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David R. Brown

Bio: David R. Brown is an academic researcher from University of Bath. The author has contributed to research in topics: Catalysis & Scrapie. The author has an hindex of 75, co-authored 451 publications receiving 20062 citations. Previous affiliations of David R. Brown include University of Göttingen & Illinois State University.


Papers
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Journal ArticleDOI
18 Dec 1997-Nature
TL;DR: Findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo, and that its amino terminus contains the octapeptide PHGGGWGQ, which is among the best-preserved regions of mammalian PrPC.
Abstract: The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. Here we show that the amino-terminal domain of PrPC exhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. At neutral pH, binding occurs with positive cooperativity, with binding affinity compatible with estimates for extracellular, labile copper. Two lines of independently derived PrPC gene-ablated (Prnp0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions. Prnp0/0 mice also have altered cellular phenotypes, including a reduction in the activity of copper/zinc superoxide dismutase and altered electrophysiological responses in the presence of excess copper. These findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo.

1,292 citations

Journal ArticleDOI
TL;DR: It is shown that mouse prion protein either as recombinant protein or immunoprecipitated from brain tissue has superoxide dismutase (SOD) activity and a direct role in cellular resistance to oxidative stress is suggested.
Abstract: We show here that mouse prion protein (PrP(C)) either as recombinant protein or immunoprecipitated from brain tissue has superoxide dismutase (SOD) activity. SOD activity was also associated with recombinant chicken PrP(C) confirming the evolutionary conserved phenotype suggested by sequence similarity. Acquisition of copper by PrP(C) during protein folding endowed SOD activity on the protein but the addition of copper following refolding did not. PrP(C) dependent SOD activity was abolished by deletion of the octapeptide-repeat region involved in copper binding. These results describe an enzymic function for PrP(C) consistent with its cellular distribution and suggest it has a direct role in cellular resistance to oxidative stress.

570 citations

Journal ArticleDOI
TL;DR: Data from ten European countries show a striking increase and unusual seasonal pattern of norovirus gastroenteritis in 2002 that occurred concurrently with the emergence of a novel genetic variant, raising questions about the biological properties of the variant and the mechanisms for its rapid dissemination.

521 citations

Journal ArticleDOI
28 Mar 1996-Nature
TL;DR: The combined direct and microglia-mediated effects of PrP106–126 are toxic to normal neurons but are insufficient to destroy neurons from mice not expressing PrPc.
Abstract: THE prion protein PrPc is a glycoprotein of unknown function1 normally found in neurons2 and glia3. It is involved in diseases such as bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt–Jakob disease4. PrPSc, an altered isoform of PrPc that is associated with disease, shows greater protease resistance and is part of the infectious agent, the prion5,6. Prion diseases are characterized by neuronal degeneration, gliosis and accumulation of PrPSc (ref. 7). Mice devoid of PrPc are resistant to scrapie8. A fragment of human PrP consisting of amino acids 106–126 that forms fibrils in vitro is toxic to cultured neurons9–11. Here we show that this toxic effect requires the presence of microglia which respond to PrP106–126 by increasing their oxygen radical production. The combined direct and microglia-mediated effects of PrP106–126 are toxic to normal neurons but are insufficient to destroy neurons from mice not expressing PrPc.

513 citations

Journal ArticleDOI
TL;DR: Cell culture experiments reveal that cerebellar cells lacking PrPc are more sensitive to oxidative stress and undergo cell death more readily than wild-type cells, and in vivo studies show that the activity of Cu/Zn superoxide dismutase is reduced in Prnp gene-ablated mice.

447 citations


Cited by
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[...]

08 Dec 2001-BMJ
TL;DR: There is, I think, something ethereal about i —the square root of minus one, which seems an odd beast at that time—an intruder hovering on the edge of reality.
Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

33,785 citations

28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

9,131 citations

Journal ArticleDOI
TL;DR: Current studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains, and microglial cells are considered the most susceptible sensors of brain pathology.
Abstract: Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

2,998 citations