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- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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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.
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- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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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.
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- Aharonian, Felix, et al.
(författare)
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Atmospheric gas dynamics in the Perseus cluster observed with Hitomi
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Tidskriftsartikel (refereegranskat)abstract
- Extending the earlier measurements reported in Hitomi collaboration (2016, Nature, 535, 117), we examine the atmospheric gas motions within the central 100 kpc of the Perseus cluster using observations obtained with the Hitomi satellite. After correcting for the point spread function of the telescope and using optically thin emission lines, we find that the line-of-sight velocity dispersion of the hot gas is remarkably low and mostly uniform. The velocity dispersion reaches a maxima of approximately 200 km s(-1) toward the central active galactic nucleus (AGN) and toward the AGN inflated northwestern ghost bubble. Elsewhere within the observed region, the velocity dispersion appears constant around 100 km s(-1). We also detect a velocity gradient with a 100 km s(-1) amplitude across the cluster core, consistent with large-scale sloshing of the core gas. If the observed gas motions are isotropic, the kinetic pressure support is less than 10% of the thermal pressure support in the cluster core. The well-resolved, optically thin emission lines have Gaussian shapes, indicating that the turbulent driving scale is likely below 100 kpc, which is consistent with the size of the AGN jet inflated bubbles. We also report the first measurement of the ion temperature in the intracluster medium, which we find to be consistent with the electron temperature. In addition, we present a new measurement of the redshift of the brightest cluster galaxy NGC 1275.
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- Aharonian, Felix, et al.
(författare)
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Atomic data and spectral modeling constraints from high-resolution X-ray observations of the Perseus cluster with Hitomi
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Tidskriftsartikel (refereegranskat)abstract
- The Hitomi Soft X-ray Spectrometer spectrum of the Perseus cluster, with similar to 5 eV resolution in the 2-9 keV band, offers an unprecedented benchmark of the atomic modeling and database for hot collisional plasmas. It reveals both successes and challenges of the current atomic data and models. The latest versions of AtomDB/APEC (3.0.8), SPEX (3.03.00), and CHIANTI (8.0) all provide reasonable fits to the broad-band spectrum, and are in close agreement on best-fit temperature, emission measure, and abundances of a few elements such as Ni. For the Fe abundance, the APEC and SPEX measurements differ by 16%, which is 17 times higher than the statistical uncertainty. This is mostly attributed to the differences in adopted collisional excitation and dielectronic recombination rates of the strongest emission lines. We further investigate and compare the sensitivity of the derived physical parameters to the astrophysical source modeling and instrumental effects. The Hitomi results show that accurate atomic data and models are as important as the astrophysical modeling and instrumental calibration aspects. Substantial updates of atomic databases and targeted laboratory measurements are needed to get the current data and models ready for the data from the next Hitomi-level mission.
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- Aharonian, Felix, et al.
(författare)
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Detection of polarized gamma-ray emission from the Crab nebula with the Hitomi Soft Gamma-ray Detector
- 2018
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Ingår i: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:6
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Tidskriftsartikel (refereegranskat)abstract
- We present the results from the Hitomi Soft Gamma-ray Detector (SGD) observation of the Crab nebula. The main part of SGD is a Compton camera, which in addition to being a spectrometer, is capable of measuring polarization of gamma-ray photons. The Crab nebula is one of the brightest X-ray / gamma-ray sources on the sky, and, the only source from which polarized X-ray photons have been detected. SGD observed the Crab nebula during the initial test observation phase of Hitomi. We performed the data analysis of the SGD observation, the SGD background estimation and the SGD Monte Carlo simulations, and, successfully detected polarized gamma-ray emission from the Crab nebula with only about 5 ks exposure time. The obtained polarization fraction of the phase-integrated Crab emission (sum of pulsar and nebula emissions) is (22.1% +/- 10.6%), and, the polarization angle is 110.degrees 7 + 13.degrees 2 /-13.degrees 0 in the energy range of 60-160 keV (The errors correspond to the 1 sigma deviation). The confidence level of the polarization detection was 99.3%. The polarization angle measured by SGD is about one sigma deviation with the projected spin axis of the pulsar, 124.degrees 0 +/- 0.degrees 1.
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