| 1. |
- 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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| 2. |
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| 3. |
- Axelsson, Magnus, et al.
(författare)
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Measuring energy dependent polarization in soft gamma-rays using compton scattering in PoGOLite
- 2007
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Ingår i: Astroparticle physics. - : Elsevier. - 0927-6505 .- 1873-2852. ; 28:3, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- Linear polarization in X-and gamma-rays is an important diagnostic of many astrophysical sources, foremost giving information about their geometry, magnetic fields, and radiation mechanisms. However, very few X-ray polarization measurements have been made, and then only mono-energetic detections, whilst several objects are assumed to have energy dependent polarization signatures. In this paper, we investigate whether detection of energy dependent polarization from cosmic sources is possible using the Compton technique, in particular with the proposed PoGOLite balloon-experiment, in the 25-100 keV range. We use Geant4 simulations of a PoGOLite model and input photon spectra based on Cygnus X-1 and accreting magnetic pulsars (100 mCrab). Effective observing times of 6 and 35 h were simulated, corresponding to a standard and a long duration flight, respectively. Both smooth and sharp energy variations of the polarization are investigated and compared to constant polarization signals using chi-square statistics. We can reject constant polarization, with energy, for the Cygnus X-1 spectrum (in the hard state), if the reflected component is assumed to be completely polarized, whereas the distinction cannot be made for weaker polarization. For the accreting pulsar, constant polarization can be rejected in the case of polarization in a narrow energy band with at least 50% polarization, and similarly for a negative step distribution from 30% to 0% polarization.
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| 4. |
- Cecconello, Marco, et al.
(författare)
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The 2.5 MeV neutron flux monitor for MAST
- 2014
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier. - 0168-9002 .- 1872-9576. ; 753, s. 72-83
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Tidskriftsartikel (refereegranskat)abstract
- A proof-of-principle collimated Neutron flux Camera (NC) monitor for the measurement of the 2.45 MeV neutron emission from the deuterium–deuterium fusion reactions has been developed, installed and put into use at the Mega Ampere Spherical Tokamak (MAST). The NC measures the spatial and time resolved volume integrated neutron emissivity in deuterium fusion plasmas in the presence of auxiliary plasma heating along two equatorial and two diagonal lines of sight whose tangency radius can be varied between plasma discharges. This paper describes the NC design principles, their technical realization and its performances illustrated with experimental observations of different plasma scenarios. Neutron count rates in the range 0.1–1.5 MHz are routinely observed allowing time resolutions as high as 1 ms with a statistical uncertainty less than 10% and an energy threshold of 0.5 MeV. Examples of the effect of plasma instabilities on the neutron emission are presented. The good results obtained will be used for the design of the neutron flux camera monitor for MAST Upgrade.
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| 5. |
- Pearce, Mark, et al.
(författare)
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PoGOLite : A balloon-borne soft gamma-ray polarimeter
- 2007
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Ingår i: Proceedings of the 30th International Cosmic Ray Conference, ICRC 2007. - : Universidad Nacional Autonoma de Mexico. ; , s. 479-482
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Konferensbidrag (refereegranskat)abstract
- Polarized gamma-rays are expected from a wide variety of sources including rotationpowered pulsars, accreting black holes and neutron stars, and jet-dominated active galaxies. Polarization measurements provide a powerful probe of the gamma-ray emission mechanism and the distribution of magnetic and radiation fields around the source. No measurements have been performed in the soft gamma-ray band where non-thermal processes are expected to produce high degrees of polarization. The PoGOLite experiment applies well-type phoswich detector technology to polarization measurements in the 25 - 80 keV energy range. The instrument uses Compton scattering and photoabsorption in an array of 217 phoswich detector cells made of plastic and BGO scintillators, and surrounded by active BGO shields. A prototype of the flight instrument has been tested with polarized gammarays and background generated with radioactive sources. The test results and computer simulations confirm that the instrument can detect 10% polarization of a 200 mCrab source in one 6 hour balloon observation. In flight, targets are constrained to within better than 5% of the field-of-view (~5 degrees squared) in order to maximize the effective detection area during observations. The pointing direction on the sky is determined by an attitude control system comprising star trackers, differential GPS receiver system, gyroscopes, accelerometers and magnetometers which provide correction signals to a reaction wheel and torque motor system. Additionally, the entire polarimeter assembly rotates around its viewing axis to minimize systematic bias during observations. Flights are foreseen to start in 2009- 2010 and will target northern sky sources including the Crab pulsar/nebula, Cygnus X-1, and Hercules X-1. These observations will provide valuable information about the pulsar emission mechanism, the geometry around the black hole, and photon transportation in the strongly magnetized neutron star surface, respectively. Future goals include a long duration balloon flight from the Esrange facility in Northern Sweden to Canada.
