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  • 1
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    Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-09
    Description: Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 ( RBM20 ), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an RBM20 R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations. Furthermore, gene expression analysis for RBM20- dependent splice variants affected sarcomeric ( TTN and LDB3 ) and calcium (Ca 2+ ) handling ( CAMK2D and CACNA1C ) genes. Indeed, RBM20 hiPSC-CMs exhibited increased sarcomeric length ( RBM20 : 1.747 ± 0.238 µm versus control: 1.404 ± 0.194 µm; P 〈 0.0001) and decreased sarcomeric width ( RBM20 : 0.791 ± 0.609 µm versus control: 0.943 ± 0.166 µm; P 〈 0.0001). Additionally, CMs showed defective Ca 2+ handling machinery with prolonged Ca 2+ levels in the cytoplasm as measured by greater area under the curve ( RBM20 : 814.718 ± 94.343 AU versus control: 206.941 ± 22.417 AU; P 〈 0.05) and higher Ca 2+ spike amplitude ( RBM20 : 35.281 ± 4.060 AU versus control:18.484 ± 1.518 AU; P 〈 0.05). β-adrenergic stress induced with 10 µ m norepinephrine demonstrated increased susceptibility to sarcomeric disorganization ( RBM20 : 86 ± 10.5% versus control: 40 ± 7%; P 〈 0.001). This study features the first hiPSC model of RBM20 familial DCM. By monitoring human cardiac disease according to stage-specific cardiogenesis, this study demonstrates RBM20 familial DCM is a developmental disorder initiated by molecular defects that pattern maladaptive cellular mechanisms of pathological cardiac remodeling. Indeed, hiPSC-CMs recapitulate RBM20 familial DCM phenotype in a dish and establish a tool to dissect disease-relevant defects in RBM20 splicing as a global regulator of heart function.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Parallel Recruitment of Multiple Genes into C4 Photosynthesis (2013)
    Oxford University Press
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    Publication Date: 2013-11-25
    Description: During the diversification of living organisms, novel adaptive traits usually evolve through the co-option of preexisting genes. However, most enzymes are encoded by gene families, whose members vary in their expression and catalytic properties. Each may therefore differ in its suitability for recruitment into a novel function. In this work, we test for the presence of such a gene recruitment bias using the example of C 4 photosynthesis, a complex trait that evolved recurrently in flowering plants as a response to atmospheric CO 2 depletion. We combined the analysis of complete nuclear genomes and high-throughput transcriptome data for three grass species that evolved the C 4 trait independently. For five of the seven enzymes analyzed, the same gene lineage was recruited across the independent C 4 origins, despite the existence of multiple copies. The analysis of a closely related C 3 grass confirmed that C 4 expression patterns were not present in the C 3 ancestors but were acquired during the evolutionary transition to C 4 photosynthesis. The significant bias in gene recruitment indicates that some genes are more suitable for a novel function, probably because the mutations they accumulated brought them closer to the characteristics required for the new function.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Characterization of a trifunctional glucosyltransferase essential for Moraxella catarrhalis lipooligosaccharide assembly (2013)
    Oxford University Press
    Details
    Publication Date: 2013-06-29
    Description: The human respiratory tract pathogen Moraxella catarrhalis expresses lipooligosaccharides (LOS), glycolipid surface moieties that are associated with enhanced colonization and virulence. Recent studies have delineated the major steps required for the biosynthesis and assembly of the M. catarrhalis LOS molecule. We previously demonstrated that the glucosyltransferase enzyme Lgt3 is responsible for the addition of at least one glucose (Glc) molecule, at the β-(1-4) position, to the inner core of the LOS molecule. Our data further suggested a potential multifunctional role for Lgt3 in LOS biosynthesis. The studies reported here demonstrate that the Lgt3 enzyme possesses two glycosyltransferase domains (A1 and A2) similar to that of other bifunctional glycosyltransferase enzymes involved in surface polysaccharide biosynthesis in Escherichia coli , Pasteurella multocida and Streptococcus pyogenes . Each Lgt3 domain contains a conserved DXD motif, shown to be involved in the catalytic activity of other glycosyltransferases. To determine the function of each domain, A1 (N-terminal), A2 (C-terminal) and double A1A2 site-directed DAD to AAA mutants were constructed and the resulting LOS phenotypes of these modified strains were analyzed. Our studies indicate that the Lgt3 N-terminal A1 catalytic domain is responsible for the addition of the first β-(1-3) Glc to the first Glc on the inner core. The C-terminal catalytic domain A2 then adds the β-(1-4) Glc and the β-(1-6) Glc, confirming the bifunctional nature of this domain. The results from these experiments demonstrate that Lgt3 is a novel, multifunctional transferase responsible for the addition of three Glcs with differing linkages onto the inner core of M. catarrhalis LOS.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
