| 1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
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| 3. |
- Meech, K. J., et al.
(author)
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EPOXI: Comet 103P/Hartley 2 Observations from a Worldwide Campaign
- 2011
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In: Astrophysical Journal Letters. - London : IOP. - 2041-8213 .- 2041-8205. ; 734:L1, s. 1-9
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Journal article (peer-reviewed)abstract
- Earth- and space-based observations provide synergistic information for space mission encounters by providing data over longer timescales, at different wavelengths and using techniques that are impossible with an in situ flyby. We report here such observations in support of the EPOXI spacecraft flyby of comet 103P/Hartley 2. The nucleus is small and dark, and exhibited a very rapidly changing rotation period. Prior to the onset of activity, the period was ~16.4?hr. Starting in 2010 August the period changed from 16.6?hr to near 19?hr in December. With respect to dust composition, most volatiles and carbon and nitrogen isotope ratios, the comet is similar to other Jupiter-family comets. What is unusual is the dominance of CO 2 -driven activity near perihelion, which likely persists out to aphelion. Near perihelion the comet nucleus was surrounded by a large halo of water-ice grains that contributed significantly to the total water production.
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| 4. |
- Elhai, M, et al.
(author)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Journal article (peer-reviewed)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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| 5. |
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| 6. |
- Amendola, L., et al.
(author)
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Cosmology and fundamental physics with the Euclid satellite
- 2018
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In: Living Reviews in Relativity. - : Springer. - 1433-8351 .- 2367-3613. ; 21:1
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Journal article (peer-reviewed)abstract
- Euclid is a European Space Agency medium-class mission selected for launch in 2020 within the cosmic vision 2015–2025 program. The main goal of Euclid is to understand the origin of the accelerated expansion of the universe. Euclid will explore the expansion history of the universe and the evolution of cosmic structures by measuring shapes and red-shifts of galaxies as well as the distribution of clusters of galaxies over a large fraction of the sky. Although the main driver for Euclid is the nature of dark energy, Euclid science covers a vast range of topics, from cosmology to galaxy evolution to planetary research. In this review we focus on cosmology and fundamental physics, with a strong emphasis on science beyond the current standard models. We discuss five broad topics: dark energy and modified gravity, dark matter, initial conditions, basic assumptions and questions of methodology in the data analysis. This review has been planned and carried out within Euclid’s Theory Working Group and is meant to provide a guide to the scientific themes that will underlie the activity of the group during the preparation of the Euclid mission.
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| 7. |
- Heald, G., et al.
(author)
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Magnetism science with the square kilometre array
- 2020
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In: Galaxies. - : MDPI AG. - 2075-4434. ; 8:8
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Journal article (peer-reviewed)abstract
- The Square Kilometre Array (SKA) will answer fundamental questions about the origin, evolution, properties, and influence of magnetic fields throughout the Universe. Magnetic fields can illuminate and influence phenomena as diverse as star formation, galactic dynamics, fast radio bursts, active galactic nuclei, large-scale structure, and dark matter annihilation. Preparations for the SKA are swiftly continuing worldwide, and the community is making tremendous observational progress in the field of cosmic magnetism using data from a powerful international suite of SKA pathfinder and precursor telescopes. In this contribution, we revisit community plans for magnetism research using the SKA, in light of these recent rapid developments. We focus in particular on the impact that new radio telescope instrumentation is generating, thus advancing our understanding of key SKA magnetism science areas, as well as the new techniques that are required for processing and interpreting the data. We discuss these recent developments in the context of the ultimate scientific goals for the SKA era.
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| 8. |
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| 9. |
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| 10. |
- Becker, M, et al.
(author)
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Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
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Journal article (peer-reviewed)abstract
- Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.MethodsInclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.ResultsOf 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.ConclusionsThe use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
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| 17. |
- O'Sullivan, Shane P., et al.
