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  • 1
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . 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.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
    In: Nature, Springer Science and Business Media LLC, Vol. 585, No. 7826 ( 2020-09-24), p. 591-596
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    RVK:
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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    detail.hit.zdb_id: 1413423-8
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: The Hayabusa2 spacecraft retrieved surface and subsurface samples from the carbonaceous near-Earth asteroid (162173) Ryugu, which was expected to be enriched in volatile species. The samples were collected from two locations, one undisturbed surface and the other including material excavated by an artificial impact. Unlike meteorites, these samples have experienced minimal alteration by Earth’s atmosphere. Ryugu is thought to have formed from material ejected (by an impact) from a parent body, which had experienced aqueous alteration (reactions with liquid water) ~4.56 billion years (Gyr) ago. Ryugu’s orbit later migrated from the main asteroid belt to become a near-Earth asteroid. RATIONALE Noble gases and nitrogen isotopes in Ryugu grains are inherited from Ryugu’s parent body and potentially provide information about the source of Earth’s volatile elements. Noble gas isotopes can also be used to assess the orbital evolution and recent surface activities of Ryugu. We pelletized ~0.8-mm-diameter Ryugu grains and investigated their mineralogy before carrying out isotope measurements. We measured the concentrations and isotopic compositions of noble gases and nitrogen, extracted by stepped heating, with mass spectrometers. RESULTS The mineralogy of the Ryugu grains is similar to Ivuna-type carbonaceous (CI) chondrite meteorites. Fine-grained hydrous silicates (phyllosilicates), produced through aqueous alteration of primary minerals, compose the major fraction of the samples. This is consistent with infrared spectroscopic observations of the asteroid. Iron oxide, iron sulfides, and carbonates are also found within the matrix. Noble gas isotopes are dominated by primordially trapped gases. Their abundances are mostly similar to the highest found in a CI chondrite, with some grains having several times higher concentrations than the highest CI value. Isotopic compositions and concentrations of nitrogen vary between the Ryugu grains, with divergence from the CI chondrite composition. The nitrogen concentrations in four Ryugu grains are one-half to one-third the CI values, and the 15 N/ 14 N ratio is also lower. The Ryugu grains with compositions farthest from the CI values are similar to the composition of a dehydrated CI chondrite. Only two surface samples, out of the 16 Ryugu grains measured, have clear signs of noble gases derived from solar wind (SW). Their abundances correspond to SW exposure durations of ≳3500 and ≳250 years at the current orbit, whereas most of the grains were exposed for ≳1 to ≳50 years. Cosmic ray–produced 21 Ne concentrations vary, with no systematic difference between the sample collection sites. The estimated cosmic ray exposure (CRE) ages for the surface and subsurface samples are 5.3 ± 0.9 and 5.2 ± 0.8 million years (Myr), assuming irradiations at 2 to 5 g cm −2 and 150 g cm −2 , respectively. This is consistent with the expected surface residence time under near-Earth impact rates. We infer that Ryugu’s orbit migrated from the main asteroid belt to the near-Earth region ~5 Myr ago. About 30% of cosmogenic 21 Ne, corresponding to a CRE age of ~1 Myr, was released in gas-extraction steps at 100°C, indicating that the Ryugu samples have not experienced heating above 100°C within the past 1 Myr. Previous studies have suggested that Ryugu experienced an orbital excursion much closer to the Sun. If this is the case, this excursion must have occurred ≳1 Myr ago. CONCLUSION The mineralogical and noble gas measurements show that the Ryugu samples are similar to CI chondrites. The nitrogen data indicate a heterogeneous distribution of nitrogen-carrying materials with different compositions, one of which has been lost from Ryugu grains to varying degrees. The CRE age of ~5 Myr and the implanted SW are records of the recent irradiation at the current near-Earth orbit of Ryugu. Inferred formation and history of Ryugu. Ryugu’s parent body formed in the early Solar System, incorporating primordial noble gases and nitrogen, followed by aqueous alteration ~4.56 Gyr ago. Ryugu formed from the accumulation of fragments of the parent body ejected by an impact, at an unknown date. Ryugu migrated to its current near-Earth orbit ~5 Myr ago. Ryugu might have experienced another change in orbit, bringing it closer to the Sun (“Path A”), or remained in the same near-Earth orbit (“Path B”).
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    Wiley ; 2007
    In:  Annals of the New York Academy of Sciences Vol. 1099, No. 1 ( 2007-03), p. 478-480
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1099, No. 1 ( 2007-03), p. 478-480
    Abstract: Abstract:  The Na + /Ca 2+ exchanger (NCX) is considered to be involved in endothelial nitric oxide (NO) production and endothelium‐dependent vasorelaxation, but little is known about the physiological and pathological roles of endothelial NCX in these processes. We examined the role of NCX1 in neovascularization in mice with hindlimb ischemia. Unilateral hindlimb ischemia was induced surgically in wild‐type and heterozygous NCX1 knockout mice (NCX1 +/− ) mice. We found that in NCX1 +/− mice, blood flow recovery was significantly augmented compared with that in wild‐type mice. N G ‐nitro‐L‐arginine methyl ester treatment eliminated enhanced angiogenesis observed in NCX1 +/− mice. These results suggest that NCX1 is involved in eNOS‐dependent angiogenesis.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
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    Language: English
    Publisher: Wiley
    Publication Date: 2007
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