| 1. |
- Namkoong, H, et al.
(författare)
-
DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
-
Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
|
|
| 2. |
|
|
| 3. |
- Wang, QBS, et al.
(författare)
-
The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
-
Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
|
|
| 4. |
- Aad, G., et al.
(författare)
-
- 2010
-
swepub:Mat__t
|
|
| 5. |
- Aad, G., et al.
(författare)
-
- 2010
-
swepub:Mat__t
|
|
| 6. |
- Aad, G., et al.
(författare)
-
- 2010
-
swepub:Mat__t
|
|
| 7. |
- Aad, G., et al.
(författare)
-
- 2010
-
swepub:Mat__t
|
|
| 8. |
- Aad, G., et al.
(författare)
-
- 2011
-
swepub:Mat__t
|
|
| 9. |
|
|
| 10. |
- Acharya, B. S., et al.
(författare)
-
Introducing the CTA concept
- 2013
-
Ingår i: Astroparticle physics. - : Elsevier BV. - 0927-6505 .- 1873-2852. ; 43, s. 3-18
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project. (C) 2013 Elsevier B.V. All rights reserved.
|
|
| 11. |
- Acero, F., et al.
(författare)
-
Prospects for Cherenkov Telescope Array Observations of the Young Supernova Remnant RX J1713.7-3946
- 2017
-
Ingår i: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 840:2
-
Tidskriftsartikel (refereegranskat)abstract
- We perform simulations for future Cherenkov Telescope Array (CTA) observations of RX J1713.7-3946, a young supernova remnant (SNR) and one of the brightest sources ever discovered in very high energy (VHE) gamma rays. Special attention is paid to exploring possible spatial (anti) correlations of gamma rays with emission at other wavelengths, in particular X-rays and CO/H I emission. We present a series of simulated images of RX J1713.7-3946 for CTA based on a set of observationally motivated models for the gamma-ray emission. In these models, VHE gamma rays produced by high-energy electrons are assumed to trace the nonthermal X-ray emission observed by XMM-Newton, whereas those originating from relativistic protons delineate the local gas distributions. The local atomic and molecular gas distributions are deduced by the NANTEN team from CO and H I observations. Our primary goal is to show how one can distinguish the emission mechanism(s) of the gamma rays (i.e., hadronic versus leptonic, or a mixture of the two) through information provided by their spatial distribution, spectra, and time variation. This work is the first attempt to quantitatively evaluate the capabilities of CTA to achieve various proposed scientific goals by observing this important cosmic particle accelerator.
|
|
| 12. |
- Abate, E., et al.
(författare)
-
Combined performance tests before installation of the ATLAS Semiconductor and Transition Radiation Tracking Detectors
- 2008
-
Ingår i: Journal of Instrumentation. - 1748-0221. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- The ATLAS (A Toroidal LHC ApparatuS) Inner Detector provides charged particle tracking in the centre of the ATLAS experiment at the Large Hadron Collider (LHC). The Inner Detector consists of three subdetectors: the Pixel Detector, the Semiconductor Tracker (SCT), and the Transition Radiation Tracker (TRT). This paper summarizes the tests that were carried out at the final stage of SCT+TRT integration prior to their installation in ATLAS. The combined operation and performance of the SCT and TRT barrel and endcap detectors was investigated through a series of noise tests, and by recording the tracks of cosmic rays. This was a crucial test of hardware and software of the combined tracker detector systems. The results of noise and cross-talk tests on the SCT and TRT in their final assembled configuration, using final readout and supply hardware and software, are reported. The reconstruction and analysis of the recorded cosmic tracks allowed testing of the offline analysis chain and verification of basic tracker performance parameters, such as efficiency and spatial resolution, in combined operation before installation.
|
|
| 13. |
- Actis, M., et al.
(författare)
-
Design concepts for the Cherenkov Telescope Array CTA : an advanced facility for ground-based high-energy gamma-ray astronomy
- 2011
-
Ingår i: Experimental astronomy. - : Springer. - 0922-6435 .- 1572-9508. ; 32:3, s. 193-316
-
Tidskriftsartikel (refereegranskat)abstract
- Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
|
|
| 14. |
|
|
| 15. |
- Emerging Risk Factors, Collaboration, et al.
(författare)
-
The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases
- 2007
-
Ingår i: Eur J Epidemiol. - 0393-2990. ; 22:12, s. 839-69
-
Tidskriftsartikel (refereegranskat)abstract
- Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
|
|
| 16. |
|
|
| 17. |
- Acharyya, A., et al.
(författare)
-
Monte Carlo studies for the optimisation of the Cherenkov Telescope Array layout
- 2019
-
Ingår i: Astroparticle physics. - : Elsevier. - 0927-6505 .- 1873-2852. ; 111, s. 35-53
-
Tidskriftsartikel (refereegranskat)abstract
- The Cherenkov Telescope Array (CTA) is the major next-generation observatory for ground-based veryhigh-energy gamma-ray astronomy. It will improve the sensitivity of current ground-based instruments by a factor of five to twenty, depending on the energy, greatly improving both their angular and energy resolutions over four decades in energy (from 20 GeV to 300 TeV). This achievement will be possible by using tens of imaging Cherenkov telescopes of three successive sizes. They will be arranged into two arrays, one per hemisphere, located on the La Palma island (Spain) and in Paranal (Chile). We present here the optimised and final telescope arrays for both CTA sites, as well as their foreseen performance, resulting from the analysis of three different large-scale Monte Carlo productions.
|
|
| 18. |
- Butler-Laporte, G, et al.