(author)
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The intergalactic magnetic field probed by a giant radio galaxy
- 2019
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 622
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Research review (peer-reviewed)abstract
- Cosmological simulations predict that an intergalactic magnetic field (IGMF) pervades the large scale structure (LSS) of the Universe. Measuring the IGMF is important to determine its origin (i.e. primordial or otherwise). Using data from the LOFAR Two Metre Sky Survey (LoTSS), we present the Faraday rotation measure (RM) and depolarisation properties of the giant radio galaxy J1235+5317, at a redshift of z = 0.34 and 3.38 Mpc in size. We find a mean RM difference between the lobes of 2.5 ±0.1 rad m -2 , in addition to small scale RM variations of ∼0.1 rad m -2 . From a catalogue of LSS filaments based on optical spectroscopic observations in the local universe, we find an excess of filaments intersecting the line of sight to only one of the lobes. Associating the entire RM difference to these LSS filaments leads to a gas density-weighted IGMF strength of ∼0.3 μG. However, direct comparison with cosmological simulations of the RM contribution from LSS filaments gives a low probability (∼5%) for an RM contribution as large as 2.5 rad m -2 , for the case of IGMF strengths of 10-50 nG. It is likely that variations in the RM from the Milky Way (on 11′ scales) contribute significantly to the mean RM difference, and a denser RM grid is required to better constrain this contribution. In general, this work demonstrates the potential of the LOFAR telescope to probe the weak signature of the IGMF. Future studies, with thousands of sources with high accuracy RMs from LoTSS, will enable more stringent constraints on the nature of the IGMF.
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| 18. |
- Oppermann, N., et al.
(author)
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Estimating extragalactic Faraday rotation
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 575
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Journal article (peer-reviewed)abstract
- Observations of Faraday rotation for extragalactic sources probe magnetic fields both inside and outside the Milky Way. Building on our earlier estimate of the Galactic contribution, we set out to estimate the extragalactic contributions. We discuss the problems involved; in particular, we point out that taking the difference between the observed values and the Galactic foreground reconstruction is not a good estimate for the extragalactic contributions. We point out a degeneracy between the contributions to the observed values due to extragalactic magnetic fields and observational noise and comment on the dangers of over-interpreting an estimate without taking into account its uncertainty information. To overcome these difficulties, we develop an extended reconstruction algorithm based on the assumption that the observational uncertainties are accurately described for a subset of the data, which can overcome the degeneracy with the extragalactic contributions. We present a probabilistic derivation of the algorithm and demonstrate its performance using a simulation, yielding a high quality reconstruction of the Galactic Faraday rotation foreground, a precise estimate of the typical extragalactic contribution, and a well-defined probabilistic description of the extragalactic contribution for each data point. We then apply this reconstruction technique to a catalog of Faraday rotation observations for extragalactic sources. The analysis is done for several different scenarios, for which we consider the error bars of different subsets of the data to accurately describe the observational uncertainties. By comparing the results, we argue that a split that singles out only data near the Galactic poles is the most robust approach. We find that the dispersion of extragalactic contributions to observed Faraday depths is most likely lower than 7 rad/m(2), in agreement with earlier results, and that the extragalactic contribution to an individual data point is poorly constrained by the data in most cases.
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| 19. |
- O'Sullivan, S. P., et al.
