Overview of Highland Valley Tailings Storage Facility

This paper presents key features of the Highland Valley tailings storage facility comprising two tailings dams, a 107 m high H-H Dam and a 166 m high L-L Dam. The construction history to date including instrumentation observations is also reviewed. Although the tailings facility is situated in a low to moderate seismic area within the Interior Plateau of British Columbia, potential earthquake sources that might have an impact on the site have been carefully assessed. Both dams are designed to have adequate seismic resistance against design earthquakes appropriate for the site. The L-L Dam valley section, involving soft lacustrine deposits beneath the Starter Dam, has been buttressed by a compacted downstream berm founded on dense glacial till. As the geometry of the tailings storage and distribution facilities and waste dumps changes with time, the quantity and relative cost of various construction materials including natural borrow, cycloned sand and pit overburden also change. Ongoing construction is planned to maintain key earthquake and flood design criteria as well as to adjust the use and placement method of various materials to achieve an efficient and cost effective tailings storage operation. Inherent in the design of the two tailings dams, both constructed by the centerline method, is the flexibility which enables the storage capacity of the tailings facility to be increased beyond the present 1.8 billion tonnes if required at some future time

Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death

International audienceBACKGROUND: Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: The effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)), ubiquinone 10 (Ub(10)) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub(0) inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub(5) did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub(10) regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub(5) induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub(0) induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism. CONCLUSIONS/SIGNIFICANCE: We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening

A Simple, Versatile and Sensitive Cell-Based Assay for Prions from Various Species

Detection and quantification of prion infectivity is a crucial step for various fundamental and applied aspects of prion research. Identification of cell lines highly sensitive to prion infection led to the development of cell-based titration procedures aiming at replacing animal bioassays, usually performed in mice or hamsters. However, most of these cell lines are only permissive to mouse-adapted prions strains and do not allow titration of prions from other species. In this study, we show that epithelial RK13, a cell line permissive to mouse and bank vole prion strains and to natural prion agents from sheep and cervids, enables a robust and sensitive detection of mouse and ovine-derived prions. Importantly, the cell culture work is strongly reduced as the RK13 cell assay procedure designed here does not require subcultivation of the inoculated cultures. We also show that prions effectively bind to culture plastic vessel and are quantitatively detected by the cell assay. The possibility to easily quantify a wider range of prions, including rodent experimental strains but also natural agents from sheep and cervids, should prompt the spread of cell assays for routine prion titration and lead to valuable information in fundamental and applied studies

Prion protein-specific antibodies that detect multiple TSE agents with high sensitivity

This paper describes the generation, characterisation and potential applications of a panel of novel anti-prion protein monoclonal antibodies (mAbs). The mAbs were generated by immunising PRNP null mice, using a variety of regimes, with a truncated form of recombinant ovine prion protein spanning residues 94–233. Epitopes of specific antibodies were mapped using solid-phase Pepscan analysis and clustered to four distinct regions within the PrP molecule. We have demonstrated the utility of these antibodies by use of Western blotting and immunohistochemistry in tissues from a range of different species affected by transmissible spongiform encephalopathy (TSE). In comparative tests against extensively-used and widely-published, commercially available antibodies, similar or improved results can be obtained using these new mAbs, specifically in terms of sensitivity of detection. Since many of these antibodies recognise native PrPC, they could also be applied to a broad range of immunoassays such as flow cytometry, DELFIA analysis or immunoprecipitation. We are using these reagents to increase our understanding of TSE pathogenesis and for use in potential diagnostic screening assays

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Incorporación de una zeolita natural chilena (clinoptilolita) a dietas de pollos broiler

The effects of including a non purified Clinoptilolite (CLI) on the feeds of male broiler and on their performance, were evaluated. 160 one day old chicks were randomized into 4 treatments: I, II, ll and IV according to the level of CLI in the diet: 0%, 2%, 4% and 6% respectively, each treatment had 4 replicates. CLI was incorporated to the diet during the whole productive cycle.At day 49, end of the experiment, no significant (p > 0,05) differences between treatments were found for live weight, feed comsuption and feed conversion efficiency.The feeding cost of weigth gain was less treatment IV during the last period (38-49 days), although treatment l showed the lower average cost considering the whole period (1-49 days).No differences (p > 0,05) were found for carcass weight, carcass yield, nor abdominal fat expressed as a percentage of live weight. Treatment ll had a significant (p 0,05) were found, at 49 days of age, for bone characteristics and mortality. The moisture content of the droppings, throughout the experiment showed a tendency to diminsh when more CLI was incorporated to the diet.Although no big improvements were found in broiler performance using this non purified CLI,,further investigations should be done with this CLI previously purfied, because the impurities may be covering the surface of the zeolite and in this way decreasing their recognized physical and chemical properties.Se evaluó una clinoptilolita (CLI) no purificada sobre el rendimiento productivo de pollos broiler. Se distribuyeron 160 pollos en 4 tratamientos: I, II, lll y IV, de acuerdo al nivel de CLI en la dieta: 0%, 2%, 4% y 6% respectivamente, cada tratamiento contó con 4 réplicas. La CLI se incorporó a las dietas durante todo el ciclo productivo Al día 49, cuando terminó la experiencia, no se apreciaron diferencias significativas (p > 0,05) para el peso vivo, consumo de alimento ni eficiencia de conversión alimenticia. El costo alimentario de la ganancia de peso fue menor en el tratamiento IV (6%) durante el último período (días 38-49); sin embargo, el tratamiento I (0%) mostró el menor costo al promediar el ciclo completo (días 1-49). No se encontraron diferencias significativas (p > 0,05) para el peso de la canal, rendimiento de ella, ni peso de la brasa abdominal expresado como porcentaje del peso vivo. El tratamiento II mostró un valor significativamente mayor (p ≤  0.05) para peso de la brasa abdominal expresado en gramos y como porcentaje de la canal. No se observaron diferencias significativas (p > 0,05) en las características óseas ni en la mortalidad al día 49 de edad. El contenido de humedad de las heces mostró una tendencia a disminuir a medida que aumentaba la cantidad de CLI en la dieta. A pesar de que no se encontraron grandes diferencias en el rendimiento productivo en pollos broiler al utilizar CLI no purificada, se sugiere realizar nuevos experimentos con CLI previamente purificada. ya que las impurezas pudieran estar recubriendo la superficie de la zeolita. con lo cual disminuirían sustancialmente sus propiedades físico-químicas