| 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. |
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| 3. |
- 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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| 4. |
- 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. ; 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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| 5. |
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| 6. |
- Grawe, H., et al.
(författare)
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The (6+) isomer in 102Sn revisited : Neutron and proton effective charges close to the double shell closure
- 2021
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Ingår i: Physics Letters B. - : Elsevier. - 0370-2693 .- 1873-2445. ; 820
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Tidskriftsartikel (refereegranskat)abstract
- In a high-energy fragmentation experiment at GSI an Iπ = (6+) isomer and its γ-decay are identified in 102Sn, the two-neutron neighbour of the doubly-magic 100Sn. Its half-life is measured to be T1/2 = 367(11) ns. The possible existence of further isomers is discussed in the framework of large-scale shell model (LSSM) calculations including up to five particle-hole excitations of the 100Sn core. From the precise B(E2; 6+ → 4+) strength and the recently remeasured value for B(E2; 8+ → 6+) in the two-proton hole neighbour 98Cd effective E2 polarization charges for protons and neutrons were inferred including LSSM corrections within the full N=4 0hω space. The results are discussed in comparison to predicted and empirically determined effective operators.
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| 7. |
- Applegate, K. E., et al.
(författare)
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Individual response of humans to ionising radiation : governing factors and importance for radiological protection
- 2020
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Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 59:2, s. 185-209
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Forskningsöversikt (refereegranskat)abstract
- Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.
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| 8. |
- Barnes, A. T., et al.
(författare)
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LEGO - II. A 3mm molecular line study covering 100 pc of one of the most actively star-forming portions within the Milky Way disc
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 497:2, s. 1972-2001
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Tidskriftsartikel (refereegranskat)abstract
- The current generation of (sub)mm-telescopes has allowed molecular line emission to become a major tool for studying the physical, kinematic, and chemical properties of extragalactic systems, yet exploiting these observations requires a detailed understanding of where emission lines originate within the Milky Way. In this paper, we present 60'' (similar to 3pc) resolution observations of many 3mm-band molecular lines across a large map of the W49 massive star-forming region (similar to 100x100pc at 11kpc), which were taken as part of the 'LEGO' IRAM-30m large project. We find that the spatial extent or brightness of the molecular line transitions are not well correlated with their critical densities, highlighting abundance and optical depth must be considered when estimating line emission characteristics. We explore how the total emission and emission efficiency (i.e. line brightness per H-2 column density) of the line emission vary as a function of molecular hydrogen column density and dust temperature. We find that there is not a single region of this parameter space responsible for the brightest and most efficiently emitting gas for all species. For example, we find that the HCN transition shows high emission efficiency at high column density (10(22)cm(-2)) and moderate temperatures (35K), whilst e.g. N2H+ emits most efficiently towards lower temperatures (10(22)cm(-2); <20K). We determine XCO(1-0)similar to 0.3 x 10(20)cm(-2)(Kkms(-1))(-1), and alpha(HCN(1-0))similar to 30M(circle dot)(Kkms(-1)pc(2))(-1), which both differ significantly from the commonly adopted values. In all, these results suggest caution should be taken when interpreting molecular line emission.
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| 9. |
- Inagaki-Kawata, Y, et al.
(författare)
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Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants
- 2020
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 578-
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Tidskriftsartikel (refereegranskat)abstract
- The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.
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