| 1. |
- 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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| 2. |
- 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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| 3. |
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| 4. |
- Forrest, ARR, et al.
(författare)
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A promoter-level mammalian expression atlas
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 507:7493, s. 462-
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Noguchi, S, et al.
(författare)
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FANTOM5 CAGE profiles of human and mouse samples
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
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Tidskriftsartikel (refereegranskat)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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| 6. |
- Abdalla, H., et al.
(författare)
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A very-high-energy component deep in the gamma-ray burst afterglow
- 2019
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 575:7783, s. 464-467
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are brief flashes of gamma-rays and are considered to be the most energetic explosive phenomena in the Universe(1). The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed(2). GRBs typically emit most of their energy via.-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments(3). However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive(4). Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and gamma-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.
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| 7. |
- Abdalla, H., et al.
(författare)
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Constraints on the emission region of 3C 279 during strong flares in 2014 and 2015 through VHE gamma-ray observations with HESS
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 627, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- The flat spectrum radio quasar 3C 279 is known to exhibit pronounced variability in the high-energy (100MeV < E < 100 GeV) gamma-ray band, which is continuously monitored with Fermi-LAT. During two periods of high activity in April 2014 and June 2015 target-of-opportunity observations were undertaken with the High Energy Stereoscopic System (H.E.S.S.) in the very-high-energy (VHE, E > 100 GeV) gamma-ray domain. While the observation in 2014 provides an upper limit, the observation in 2015 results in a signal with 8 : 7 sigma significance above an energy threshold of 66 GeV. No VHE variability was detected during the 2015 observations. The VHE photon spectrum is soft and described by a power-law index of 4.2 +/- 0.3. The H.E.S.S. data along with a detailed and contemporaneous multiwavelength data set provide constraints on the physical parameters of the emission region. The minimum distance of the emission region from the central black hole was estimated using two plausible geometries of the broad-line region and three potential intrinsic spectra. The emission region is confidently placed at r greater than or similar to 1 : 7 X 1017 cm from the black hole, that is beyond the assumed distance of the broad-line region. Time-dependent leptonic and lepto-hadronic one-zone models were used to describe the evolution of the 2015 flare. Neither model can fully reproduce the observations, despite testing various parameter sets. Furthermore, the H.E.S.S. data were used to derive constraints on Lorentz invariance violation given the large redshift of 3C 279.
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| 8. |
- Abdalla, H., et al.
(författare)
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Detection of very-high-energy gamma-ray emission from the colliding wind binary eta Car with HESS
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Aims. Colliding wind binary systems have long been suspected to be high-energy (HE; 100 MeV < E < 100 GeV) gamma-ray emitters. eta Car is the most prominent member of this object class and is confirmed to emit phase-locked HE gamma rays from hundreds of MeV to 100 GeV energies. This work aims to search for and characterise the very-high-energy (VHE; E >100 GeV) gamma-ray emission from eta Car around the last periastron passage in 2014 with the ground-based High Energy Stereoscopic System (H.E.S.S.).Methods. The region around eta Car was observed with H.E.S.S. between orbital phase p = 0.78-1.10, with a closer sampling at p approximate to 0.95 and p approximate to 1.10 (assuming a period of 2023 days). Optimised hardware settings as well as adjustments to the data reduction, reconstruction, and signal selection were needed to suppress and take into account the strong, extended, and inhomogeneous night sky background (NSB) in the eta Car field of view. Tailored run-wise Monte-Carlo simulations (RWS) were required to accurately treat the additional noise from NSB photons in the instrument response functions.Results. H.E.S.S. detected VHE gamma-ray emission from the direction of eta Car shortly before and after the minimum in the X-ray light-curve close to periastron. Using the point spread function provided by RWS, the reconstructed signal is point-like and the spectrum is best described by a power law. The overall flux and spectral index in VHE gamma rays agree within statistical and systematic errors before and after periastron. The gamma-ray spectrum extends up to at least 400 GeV. This implies a maximum magnetic field in a leptonic scenario in the emission region of 0.5 Gauss. No indication for phase-locked flux variations is detected in the H.E.S.S. data.
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| 9. |
- Abdalla, H., et al.