(författare)
-
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
-
Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
|
|
| 19. |
|
|
| 20. |
- Abdesselam, A., et al.
(författare)
-
Engineering for the ATLAS SemiConductor Tracker (SCT) end-cap
- 2008
-
Ingår i: Journal of Instrumentation. - 1748-0221. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- The ATLAS SemiConductor Tracker (SCT) is a silicon-strip tracking detector which forms part of the ATLAS inner detector. The SCT is designed to track charged particles produced in proton-proton collisions at the Large Hadron Collider (LHC) at CERN at an energy of 14 TeV. The tracker is made up of a central barrel and two identical end-caps. The barrel contains 2112 silicon modules, while each end-cap contains 988 modules. The overall tracking performance depends not only on the intrinsic measurement precision of the modules but also on the characteristics of the whole assembly, in particular, the stability and the total material budget. This paper describes the engineering design and construction of the SCT end-caps, which are required to support mechanically the silicon modules, supply services to them and provide a suitable environment within the inner detector. Critical engineering choices are highlighted and innovative solutions are presented - these will be of interest to other builders of large-scale tracking detectors. The SCT end-caps will be fully connected at the start of 2008. Further commissioning will continue, to be ready for proton-proton collision data in 2008.
|
|
| 21. |
|
|
| 22. |
- Bevilacqua, R., et al.
(författare)
-
Neutron induced light-ion production from Iron and Bismuth at 175 MeV
- 2010
-
Ingår i: CNR*09 - Second International Workshop on Compound Nuclear Reactions and Related Topics. - : EDP Sciences. - 9782759805211 ; , s. 05005-
-
Konferensbidrag (refereegranskat)abstract
- We have measured light-ion (p, d, t, 3He and α) production in the interaction of 175 MeV neutrons with iron and bismuth, using the MEDLEY setup. A large set of measurements at 96 MeV has been recently completed and published, and now higher energy region is under investigation. MEDLEY is a conventional spectrometer system that allows low-energy thresholds and offers measurements over a wide angular range. The system consists of eight telescopes, each of them composed of two silicon surface barrier detectors, to perform particle identification, and a CsI(Tl) scintillator to fully measure the kinetic energy of the produced light-ions. The telescopes are placed at angles from 20° to 160°, in steps of 20°. Measurements have been performed at The Svedberg Laboratory, Uppsala (Sweden), where a quasi mono-energetic neutron beam is available and well characterized. Time of flight techniques are used to select light-ion events induced by neutrons in the main peak of the source neutron spectrum. We report preliminary double differential cross sections for production of protons, deuterons and tritons in comparison with model calculations using TALYS-1.0 code.
|
|
| 23. |
- Bevilacqua, Riccardo, et al.
(författare)
-
Neutron induced light-ion production from iron and bismuth at 175 MeV
- 2010
-
Ingår i: RADIATION MEASUREMENTS. - : Elsevier BV. ; 45:10, s. 1145-1150
-
Konferensbidrag (refereegranskat)abstract
- We have measured light-ion (p, d, t, He-3 and alpha) production in the interaction of 175 MeV neutrons with iron and bismuth with low-energy thresholds and for a wide angular range (from 20 degrees to 160 degrees, in steps of 20 degrees). Measurements have been performed with the Medley setup, semi-permanently installed at the The Svedberg Laboratory, Uppsala (Sweden), where a quasi-monoenergetic neutron beam is available and well characterized. Medley is a conventional spectrometer system and consists of eight telescopes, each of them composed of two silicon surface barrier detectors, to perform particle identification, and a CsI(Tl) scintillator to fully measure the kinetic energy of the produced light-ions. We report preliminary double-differential cross sections for production of protons, deuterons and tritons in comparison with model calculations using TALYS-1.0 code. These show better agreement for the production of protons, while the theoretical calculations seem to overestimate the experimental production of deuterons and tritons.
|
|
| 24. |
- Bevilacqua, Riccardo, 1974-, et al.
(författare)
-
Study of pre-equilibrium emission of light complex particles from Fe and Bi induced by intermediate energy neutrons
- 2011
-
Ingår i: Journal of Physics, Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 312:SECTION 8, s. 082013-, s. 082013-
-
Tidskriftsartikel (refereegranskat)abstract
- We have measured double differential cross sections (DDX) for emission of hydrogen- and helium-isotopes in the interaction of 175 MeV quasi-monoenergetic neutrons with Fe and Bi using the Medley setup at the The Svedberg Laboratory (Uppsala, Sweden). We compared experimental DDX with calculations with the TALYS code, which includes exciton model and Kalbach systematics; the code fails to reproduce the emission of complex light ions, generally overestimating it. We propose an correction for the application of the Kalbach phenomenological model in the TALYS code by introducing a new energy dependence for the nucleon transfer mechanism in the pre-equilibrium emission region. Our results suggest also evidence for multiple pre-equilibrium emission of composite particles at 175 MeV.
|
|
| 25. |
- Danesh, John, et al.
(författare)
-
Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis
- 2005
-
Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 294:14, s. 1799-1809
-
Forskningsöversikt (refereegranskat)abstract
- CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.
|
|
