| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)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. |
- Elhai, M, et al.
(författare)
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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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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Tidskriftsartikel (refereegranskat)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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| 4. |
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| 5. |
- Meech, K. J., et al.
(författare)
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EPOXI: Comet 103P/Hartley 2 Observations from a Worldwide Campaign
- 2011
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Ingår i: Astrophysical Journal Letters. - London : IOP. - 2041-8213 .- 2041-8205. ; 734:L1, s. 1-9
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Becker, M, et al.
(författare)
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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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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Amendola, L., et al.
(författare)
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Cosmology and fundamental physics with the Euclid satellite
- 2018
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Ingår i: Living Reviews in Relativity. - : Springer. - 1433-8351 .- 2367-3613. ; 21:1
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Chyz̊y, K.T., et al.
(författare)
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LOFAR MSSS: Flattening low-frequency radio continuum spectra of nearby galaxies
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 619
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Tidskriftsartikel (refereegranskat)abstract
- Aims. The shape of low-frequency radio continuum spectra of normal galaxies is not well understood, the key question being the role of physical processes such as thermal absorption in shaping them. In this work we take advantage of the LOFAR Multifrequency Snapshot Sky Survey (MSSS) to investigate such spectra for a large sample of nearby star-forming galaxies. Methods. Using the measured 150 MHz flux densities from the LOFAR MSSS survey and literature flux densities at various frequencies we have obtained integrated radio spectra for 106 galaxies characterised by different morphology and star formation rate. The spectra are explained through the use of a three-dimensional model of galaxy radio emission, and radiation transfer dependent on the galaxy viewing angle and absorption processes. Results. Our galaxies' spectra are generally flatter at lower compared to higher frequencies: the median spectral index αlow measured between ≈ 50 MHz and 1.5 GHz is -0.57 ± 0.01 while the high-frequency one αhigh, calculated between 1.3 GHz and 5 GHz, is -0.77 ± 0.03. As there is no tendency for the highly inclined galaxies to have more flattened low-frequency spectra, we argue that the observed flattening is not due to thermal absorption, contradicting the suggestion of Israel & Mahoney (1990, ApJ, 352, 30). According to our modelled radio maps for M 51-like galaxies, the free-free absorption effects can be seen only below 30 MHz and in the global spectra just below 20 MHz, while in the spectra of starburst galaxies, like M 82, the flattening due to absorption is instead visible up to higher frequencies of about 150 MHz. Starbursts are however scarce in the local Universe, in accordance with the weak spectral curvature seen in the galaxies of our sample. Locally, within galactic disks, the absorption effects are distinctly visible in M 51-like galaxies as spectral flattening around 100-200 MHz in the face-on objects, and as turnovers in the edge-on ones, while in M 82-like galaxies there are strong turnovers at frequencies above 700 MHz, regardless of viewing angle. Conclusions. Our modelling of galaxy spectra suggests that the weak spectral flattening observed in the nearby galaxies studied here results principally from synchrotron spectral curvature due to cosmic ray energy losses and propagation effects. We predict much stronger effects of thermal absorption in more distant galaxies with high star formation rates. Some influence exerted by the Milky Way's foreground on the spectra of all external galaxies is also expected at very low frequencies.
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| 9. |
- Heald, G., et al.
(författare)
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Magnetism science with the square kilometre array
- 2020
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Ingår i: Galaxies. - : MDPI AG. - 2075-4434. ; 8:8
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Tidskriftsartikel (refereegranskat)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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| 10. |
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| 11. |
- Govoni, F., et al.
(författare)
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A radio ridge connecting two galaxy clusters in a filament of the cosmic web
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6444, s. 981-984
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Tidskriftsartikel (refereegranskat)abstract
- Galaxy clusters are the most massive gravitationally bound structures in the Universe. They grow by accreting smaller structures in a merging process that produces shocks and turbulence in the intracluster gas. We observed a ridge of radio emission connecting the merging galaxy clusters Abell 0399 and Abell 0401 with the Low-Frequency Array (LOFAR) telescope network at 140 megahertz. This emission requires a population of relativistic electrons and a magnetic field located in a filament between the two galaxy clusters. We performed simulations to show that a volume-filling distribution of weak shocks may reaccelerate a preexisting population of relativistic particles, producing emission at radio wavelengths that illuminates the magnetic ridge.
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| 12. |
- Azzu, V., et al.
(författare)
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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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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 48
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Tidskriftsartikel (refereegranskat)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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| 13. |
- Carretti, Ettore, et al.
(författare)
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Magnetic field strength in cosmic web filaments
- 2022
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 512:1, s. 945-959
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Tidskriftsartikel (refereegranskat)abstract
- We used the rotation measure (RM) catalogue derived from the LOFAR Two-metre Sky Survey Data Release 2 (LoTSS DR2) at 144MHz to measure the evolution with redshift of the extragalactic RM (RRM: Residual RM) and the polarization fraction (p) of sources in low-density environments. We also measured the same at 1.4 GHz by cross-matching with the NRAO VLA Sky Survey RM catalogue. We find that RRM versus redshift is flat at 144 MHz, but, once redshift-corrected, it shows evolution at high significance. Also, p evolves with redshift with a decrement by a factor of similar to 8 at z similar to 2. Comparing the 144-MHz and 1.4-GHz data, we find that the observed RRM and p are most likely to have an origin local to the source at 1.4 GHz, while a cosmic web filament origin is favoured at 144 MHz. If we attribute the entire signal to filaments, we infer a mean rest-frame RRM per filament of RRM0,f = 0.71 +/- 0.07 rad m(-2) and a magnetic field per filament of B-f = 32 +/- 3 nG. This is in agreement with estimates obtained with a complementary method based on synchrotron emission stacking, and with cosmological simulations if primordial magnetic fields are amplified by astrophysical source field seeding. The measurement of an RRM0, f supports the presence of diffuse baryonic gas in filaments. We also estimated a conservative upper limit of the filament magnetic turbulence of sigma(RRM0,f) = 0.039 +/- 0.001 rad m(-2), concluding that the ordered magnetic field component dominates in filaments.