(författare)
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HESS and Fermi-LAT observations of PSR B1259-63/LS 2883 during its 2014 and 2017 periastron passages
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 633, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Context. PSR B1259-63/LS 2883 is a gamma-ray binary system consisting of a pulsar in an eccentric orbit around a bright Oe stellar-type companion star that features a dense circumstellar disc. The bright broad-band emission observed at phases close to periastron offers a unique opportunity to study particle acceleration and radiation processes in binary systems. Observations at gamma-ray energies constrain these processes through variability and spectral characterisation studies. Aims. The high- and very-high-energy (HE, VHE) gamma-ray emission from PSR B1259-63/LS 2883 around the times of its periastron passage are characterised, in particular, at the time of the HE gamma-ray flares reported to have occurred in 2011, 2014, and 2017. Short-term and average emission characteristics of PSR B1259-63/LS 2883 are determined. Super-orbital variability is searched for in order to investigate possible cycle-to-cycle VHE flux changes due to different properties of the companion star's circumstellar disc and/or the conditions under which the HE gamma-ray flares develop. Methods. Spectra and light curves were derived from observations conducted with the H.E.S.S-II array in 2014 and 2017. Phase-folded light curves are compared with the results obtained in 2004, 2007, and 2011. Fermi-LAT observations from 2010/11, 2014, and 2017 are analysed. Results. A local double-peak profile with asymmetric peaks in the VHE light curve is measured, with a flux minimum at the time of periastron t(p) and two peaks coinciding with the times at which the neutron star crosses the companion's circumstellar disc (similar to t(p) 16 d). A high VHE gamma-ray flux is also observed at the times of the HE gamma-ray flares (similar to t(p) + 30 d) and at phases before the first disc crossing (similar to t(p) - 35 d). The spectral energy range now extends to below 200 GeV and up to similar to 45 TeV. Conclusions. PSR B1259-63/LS 2883 displays periodic flux variability at VHE gamma-rays without clear signatures of super-orbital modulation in the time span covered by the monitoring of the source with the H.E.S.S. telescopes. This flux variability is most probably caused by the changing environmental conditions, particularly at times close to periastron passage at which the neutron star is thought to cross the circumstellar disc of the companion star twice. In contrast, the photon index remains unchanged within uncertainties for about 200 d around periastron. At HE gamma-rays, PSR B1259-63/LS 2883 has now been detected also before and after periastron, close to the disc crossing times. Repetitive flares with distinct variability patterns are detected in this energy range. Such outbursts are not observed at VHEs, although a relatively high emission level is measured. The spectra obtained in both energy regimes displays a similar slope, although a common physical origin either in terms of a related particle population, emission mechanism, or emitter location is ruled out.
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| 10. |
- Abdalla, H., et al.
(författare)
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Probing the Magnetic Field in the GW170817 Outflow Using HESS Observations
- 2020
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Ingår i: Astrophysical Journal Letters. - : Institute of Physics Publishing (IOPP). - 2041-8205 .- 2041-8213. ; 894:2, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- The detection of the first electromagnetic counterpart to the binary neutron star (BNS) merger remnant GW170817 established the connection between short gamma-ray bursts and BNS mergers. It also confirmed the forging of heavy elements in the ejecta (a so-called kilonova) via the r-process nucleosynthesis. The appearance of nonthermal radio and X-ray emission, as well as the brightening, which lasted more than 100 days, were somewhat unexpected. Current theoretical models attempt to explain this temporal behavior as either originating from a relativistic off-axis jet or a kilonova-like outflow. In either scenario, there is some ambiguity regarding how much energy is transported in the nonthermal electrons versus the magnetic field of the emission region. Combining the Very Large Array (radio) and Chandra (X-ray) measurements with observations in the GeV-TeV domain can help break this ambiguity, almost independently of the assumed origin of the emission. Here we report for the first time on deep H.E.S.S. observations of GW170817/GRB 170817A between 124 and 272 days after the BNS merger with the full H.E.S.S. array of telescopes, as well as on an updated analysis of the prompt (<5 days) observations with the upgraded H.E.S.S. phase-I telescopes. We discuss implications of the H.E.S.S. measurement for the magnetic field in the context of different source scenarios.
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