Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions

: The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested

Development and implementation of a decommissioning and closure plan at the Premier Gold Project

This paper describes the development and implementation of a decommissioning and closure plan at the Premier Gold Project. The Property is located approximately 18 km north of Stewart, British Columbia, Canada and 2.4 km northeast of the BC/Alaska border. The site has been used for gold and silver mining since the turn of last century and Boliden Limited has owned and operated the site since 1988. Mining operations ceased in 1996 and the mine is proceeding through a closure phase. The main objective of the decommissioning and closure plan is to minimize the impact of tailings, contaminated water discharges, waste rock dumps and other aspects of the site on the receiving environment. The main aspects of the closure plan include decommissioning and closure of the Tailings Storage Facility (TSF), demolition of buildings, disturbed areas re-vegetation and environmental performance monitoring. The closure plan for the TSF calls for a partial wet closure and consists of tailings relocation, grouting of decants pipes and under-drain pipes through the dam, grouting of drainage pipe left through the dam, surface water management, construction of a filter berm at the toe of the tailings dam, construction of a closure spillway, overflow channel construction, diversion channel upgrade and construction of field trials for engineered covers. Decommissioning and closure of waste rock dumps included re-sloping and re-vegetation. The paper discusses the challenges and opportunities experienced through the implementation of the closure plan together with potential avenues to generate funds to cover post closure liabilities. Finally, the paper gives a summary of the lessons learned.Non UBCUnreviewedOthe

Yield-density responses in monocultures and mixtures of Beans (Phaseolus vulgaris L.) and Beets (Beta vulgaris L.)

Interference among neighbouring plants, often due to competition for limited resources, is central to subjects such as yield-density relationships, intercropping, self-thinning in dense plant stands and low reproductive yield in certain crops. An experiment was conducted to investigate plant interference in associated populations of beans {Phaseolus vulgaris L.) and beets [Beta vulgaris L.). Plants of the two species were grown at different total densities and at different mixture proportions in a randomized complete block design. Several analytical procedures were used to interpret and define treatment effects. The analysis of variance indicated that yield was significantly reduced with either increasing total population density or increasing bean proportions in mixtures. The interactions of total population density and mixture proportions were only occasionally significant. Parameters of non-linear models used to define yield-density relationships indicated that beans were the superior competitor, both against themselves and against beets. The model parameters were also used to determine differential yield responses on total dry weight, leaf dry weight, leaf number and leaf area in the bean-beet mixtures. Yield advantage was observed in leaf dry weight and leaf number when model parameters were used in calculating land equivalent ratios whereas total dry weight and leaf area showed yield disadvantage. Using observed values to calculate land equivalent ratios indicated yield advantage in all four variables. Plant size inequalities, as determined by the Gini coefficient tended to decrease in beet monocultures with increasing population density. In monocultures of beans and in the bean-beet mixtures, plant size distribution was not systematically changed by density and mixture treatments. Yield component analysis indicated that the variation in total yield due, to either population density or mixture treatments increased with age; the variation due to the population density by mixture proportions Interaction remained relatively constant throughout the growing season. Leaf number per plant was the yield component which was most frequently a significant source of yield variation both in the forward and backward yield component analysis. Plant growth analysis indicated that leaf area ratio and specific leaf weight were higher at higher population densities and at higher bean proportions. Harvest index decreased with increasing population density and with increasing proportions of the competing species in beets. Absolute growth, relative growth and unit leaf rates increased with time and declined after reaching a peak at about 68 days after planting. Both the lowest population density of 16 plants m ̄² and the mixture treatment with the least proportion of beans had the greatest increase in absolute growth, relative growth and unit leaf rates. Allometric relationships between total plant dry weight and any secondary measure per plant were influenced in different ways by density and mixture treatments and by time of harvest. The composition of models also varied considerably. The interpretation of plant interference, therefore is strongly influenced by the choice of plant characteristics which are measured, and by the time of measurement.Land and Food Systems, Faculty ofGraduat

Studies into the application of controlled recirculation ventilation in Canadian underground mines

