68 research outputs found

    A toxin hunter in the microworld of bacteria: a project on novel inhibitors against bacterial AB5 toxins

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    [要旨] 病原性細菌が産生する蛋白性のAB5型トキシンは1個のAサブユニットと5個のBサブユニットから構成される外毒素である。両サブユニットはそれぞれ特徴的な役割を持ち,互いに巧妙に機能分担をして一つのトキシンを形成している。Aサブユニットは主に毒性に直接関与する特異的な酵素活性を有する。一方,Bサブユニットは標的細胞のレセプターに対する結合能を有し,AB5型トキシンを標的細胞に吸着させる。ここでは毒性が全く異なるAB5型トキシンとして,コレラ菌が産生するコレラトキシン(CT),腸管出血性大腸菌が産生する志賀様トキシン(Stx),及び志賀トキシン産生大腸菌が産生するサブチラーゼサイトトキシン(SubAB)の3種類に関して,その作用メカニズムに着目した毒性を抑制する阻害因子の探索などの研究を紹介する。これらの3種類のAB5型トキシンに着目した理由は,それぞれのトキシンを産生する病原菌による感染症が世界的に流行し,社会問題となっているからである。つまり,コレラ菌は依然として発展途上国で大きな問題であり,腸管出血性大腸菌のO157:H7による集団食中毒は我国でも依然として多い。さらに21世紀になり,血清型がO157:H7以外の腸管出血性大腸菌による集団食中毒が世界的に急増しているためである。いずれも抗生物質を使用した後の残留トキシンによる病態悪化が指摘されており,トキシンを効率よく無毒化する事が急務である。[SUMMARY] Bacterial AB5 toxins are proteins, produced by pathogenic bacteria including of Vibrio cholerae, Shigella dysenteriae, and enterohaemorrhagic Escherichia coli, which are usually released into the extracellular medium and cause disease by killing or altering the metabolism of target eukaryotic cells. The toxins are usually composed of one A subunit(a toxic domain) and five B subunits(a receptor-binding domain). This article overviews the characteristics and mode of actions of AB5 toxins including cholera toxin, Shiga-like toxin, and subtilase cytotoxin, and highlights a project on the novel inhibitors against these bacterial AB5 toxins

    Genomic additive and dominance relationships by Definitions I-VI for parent-offspring (239 pairs), full-sibs (48 pairs) and half-sibs (23,941) of the Holstein sample.

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    <p>Genomic additive and dominance relationships by Definitions I-VI for parent-offspring (239 pairs), full-sibs (48 pairs) and half-sibs (23,941) of the Holstein sample.</p

    Quantitative Genetics Model as the Unifying Model for Defining Genomic Relationship and Inbreeding Coefficient

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    <div><p>The traditional quantitative genetics model was used as the unifying approach to derive six existing and new definitions of genomic additive and dominance relationships. The theoretical differences of these definitions were in the assumptions of equal SNP effects (equivalent to across-SNP standardization), equal SNP variances (equivalent to within-SNP standardization), and expected or sample SNP additive and dominance variances. The six definitions of genomic additive and dominance relationships on average were consistent with the pedigree relationships, but had individual genomic specificity and large variations not observed from pedigree relationships. These large variations may allow finding least related genomes even within the same family for minimizing genomic relatedness among breeding individuals. The six definitions of genomic relationships generally had similar numerical results in genomic best linear unbiased predictions of additive effects (GBLUP) and similar genomic REML (GREML) estimates of additive heritability. Predicted SNP dominance effects and GREML estimates of dominance heritability were similar within definitions assuming equal SNP effects or within definitions assuming equal SNP variance, but had differences between these two groups of definitions. We proposed a new measure of genomic inbreeding coefficient based on parental genomic co-ancestry coefficient and genomic additive correlation as a genomic approach for predicting offspring inbreeding level. This genomic inbreeding coefficient had the highest correlation with pedigree inbreeding coefficient among the four methods evaluated for calculating genomic inbreeding coefficient in a Holstein sample and a swine sample.</p></div

    Statistical summary of diagonal values of additive and dominance relationships.

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    <p>Statistical summary of diagonal values of additive and dominance relationships.</p

    Correlation (r) between genomic and pedigree inbreeding coefficients.

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    <p>F-I, F-II, F-IV, F-V, F-IVb, F<sub>A</sub>-I, F<sub>A</sub>-II, F<sub>A</sub>-IV, F<sub>A</sub>-V, F<sub>γ</sub>-III and F<sub>γ</sub>-VI are defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114484#pone-0114484-t004" target="_blank">Table 4</a>. F<sub>p</sub> is the pedigree inbreeding coefficient.</p><p>Correlation (r) between genomic and pedigree inbreeding coefficients.</p

    Genomic and pedigree relationships of the Holstein sample.

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    <p>Genomic and pedigree relationships of the Holstein sample.</p

    Genomic and pedigree relationships of the swine sample.

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    <p>Genomic and pedigree relationships of the swine sample.</p

    Six definitions of genomic additive and dominance relationships.

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    <p>Six definitions of genomic additive and dominance relationships.</p

    Estimated genomic heritabilities from the swine sample.

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    <p>  =  additive heritability,  =  dominance heritability, and  =  total heritability (or heritability in the broad sense).</p><p>Estimated genomic heritabilities from the swine sample.</p

    Statistical summary of genomic inbreeding coefficients of 1022 individuals with genotyped parents in the swine sample.

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    <p>Definition IVb: The individual's diagonal element of genomic additive relationship of each SNP is 1/p<sub>2</sub>, 0 and 1/p<sub>1</sub> for , and genotypes respectively, where p<sub>1</sub>  =  allele frequency of <i>A</i><sub>1</sub>, and p<sub>2</sub> = 1−p<sub>1</sub><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114484#pone.0114484-Yang1" target="_blank">[4]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0114484#pone.0114484-Keller1" target="_blank">[12]</a>. F<sub>p</sub> is the pedigree inbreeding coefficient.</p><p>Statistical summary of genomic inbreeding coefficients of 1022 individuals with genotyped parents in the swine sample.</p
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