| 1. |
- de Rojas, I., et al.
(författare)
-
Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
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).
|
|
| 2. |
|
|
| 3. |
- Meech, K. J., et al.
(författare)
-
EPOXI: Comet 103P/Hartley 2 Observations from a Worldwide Campaign
- 2011
-
Ingår i: Astrophysical Journal Letters. - London : IOP. - 2041-8213 .- 2041-8205. ; 734:L1, s. 1-9
-
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.
|
|
| 4. |
- Elhai, M, et al.
(författare)
-
Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
-
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.
|
|
| 5. |
|
|
| 6. |
- Becker, M, et al.
(författare)
-
Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
- 2019
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
-
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.
|
|
| 7. |
- Govaere, O., et al.
(författare)
-
Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
-
Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
-
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
|
|
| 8. |
- Pellegrinelli, V, et al.
(författare)
-
Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance
- 2022
-
Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 4:4, s. 476-
-
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.
|
|
| 9. |
- Govoni, F., et al.
(författare)
-
A radio ridge connecting two galaxy clusters in a filament of the cosmic web
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6444, s. 981-984
-
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.
|
|
| 10. |
- Chyz̊y, K.T., et al.
(författare)
-
LOFAR MSSS: Flattening low-frequency radio continuum spectra of nearby galaxies
- 2018
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 619
-
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.
|
|
