| 1. |
- Aad, G., et al.
(författare)
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- 2011
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swepub:Mat__t (refereegranskat)
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| 2. |
- Aad, G., et al.
(författare)
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- 2011
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Aad, G., et al.
(författare)
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- 2012
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Ingår i: Nuclear Physics, Section B. - : Elsevier BV. - 0550-3213 .- 1873-1562. ; 864:3, s. 341-381
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Tidskriftsartikel (refereegranskat)
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| 4. |
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| 5. |
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| 6. |
- Akkoyun, S., et al.
(författare)
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AGATA - Advanced GAmma Tracking Array
- 2012
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 0167-5087 .- 1872-9576. ; 668, s. 26-58
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) is a European project to develop and operate the next generation γ-ray spectrometer. AGATA is based on the technique of γ-ray energy tracking in electrically segmented high-purity germanium crystals. This technique requires the accurate determination of the energy, time and position of every interaction as a γ ray deposits its energy within the detector volume. Reconstruction of the full interaction path results in a detector with very high efficiency and excellent spectral response. The realisation of γ-ray tracking and AGATA is a result of many technical advances. These include the development of encapsulated highly segmented germanium detectors assembled in a triple cluster detector cryostat, an electronics system with fast digital sampling and a data acquisition system to process the data at a high rate. The full characterisation of the crystals was measured and compared with detector- response simulations. This enabled pulse-shape analysis algorithms, to extract energy, time and position, to be employed. In addition, tracking algorithms for event reconstruction were developed. The first phase of AGATA is now complete and operational in its first physics campaign. In the future AGATA will be moved between laboratories in Europe and operated in a series of campaigns to take advantage of the different beams and facilities available to maximise its science output. The paper reviews all the achievements made in the AGATA project including all the necessary infrastructure to operate and support the spectrometer. © 2011 Elsevier B.V. All rights reserved.
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| 7. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 8. |
- Valiente-Dobon, J. J., et al.
(författare)
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Conceptual design of the AGATA 2 pi array at LNL
- 2023
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 1049
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) has been installed at Laboratori Nazionali di Legnaro (LNL), Italy. In this installation, AGATA will consist, at the beginning, of 13 AGATA triple clusters (ATCs) with an angular coverage of 1n,and progressively the number of ATCs will increase up to a 2 pi angular coverage. This setup will exploit both stable and radioactive ion beams delivered by the Tandem-PIAVE-ALPI accelerator complex and the SPES facility. The new implementation of AGATA at LNL will be used in two different configurations, firstly one coupled to the PRISMA large-acceptance magnetic spectrometer and lately a second one at Zero Degrees, along the beam line. These two configurations will allow us to cover a broad physics program, using different reaction mechanisms, such as Coulomb excitation, fusion-evaporation, transfer and fission at energies close to the Coulomb barrier. These setups have been designed to be coupled with a large variety of complementary detectors such as charged particle detectors, neutron detectors, heavy-ion detectors, high-energy gamma-ray arrays, cryogenic and gasjet targets and the plunger device for lifetime measurements. We present in this paper the conceptual design, characteristics and performance figures of this implementation of AGATA at LNL.
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| 9. |
- Klintefjord, M., et al.
(författare)
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Measurement of lifetimes in Fe-62,Fe-64, Co-61,Co-63, and Mn-59
- 2017
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Ingår i: PHYSICAL REVIEW C. - 2469-9985. ; 95:2
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Tidskriftsartikel (refereegranskat)abstract
- Lifetimes of the 4(1)(+) states in Fe-62,Fe-64 and the 11/2(1)(-) states in Co-61,Co-63 and Mn-59 were measured at the Grand Accelerateur National d'Ions Lourds (GANIL) facility by using the Advanced Gamma Tracking Array (AGATA) and the large-acceptance variable mode spectrometer (VAMOS++). The states were populated through multinucleon transfer reactions with a U-238 beam impinging on a Ni-64 target, and lifetimes in the picosecond range were measured by using the recoil distance Doppler shift method. The data show an increase of collectivity in the iron isotopes approaching N = 40. The reduction of the subshell gap between the nu 2p(1/2) and nu 1g(9/2) orbitals leads to an increased population of the quasi-SU(3) pair (nu 1g(9/2), nu 2d(5/2)), which causes an increase in quadrupole collectivity. This is not observed for the cobalt isotopes withN < 40 for which the neutron subshell gap is larger due to the repulsive monopole component of the tensor nucleon-nucleon interaction. The extracted experimental B(E2) values are compared with large-scale shell-model calculations and with beyond-mean-field calculations with the Gogny D1S interaction. A good agreement between calculations and experimental values is found, and the results demonstrate in particular the spectroscopic quality of the Lenzi, Nowacki, Poves, and Sieja (LNPS) shell-model interaction.
