Transmissible and genetic prion diseases share a common pathway of neurodegeneration

Prion diseases can be infectious, sporadic and genetic. The infectious forms of these diseases, including bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, are usually characterized by the accumulation in the brain of the transmissible pathogen, an abnormally folded isoform of the prion protein (PrP) termed PrPSc. However, certain inherited PrP mutations appear to cause neurodegeneration in the absence of PrPSc, working instead by favoured synthesis of CtmPrP, a transmembrane form of PrP. The relationship between the neurodegeneration seen in transmissible prion diseases involving PrPSc and that associated with ctmPrP has remained unclear. Here we find that the effectiveness of accumulated PrPSc in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in the ctmPrP form. Furthermore, the time course of PrPSc accumulation in transmissible prion disease is followed closely by increased generation of CtmPrP. Thus, the accumulation of PrPSc appears to modulate in trans the events involved in generating or metabolising CtmPrP. Together, these data suggest that the events of CtmPrP-mediated neurodegeneration may represent a common step in the pathogenesis of genetic and infectious prion diseases.     

东北区主要粮豆作物气候生产潜力实现率及其提高途径

在计算机东北各地主要粮豆作物光合,光温和气候生产潜力的基础上,根据现实产占各级资源生产斩比较,分析了各地主要作物光合,光温,气候生产潜力实现率及其地理分布。     

The pleiotropic functions of aspirin: mechanisms of action

Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores, increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding κB site (NF-κB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy. Received 1 February 1999; received after revision 1 April 1999; accepted 7 May 1999     

Polymorphism in the regulatory sequence of the human hsp70-1 gene does not affect heat shock factor binding or heat shock protein synthesis

A bi-allelic polymorphism found in the regulatory region of the human heat shock (HS) protein (HSP) hsp70-1 gene, which comprises an A-->C transversion, 3 bp upstream of the HS element (HSE), has been associated with extended HLA haplotypes. In view of the chaperoning and protective functions of Hsp70, we investigated whether this hsp70-1 bi-allelic polymorphism could modulate the stress response, which may relate to enhanced resistance or susceptibility to certain diseases. We compared the basal and HS-induced HS factor (HSF)-binding activity of the two polymorphic HSEs, hsp70-1 mRNA accumulation and HSP expression in two human Epstein Barr virus (EBV)-transformed B cell lines typed for hsp70-1 promoter alleles. Our results suggest that hsp70-1 promoter polymorphism does not influence HSF-binding activity, hsp70 mRNA accumulation or synthesis in human EBV-transformed B cell lines.     

Antigen-specific T cells in autoimmune diseases with a focus on multiple sclerosis and experimental allergic encephalomyelitis

Although the pathogenesis of autoimmune diseases remains poorly understood, the current view is that autoaggresive antigen-specific T cells play a central role in the cascade of events leading to most autoimmune diseases. A major event in the development of autoimmune diseases is the activation of antigen-specific T cells-how, when and where does this activation take place? This review addresses questions concerning the occurrence of unique autoantigens triggering autoimmune diseases, the factors influencing the balance between self-tolerance and autoaggresive immunity, and the mechanisms by which dendritic cells mediate immunity and tolerance to antigen-specific T cells. Knowledge of how antigen-specific T cells are activated is now being used to develop therapeutic approaches to control autoimmune diseases. We discuss tolerance to antigen-specific T cells and tolerance induction as treatment of T-cell-mediated autoimmune diseases. Therapeutic modalities have been established which selectively target the pathogenic T cells. leaving the remainder of the immune system intact.     

Permeability of rat heart myocytes to cytochrome c

Rat heart myocytes undergoing progressive damage demonstrate morphological changes of shortening and swelling followed by the formation of intracellular vacuoles and plasma membrane blebbing. The damaged myocytes displayed impaired N,N'-tetramethyl-p-phenyldiamine (TMPD) ascorbate-stimulated respiratory activity which was restored by the addition of reduced cytochrome c to the cell culture medium. To clarify the role played by cytochrome c in the impairment of cell respiration, polarographic, spectrophotometric and fluorescence as well as electron microscopy imaging experiments were performed. TMPD/ascorbate-stimulated respiratory activity returned to control levels, at approximately 20 microM cytochrome c, establishing the threshold below which the turnover rate by cytochrome c oxidase in the cell depends on cytochrome concentration. Mildly damaged cardiac myocytes, as indicated by cell shortening, retention of visible striations and free-fluorescein exclusion, together with the absence of lactate dehydrogenase leakage and exclusion of trypan blue, were able to oxidize exogenous cytochrome c and were permeable to fluorescein-conjugated cytochrome c. The results, while consistent with an early cytochrome c release observed at the beginning of cell death, elucidate the role played by cytochrome c in the kinetic control of mitochondrial electron transfer under pathological conditions, particularly those involving the terminal part of the respiratory chain. These data are the first to demonstrate that the sarcolemma of cardiac myocytes, damaged but still viable, is permeable to cytochrome c.     

Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1

Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned; the human homologue, CUBN, was mapped to the same region. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.