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  • 1
    Publication Date: 2015-11-06
    Description: Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 ( PRDM5 ) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 ( PRDM5 exons 9–14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and exons 9–14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures ( COL13A1 , COL15A1 , NTN1 , CDH5 ) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9–14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and exons 9–14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    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
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  • 3
    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.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 4
    Publication Date: 2015-02-27
    Description: Motivation: Modern lipidomics is largely dependent upon structural ontologies because of the great diversity exhibited in the lipidome, but no automated lipid classification exists to facilitate this partitioning. The size of the putative lipidome far exceeds the number currently classified, despite a decade of work. Automated classification would benefit ongoing classification efforts by decreasing the time needed and increasing the accuracy of classification while providing classifications for mass spectral identification algorithms. Results: We introduce a tool that automates classification into the LIPID MAPS ontology of known lipids with 〉95% accuracy and novel lipids with 63% accuracy. The classification is based upon simple chemical characteristics and modern machine learning algorithms. The decision trees produced are intelligible and can be used to clarify implicit assumptions about the current LIPID MAPS classification scheme. These characteristics and decision trees are made available to facilitate alternative implementations. We also discovered many hundreds of lipids that are currently misclassified in the LIPID MAPS database, strongly underscoring the need for automated classification. Availability and implementation: Source code and chemical characteristic lists as SMARTS search strings are available under an open-source license at https://www.github.com/princelab/lipid_classifier . Contact: ryanmt@byu.net Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
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  • 5
    Publication Date: 2015-03-01
    Description: The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 6
    Publication Date: 2014-04-15
    Description: As proliferating cells transit from interphase into M-phase, chromatin undergoes extensive reorganization, and topoisomerase (topo) IIα, the major isoform of this enzyme present in cycling vertebrate cells, plays a key role in this process. In this study, a human cell line conditional null mutant for topo IIα and a derivative expressing an auxin-inducible degron (AID)-tagged version of the protein have been used to distinguish real mitotic chromosome functions of topo IIα from its more general role in DNA metabolism and to investigate whether topo IIβ makes any contribution to mitotic chromosome formation. We show that topo IIβ does contribute, with endogenous levels being sufficient for the initial stages of axial shortening. However, a significant effect of topo IIα depletion, seen with or without the co-depletion of topo IIβ, is the failure of chromosomes to hypercompact when delayed in M-phase. This requires much higher levels of topo II protein and is impaired by drugs or mutations that affect enzyme activity. A prolonged delay at the G2/M border results in hyperefficient axial shortening, a process that is topo IIα-dependent. Rapid depletion of topo IIα has allowed us to show that its function during late G2 and M-phase is truly required for shaping mitotic chromosomes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 7
    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.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 8
    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.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 9
    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
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  • 10
    Publication Date: 2014-11-16
    Description: The long and complex history of southern Africa makes it a geological nexus for understanding how crust forms, evolves and survives plate tectonic processes over billions of years. The goal of this study is to characterize the crustal thickness, composition, and Moho impedance contrasts across the Kaapvaal and Zimbabwe Cratons and surrounding mobile belts, which range in age from Archean to Palaeozoic. We use data gathered from the 1997–1999 Southern Africa Seismic Experiment, the Africa Array (2006–2007) and the Global Seismographic Network (1993–2009) to generate P -wave receiver function Gaussian-weighted common conversion point stacks across the region in order to provide a continuous 3-D image of crustal variations throughout southern Africa. We observe thickened crust associated with mobile belts and the intrusion of the Bushveld Complex relative to the less-deformed cratons. The southern Kaapvaal and eastern Zimbabwe Cratons have a well-defined Moho with an average depth of ~34 km and Vp / Vs of ~1.73, indicative of felsic average crustal composition. We explain the felsic composition observed in the Kaapvaal Craton in the context of significant crustal modification related to the deposition of the Ventersdorp lavas. We find that the Bushveld Province, the site of the world's largest layered mafic intrusion, has a thick (〉40 km) crust with a Vp / Vs 〉 1.8, indicative of a mafic average crustal composition. The magnitude of Moho conversions beneath the Bushveld Province is variable, with the lowest amplitude conversion appearing between the eastern and western limbs of the Bushveld Complex, indicative of mafic underplating beneath the region. In the Limpopo Belt and western Zimbabwe Craton, we observe low amplitude Moho conversions beneath the Okavango Dyke Swarm, and attribute this to the reworking of the crust by mafic underplating and intrusion during the Jurassic rifting of Gondwanaland. The Namaqua-Natal event thickened the crust and created a gradational transition from crust to mantle as seen by low amplitude Ps arrivals from receiver functions. Evidence for the presence of a mafic lower crust beneath the Namaqua-Natal Belt is observed in high Vp / Vs values (~1.8) and a high concentration of granulite xenoliths in kimberlite intrusions. In contrast to past interpretations for craton formation that suggest sharp Moho boundaries and low Vp / Vs ratios are characteristic of undisturbed cratons, we propose that these crustal properties are more controlled by tectonic events that later modify the existing cratonic crust. We cannot rule out secular crustal formation variations in the early Earth, but we propose that the southern African cratonic crust has been too heavily modified by later tectonic events to be used in arguments for secular variation, as may be the case for other cratons as well. Thus, it is important to consider the regional geological history of cratons to ensure that secular variation is not confused with the effects of later tectonic deformation and crustal modification.
    Keywords: Seismology
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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