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  • 1
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    Use of the HPRT gene to study nuclease-induced DNA double-strand break repair (2015)
    Oxford University Press
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    Publication Date: 2015-11-21
    Description: Understanding the mechanisms of chromosomal double-strand break repair (DSBR) provides insight into genome instability, oncogenesis and genome engineering, including disease gene correction. Research into DSBR exploits rare-cutting endonucleases to cleave exogenous reporter constructs integrated into the genome. Multiple reporter constructs have been developed to detect various DSBR pathways. Here, using a single endogenous reporter gene, the X-chromosomal disease gene encoding hypoxanthine phosphoribosyltransferase ( HPRT ), we monitor the relative utilization of three DSBR pathways following cleavage by I-Sce I or CRISPR/Cas9 nucleases. For I-Sce I, our estimated frequencies of accurate or mutagenic non-homologous end-joining and gene correction by homologous recombination are 4.1, 1.5 and 0.16%, respectively. Unexpectedly, I-Sce I and Cas9 induced markedly different DSBR profiles. Also, using an I-Sce I-sensitive HPRT minigene, we show that gene correction is more efficient when using long double-stranded DNA than single- or double-stranded oligonucleotides. Finally, using both endogenous HPRT and exogenous reporters, we validate novel cell cycle phase-specific I-Sce I derivatives for investigating cell cycle variations in DSBR. The results obtained using these novel approaches provide new insights into template design for gene correction and the relationships between multiple DSBR pathways at a single endogenous disease gene.
    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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    Collisional excitation of [C II], [O I] and CO in massive galaxies (2015)
    Oxford University Press
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    Publication Date: 2015-11-28
    Description: Many massive galaxies at the centres of relaxed galaxy clusters and groups have vast reservoirs of warm (~10 000 K) and cold (100 K) gas. In many such low-redshift systems this gas is lifted into the hot interstellar medium in filamentary structures, which are long lived and are typically not forming stars. Two important questions are how far do these reservoirs cool and if cold gas is abundant what is the cause of the low star formation efficiency? Heating and excitation of the filaments from collisions and mixing of hot particles in the surrounding X-ray gas describes well the optical and near infrared line ratios observed in the filaments. In this paper we examine the theoretical properties of dense, cold clouds emitting in the far infrared and sub-millimetre through the bright lines of [C  ii ] 157 μm , [O  i ] 63 μm and CO, exposed to such energetic ionizing particles. We find that optical depth effects and thermal pressure support alone cannot account for the line ratios; however, a very modest additional pressure support can fit the observed [O  i ] 63 μm/[C  ii ] 157 μm line ratios by decreasing the density of the gas. This may also help stabilize the filaments against collapse leading to the low rates of star formation. We make predictions for the line ratios expected from cold gas under these conditions and present diagnostic diagrams for comparison with further observations. We provide our code as an Appendix.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    Modelling the ages and metallicities of early-type galaxies in Fundamental Plane space (2014)
    Oxford University Press
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    Publication Date: 2014-10-26
    Description: Recent observations have probed the formation histories of nearby elliptical galaxies by tracking correlations between the stellar population parameters, age and metallicity, and the structural parameters that enter the Fundamental Plane, size R e , and velocity dispersion . These studies have found intriguing correlations between these four parameters. In this work, we make use of a semi-analytic model, based on halo merger trees extracted from the Bolshoi cosmological simulation, that predicts the structural properties of spheroid-dominated galaxies based on an analytic model that has been tested and calibrated against an extensive suite of hydrodynamic+ N -body binary merger simulations. We predict the R e , , luminosity, age, and metallicity of spheroid-dominated galaxies, enabling us to compare directly to observations. Our model predicts a strong correlation between age and for early-type galaxies, and no significant correlation between age and radius, in agreement with observations. In addition, we predict a strong correlation between metallicity and , and a weak correlation between metallicity and R e , in qualitative agreement with observations. We find that the correlations with arise as a result of the strong link between and the galaxy's assembly time. Minor mergers produce a large change in radius while leaving nearly the same, which explains the weaker trends with radius.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 4
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    Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus (2014)
    Oxford University Press
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    Publication Date: 2014-09-20
    Description: Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 ( PRDM5 ) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus ( P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Understanding the structural scaling relations of early-type galaxies (2014)
    Oxford University Press
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    Publication Date: 2014-08-29
    Description: We use a large suite of hydrodynamical simulations of binary galaxy mergers to construct and calibrate a physical prescription for computing the effective radii and velocity dispersions of spheroids. We implement this prescription within a semi-analytic model embedded in merger trees extracted from the Bolshoi cold dark matter N -body simulation, accounting for spheroid growth via major and minor mergers and disc instabilities. We find that without disc instabilities, our model does not predict sufficient numbers of intermediate-mass early-type galaxies in the local Universe. Spheroids also form earlier in models with spheroid growth via disc instabilities. Our model correctly predicts the normalization, slope, and scatter of the low-redshift size–mass and Fundamental Plane relations for early-type galaxies. It predicts a degree of curvature in the Faber–Jackson relation that is not seen in local observations, but this could be alleviated if higher mass spheroids have more bottom-heavy initial mass functions. The model also correctly predicts the observed strong evolution of the size–mass relation for spheroids out to higher redshifts, as well as the slower evolution in the normalization of the Faber–Jackson relation. We emphasize that these are genuine predictions of the model since it was tuned to match hydrodynamical simulations and not these observations.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1) (2014)
