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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    In: Applied and Environmental Microbiology, American Society for Microbiology, Vol. 84, No. 17 ( 2018-09)
    Abstract: Bifidobacteria are a major component of the intestinal microbiota in humans, particularly breast-fed infants. Therefore, elucidation of the mechanisms by which these bacteria colonize the intestine is desired. One approach is transposon mutagenesis, a technique currently attracting much attention because, in combination with next-generation sequencing, it enables exhaustive identification of genes that contribute to microbial fitness. We now describe a transposon mutagenesis system for Bifidobacterium longum subsp. longum 105-A (JCM 31944) based on IS Blo11 , a native IS 3 family insertion sequence. To build this system, xylose-inducible or constitutive bifidobacterial promoters were tested to drive the expression of full-length or a truncated form at the N terminus of the IS Blo11 transposase. An artificial transposon plasmid, pBFS12, in which IS Blo11 terminal inverted repeats are separated by a 3-bp spacer, was also constructed to mimic the transposition intermediate of IS 3 elements. The introduction of this plasmid into a strain expressing transposase resulted in the insertion of the plasmid with an efficiency of 〉 10 3 CFU/μg DNA. The plasmid targets random 3- to 4-bp sequences, but with a preference for noncoding regions. This mutagenesis system also worked at least in B. longum NCC2705. Characterization of a transposon insertion mutant revealed that a putative α-glucosidase mediates palatinose and trehalose assimilation, demonstrating the suitability of transposon mutagenesis for loss-of-function analysis. We anticipate that this approach will accelerate functional genomic studies of B. longum subsp. longum . IMPORTANCE Several hundred species of bacteria colonize the mammalian intestine. However, the genes that enable such bacteria to colonize and thrive in the intestine remain largely unexplored. Transposon mutagenesis, combined with next-generation sequencing, is a promising tool to comprehensively identify these genes but has so far been applied only to a small number of intestinal bacterial species. In this study, a transposon mutagenesis system was established for Bifidobacterium longum subsp. longum , a representative health-promoting Bifidobacterium species. The system enables the identification of genes that promote colonization and survival in the intestine and should help illuminate the physiology of this species.
    Type of Medium: Online Resource
    ISSN: 0099-2240 , 1098-5336
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    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
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  • 6
    In: Protein Science, Wiley, Vol. 18, No. 1 ( 2009-01), p. 80-91
    Abstract: The muscleblind‐like (MBNL) proteins 1, 2, and 3, which contain four CCCH zinc finger motifs (ZF1–4), are involved in the differentiation of muscle inclusion by controlling the splicing patterns of several pre‐mRNAs. Especially, MBNL1 plays a crucial role in myotonic dystrophy. The CCCH zinc finger is a sequence motif found in many RNA binding proteins and is suggested to play an important role in the recognition of RNA molecules. Here, we solved the solution structures of both tandem zinc finger (TZF) motifs, TZF12 (comprising ZF1 and ZF2) and TZF34 (ZF3 and ZF4), in MBNL2 from Homo sapiens . In TZF12 of MBNL2, ZF1 and ZF2 adopt a similar fold, as reported previously for the CCCH‐type zinc fingers in the TIS11d protein. The linker between ZF1 and ZF2 in MBNL2 forms an antiparallel β‐sheet with the N‐terminal extension of ZF1. Furthermore, ZF1 and ZF2 in MBNL2 interact with each other through hydrophobic interactions. Consequently, TZF12 forms a single, compact global fold, where ZF1 and ZF2 are approximately symmetrical about the C2 axis. The structure of the second tandem zinc finger (TZF34) in MBNL2 is similar to that of TZF12. This novel three‐dimensional structure of the TZF domains in MBNL2 provides a basis for functional studies of the CCCH‐type zinc finger motifs in the MBNL protein family.
    Type of Medium: Online Resource
    ISSN: 0961-8368 , 1469-896X
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2009
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  • 7
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  Journal of Experimental Botany Vol. 73, No. 18 ( 2022-10-18), p. 6475-6489
    In: Journal of Experimental Botany, Oxford University Press (OUP), Vol. 73, No. 18 ( 2022-10-18), p. 6475-6489
    Abstract: Decreasing cadmium (Cd) concentrations in rice grains can effectively reduce potential risks to human health because rice is the major contributor to Cd intake in many diets. Among several genes involved in rice Cd accumulation, the loss of function of OsNRAMP5 is known to be effective in reducing grain concentration by inhibiting root uptake. However, disruption of this gene simultaneously decreases manganese (Mn) uptake because OsNRAMP5 is a major Mn transporter. With the aim of improving Mn uptake in OsNRAMP5 mutants while still restricting the grain Cd concentration below the upper limit of international standards, we identified a novel OsNRAMP5 allele encoding a protein in which glutamine (Q) at position 337 was replaced by lysine (K). The mutant carrying the OsNRAMP5-Q337K allele showed intermediate Cd and Mn accumulation between that of the wild-type and OsNRAMP5-knockout lines, and exhibited more resistance to Mn deficiency than the knockout lines. Different amino acid substitutions at position Q337 significantly affected the Cd and Mn transport activity in yeast cells, indicating that it is one of the crucial sites for OsNRAMP5 function. Our results suggest that the OsNRAMP5-Q337K allele might be useful for reducing grain Cd concentrations without causing severe Mn deficiency in rice cultivars through DNA marker-assisted breeding.
