245 research outputs found
The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public
No full textAmyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting one in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7500 controls at 30× coverage. Here, we present the Project MinE data browser ( databrowser.projectmine.com ), a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4366 ALS cases and 1832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources
Offsetting of CO₂ emissions by air capture in mine tailings at the Mount Keith Nickel Mine, Western Australia: Rates, controls and prospects for carbon neutral mining
No full textThe hydrated Mg-carbonate mineral, hydromagnesite [Mg₅(CO₃)₄(OH)₂•4H₂O], precipitates within mine tailings at the Mount Keith Nickel Mine, Western Australia as a direct result of mining operations. We have used quantitative mineralogical data and δ¹³C, δ¹⁸O and F¹⁴C isotopic data to quantify the amount of CO₂fixation and identify carbon sources. Our radiocarbon results indicate that at least 80% of carbon stored in hydromagnesite has been captured from the modern atmosphere. Stable isotopic results indicate that dissolution of atmospheric CO₂ into mine tailings water is kinetically limited, which suggests that the current rate of carbon mineralization could be accelerated. Reactive transport modeling is used to describe the observed variation in tailings mineralogy and to estimate rates of CO₂ fixation. Based on our assessment, approximately 39,800 t/yr of atmospheric CO₂ are being trapped and stored in tailings at Mount Keith. This represents an offsetting of approximately 11% of the mine's annual greenhouse gas emissions. Thus, passive sequestration via enhanced weathering of mineral waste can capture and store a significant amount of CO₂. Recommendations are made for changes to tailings management and ore processing practices that have potential to accelerate carbonation of tailings and further reduce or completely offset the net greenhouse gas emissions at Mount Keith and many other mines
Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis [preprint]
No full textFull author list omitted for brevity. For the full list of authors, see article.The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility of disease. We have therefore begun Project MinE, an international collaboration that seeks to analyse whole-genome sequence data of at least 15,000 ALS patients and 7,500 controls. Here, we report on the design of Project MinE and pilot analyses of newly whole-genome sequenced 1,264 ALS patients and 611 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public data sets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests
The Effect of SMN Gene Dosage on ALS Risk and Disease Severity
No full textOBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697
Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene
No full textAmyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.sponsorship: This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (no. 772376 -EScORIAL). The project is supported through the following funding organizations under the aegis of JPND: Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health to stimulate public-private partnerships. We acknowledge support from a Lee Newton PhD studentship (T.M.), ``My Name''5 Doddie Foundation (J.P.F.), the Wellcome Trust (J.C.-K., 216596/Z/19/Z; D.B., 213501/Z/18/Z), and NIHR (P.J.S. and A.A.C.). This work was also supported by the NIHR Sheffield Biomedical Research Centre for Translational Neuroscience. Biosample collection was supported by the MND Association and the Wellcome Trust (P.J.S.). We are very grateful to those ALS patients and control subjects who generously donated biosamples. (European Research Council (ERC) under the European Union|772376 -EScORIAL, aegis of JPND: Medical Research Council|MR/L501529/1, aegis of JPND: Medical Research Council|MR/R024804/1, Economic and Social Research Council|ES/L008238/1, Lee Newton PhD studentship, Wellcome Trust, NIHR, NIHR Sheffield Biomedical Research Centre for Translational Neuroscience, MND Association, MRC|MR/R024804/1, MRC|G0600974, Academy of Medical Sciences (AMS)|SGL018\\1007, National Institute for Health Research|CL-2015-04-001)status: Publishe
Erratum: Rare variant burden analysis within enhancers identifies CAV1 as an ALS risk gene (Cell Reports (2020) 33(9), (S2211124720314455), (10.1016/j.celrep.2020.108456))
No full text(Cell Reports 33, 108456-1–108456-8.e1–e5; December 1, 2020) In the originally published version of this article, Eran Elhaik was incorrectly spelled in the author list. The corrected author list appears here and with the article online. The authors regret the error
TECHNICAL CHARACTERIZATION OF CALLIOLAB, THE NEW UNDERGROUND LABORATORY FOR PHYSICS RESEARCH IN PYHÄSALMI MINE
