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- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 3. |
- Pagnamenta, A. T., et al.
(författare)
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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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| 4. |
- Hursin, Mathieu, et al.
(författare)
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Modeling noise experiments performed at AKR-2 and CROCUS zero-power reactors
- 2023
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Ingår i: Annals of Nuclear Energy. - 0306-4549 .- 1873-2100. ; 194
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Tidskriftsartikel (refereegranskat)abstract
- CORTEX is a EU H2020 project (2017-2021) devoted to the analysis of ’reactor neutron noise’ in nuclear reactors, i.e. the small fluctuations occurring around the stationary state due to external or internal disturbances in the core. One important aspect of CORTEX is the development of neutron noise simulation codes capable of modeling the spatial variations of the noise distribution in a reactor. In this paper we illustrate the validation activities concerning the comparison of the simulation results obtained by several noise simulation codes with respect to experimental data produced at the zero-power reactors AKR-2 (operated at TUD, Germany) and CROCUS (operated at EPFL, Switzerland). Both research reactors are modeled in the time and frequency domains, using transport or diffusion theory. Overall, the noise simulators managed to capture the main features of the neutron noise behavior observed in the experimental campaigns carried out in CROCUS and AKR-2, even though computational biases exist close to the region where the noise-inducing mechanical vibration was located (the so-called ”noise source”). In some of the experiments, it was possible to observe the spatial variation of the relative neutron noise, even relatively far from the noise source. This was achieved through reduced uncertainties using long measurements, the installation of numerous, robust and efficient detectors at a variety of positions in the near vicinity or inside the core, as well as new post-processing methods. For the numerical simulation tools, modeling the spatial variations of the neutron noise behavior in zero-power research reactors is an extremely challenging problem, because of the small magnitude of the noise field; and because deviations from a point-kinetics behavior are most visible in portions of the core that are especially difficult to be precisely represented by simulation codes, such as experimental channels. Nonetheless the limitations of the simulation tools reported in the paper were not an issue for the CORTEX project, as most of the computational biases are found close to the noise source.
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| 5. |
- Asgari, Parham, et al.
(författare)
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Catalytic hydrogen atom transfer from hydrosilanes to vinylarenes for hydrosilylation and polymerization
- 2019
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Ingår i: Nature Catalysis. - : Nature Publishing Group. - 2520-1158. ; 2:2, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- Because of the importance of hydrogen atom transfer (HAT) in biology and chemistry, there is increased interest in new strategies to perform HAT in a sustainable manner. Here, we describe a sustainable, net redox-neutral HAT process involving hydrosilanes and alkali metal Lewis base catalysts-eliminating the use of transition metal catalysts-and report an associated mechanism concerning Lewis base-catalysed, complexation-induced HAT. The catalytic Lewis base-catalysed, complexation-induced HAT is capable of accessing both branch-specific hydrosilylation and polymerization of vinylarenes in a highly selective fashion, depending on the Lewis base catalyst used. In this process, the Earth-abundant, alkali metal Lewis base catalyst plays a dual role. It first serves as a HAT initiator and subsequently functions as a silyl radical stabilizing group, which is critical to highly selective cross-radical coupling. An electron paramagnetic resonance study identified a potassiated paramagnetic species, and multistate density functional theory revealed a high HAT character, yet multiconfigurational nature in the transition state of the reaction.
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| 6. |
- Herb, Joachim, et al.
(författare)
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Sensitivity analysis in core diagnostics
- 2022
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Ingår i: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549 .- 1873-2100. ; 178
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Tidskriftsartikel (refereegranskat)abstract
- In the CORTEX project, methods to simulate neutron flux oscillations were enhanced and machine-learning based tools to determine the causes of measured neutron flux oscillations were developed, using the results of simulations as training and validation data. For a selected combination of those methods and tools, several sensitivity analyses were performed to assess their robustness and trustworthiness. The neutron flux oscillations were simulated using the tool CORE SIM+. It calculates the three-dimensional field of the neutron flux oscillations, which can be used to determine the response of neutron detectors at given locations. For the sensitivity analysis, the neutron flux oscillations were assumed to be caused by the vibration of one fuel element. It was investigated how selected input parameters like the core loading pattern, the burn up of the fuel elements, the neutronic core data, the geometry details of the vibrating fuel element, the chosen detectors, and other noise source parameters like the amplitude of the fuel element vibrations, affect the simulated neutron flux oscillations. A three dimensional fully convolutional neural network had been developed and trained during the CORTEX project to determine the cause and location of perturbations causing given measurements of in-core detectors in pressurized water reactors. The robustness of this network was tested by applying it to the simulated detector readings created during the sensitivity analysis.
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