    Type of Medium: Online Resource
    ISSN: 0022-0957 , 1460-2431
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    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 8
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: Surface material from the near-Earth carbonaceous (C-type) asteroid (162173) Ryugu was collected and brought to Earth by the Hayabusa2 spacecraft. Ryugu is a dark, primitive asteroid containing hydrous minerals that are similar to the most hydrated carbonaceous meteorites. C-type asteroids are common in the asteroid belt and have been proposed as the parent bodies of carbonaceous meteorites. The samples of Ryugu provide an opportunity to investigate organic compounds for comparison with those from carbonaceous meteorites. Unlike meteorites, the Ryugu samples were collected and delivered for study under controlled conditions, reducing terrestrial contamination and the effects of atmospheric entry. RATIONALE Primitive carbonaceous chondrite meteorites are known to contain a variety of soluble organic molecules (SOMs), including prebiotic molecules such as amino acids. Meteorites might have delivered amino acids and other prebiotic organic molecules to the early Earth and other rocky planets. Organic matter in the Ryugu samples is the product of physical and chemical processes that occurred in the interstellar medium, the protosolar nebula, and/or on the planetesimal that became Ryugu’s parent body. We investigated SOMs in Ryugu samples principally using mass spectrometry coupled with liquid or gas chromatography. RESULTS We identified numerous organic molecules in the Ryugu samples. Mass spectroscopy detected hundreds of thousands of ion signals, which we assigned to ~20,000 elementary compositions consisting of carbon, hydrogen, nitrogen, oxygen, and/or sulfur. Fifteen amino acids, including glycine, alanine, and α-aminobutyric acid, were identified. These were present as racemic mixtures (equal right- and left-handed abundances), consistent with an abiotic origin. Aliphatic amines (such as methylamine) and carboxylic acids (such as acetic acid) were also detected, likely retained on Ryugu as organic salts. The presence of aromatic hydrocarbons, including alkylbenzenes, fluoranthene, and pyrene, implies hydrothermal processing on Ryugu’s parent body and/or presolar synthesis in the interstellar medium. Nitrogen-containing heterocyclic compounds were identified as their alkylated homologs, which could have been synthesized from simple aldehydes and ammonia. In situ analysis of a grain surface showed heterogeneous spatial distribution of alkylated homologs of nitrogen- and/or oxygen-containing compounds. CONCLUSION The wide variety of molecules identified indicates that prolonged chemical processes contributed to the synthesis of soluble organics on Ryugu or its parent body. The highly diverse mixture of SOMs in the samples resembles that seen in some carbonaceous chondrites. However, the SOM concentration in Ryugu is less than that in moderately aqueously altered CM (Mighei-type) chondrites, being more similar to that seen in warm aqueously altered CI (Ivuna-type) chondrites. The chemical diversity with low SOM concentration in Ryugu is consistent with aqueous organic chemistry at modest temperatures on Ryugu’s parent asteroid. The samples collected from the surface of Ryugu were exposed to the hard vacuum of space, energetic particle irradiation, heating by sunlight, and micrometeoroid impacts, but the SOM is still preserved, likely by being associated with minerals. The presence of prebiotic molecules on the asteroid surface suggests that these molecules can be transported throughout the Solar System. SOMs detected in surface samples of asteroid Ryugu. Chemical structural models are shown for example molecules from several classes identified in the Ryugu samples. Gray balls are carbon, white are hydrogen, red are oxygen, and blue are nitrogen. Clockwise from top: amines (represented by ethylamine), nitrogen-containing heterocycles (pyridine), a photograph of the sample vials for analysis, polycyclic aromatic hydrocarbons (PAHs) (pyrene), carboxylic acids (acetic acid), and amino acids (β-alanine). The central hexagon shows a photograph of the Ryugu sample in the sample collector of the Hayabusa2 spacecraft. The background image shows Ryugu in a photograph taken by Hayabusa2. CREDIT: JAXA, University of Tokyo, Kochi University, Rikkyo University, Nagoya University, Chiba Institute of Technology, Meiji University, University of Aizu, AIST, NASA, Dan Gallagher.
    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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  • 9
    Online Resource
    Online Resource
    Radiation Research Society ; 2007
    In:  Radiation Research Vol. 168, No. 5 ( 2007-11), p. 545-551
    In: Radiation Research, Radiation Research Society, Vol. 168, No. 5 ( 2007-11), p. 545-551
    Type of Medium: Online Resource
    ISSN: 0033-7587 , 1938-5404
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    Language: English
    Publisher: Radiation Research Society
    Publication Date: 2007
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  • 10
    In: Journal of Virological Methods, Elsevier BV, Vol. 204 ( 2014-08), p. 73-80
    Type of Medium: Online Resource
    ISSN: 0166-0934
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
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