No full textAbstractThe development of the infrastructure for scientific work in the Pyhäsalmi mine is currently administered under the Calliolab project, which is managed by a consortium of the Universities of Oulu and Jyväskylä and regional organizations. A new laboratory has been developed in one of the tunnels at 1430 m depth in Pyhäsalmi mine. At this depth the cosmic-ray muon flux is attenuated down to one ppm compared to that on the surface, making the new laboratory an excellent location to conduct astro-particle physics research and material testing, which require ultra-low cosmic-ray background environment. The floor area of the new laboratory, is currently 120 m² and the average height is 9 m providing the volume of 1080 m³ for working space. The laboratory is located 400 m from the main service level of the Pyhäsalmi mine, which is accessible with an elevator from the surface. The laboratory is also connected to the 11 km long maintenance road and it is accessible with a truck.In this presentation we discuss the current status of Calliolab and it’s technical characterization, such as radon and other radiation background monitoring, ventilation, electricity and the isolation of the laboratory from mining operations We also review the main results from the FP7 design study for utilizing the mine for major neutrino physics experiments. 19.2 Particle and Nuclear Physics Poster 225Abstract
The development of the infrastructure for scientific work in the Pyhäsalmi mine is currently administered under the Calliolab project, which is managed by a consortium of the Universities of Oulu and Jyväskylä and regional organizations. A new laboratory has been developed in one of the tunnels at 1430 m depth in Pyhäsalmi mine. At this depth the cosmic-ray muon flux is attenuated down to one ppm compared to that on the surface, making the new laboratory an excellent location to conduct astro-particle physics research and material testing, which require ultra-low cosmic-ray background environment. The floor area of the new laboratory, is currently 120 m² and the average height is 9 m providing the volume of 1080 m³ for working space. The laboratory is located 400 m from the main service level of the Pyhäsalmi mine, which is accessible with an elevator from the surface. The laboratory is also connected to the 11 km long maintenance road and it is accessible with a truck.
In this presentation we discuss the current status of Calliolab and it’s technical characterization, such as radon and other radiation background monitoring, ventilation, electricity and the isolation of the laboratory from mining operations We also review the main results from the FP7 design study for utilizing the mine for major neutrino physics experiments. 19.2 Particle and Nuclear Physics Poster 22
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Fuelcell-Hybrid Mine loader (LHD)
No full textThe fuel cell hybrid mine loader project, sponsored by a government-industry consortium, was implemented to determine the viability of proton exchange membrane (PEM) fuel cells in underground mining applications. The Department of Energy (DOE) sponsored this project with cost-share support from industry. The project had three main goals: (1) to develop a mine loader powered by a fuel cell, (2) to develop associated metal-hydride storage and refueling systems, and (3) to demonstrate the fuel cell hybrid loader in an underground mine in Nevada. The investigation of a zero-emissions fuel cell power plant, the safe storage of hydrogen, worker health advantages (over the negative health effects associated with exposure to diesel emissions), and lower operating costs are all key objectives for this project
Value of systematic genetic screening of patients with amyotrophic lateral sclerosis
No full textThe clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis is uncertain. Our
aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a
significant impact on clinical care and disease subclassification. We performed targeted
sequencing of a 44 gene panel in a prospective case series of 100 consecutive ALS patients
recruited sequentially from the Sheffield Motor Neuron Disorders Clinic, United Kingdom. All
participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had
familial ALS, but the majority were apparently sporadic cases.
21% of ALS patients carried a confirmed pathogenic or likely-pathogenic mutation, of whom 93%
had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial.
5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS).
An additional 21% of ALS patients carried a VUS in an ALS-associated gene. Overall, 13% of
patients carried more than one genetic variant (pathogenic or VUS). ALS patients carrying two
variants developed disease at a significantly earlier age compared to patients with a single variant
(median age of onset = 56 versus 60 years, p=0.0074).
In conclusion, routine screening for ALS-associated pathogenic mutations in a specialised ALS
referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants
in the ALS gene panel currently of unconfirmed significance after removing non-specific or
predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical
importance in 42% of patients
HYDRIDE BED/FUELCELL PROJECT
No full textAbstract The Hydride Bed/Fuelcell Project will result in the development and production of a prototype Fuelcell Powerplant for Mining/Tunneling Locomotives. This powerplant will replace and outperform batteries, currently utilized for mining and tunneling. The Mine Locomotive Project is a project of the Fuelcell Propulsion Institute (FCPI) consortium
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