| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
- 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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| 5. |
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| 6. |
- 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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| 7. |
- Abe, K., et al.
(författare)
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Neutron tagging following atmospheric neutrino events in a water Cherenkov detector
- 2022
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Ingår i: Journal of Instrumentation. - : Institute of Physics (IOP). - 1748-0221 .- 1748-0221. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- We present the development of neutron-tagging techniques in Super-Kamiokande IV using a neural network analysis. The detection efficiency of neutron capture on hydrogen is estimated to be 26%, with a mis-tag rate of 0.016 per neutrino event. The uncertainty of the tagging efficiency is estimated to be 9.0%. Measurement of the tagging efficiency with data from an Americium-Beryllium calibration agrees with this value within 10%. The tagging procedure was performed on 3,244.4 days of SK-IV atmospheric neutrino data, identifying 18,091 neutrons in 26,473 neutrino events. The fitted neutron capture lifetime was measured as 218 +/- 9 mu s.
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| 8. |
- Dollet, L, et al.
(författare)
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Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 71:4, s. 624-636
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes–associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.
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| 9. |
- Behrens, E., et al.
(författare)
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Tracing Interstellar Heating: An ALCHEMI Measurement of the HCN Isomers in NGC 253
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 939:2
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Tidskriftsartikel (refereegranskat)abstract
- We analyze HCN and HNC emission in the nearby starburst galaxy NGC 253 to investigate its effectiveness in tracing heating processes associated with star formation. This study uses multiple HCN and HNC rotational transitions observed using the Atacama Large Millimeter/submillimeter Array via the ALCHEMI Large Program. To understand the conditions and associated heating mechanisms within NGC 253's dense gas, we employ Bayesian nested sampling techniques applied to chemical and radiative transfer models, which are constrained using our HCN and HNC measurements. We find that the volume density n H 2 and cosmic-ray ionization rate (CRIR) ζ are enhanced by about an order of magnitude in the galaxy’s central regions as compared to those further from the nucleus. In NGC 253's central giant molecular clouds (GMCs), where observed HCN/HNC abundance ratios are the lowest, n ∼ 105.5 cm−3 and ζ ∼ 10−12 s−1 (greater than 104 times the average Galactic rate). We find a positive correlation in the association of both density and CRIR with the number of star formation-related heating sources (supernova remnants, H ii regions, and super hot cores) located in each GMC, as well as a correlation between CRIRs and supernova rates. Additionally, we see an anticorrelation between the HCN/HNC ratio and CRIR, indicating that this ratio will be lower in regions where ζ is higher. Though previous studies suggested HCN and HNC may reveal strong mechanical heating processes in NGC 253's CMZ, we find cosmic-ray heating dominates the heating budget, and mechanical heating does not play a significant role in the HCN and HNC chemistry.
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| 10. |
- Falstad, Niklas, 1987, et al.
(författare)
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CON-quest: Searching for the most obscured galaxy nuclei
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
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Tidskriftsartikel (refereegranskat)abstract
- Context. Some luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs) host extremely compact (r < 100 pc) and dusty nuclei. The high extinction associated with large column densities of gas and dust toward these objects render them hard to detect at many wavelengths. The intense infrared radiation arising from warm dust in these sources can provide a significant fraction of the bolometric luminosity of the galaxy and is prone to excite vibrational levels of molecules such as HCN. This results in emission from the rotational transitions of vibrationally excited HCN (HCN-vib); the brightest emission is found in compact obscured nuclei (CONs; ςHCN-vib > 1 L⊙ pc-2 in the J = 3-2 transition). However, there have been no systematic searches for CONs, and it is unknown how common they are. Aims. We aim to establish how common CONs are in the local Universe (z < 0.08), and whether their prevalence depends on the luminosity or other properties of the host galaxy. Methods. We conducted an Atacama Large Millimeter/submillimeter Array survey of the rotational J = 3-2 transition of HCN-vib in a volume-limited sample of 46 far-infrared luminous galaxies. Results. Compact obscured nuclei are identified in 38-13+18% of the ULIRGs, 21-6+12% of the LIRGs, and 0-0+9% of the lower luminosity galaxies. We find no dependence on the inclination of the host galaxy, but strong evidence of lower IRAS 25 μm to 60 μm flux density ratios (f25/f60) in CONs (with the exception of one galaxy, NGC 4418) compared to the rest of the sample. Furthermore, we find that CONs have stronger silicate features (s9.7 μm), but similar polycyclic aromatic hydrocarbon equivalent widths (EQW6.2 μm) compared to other galaxies. Along with signatures of molecular inflows seen in the far-infrared in most CONs, submillimeter observations also reveal compact, often collimated, outflows. Conclusions. In the local Universe, CONs are primarily found in (U)LIRGs, in which they are remarkably common. As such systems are often highly disturbed, inclinations are difficult to estimate, and high-resolution continuum observations of the individual nuclei are required to determine if the CON phenomenon is related to the inclinations of the nuclear disks. Further studies of the in- A nd outflow properties of CONs should also be conducted to investigate how these are connected to each other and to the CON phenomenon. The lower f25/f60 ratios in CONs as well as the results for the mid-infrared diagnostics investigated (EQW6.2 μm and s9.7 μm) are consistent with the notion that large dust columns gradually shift the radiation from the hot nucleus to longer wavelengths, making the mid- A nd far-infrared "photospheres"significantly cooler than the interior regions. Finally, to assess the importance of CONs in the context of galaxy evolution, it is necessary to extend this study to higher redshifts where (U)LIRGs are more common.
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