    Oxford University Press
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    Publication Date: 2014-10-22
    Description: Niemann–Pick C1 (NPC1) disease is a rare, neurodegenerative lysosomal cholesterol storage disorder, typified by progressive cognitive and motor function impairment. Affected individuals usually succumb to the disease in adolescence. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) has emerged as a promising intervention that reduces lipid storage and prolongs survival in NPC1 disease animal models. A barrier to the development of HP-β-CD and other treatments for NPC disease has been the lack of validated biochemical measures to evaluate efficacy. Here we explored whether cholesterol homeostatic responses resulting from HP-β-CD-mediated redistribution of sequestered lysosomal cholesterol could provide biomarkers to monitor treatment. Upon direct CNS delivery of HP-β-CD, we found increases in plasma 24( S )-HC in two independent NPC1 disease animal models, findings that were confirmed in human NPC1 subjects receiving HP-β-CD. Since circulating 24( S )-HC is almost exclusively CNS-derived, the increase in plasma 24( S )-HC provides a peripheral, non-invasive measure of the CNS effect of HP-β-CD. Our findings suggest that plasma 24( S )-HC, along with the other cholesterol-derived markers examined in this study, can serve as biomarkers that will accelerate development of therapeutics for NPC1 disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Accurate determination of the free-free Gaunt factor - II. Relativistic Gaunt factors (2015)
    Oxford University Press
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    Publication Date: 2015-03-29
    Description: When modelling an ionized plasma, all spectral synthesis codes need the thermally averaged free–free Gaunt factor defined over a very wide range of parameter space in order to produce an accurate prediction for the spectrum. Until now no data set exists that would meet these needs completely. We have therefore produced a table of relativistic Gaunt factors over a much wider range of parameter space than has ever been produced before. We present tables of the thermally averaged Gaunt factor covering the range 10 log 2  = –6 to 10 and 10 log u  = –16 to 13 for all atomic numbers Z  = 1 through 36. The data were calculated using the relativistic Bethe–Heitler–Elwert (BHE) approximation and were subsequently merged with accurate non-relativistic results in those parts of the parameter space where the BHE approximation is not valid. These data will be incorporated in the next major release of the spectral synthesis code cloudy . We also produced tables of the frequency integrated Gaunt factor covering the parameter space 10 log 2  = –6 to +10 for all values of Z between 1 and 36. All the data presented in this paper are available online.
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    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 8
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    Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1 (2012)
    Oxford University Press
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    Publication Date: 2012-07-28
    Description: Niemann–Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1 –/– survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.
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    Topics: Biology , Medicine
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  • 9
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    Radiative cooling II: effects of density and metallicity (2014)
    Oxford University Press
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    Publication Date: 2014-04-19
    Description: This work follows Lykins et al. discussion of classic plasma cooling function at low density and solar metallicity. Here, we focus on how the cooling function changes over a wide range of density ( n H 〈10 12 cm –3 ) and metallicity ( Z  〈 30 Z ). We find that high densities enhance the ionization of elements such as hydrogen and helium until they reach local thermodynamic equilibrium. By charge transfer, the metallicity changes the ionization of hydrogen when it is partially ionized. We describe the total cooling function as a sum of four parts: those due to H&He, the heavy elements, electron–electron bremsstrahlung and grains. For the first three parts, we provide a low-density limit cooling function, a density dependence function, and a metallicity-dependent function. These functions are given with numerical tables and analytical fit functions. We discuss grain cooling only in the interstellar medium case. We then obtain a total cooling function that depends on density, metallicity and temperature. As expected, collisional de-excitation suppresses the heavy elements cooling. Finally, we provide a function giving the electron fraction, which can be used to convert the cooling function into a cooling rate.
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    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Implications of coronal line emission in NGC 4696 (2014)
    Oxford University Press
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    Publication Date: 2014-11-21
    Description: We announce a new facility in the spectral code cloudy that enables tracking the evolution of a cooling parcel of gas with time. For gas cooling from temperatures relevant to galaxy clusters, earlier calculations estimated the [Fe  xiv ] 5303/[Fe  x ] 6375 luminosity ratio, a critical diagnostic of a cooling plasma, to slightly less than unity. By contrast, our calculations predict a ratio of ~3. We revisit recent optical coronal line observations along the X-ray cool arc around NGC 4696 by Canning et al., which detected [Fe  x ] 6375, but not [Fe  xiv ] 5303. We show that these observations are not consistent with predictions of cooling flow models. Differential extinction could in principle account for the observations, but it requires extinction levels ( A V  〉 3.625) incompatible with previous observations. The non-detection of [Fe  xiv ] implies a temperature ceiling of 2.1 million K. Assuming cylindrical geometry and transonic turbulent pressure support, we estimate the gas mass at ~1 million M . The coronal gas is cooling isochorically. We propose that the coronal gas has not condensed out of the intracluster medium, but instead is the conductive or mixing interface between the X-ray plume and the optical filaments. We present a number of emission lines that may be pursued to test this hypothesis and constrain the amount of intermediate-temperature gas in the system.
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    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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