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| 14. |
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| 15. |
- Indriolo, Nick, et al.
(författare)
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SOFIA/EXES observations of water absorption in the protostar AFGL 2591 at high spectral resolution
- 2015
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Ingår i: Astrophysical Journal Letters. - 2041-8213. ; 802:2
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Tidskriftsartikel (refereegranskat)abstract
- We present high spectral resolution (similar to 3 km s(-1)) observations of the nu(2) ro-vibrational band of H2O in the 6.086-6.135 mu m range toward the massive protostar AFGL 2591 using the Echelon-Cross-Echelle Spectrograph (EXES) on the Stratospheric Observatory for Infrared Astronomy (SOFIA). Ten absorption features are detected in total, with seven caused by transitions in the nu(2) band of H2O, two by transitions in the first vibrationally excited nu(2) band of H2O, and one by a transition in the nu(2) band of (H2O)-O-18. Among the detected transitions is the nu(2) 1(1,1)-0(0,0) line that probes the lowest-lying rotational level of para-H2O. The stronger transitions appear to be optically thick, but reach maximum absorption at a depth of about 25%, suggesting that the background source is only partially covered by the absorbing gas or that the absorption arises within the 6 mu m emitting photosphere. Assuming a covering fraction of 25%, the H2O column density and rotational temperature that best fit the observed absorption lines are N(H2O) = (1.3 +/- 0.3) x 10(19) cm(-2) and T = 640 +/- 80 K.
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| 16. |
- Kowal-Bielecka, Otylia, et al.
(författare)
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Update of EULAR recommendations for the treatment of systemic sclerosis
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76, s. 1327-1339
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
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| 17. |
- O'Sullivan, S. P., et al.
(författare)
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The Faraday Rotation Measure Grid of the LOFAR Two-metre Sky Survey: Data Release 2
- 2023
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 519:4, s. 5723-5742
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Tidskriftsartikel (refereegranskat)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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| 18. |
- Vacca, V., et al.
(författare)
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Statistical methods for the analysis of rotation measure grids in large scale structures in the SKA era
- 2015
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Ingår i: Proceedings of Science. - 1824-8039. ; 9-13-June-2014
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Konferensbidrag (refereegranskat)abstract
- Determining magnetic field properties in different environments of the cosmic large-scale structure as well as their evolution over redshift is a fundamental step toward uncovering the origin of cosmic magnetic fields. Radio observations permit the study of extragalactic magnetic fields via measurements of the Faraday depth of extragalactic radio sources. Our aim is to investigate how much different extragalactic environments contribute to the Faraday depth variance of these sources. We develop a Bayesian algorithm to distinguish statistically Faraday depth variance contributions intrinsic to the source from those due to the medium between the source and the observer. In our algorithm the Galactic foreground and the measurement noise are taken into account as the uncertainty correlations of the galactic model. Additionally, our algorithm allows for the investigation of possible redshift evolution of the extragalactic contribution. This work presents the derivation of the algorithm and tests performed on mock observations. With cosmic magnetism being one of the key science projects of the new generation of radio interferometers we have made predictions for the algorithm's performance on data from the next generation of radio interferometers. Applications to real data are left for future work.
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| 19. |
- Vacca, V., et al.
(författare)
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Using rotation measure grids to detect cosmological magnetic fields: A Bayesian approach
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 591, s. Art. no. A13-
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Tidskriftsartikel (refereegranskat)abstract
- Determining magnetic field properties in different environments of the cosmic large-scale structure as well as their evolution over redshift is a fundamental step toward uncovering the origin of cosmic magnetic fields. Radio observations permit the study of extragalactic magnetic fields via measurements of the Faraday depth of extragalactic radio sources. Our aim is to investigate how much different extragalactic environments contribute to the Faraday depth variance of these sources. We develop a Bayesian algorithm to distinguish statistically Faraday depth variance contributions intrinsic to the source from those due to the medium between the source and the observer. In our algorithm the Galactic foreground and measurement noise are taken into account as the uncertainty correlations of the Galactic model. Additionally, our algorithm allows for the investigation of possible redshift evolution of the extragalactic contribution. This work presents the derivation of the algorithm and tests performed on mock observations. Because cosmic magnetism is one of the key science projects of the new generation of radio interferometers, we have predicted the performance of our algorithm on mock data collected with these instruments. According to our tests, high-quality catalogs of a few thousands of sources should already enable us to investigate magnetic fields in the cosmic structure.
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| 20. |
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| 21. |
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| 22. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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| 23. |
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| 24. |
- O'Sullivan, Shane P., et al.
(författare)
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The intergalactic magnetic field probed by a giant radio galaxy
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 622
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Forskningsöversikt (refereegranskat)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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| 25. |
- Pellegrinelli, V, et al.
(författare)
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Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance
- 2022
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 4:4, s. 476-
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Tidskriftsartikel (refereegranskat)abstract
- Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes. Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.
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