| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- 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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| 4. |
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| 5. |
- 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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| 6. |
- Fernández, A., et al.
(författare)
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Mirror energy differences above the 0f7/2 shell: First γ-ray spectroscopy of the Tz=−2 nucleus 56Zn
- 2021
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693. ; 823
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in 56Zn were populated following one-neutron removal from a 57Zn beam impinging on a Be target at intermediate energies in an experiment conducted at the Radioactive Isotope Beam Factory at RIKEN. Three γ rays were observed and tentatively assigned to the 6+ → 4+ → 2+ → 0+ yrast sequence. This turns 56Zn into the heaviest Tz=−2 nucleus in which excited states are known. The excitation-energy differences between these levels and the isobaric analogue states in the Tz=+2 mirror partner, 56Fe, are compared with large-scale shell-model calculations considering the full pf valence space and various isospin-breaking contributions. This comparison, together with an analysis of the mirror energy differences in the A=58, Tz=±1 pair 58Zn and 58Ni, provides valuable information with respect to the size of the monopole radial and the isovector multipole isospin-breaking terms in the region above doubly-magic 56Ni.
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| 7. |
- Kitamura, N., et al.
(författare)
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Direct observations of energy transfer from resonant electrons to whistler-mode waves in magnetosheath of Earth
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Excitation of whistler-mode waves by cyclotron instability is considered as the likely generation process of the waves. Here, the authors show direct observational evidence for locally ongoing secular energy transfer from the resonant electrons to the whistler-mode waves in Earth's magnetosheath. Electromagnetic whistler-mode waves in space plasmas play critical roles in collisionless energy transfer between the electrons and the electromagnetic field. Although resonant interactions have been considered as the likely generation process of the waves, observational identification has been extremely difficult due to the short time scale of resonant electron dynamics. Here we show strong nongyrotropy, which rotate with the wave, of cyclotron resonant electrons as direct evidence for the locally ongoing secular energy transfer from the resonant electrons to the whistler-mode waves using ultra-high temporal resolution data obtained by NASA's Magnetospheric Multiscale (MMS) mission in the magnetosheath. The nongyrotropic electrons carry a resonant current, which is the energy source of the wave as predicted by the nonlinear wave growth theory. This result proves the nonlinear wave growth theory, and furthermore demonstrates that the degree of nongyrotropy, which cannot be predicted even by that nonlinear theory, can be studied by observations.
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| 8. |
- Kitamura, N., et al.
(författare)
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Observations of the Source Region of Whistler Mode Waves in Magnetosheath Mirror Structures
- 2020
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Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 125:5
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Tidskriftsartikel (refereegranskat)abstract
- In the magnetosheath, intense whistler mode waves, called "Lion roars," are often detected in troughs of magnetic field intensity in mirror mode structures. Using data obtained by the four Magnetospheric Multiscale (MMS) spacecraft, we show that reversals of gradient of magnetic field intensity along the magnetic field correspond to reversals of the field-aligned component of Poynting flux of whistler mode waves in the troughs. Such a characteristic is consistent with the idea that the whistler mode waves are effectively generated near the local minima of magnetic field intensity because of the smallest cyclotron resonance velocity and propagate toward regions of larger magnetic field intensity along the magnetic field lines on both sides. We use the reversal of the Poynting flux as an indicator of wave source regions. In these regions, we find that pancake or an outer edge of butterfly electron distributions above similar to 100 eV are good candidates for wave generation. Unclear correlations of phase difference and amplitude variations of whistler mode waves in cases of similar to 40 km spacecraft separation indicate that a simple plane wave approximation with a constant amplitude is not valid at this spatial scale that is much smaller than the ion gyroradius. The whistler mode waves consist of small coherent wave packets from multiple sources with spatial scales smaller than tens of electron gyroradii transverse to the background magnetic field in a mirror mode structure.
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| 9. |
- Amano, T., et al.
(författare)
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Observational Evidence for Stochastic Shock Drift Acceleration of Electrons at the Earth's Bow Shock
- 2020
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Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 124:6
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Tidskriftsartikel (refereegranskat)abstract
- The first-order Fermi acceleration of electrons requires an injection of electrons into a mildly relativistic energy range. However, the mechanism of injection has remained a puzzle both in theory and observation. We present direct evidence for a novel stochastic shock drift acceleration theory for the injection obtained with Magnetospheric Multiscale observations at the Earth's bow shock. The theoretical model can explain electron acceleration to mildly relativistic energies at high-speed astrophysical shocks, which may provide a solution to the long-standing issue of electron injection.
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| 10. |
- Isobe, T, et al.
(författare)
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Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4501-
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Tidskriftsartikel (refereegranskat)abstract
- KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
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