泥在颗粒污泥上的附着主要发生在颗粒的空穴.而颗粒污泥的沉降性能和强度都得到了极大的改善,颗粒沉降速率和完整性系数分别由最初的72m/h和56.8%提高到110m/h和65.8%.新加入的活性污泥除了部分用于修复解体颗粒污泥,其余在选择压力等的作用下形成了新的好氧颗粒污泥. 相似文献
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Spillane C Schmid KJ Laoueillé-Duprat S Pien S Escobar-Restrepo JM Baroux C Gagliardini V Page DR Wolfe KH Grossniklaus U 《Nature》2007,448(7151):349-352
In mammals and seed plants, a subset of genes is regulated by genomic imprinting where an allele's activity depends on its parental origin. The parental conflict theory suggests that genomic imprinting evolved after the emergence of an embryo-nourishing tissue (placenta and endosperm), resulting in an intragenomic parental conflict over the allocation of nutrients from mother to offspring. It was predicted that imprinted genes, which arose through antagonistic co-evolution driven by a parental conflict, should be subject to positive darwinian selection. Here we show that the imprinted plant gene MEDEA (MEA), which is essential for seed development, originated during a whole-genome duplication 35 to 85 million years ago. After duplication, MEA underwent positive darwinian selection consistent with neo-functionalization and the parental conflict theory. MEA continues to evolve rapidly in the out-crossing species Arabidopsis lyrata but not in the self-fertilizing species Arabidopsis thaliana, where parental conflicts are reduced. The paralogue of MEA, SWINGER (SWN; also called EZA1), is not imprinted and evolved under strong purifying selection because it probably retained the ancestral function of the common precursor gene. The evolution of MEA suggests a late origin of genomic imprinting within the Brassicaceae, whereas imprinting is thought to have originated early within the mammalian lineage. 相似文献
49.
Mavrakis KJ Van Der Meulen J Wolfe AL Liu X Mets E Taghon T Khan AA Setty M Setti M Rondou P Vandenberghe P Delabesse E Benoit Y Socci NB Leslie CS Van Vlierberghe P Speleman F Wendel HG 《Nature genetics》2011,43(7):673-678
The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer. 相似文献
50.
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity 总被引:57,自引:0,他引:57
Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 --> TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease. 相似文献