Increasing energy costs and the need to conserve energy compounded with low mineral prices have prompted some Canadian mines especially potash producers, to examine their operations and identify potential saving methods. Re-using or recirculating a fraction of ventilating air may enable these mines to reduce winter heating costs. Gas and dust concentrations were monitored in the intake and exhaust airways to assess the potential for recirculating exhaust air. The results indicate that the mine pollutant concentrations in potash mines are low and stable. Trial recirculation experiments returning 20 - 47% exhaust air into the fresh air airway did not cause significant increases in mixed intake pollutant levels. Two types of recirculation systems - namely variable and fixed quantity - are developed. Detailed designs of recirculation systems for Central Canada Potash of Noranda Minerals Inc. and Rocanville Division, Potash Corporation of Saskatchewan are discussed and recommendations made for the selection and positioning of on-line monitoring, control and telemetry systems. A controlled recirculation system conceptual design for the H-W mine is given. The economic payback periods for systems proposed for Rocanville Division and CCP are 2 and 3 years respectively. Recirculation percentages of 30%, 64.4% and 23% are feasible for CCP, Rocanville Division and the H-W mine. The recirculation percentages for the proposed systems were determined using Air Quality Index criteria. Dust deposition studies conducted at CCP in return airways indicate that 65% of dust by weight is deposited within a distance of 550 metres from the face. In terms of dust and other contaminant conditions in the return airways, it can be concluded that there is potential for use of recirculation in the face area. Guidelines for recirculation systems in gassy and dusty mines are developed. The main features for these recirculation system design guidelines are safety, economic gain, and system performance. The author's attribution to ventilation is in the use of controlled recirculation to reduce winter heating costs and increase underground airflow, also the guidelines developed for recirculation in gassy and dusty mines. The overall conclusion is that controlled recirculation is a practical method of reducing winter heating cost and/or increasing mine airflows. The financial potential and technology to implement a working system exist.Applied Science, Faculty ofMining Engineering, Keevil Institute ofGraduat

Planning and implementation initiatives for an afforestation project in an arid environment, northern Chile

This paper describes a community forest project located in the township of Calama, Region II, Northern Chile. The project was initiated in 1996 with a goal to create a 100 hectares of self-sustaining forested ecosystem for a valued oasis in the Atacama Desert. The objectives of the project are: to create a selfsustaining ecosystem with minimal maintenance using native plant species that are drought resistant and to undertake initiatives that will speed up natural successional changes. To meet the above objectives, a local drought-resistant species known as 'algarrobo' (Prosopis chilensis) was selected for the project. The afforestation program includes key elements such as seed preparation; sowing of seeds in greenhouse containers and maintenance; land preparation; transplanting the individual seedlings into the field; and on-going field maintenance and monitoring.Non UBCUnreviewedOthe

Environmental management considerations for a mine site under long-term care and maintenance

Environmental planning for a mine site under long-term care and maintenance (LTCM) plays a key role in ensuring organized and efficient use of limited resources. The objective is to minimize operating and maintenance costs and future environmental liabilities. Significant environmental aspects must be identified during the planning phase to minimize environmental liabilities and risks associated with major site components. Some of the major aspects considered during the planning phase for LTCM include, risk assessment, environmental audit, chemical and reagent inventory, development of a decommissioning and closure plan, geochemical characterization of waste rock dumps and tailings, review of environmental monitoring data and reclamation programs and permit requirements, mixed chemical and reagent destruction program, government consultation, emergency preparedness and internal and external communication protocols. This paper discusses the environmental management considerations for a mine site that is currently under long-term care and maintenance together with lessons learned during the implementation of the plan.Non UBCUnreviewedOthe

Reclamation of mine openings at the historic Highland Mine and Kootenay-Florence Mines, Ainsworth, British Columbia

This paper discusses mine closure aspects of an abandoned mine workings located in southeast British Columbia. The Highland Mine and adjacent mines were discovered in the 1890's and produced at various intervals until the late 1950's. During the summer of 1997, one of the old Highland Mine portals collapsed and released an unknown quantity of iron-rich water into Cedar Creek. This event led to a review of all the surface openings of the Company's Ainsworth lands in terms of meeting the BC Health, Safety and Reclamation Code requirements. The closure aspects considered included preliminary assessment, site investigations, decommissioning and reclamation work planning, design implementation, cost estimates, alternative evaluation, contractor selection and implementation. The paper will also address environmental, stakeholder consultation aspects and follow-up.Non UBCUnreviewedOthe