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| 10. |
- Perez-Vidal, R. M., et al.
(författare)
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Evidence of Partial Seniority Conservation in the pi g9/2 Shell for the N=50 Isotones
- 2022
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 129:11
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Tidskriftsartikel (refereegranskat)abstract
- The reduced transition probabilities for the 4+1 -2+1 and 2+1 -0+1 transitions in 92Mo and 94Ru and for the 4+1 -2+1 and 6+1 -4+1 transitions in 90Zr have been determined in this experiment making use of a multinucleon transfer reaction. These results have been interpreted on the basis of realistic shell-model calculations in the f5=2, p3=2, p1=2, and g9=2 proton valence space. Only the combination of extensive lifetime information and large scale shell-model calculations allowed the extent of the seniority conservation in the N = 50 g9=2 orbital to be understood. The conclusion is that seniority is largely conserved in the first 71g9=2 orbital.
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| 11. |
- Zanon, I., et al.
(författare)
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High-Precision Spectroscopy of 20O Benchmarking Ab Initio Calculations in Light Nuclei
- 2023
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 131:26
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Tidskriftsartikel (refereegranskat)abstract
- The excited states of unstable 20O were investigated via γ-ray spectroscopy following the 19O(d,p)20O reaction at 8 AMeV. By exploiting the Doppler shift attenuation method, the lifetimes of the 2+2 and 3+1 states were firmly established. From the γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2+2 and 3+1 states, the B(E2) and B(M1) were determined. Various chiral effective field theory Hamiltonians, describing the nuclear properties beyond ground states, along with a standard USDB interaction, were compared with the experimentally obtained data. Such a comparison for a large set of γ-ray transition probabilities with the valence space in medium similarity renormalization group ab initio calculations was performed for the first time in a nucleus far from stability. It was shown that the ab initio approaches using chiral effective field theory forces are challenged by detailed high-precision spectroscopic properties of nuclei. The reduced transition probabilities were found to be a very constraining test of the performance of the ab initio models.
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| 12. |
- Clement, E., et al.
(författare)
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Conceptual design of the AGATA 1 π array at GANIL
- 2017
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 855, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) has been installed at the GANIL facility, Caen-France. This setup exploits the stable and radioactive heavy-ions beams delivered by the cyclotron accelerator complex of GANIL. Additionally, it benefits from a large palette of ancillary detectors and spectrometers to address in-beam γ-ray spectroscopy of exotic nuclei. The set-up has been designed to couple AGATA with a magnetic spectrometer, charged-particle and neutron detectors, scintillators for the detection of high-energy γ rays and other devices such as a plunger to measure nuclear lifetimes. In this paper, the design and the mechanical characteristics of the set-up are described. Based on simulations, expected performances of the AGATA l π array are presented.
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| 13. |
- Korten, W., et al.
(författare)
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Physics opportunities with the Advanced Gamma Tracking Array : AGATA
- 2020
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 56:5
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Forskningsöversikt (refereegranskat)abstract
- New physics opportunities are opening up by the Advanced Gamma Tracking Array, AGATA, as it evolves to the full 4 pi instrument. AGATA is a high-resolution gamma -ray spectrometer, solely built from highly segmented high-purity Ge detectors, capable of measuring gamma rays from a few tens of keV to beyond 10 MeV, with unprecedented efficiency, excellent position resolution for individual gamma -ray interactions, and very high count-rate capability. As a travelling detector AGATA will be employed at all major current and near-future European research facilities delivering stable and radioactive ion beams.
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| 14. |
- Siciliano, M., et al.
