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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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  • 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
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 19 ( 2004-05-11), p. 7323-7328
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 19 ( 2004-05-11), p. 7323-7328
    Abstract: Mammalian oocytes are arrested at the prophase of meiosis before induction of maturation by the preovulatory luteinizing hormone (LH) surge. LH also promotes the survival of meiotic male germ cells in the testis. Because LH binds somatic cells, the mechanism underlying its regulation of germ cell function is unclear. We found that LH stimulates Leydig insulin-like 3 (INSL3) transcripts in ovarian theca and testicular Leydig cells. INSL3, in turn, binds a G protein-coupled receptor, LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8), expressed in germ cells to activate the inhibitory G protein, thus leading to decreases in cAMP production. Treatment with INSL3 initiates meiotic progression of arrested oocytes in preovulatory follicles in vitro and in vivo and suppresses male germ cell apoptosis in vivo , thus demonstrating the importance of the INSL3-LGR8 paracrine system in mediating gonadotropin actions.
    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: 2004
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  • 5
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 9 ( 2001-04-24), p. 5175-5180
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 9 ( 2001-04-24), p. 5175-5180
    Abstract: Airway hyperresponsiveness (AHR), goblet cell metaplasia, and mucus overproduction are important features of bronchial asthma. To elucidate the molecular mechanisms behind these pulmonary pathologies, we examined for genes preferentially expressed in the lungs of a murine model of allergic asthma by using suppression subtractive hybridization (SSH). We identified a gene called gob-5 that had a selective expression pattern in the airway epithelium with AHR. Here, we show that gob-5 , a member of the calcium-activated chloride channel family, is a key molecule in the induction of murine asthma. Intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction. In contrast, overexpression of gob-5 in airway epithelia by using an adenoviral vector exacerbated the asthma phenotype. Introduction of either gob-5 or hCLCA1 , the human counterpart of gob-5 , into the human mucoepidermoid cell line NCI-H292 induced mucus production as well as MUC5AC expression. Our results indicated that gob-5 may play a critical role in murine asthma, and its human counterpart hCLCA1 is therefore a potential target for asthma therapy.
    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: 2001
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  • 6
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: The Hayabusa2 spacecraft made two landings on the asteroid (162173) Ryugu in 2019, during which it collected samples of the surface material. Those samples were delivered to Earth in December 2020. The colors, shapes, and morphologies of the returned samples are consistent with those observed on Ryugu by Hayabusa2, indicating that they are representative of the asteroid. Laboratory analysis of the samples can determine the chemical composition of Ryugu and provide information on its formation and history. RATIONALE We used laboratory analysis to inform the following questions: (i) What are the elemental abundances of Ryugu? (ii) What are the isotopic compositions of Ryugu? (iii) Does Ryugu consist of primary materials produced in the disk from which the Solar System formed or of secondary materials produced in the asteroid or on a parent asteroid? (iv) When were Ryugu’s constituent materials formed? (v) What, if any, relationship does Ryugu have with meteorites? RESULTS We quantified the abundances of 66 elements in the Ryugu samples: H, Li, Be, C, O, Na, Mg, Al, Si, P, S, Cl, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Te, Cs, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Tl, Pb, Bi, Th, and U. There is a slight variation in chemical compositions between samples from the first and second touchdown sites, but the variations could be due to heterogeneity among the samples that were analyzed. The Cr-Ti isotopes and abundance of volatile elements are similar to those of carbonaceous meteorites in the CI (Ivuna-like) chondrite group. The Ryugu samples consist of the minerals magnetite, breunnerite, dolomite, and pyrrhotite as grains embedded in a matrix composed of serpentine and saponite. This mineral assemblage and the texture are also similar to those of CI meteorites. Anhydrous silicates are almost absent, which indicates extensive liquid water–rock reactions (aqueous alteration) in the material. We conclude that the samples mainly consist of secondary materials that were formed by aqueous alteration in a parent body, from which Ryugu later formed. The oxygen isotopes in the bulk Ryugu samples are also similar to those in CI chondrites. We used oxygen isotope thermometry to determine the temperature at which the dolomite and magnetite precipitated from an aqueous solution, which we found to be 37° ± 10°C. The 53 Mn- 53 Cr isotopes date the aqueous alteration at 5.2 − 0.7 + 0.8 million (statistical) or 5.2 − 2.1 + 1.6 million (systematic) years after the birth of the Solar System. Phyllosilicate minerals are the main host of water in the Ryugu samples. The amount of structural water in Ryugu is similar to that in CI chondrites, but interlayer water is largely absent in Ryugu, which suggests a loss of interlayer water to space. The abundance of structural water and results from dehydration experiments indicate that the Ryugu samples remained below ~100°C from the time of aqueous alteration until the present. We ascribe the removal of interlayer water to a combination of impact heating, solar heating, solar wind irradiation, and long-term exposure to the ultrahigh vacuum of space. The loss of interlayer water from phyllosilicates could be responsible for the comet-like activity of some carbonaceous asteroids and the ejection of solid material from the surface of asteroid Bennu. CONCLUSION The Ryugu samples are most similar to CI chondrite meteorites but are more chemically pristine. The chemical composition of the Ryugu samples is a closer match to the Sun’s photosphere than to the composition of any other natural samples studied in laboratories. CI chondrites appear to have been modified on Earth or during atmospheric entry. Such modification of CI chondrites could have included the alteration of the structures of organics and phyllosilicates, the adsorption of terrestrial water, and the formation of sulfates and ferrihydrites. Those issues do not affect the Ryugu samples. Those modifications might have changed the albedo, porosity, and density of the CI chondrites, causing the observed differences between CI meteorites, Hayabusa2 measurements of Ryugu’s surface, and the Ryugu samples returned to Earth. Representative petrography of a Ryugu sample, designated C0002-C1001. Colors indicate elemental abundances determined from x-ray spectroscopy. Lines of iron, sulfur, and calcium are shown as red, green, and blue (RGB) color channels in that order. Combinations of these elements are assigned to specific minerals, as indicated in the legend. All visible minerals were formed by aqueous alteration on Ryugu’s parent body.
    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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  • 7
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 1994
    In:  Nature Vol. 372, No. 6501 ( 1994-11), p. 50-50
    In: Nature, Springer Science and Business Media LLC, Vol. 372, No. 6501 ( 1994-11), p. 50-50
    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: 1994
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  • 8
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 26 ( 2006-06-27), p. 10074-10079
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 26 ( 2006-06-27), p. 10074-10079
    Abstract: The circadian clock is driven by cell-autonomous transcription/translation feedback loops. The BMAL1 transcription factor is an indispensable component of the positive arm of this molecular oscillator in mammals. Here, we present a molecular genetic screening assay for mutant circadian clock proteins that is based on real-time circadian rhythm monitoring in cultured fibroblasts. By using this assay, we identified a domain in the extreme C terminus of BMAL1 that plays an essential role in the rhythmic control of E-box-mediated circadian transcription. Remarkably, the last 43 aa of BMAL1 are required for transcriptional activation, as well as for association with the circadian transcriptional repressor CRYPTOCHROME 1 (CRY1), depending on the coexistence of CLOCK protein. C-terminally truncated BMAL1 mutant proteins still associate with mPER2 (another protein of the negative feedback loop), suggesting that an additional repression mechanism may converge on the N terminus. Taken together, these results suggest that the C-terminal region of BMAL1 is involved in determining the balance between circadian transcriptional activation and suppression.
    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: 2006
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