Impact of contaminated sites legislation on closure of an acid generating mine site in British Columbia

In the past few years, numerous mine closure and reclamation projects have been subjected to the provincial Contaminated Sites Regulation (CSR) in British Columbia. A mine decommissioning and closure plan should contain among other things a Detailed Site Investigation report, a Remedial Action Plan and the necessary financial security to ensure funds are available to carry out the remediation work. The intent of the CSR has been to facilitate the complete sign off of long-term environmental liability to a company by government from a particular site through requiring a company to meet all the requirements defined in the regulation. This sign off can be in the form of a Certificate of Compliance, Conditional Certificate of Compliance or Letter of Comfort. Contaminated Sites Regulations have been developed predominantly for industrial or commercial sites usually in an urban environment with clearly defined contaminants associated with the particular industry. Problems associated with acid rock drainage and acid generating sulphide waste contamination are not clearly defined in these regulations. Complications arise when applying the CSR to the mining sector. In particular, the interpretation of a regulation which defines "contaminated site" based on concentrations of naturally occurring inorganic substances (metals) in soil and groundwater In addition, the CSR bureaucratic process has not been generally structured to blend with more traditional mine closure plans required under the Mines Act even though the regulations are somewhat linked. While the intent of government has been to link and harmonize the CSR with the mine closure regulations, in BC, the harmonization of the regulations and various ministries has yet to be tested fully and it is anticipated will require modification to the regulations. This paper will give an overview of the environmental regulatory context in British Columbia with particular reference to CSR requirements at acid generating mine sites. In addition, technical and administrative requirements will be given together with a discussion of the impacts of these regulations on the mining industry and ways to plan and manage associated liabilities.Non UBCUnreviewedOthe

Sammenlignings- og holdbarhetsstudie av citrat-plasma mot EDTA-plasma med hensyn til PT-INR analyse.

Oppgaven ble foreslått av Medisinsk biokjemi avdeling, seksjon Kristiansund. De ønsket å finne ut om EDTA-plasma kan brukes alternativt til citrat-plasma til PT-INR analysen. EDTA- plasma er som oftest lett tilgjengelig prøvemateriale fra pasienter. Hvis studien viser at EDTA-plasma kan brukes til PT-INR analyse, er dette positivt for pasienter, fordi på denne måten unngår å bli stukket enda en gang, når leger bestiller PT-INR analyse i ettertid av prøvetaking. I tillegg ble det utført en holdbarhetsstudie, som består av to deler

Field performance evaluation of soil-based cover systems to mitigate ARD for the closure of a potentially acid-generating tailings storage facility

This paper summarizes field performance results of three engineered soil-based cover systems and one control system intended to mitigate potential acid rock drainage and metal leaching at a tailings disposal site. The field performance evaluation commenced in 2002 on the tailings beach of the Premier Gold Project (PGP) site near Stewart, British Columbia, Canada (~ 56˚05’N, 130˚00’W). Four 15 m by 15 m test plots were constructed using the barrier layers of either 1) a geosynthetic clay liner (GCL) Bentomat® ST, 2) 0.6 m of local sand and gravel plus 6% EnviroGel® 8 Wyoming sodium bentonite by eight, 3) 0.8-m loose till, or 4) no barrier (control system). Two years of monitoring results indicate that the barrier layers did not freeze which may be attributed to the insulating effect of approximately 2 m of snow pack at the site. Of the four systems studied, the sand-bentonite (S-B) system performed best when considering performance indicators such as percolation, interflow (lateral drainage above the barrier), and oxygen diffusion. Field and laboratory results indicated that the ‘as-is till’ layer would have to be more than 2 m thick to reduce oxygen diffusion adequately. Field oxygen concentrations and oxygen flux modeling indicated that the GCL system would have to be upgraded substantially (e.g. by incorporating another layer of GCL or a low permeability soil layer) to adequately reduce oxygen diffusion. Unit costs for the as-built S-B cover system without instrumentation were 1.9 and 2.0 times as expensive as the as-built till and the as-built GCL cover systems, respectively.Non UBCUnreviewedOthe