(författare)
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Pairing-quadrupole interplay in the neutron-deficient tin nuclei : First lifetime measurements of low-lying states in Sn-106,Sn-108
- 2020
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Ingår i: Physics Letters B. - : ELSEVIER. - 0370-2693 .- 1873-2445. ; 806
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Tidskriftsartikel (refereegranskat)abstract
- The lifetimes of the low-lying excited states 2(+) and 4(+) have been directly measured in the neutron-deficient Sn-106,Sn-108 isotopes. The nuclei were populated via a deep-inelastic reaction and the lifetime measurement was performed employing a differential plunger device. The emitted gamma rays were detected by the AGATA array, while the reaction products were uniquely identified by the VAMOS++ magnetic spectrometer. Large-Scale Shell-Model calculations with realistic forces indicate that, independently of the pairing content of the interaction, the quadrupole force is dominant in the B(E2; 2(1)(+) -> 0(g.s)(+)) values and it describes well the experimental pattern for Sn104-114 ; the B(E2;(+)(4) -> 2(1)(+)) values, measured here for the first time, depend critically on a delicate pairing-quadrupole balance, disclosed by the very precise results in Sn-108.
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| 15. |
- Siciliano, M., et al.
(författare)
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Lifetime measurements in the even-even 102-108Cd isotopes
- 2021
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Ingår i: Physical Review C. - : American Physical Society. - 2469-9985 .- 2469-9993. ; 104:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: The heaviest T-z = 0 doubly-magic nucleus, Sn-100, and the neighboring nuclei offer unique opportunities to investigate the properties of nuclear interaction. For instance, the structure of light-Sn nuclei has been shown to be affected by the delicate balance between nuclear-interaction components, such as pairing and quadrupole correlations. From Cd to Te, many common features and phenomena have been observed experimentally along the isotopic chains, leading to theoretical studies devoted to a more general and comprehensive study of the region. In this context, having only two proton holes in the Z = 50 shell, the Cd isotopes are expected to present properties similar to those found in the Sn isotopic chain.Purpose: The aim of this work was to measure lifetimes of excited states in neutron-deficient nuclei in the vicinity of Sn-100.Methods: The neutron-deficient nuclei in the N approximate to Z approximate to 50 region were populated using a multinucleon transfer reaction with a Cd-106 beam and a Mo-92 target. The beamlike products were identified by the VAMOS++ spectrometer, while the gamma rays were detected using the AGATA array. Lifetimes of excited states were determined using the recoil distance Doppler-shift method, employing the Cologne differential plunger.Results: Lifetimes of low-lying states were measured in the even-mass Cd-102-(108) isotopes. In particular, multiple states with excitation energy up to MeV, belonging to various bands, were populated in approximate to 3 Cd-106 via inelastic scattering. The transition strengths corresponding to the measured lifetimes were compared with those resulting from state-of-the-art beyond-mean-field calculations using the symmetry-conserving configuration-mixing approach.Conclusions: Despite the similarities in the electromagnetic properties of the low-lying states, there is a fundamental structural difference between the ground-state bands in the Z = 48 and Z = 50 isotopes. The comparison between experimental and theoretical results revealed a rotational character of the Cd nuclei, which have prolate-deformed ground states with beta(2) approximate to 0.2. At this deformation Z = 48 becomes a closed-shell configuration, which is favored with respect to the spherical one.
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| 16. |
- Söderström, Pär-Anders, et al.
(författare)
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Interaction position resolution simulations and in-beam measurements of the AGATA HPGe detectors
- 2011
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 638:1, s. 96-109
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Tidskriftsartikel (refereegranskat)abstract
- The interaction position resolution of the segmented HPGe detectors of an AGATA triple cluster detector has been studied through Monte Carlo simulations and in an in-beam experiment. A new method based on measuring the energy resolution of Doppler-corrected γ-ray spectra at two different target to detector distances is described. This gives the two-dimensional position resolution in the plane perpendicular to the direction of the emitted γ-ray. The γ-ray tracking was used to determine the full energy of the γ-rays and the first interaction point, which is needed for the Doppler correction. Five different heavy-ion induced fusion-evaporation reactions and a reference reaction were selected for the simulations. The results of the simulations show that the method works very well and gives a systematic deviation of in the FWHM of the interaction position resolution for the γ-ray energy range from 60 keV to 5 MeV. The method was tested with real data from an in-beam measurement using a 30Si beam at 64 MeV on a thin 12C target. Pulse-shape analysis of the digitized detector waveforms and γ-ray tracking was performed to determine the position of the first interaction point, which was used for the Doppler corrections. Results of the dependency of the interaction position resolution on the γ-ray energy and on the energy, axial location and type of the first interaction point, are presented. The FWHM of the interaction position resolution varies roughly linearly as a function of γ-ray energy from 8.5 mm at 250 keV to 4 mm at 1.5 MeV, and has an approximately constant value of about 4 mm in the γ-ray energy range from 1.5 to 4 MeV.