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| 6. |
- Cecconello, Marco, et al.
(författare)
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Measurement of the gamma-ray energy resolution function of EJ301 liquid scintillator using a dual channel ADC
- 2014
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 753, s. 34-37
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Tidskriftsartikel (refereegranskat)abstract
- A comparison of three different methods for the energy calibration of liquid scintillators using gamma-ray sources using only a delay unit and a dual channel ADC is presented. Single Compton edge measurements combined with MCNP simulations of the pulse height spectra are compared with the results obtained using Compton coincidence methods. Good agreement between the three methods is found. Measurements from the three different methods are then combined to provide the best estimate of the energy resolution function. The technique here presented could be easily used in laboratory courses as high performing ADCs become more common and affordable. (C) 2014 Elsevier B.V. All rights reserved.
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| 7. |
- Kanai, Y., et al.
(författare)
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Beam test of a prototype phoswich detector assembly for the PoGOLite astronomical soft gamma-ray polarimeter
- 2007
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 570:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- We report about the beam test on a prototype of the balloon-based astronomical soft gamma-ray polarimeter, PoGOLite (Polarized Gamma-ray Observer-Light Version) conducted at KEK Photon Factory, a synchrotron radiation facility in Japan. The synchrotron beam was set at 30, 50, and 70 keV and its polarization was monitored by a calibrated polarimeter. The goal of the experiment was to validate the flight design of the polarimeter. PoGOLite is designed to measure polarization by detecting a Compton scattering and the subsequent photo-absorption in an array of 217 well-type phoswich detector cells (PDCs). The test setup included a first flight model PDC and a front-end electronics to select and reconstruct valid Compton scattering events. The experiment has verified that the flight PDC can detect recoil electrons and select valid Compton scattering events down to 30 keV from background. The measure azimuthal modulations (34.4%, 35.8% and 37.2% at 30, 50, and 70 keV, respectively) agreed within 10% (relative) with the predictions by Geant4 implemented with dependence on the initial and final photon polarizations.
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| 8. |
- Tanaka, T., et al.
(författare)
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Data acquisition system for the PoGOLite astronomical hard X-ray polarimeter
- 2007
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Ingår i: Nuclear Science Symposium Conference Record, 2007. - 9781424409228 ; , s. 445-449, s. 445-449
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The PoGOLite is a new balloon-borne instrument to measure the polarization of hard X-rays/soft gamma-rays in the 25-80 keV energy range for the first time. In order to detect the polarization, PoGOLite measures the azimuthal angle asymmetry of Compton scattering and the subsequent photo-absorption in an array of detectors. This array consists of 217 well-type phoswich detector cells (PDCs) surrounded by a side anti-coincidence shield (SAS) composed of 54 segments of BGO crystals. At balloon altitude, the intensity of backgrounds due to cosmic-ray charged particles, atmospheric gamma-rays and neutrons is extremely high, typically a few hundred Hz per unit. Hence the data acquisition (DAQ) system of PoGOLite is required to handle more than 270 signals simultaneously, and detect weak signals from astrophysical objects (100mCrab, 1.5 cs(-1) in 25-80 keV) under such a severe environment. We have developed a new DAQ system consisting of front-end electronics, waveform digitizer, Field Programmable Gate Array (FPGA) and a microprocessor. In this system, all output signals of PDC / SAS are fed into individual charge-sensitive amplifier and then digitized to 12 bit accuracy at 24 MSa/s by pipelined analog to digital converters. A DAQ board for the PDC records waveforms which will be examined in an off-line analysis to distinguish signals from the background events and measure the energy spectrum and polarization of targets. A board for the SAS records hit pattern to be used for background rejection. It also continuously records a pulse-height analysis (PHA) histogram to monitor incident background flux. These basic functions of the DAQ system were verified in a series of beam tests.
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