(author)
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The Faraday Rotation Measure Grid of the LOFAR Two-metre Sky Survey: Data Release 2
- 2023
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 519:4, s. 5723-5742
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Journal article (peer-reviewed)abstract
- A Faraday rotation measure (RM) catalogue, or RM Grid, is a valuable resource for the study of cosmic magnetism. Using the second data release (DR2) from the LOFAR Two-metre Sky Survey (LoTSS), we have produced a catalogue of 2461 extragalactic high-precision RM values across 5720 deg(2) of sky (corresponding to a polarized source areal number density of similar to 0.43 deg(-2)). The linear polarization and RM properties were derived using RM synthesis from the Stokes Q and U channel images at an angular resolution of 20 arcsec across a frequency range of 120 to 168 MHz with a channel bandwidth of 97.6 kHz. The fraction of total intensity sources (>1 mJy beam(-1)) found to be polarized was similar to 0.2 percent. The median detection threshold was 0.6 mJy beam(-1) (8 sigma(QU)), with a median RM uncertainty of 0.06 rad m(-2) (although a systematic uncertainty of up to 0.3 radm(-2) is possible, after the ionosphere RM correction). The median degree of polarization of the detected sources is 1.8 percent, with a range of 0.05 percent to 31 percent. Comparisons with cm-wavelength RMs indicate minimal amounts of Faraday complexity in the LoTSS detections, making them ideal sources for RM Grid studies. Host galaxy identifications were obtained for 88 percent of the sources, along with redshifts for 79 percent (both photometric and spectroscopic), with the median redshift being 0.6. The focus of the current catalogue was on reliability rather than completeness, and we expect future versions of the LoTSS RM Grid to have a higher areal number density. In addition, 25 pulsars were identified, mainly through their high degrees of linear polarization.
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| 20. |
- Azzu, V., et al.
(author)
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Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression
- 2021
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In: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 48
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Journal article (peer-reviewed)abstract
- Objective: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH. (C) 2021 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 21. |
- Boschini, M. J., et al.
(author)
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A Hint of a Low-energy Excess in Cosmic-Ray Fluorine
- 2022
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 925:2
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Journal article (peer-reviewed)abstract
- Since its launch, the Alpha Magnetic Spectrometer–02 (AMS-02) has delivered outstanding quality measurements of the spectra of cosmic-ray (CR) species (, e±) and nuclei (H–O, Ne, Mg, Si, Fe), which resulted in a number of breakthroughs. The most recent AMS-02 result is the measurement of the spectrum of CR fluorine up to ∼2 TV. Given its very low solar system abundance, fluorine in CRs is thought to be mostly secondary, produced in fragmentations of heavier species, predominantly Ne, Mg, and Si. Similar to the best-measured secondary-to-primary boron to carbon nuclei ratio that is widely used to study the origin and propagation of CR species, the precise fluorine data would allow the origin of Si-group nuclei to be studied independently. Meanwhile, the secondary origin of CR fluorine has never been tested in a wide energy range due to the lack of accurate CR data. In this paper, we use the first ever precise measurements of the fluorine spectrum by AMS-02 together with ACE-CRIS and Voyager 1 data to actually test this paradigm. Our detailed modeling shows an excess below 10 GV in the fluorine spectrum that may hint at a primary fluorine component. We also provide an updated local interstellar spectrum (LIS) of fluorine in the rigidity range from a few MV to ∼2 TV. Our calculations employ the self-consistent GalProp–HelMod framework that has proved to be a reliable tool in deriving the LIS of CR and e−, and nuclei Z ≤ 28.
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| 22. |
- Boschini, M. J., et al.
(author)
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Deciphering the Local Interstellar Spectra of Primary Cosmic-Ray Species with HELMOD
- 2018
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 858:1
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Journal article (peer-reviewed)abstract
- Local interstellar spectra (LIS) of primary cosmic ray (CR) nuclei, such as helium, oxygen, and mostly primary carbon are derived for the rigidity range from 10 MV to similar to 200 TV using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and HELMOD, are combined into a single framework that is used to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. The developed iterative maximum-likelihood method uses GALPROP-predicted LIS as input to HELMOD, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The interstellar and heliospheric propagation parameters derived in this study are consistent with our prior analyses using the same methodology for propagation of CR protons, helium, antiprotons, and electrons. The resulting LIS accommodate a variety of measurements made in the local interstellar space (Voyager 1) and deep inside the heliosphere at low (ACE/CRIS, HEAO-3) and high energies (PAMELA, AMS-02).
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| 23. |
- Boschini, M. J., et al.