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| 17. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 18. |
- Lalovic, Natasa, et al.
(författare)
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Analysis of the Response of AGATA Detectors at GSI
- 2015
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Ingår i: EPJ Web of Conferences. - : EDP Sciences. - 2101-6275 .- 2100-014X. - 9782759817948 ; 93, s. 07007-07007
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Konferensbidrag (refereegranskat)abstract
- In 2012 and 2014 the γ-ray tracking spectrometer AGATA was operated at the SIS/FRS facility at GSI in Darmstadt, Germany. The performance of the array is discussed, outlining some important aspects of the offline data processing and analysis. Relying on the data obtained from measurements with standard γ-ray sources, a first estimate of the photopeak efficiency and peak-to-total (P/T) is presented.
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| 19. |
- Lalovic, Natasa, et al.
(författare)
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Performance of the AGATA gamma-ray spectrometer in the PreSPEC set-up at GSI
- 2016
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576 .- 0167-5087. ; 806, s. 258-266
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Tidskriftsartikel (refereegranskat)abstract
- In contemporary nuclear physics, the European Advanced GAmma Tracking Array (AGATA) represents a crucial detection system for cutting-edge nuclear structure studies. AGATA consists of highly segmented high-purity germanium crystals and uses the pulse-shape analysis technique to determine both the position and the energy of the y-ray interaction points in the crystals. It is the tracking algorithms that deploy this information and enable insight into the sequence of interactions, providing information on the full or partial absorption of the 7 ray. A series of dedicated performance measurements for an AGATA set-up comprising 21 crystals is described. This set-up was used within the recent PreSPEC-AGATA experimental campaign at the GSI Helmholtzzentrum fur Schwerionenforschung. Using the radioactive sources Co-56, Co-60 and Eu-152, absolute and normalized efficiencies and the peak-to-total of the array were measured. These quantities are discussed using different data analysis procedures. The quality of the pulse-shape analysis and the tracking algorithm are evaluated. The agreement between the experimental data and the Geant4 simulations is also investigated.
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| 20. |
- Larsbrink, Johan, et al.
(författare)
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A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 506:7489, s. 498-502
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Tidskriftsartikel (refereegranskat)abstract
- A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables(1). Owing to the paucity of alimentary enzymes encoded by the human genome(2), our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut(3,4). The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides(5,6) whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear(1,7,8). Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health(9-12).
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| 21. |
- de Angelis, G., et al.
(författare)
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AGATA : nuclear structure advancements with fusion-evaporation reactions
- 2023
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Ingår i: European Physical Journal A. - : Springer Nature. - 1434-6001 .- 1434-601X. ; 59:7
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear-structure studies using fusion reactions are reviewed in terms of prospects for advancement using the next generation of ?-ray tracking arrays such as AGATA. Properties discussed include those of light N = Z nuclei and rotational behaviour in heavy nuclei at high values of angular momentum and internal excitation energy.
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| 22. |
- Fougeres, Chloe, et al.
(författare)
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Search for Na-22 in novae supported by a novel method for measuring femtosecond nuclear lifetimes
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Classical novae are thermonuclear explosions in stellar binary systems, and important sources of Al-26 and Na-22. While ? rays from the decay of the former radioisotope have been observed throughout the Galaxy, Na-22 remains untraceable. Its half-life (2.6 yr) would allow the observation of its 1.275 MeV ?-ray line from a cosmic source. However, the prediction of such an observation requires good knowledge of its nucleosynthesis. The Na-22(p, ?)Mg-23 reaction remains the only source of large uncertainty about the amount of Na-22 ejected. Its rate is dominated by a single resonance on the short-lived state at 7785.0(7) keV in Mg-23. Here, we propose a combined analysis of particle-particle correlations and velocity-difference profiles to measure femtosecond nuclear lifetimes. The application of this method to the study of the Mg-23 states, places strong limits on the amount of Na-22 produced in novae and constrains its detectability with future space-borne observatories. The authors report a particle-particle correlation and velocity-difference profile method to measure nuclear lifetime. The results obtained for excited states of 23Mg are used to constrain the production of 22Na in the astrophysical novae explosions.
