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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. 621, No. 7977 ( 2023-09-07), p. E7-E26
    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: 2023
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    detail.hit.zdb_id: 1413423-8
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  • 3
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Abstract: The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
    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: 2021
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  • 4
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: Organic compounds in asteroids and comets contain information about the early history of the Solar System. They could also have delivered organic material to early Earth. The Hayabusa2 spacecraft visited the carbonaceous asteroid Ryugu and collected samples of its surface materials, which were brought to Earth in December 2020. RATIONALE We investigated the macromolecular organic matter in the Ryugu samples, measuring its elemental, isotopic, and functional group compositions along with its small-scale structures and morphologies. Analytical methods used included spectro-microscopies, electron microscopy, and isotopic microscopy. We examined intact Ryugu grains and insoluble carbonaceous residues isolated by acid treatment of the Ryugu samples. RESULTS Organic matter is abundant in the Ryugu grains, distributed as submicrometer-sized organic grains and as organic matter dispersed in matrix. The Ryugu organic matter consists of aromatic carbons, aliphatic carbons, ketones, and carboxyls. The functional group compositions are consistent with those of insoluble organic matter (IOM) from primitive carbonaceous CI (Ivuna-type) and CM (Mighei-type) chondritic meteorites. Those meteorites experienced aqueous alteration (reactions with liquid water) on their parent bodies, which implies that the Ryugu organic material was also modified by aqueous alteration on the asteroid parent body. The functional group distributions of the Ryugu organic matter vary on submicrometer scales in ways that relate to the morphologies: nanoparticulate and/or nanoglobular regions are aromatic-rich, whereas organic matter associated with Mg-rich phyllosilicate matrix and carbonates is IOM-like or occurs as diffuse carbon. The observed macromolecular diversity provides further evidence that the organics were modified by aqueous alteration on Ryugu’s parent body. The diffuse carbon is similar to clay-bound organic matter that occurs in CI chondrites and the ungrouped C2-type meteorite Tagish Lake. No graphite-like material was found, which indicates that the Ryugu organic matter was not subjected to heating events on the parent body. The bulk hydrogen and nitrogen isotopic ratios of the Ryugu grains are between the bulk values of CI chondrites and the IOM in CI chondrites. Some carbonaceous grains showed extreme deuterium (D) and/or nitrogen-15 ( 15 N) enrichments or depletions. These indicate an origin in the interstellar medium or presolar nebula. The bulk hydrogen isotopic ratios of insoluble carbonaceous residues from the Ryugu samples are lower than those in CI and CM chondrites. The range of D enrichments are consistent with the ranges of CI, CM, and Tagish Lake chondrites. The nitrogen isotopic ratios of the IOM from Ryugu samples were close to those in CI chondrites. CONCLUSION The organic matter in Ryugu probably consists of primordial materials that formed during (or before) the early stages of the Solar System’s formation, which were later modified by heterogeneous aqueous alteration on Ryugu’s parent body asteroid. Although the surface of Ryugu is exposed to solar wind, impacts, and heating by sunlight, the macromolecular organics in the surface grains of Ryugu are similar in their chemical, isotopic, and morphological compositions to those seen in primitive carbonaceous chondrites. The properties of Ryugu’s organic matter could explain the low albedo of the asteroid’s surface. Chemical evolution of macromolecular organic matter in samples of asteroid Ryugu. Organic matter formed in the interstellar medium or in the outer region of the protoplanetary disk that formed the Solar System. It was then incorporated into a planetesimal—Ryugu’s parent body—where it experienced varying degrees of reactions with liquid water. An impact ejected material from the parent body, which reassembled to form Ryugu. Samples were brought to Earth by Hayabusa2. CREDIT: HIROSHIMA UNIVERSITY, JAXA, UNIVERSITY OF TOKYO, KOCHI UNIVERSITY, RIKKYO UNIVERSITY, NAGOYA UNIVERSITY, CHIBA INSTITUTE OF TECHNOLOGY, MEIJI UNIVERSITY, UNIVERSITY OF AIZU, AIST
    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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  • 5
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 13 ( 2013-03-26), p. 5016-5021
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 13 ( 2013-03-26), p. 5016-5021
    Abstract: In both randomly moving Dictyostelium and mammalian cells, phosphatidylinositol (3,4,5)-trisphosphate and F-actin are known to propagate as waves at the membrane and act to push out the protruding edge. To date, however, the relationship between the wave geometry and the patterns of amoeboid shape change remains elusive. Here, by using phase map analysis, we show that morphology dynamics of randomly moving Dictyostelium discoideum cells can be characterized by the number, topology, and position of spatial phase singularities, i.e., points that represent organizing centers of rotating waves. A single isolated singularity near the cellular edge induced a rotational protrusion, whereas a pair of singularities supported a symmetric extension. These singularities appeared by strong phase resetting due to de novo nucleation at the back of preexisting waves. Analysis of a theoretical model indicated excitability of the system that is governed by positive feedback from phosphatidylinositol (3,4,5)-trisphosphate to PI3-kinase activation, and we showed experimentally that this requires F-actin. Furthermore, by incorporating membrane deformation into the model, we demonstrated that geometries of competing waves explain most of the observed semiperiodic changes in amoeboid morphology.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
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    detail.hit.zdb_id: 1461794-8
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