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  • 1
    Publication Date: 2012-08-28
    Description: Biallelic mutations in the gene encoding DHOdehase [dihydroorotate dehydrogenase ( DHODH )], an enzyme required for de novo pyrimidine biosynthesis, have been identified as the cause of Miller (Genée–Weidemann or postaxial acrofacial dysostosis) syndrome (MIM 263750). We report compound heterozygous DHODH mutations in four additional families with typical Miller syndrome. Complementation in auxotrophic yeast demonstrated reduced pyrimidine synthesis and in vitro enzymatic analysis confirmed reduced DHOdehase activity in 11 disease-associated missense mutations, with 7 alleles showing discrepant activity between the assays. These discrepancies are partly explained by the domain structure of DHODH and suggest both assays are useful for interpretation of individual alleles. However, in all affected individuals, the genotype predicts that there should be significant residual DHOdehase activity. Urine samples obtained from two mutation-positive cases showed elevated levels of orotic acid (OA) but not dihydroorotate (DHO), an unexpected finding since these represent the product and the substrate of DHODH enzymatic activity, respectively. Screening of four unrelated cases with overlapping but atypical clinical features showed no mutations in either DHODH or the other de novo pyrimidine biosynthesis genes ( CAD , UMPS ), with these cases also showing normal levels of urinary OA and DHO. In situ analysis of mouse embryos showed Dhodh , Cad and Umps to be strongly expressed in the pharyngeal arch and limb bud, supporting a site- and stage-specific requirement for de novo pyrimidine synthesis. The developmental sensitivity to reduced pyrimidine synthesis capacity may reflect the requirement for an exceptional mitogenic response to growth factor signalling in the affected tissues.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2015-06-11
    Description: The High-Energy Stereoscopic System (HESS) has detected diffuse TeV emission correlated with the distribution of molecular gas along the Ridge at the Galactic Centre. Diffuse, non-thermal emission is also seen by the Fermi large area telescope ( Fermi -LAT) in the GeV range and by radio telescopes in the GHz range. Additionally, there is a distinct, spherically symmetric excess of gamma rays seen by Fermi -LAT in the GeV range. A cosmic ray flare, occurring in the Galactic Centre, 10 4 yr ago has been proposed to explain the TeV Ridge. An alternative, steady-state model explaining all three data sets (TeV, GeV, and radio) invokes purely leptonic processes. We show that the flare model from the Galactic Centre also provides an acceptable fit to the GeV and radio data, provided the diffusion coefficient is energy independent. However, if Kolmogorov-type turbulence is assumed for the diffusion coefficient, we find that two flares are needed, one for the TeV data (occurring approximately 10 4 yr ago) and an older one for the GeV data (approximately 10 5 yr old). We find that the flare models we investigate do not fit the spherically symmetric GeV excess as well as the usual generalized Navarro–Frenk–White spatial profile, but are better suited to explain the Ridge. We also show that a range of single-zone, steady-state models are able to explain all three spectral data sets. Large gas densities equal to the volumetric average in the region can be accommodated by an energy-independent diffusion or streaming based steady-state model. Additionally, we investigate how the flare and steady-state models may be distinguished with future gamma-ray data looking for a spatial dependence of the gamma-ray spectral index.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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