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| 23. |
- Ravishankar, Raman, et al.
(författare)
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Characterization of Nanosized Material Extracted from Clear Suspensions for MFI Zeolite Synthesis
- 1999
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 103:24, s. 4960-4964
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Tidskriftsartikel (refereegranskat)abstract
- The silica species contained in an aged clear suspension, which upon heating gives rise to the crystallization of Silicalite-1, were extracted with 80% efficiency using a sequence of acidification, salting out, phase transfer into organic solvent, and freeze-drying methods. This silica powder was characterized by X-ray scattering, transmission electron microscopy, atomic force microscopy, and 29Si magic angle spinning nuclear magnetic resonance. These techniques gave evidence for the presence of a very specific morphology, corresponding to slab shaped particles, with dimensions of 1.3 × 4.0 × 4.0 nm. The nanoslabs have the MFI structure with nine channel intersections per particle, each containing a TPA cation. The identity of the extracted nanoslabs with the species in suspension is evidenced with in situ and ex situ X-ray scattering.
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| 24. |
- Ravishankar, Raman, et al.
(författare)
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Physicochemical characterization of silicalite-1 nanophase material
- 1998
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 102:15, s. 2633-2639
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Tidskriftsartikel (refereegranskat)abstract
- A silicalite-1 nanophase material with an elementary particle size of 18-100 nm is synthesized from clear solution and isolated and purified using supercentrifugation. The nanopowder is characterized in detail using scanning electron microscopy, high-resolution transmission electron microscopy, attenuated force microscopy, 29Si magic angle spinning NMR, 13C cross polarization magic angle spinning NMR, X-ray diffraction, dinitrogen physisorption, and thermogravimetric analysis and compared with micrometer-sized silicalite-1. The nanosized and micrometer-sized materials have many common properties including the refined structure and the nature and concentrations of tetrapropylammonium species incorporated during the synthesis. Unique properties of the nanophase are a splitting of the characteristic framework vibration at 550 cm-1 into a doublet at 555 and 570 cm-1, a high concentration of defect sites, and a strain in the crystallites along the "a" crystallographic direction. The nanophase exhibits a two-stage dinitrogen physisorption in the low-pressure region, ascribed to adsorptions in micropores created by the stacking of the nanoparticles in addition to adsorptions in the intracrystalline micropores.
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| 25. |
- Smid, Marcel, et al.
(författare)
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The circular RNome of primary breast cancer
- 2019
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 29:3, s. 356-366
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Tidskriftsartikel (refereegranskat)abstract
- Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R <0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.
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| 26. |
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| 27. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 28. |
- Brinkman, Arie B., et al.
(författare)
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Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
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| 29. |
- Davies, Helen R., et al.
(författare)
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HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 23:4, s. 517-525
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
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| 30. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 31. |
- Glodzik, Dominik, et al.
(författare)
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A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 341-348
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Tidskriftsartikel (refereegranskat)abstract
- Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
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| 32. |
- Smid, Marcel, et al.
(författare)
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Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.
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| 33. |
- Zair, A, et al.
(författare)
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Time-resolved measurements of high order harmonics confined by polarization gating
- 2004
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Ingår i: Applied Physics B. - : Springer Science and Business Media LLC. - 0946-2171 .- 1432-0649. ; 78:7-8, s. 869-872
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the temporal confinement of high order harmonic pulses generated by a femtosecond (fs) infrared (IR) pulse with a time varying polarization. We use a set of two birefringent quartz plates to modulate the IR polarization. It produces a short temporal gate of linear polarization where harmonics are efficiently generated during a small fraction of the IR pulse. By rotating one of the plates, the gate width can be continuously varied between 70 fs down to 7 fs. The XUV pulse duration is measured by cross-correlation with a probe IR pulse of 12 fs. When the gate width is decreased, a clear temporal confinement of the XUV emission is observed through the cross correlation signal. This experiment is the first direct experimental evidence in the temporal domain that the polarization gating technique can be used to significantly shorten the harmonic pulse duration.
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