(author)
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HelMod in the Works : From Direct Observations to the Local Interstellar Spectrum of Cosmic-Ray Electrons
- 2018
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 854:2
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Journal article (peer-reviewed)abstract
- The local interstellar spectrum (LIS) of cosmic-ray (CR) electrons for the energy range 1 MeV to 1 TeV is derived using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and HELMOD, are combined to provide a single framework that is run to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. An iterative maximum-likelihood method is developed that uses GALPROP-predicted LIS as input to HELMOD, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The optimized HelMod parameters are then used to adjust GALPROP parameters to predict a refined LIS with the procedure repeated subject to a convergence criterion. The parameter optimization uses an extensive data set of proton spectra from 1997 to 2015. The proposed CR electron LIS accommodates both the low-energy interstellar spectra measured by Voyager 1 as well as the high-energy observations by PAMELA and AMS-02 that are made deep in the heliosphere; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The interstellar and heliospheric propagation parameters derived in this study agree well with our earlier results for CR protons, helium nuclei, and anti-protons propagation and LIS obtained in the same framework.
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| 24. |
- Boschini, M. J., et al.
(author)
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Solution of Heliospheric Propagation : Unveiling the Local Interstellar Spectra of Cosmic-ray Species
- 2017
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 840:2
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Journal article (peer-reviewed)abstract
- Local interstellar spectra (LIS) for protons, helium, and antiprotons are built using the most recent experimental results combined with state-of-the-art models for propagation in the Galaxy and heliosphere. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of cosmic-ray (CR) species at different modulation levels and at both polarities of the solar magnetic field. To do so in a self-consistent way, an iterative procedure was developed, where the GALPROP LIS output is fed into HelMod, providing modulated spectra for specific time periods of selected experiments to compare with the data; the HelMod parameter optimization is performed at this stage and looped back to adjust the LIS using the new GALPROP run. The parameters were tuned with the maximum likelihood procedure using an extensive data set of proton spectra from 1997 to 2015. The proposed LIS accommodate both the low-energy interstellar CR spectra measured by Voyager 1 and the high-energy observations by BESS, Pamela, AMS-01, and AMS-02 made from the balloons and near-Earth payloads; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The found solution is in a good agreement with proton, helium, and antiproton data by AMS-02, BESS, and PAMELA in the whole energy range.
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| 25. |
- Boschini, M. J., et al.
(author)
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Spectra of Cosmic-Ray Sodium and Aluminum and Unexpected Aluminum Excess
- 2022
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 933:2
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Journal article (peer-reviewed)abstract
- Since its launch, the Alpha Magnetic Spectrometer-02 (AMS-02) has delivered outstanding quality measurements of the spectra of cosmic-ray (CR) species, , e±, and nuclei (H–Si, Fe), which resulted in a number of breakthroughs. The most recent AMS-02 result is the measurement of the spectra of CR sodium and aluminum up to ∼2 TV. Given their low solar system abundances, a significant fraction of each element is produced in fragmentations of heavier species, predominantly Ne, Mg, and Si. In this paper, we use precise measurements of the sodium and aluminum spectra by AMS-02 together with ACE-CRIS and Voyager 1 data to test their origin. We show that the sodium spectrum agrees well with the predictions made with the GalProp-HelMod framework, while the aluminum spectrum shows a significant excess in the rigidity range from 2–7 GV. In this context, we discuss the origin of other low-energy excesses in Li, F, and Fe found earlier. The observed excesses in Li, F, and Al appear to be consistent with the local Wolf-Rayet stars hypothesis, invoked to reproduce anomalous 22Ne/20Ne, 12C/16O, and 58Fe/56Fe ratios in CRs, while excess in Fe is likely connected with a past supernova activity in the solar neighborhood. We also provide updated local interstellar spectra (LIS) of sodium and aluminum in the rigidity range from a few megavolts to ∼2 TV. Our calculations employ the self-consistent GalProp-HelMod framework, which has proved to be a reliable tool in deriving the LIS of CR , e−, and nuclei Z ≤ 28.
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