    Electronic Resource
    Electronic Resource
    Fate of Spermatozoa penetrating into the Tissues of the Fallopian Tube (1959)
    [s.l.] : Nature Publishing Group
    Nature 183 (1959), S. 1744-1745 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The Fallopian tubes of five mice were examined in detail. Four of them had been autopsied 12 hr. after mating, the fifth 24 hr. after mating. Many labelled spermatozoa were found between the nuclei of the mucosal cells, which is to be expected from previous work1"3, though the displacement of some ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/1831744a0
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  • 5
    Electronic Resource
    Electronic Resource
    Human Blastocysts grown in Culture (1971)
    [s.l.] : Nature Publishing Group
    Nature 229 (1971), S. 132-133 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Six embryos were cultured. The pH of the medium was 7.3, the osmotic pressure 300 mOsmol/kg, and the gas phase consisted of 5 % oxygen, 5 % carbon dioxide and 90 % nitrogen. Two of the embryos developed to early morulae, one having more than twenty-three nuclei, and the other twenty-nine nuclei and ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/229132a0
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  • 6
    Electronic Resource
    Electronic Resource
    Effects of Duchenne muscular dystrophy on muscle protein synthesis (1982)
    [s.l.] : Nature Publishing Group
    Nature 296 (1982), S. 165-167 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] We studied seven normal fed adult men aged 22-65 yr and five boys with Duchenne muscular dystrophy, aged 12-1 Syr. Three of the patients were wheelchair bound and the two youngest were on the verge of becoming so. Investigations of these subjects using radioactive isotopes would not have been ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/296165a0
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  • 7
    Electronic Resource
    Electronic Resource
    Control of the Sex Ratio at Full Term in the Rabbit by transferring Sexed Blastocysts (1968)
    [s.l.] : Nature Publishing Group
    Nature 218 (1968), S. 346-348 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] An important step forward has been made in controlling the sex of rabbits by sexing pre-implantation embryos and transferring the sexed embryos into recipient females. In the experiments, foetuses were surgically delivered and their sex was found to have been correctly predicted at the blastocyst ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/218346a0
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  • 8
    Electronic Resource
    Electronic Resource
    Sexing of Live Rabbit Blastocysts (1967)
    [s.l.] : Nature Publishing Group
    Nature 214 (1967), S. 576-577 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Sexing live mammalian embryos before their transfer to recipient females could be of great importance in agriculture and human affairs. A first step in this direction is the use of fluorescence microscopy to score sex chromatin and so identify male and female embryos only five days after ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/214576a0
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  • 9
    Electronic Resource
    Electronic Resource
    Immunological Control of Fertility in Female Mice (1964)
    [s.l.] : Nature Publishing Group
    Nature 203 (1964), S. 50-53 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] THE advantages and possibilities of an immunological method for the control of fertility have been discussed repeatedly1. The recent publication by Dr. Anne McLaren2 on the immunological control of fertility in mice prompts the present communication of my results in this field and on the same ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/203050a0
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  • 10
    Electronic Resource
    Electronic Resource
    Maturation in vitro of Mouse, Sheep, Cow, Pig, Rhesus Monkey and Human Ovarian Oocytes (1965)
    [s.l.] : Nature Publishing Group
    Nature 208 (1965), S. 349-351 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] THE investigation of early development in many mammalian species is restricted by the difficulty of obtaining sufficient numbers of oocytes and embryos at particular stages of development. Post-dietyate ovarian oocytes are usually obtained after stimulation by luteiniz-ing hormone (LH) either ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/208349a0
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