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  • 1
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    A disc wind interpretation of the strong Fe K{alpha} features in 1H 0707-495 (2016)
    Oxford University Press
    Details
    Publication Date: 2016-07-25
    Description: 1H 0707–495 is the most convincing example of a supermassive black hole with an X-ray spectrum being dominated by extremely smeared, relativistic reflection, with the additional requirement of strongly supersolar iron abundance. However, here we show that the iron features in its 2–10 keV spectrum are rather similar to the archetypal wind dominated source, PDS 456. We fit all the 2–10 keV spectra from 1H 0707–495 using the same wind model as used for PDS 456, but viewed at higher inclination so that the iron absorption line is broader but not so blueshifted. This gives a good overall fit to the data from 1H 0707–495, and an extrapolation of this model to higher energies also gives a good match to the NuSTAR data. Small remaining residuals indicate that the iron line emission is stronger than in PDS 456. This is consistent with the wider angle wind expected from a continuum-driven wind from the super-Eddington mass accretion rate in 1H 0707–495, and/or the presence of residual reflection from the underlying disc though the presence of the absorption line in the model removes the requirement for highly relativistic smearing, and highly supersolar iron abundance. We suggest that the spectrum of 1H 0707–495 is sculpted more by absorption in a wind than by extreme relativistic effects in strong gravity.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 2
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    Complete Genome Sequence of Streptococcus dysgalactiae subsp. equisimilis 167 Carrying Lancefield Group C Antigen and Comparative Genomics of S. dysgalactiae subsp. equisimilis Strains (2013)
    Oxford University Press
    Details
    Publication Date: 2013-09-19
    Description: Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging human pathogen that causes life-threatening invasive infections such as streptococcal toxic shock syndrome. Recent epidemiological studies reveal that invasive SDSE infections have been increasing in Asia, Europe, and the United States. Almost all SDSE carry Lancefield group G or C antigen. We have determined the complete genome sequence of a human group C SDSE 167 strain. A comparison of its sequence with that of four SDSE strains, three in Lancefield group G and one in Lancefield group A, showed approximately 90% coverage. Most regions showing little or no homology were located in the prophages. There was no evidence of massive rearrangement in the genome of SDSE 167. Bayesian phylogeny using entire genome sequences showed that the most recent common ancestor of the five SDSE strains appeared 446 years ago. Interestingly, we found that SDSE 167 harbors sugar metabolizing enzymes in a unique region and streptodornase in the phage region, which presumably contribute to the degradation of host tissues and the prompted covRS mutation, respectively. A comparison of these five SDSE strains, which differ in Lancefield group antigens, revealed a gene cluster presumably responsible for the synthesis of the antigenic determinant. These results may provide the basis for molecular epidemiological research of SDSE.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Cdt1-binding protein GRWD1 is a novel histone-binding protein that facilitates MCM loading through its influence on chromatin architecture (2015)
    Oxford University Press
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    Publication Date: 2015-07-12
    Description: Efficient pre-replication complex (pre-RC) formation on chromatin templates is crucial for the maintenance of genome integrity. However, the regulation of chromatin dynamics during this process has remained elusive. We found that a conserved protein, GRWD1 (glutamate-rich WD40 repeat containing 1), binds to two representative replication origins specifically during G1 phase in a CDC6- and Cdt1-dependent manner, and that depletion of GRWD1 reduces loading of MCM but not CDC6 and Cdt1. Furthermore, chromatin immunoprecipitation coupled with high-throughput sequencing (Seq) revealed significant genome-wide co-localization of GRWD1 with CDC6. We found that GRWD1 has histone-binding activity. To investigate the effect of GRWD1 on chromatin architecture, we used formaldehyde-assisted isolation of regulatory elements (FAIRE)-seq or FAIRE-quantitative PCR analyses, and the results suggest that GRWD1 regulates chromatin openness at specific chromatin locations. Taken together, these findings suggest that GRWD1 may be a novel histone-binding protein that regulates chromatin dynamics and MCM loading at replication origins.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Identification of novel Arabidopsis thaliana upstream open reading frames that control expression of the main coding sequences in a peptide sequence-dependent manner (2015)
    Oxford University Press
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    Publication Date: 2015-02-18
    Description: Upstream open reading frames (uORFs) are often found in the 5'-leader regions of eukaryotic mRNAs and can negatively modulate the translational efficiency of the downstream main ORF. Although the effects of most uORFs are thought to be independent of their encoded peptide sequences, certain uORFs control translation of the main ORF in a peptide sequence-dependent manner. For genome-wide identification of such peptide sequence-dependent regulatory uORFs, exhaustive searches for uORFs with conserved amino acid sequences have been conducted using bioinformatic analyses. However, whether the conserved uORFs identified by these bioinformatic approaches encode regulatory peptides has not been experimentally determined. Here we analyzed 16 recently identified Arabidopsis thaliana conserved uORFs for the effects of their amino acid sequences on the expression of the main ORF using a transient expression assay. We identified five novel uORFs that repress main ORF expression in a peptide sequence-dependent manner. Mutational analysis revealed that, in four of them, the C-terminal region of the uORF-encoded peptide is critical for the repression of main ORF expression. Intriguingly, we also identified one exceptional sequence-dependent regulatory uORF, in which the stop codon position is not conserved and the C-terminal region is not important for the repression of main ORF expression.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The origin of ultrafast outflows in AGN: Monte Carlo simulations of the wind in PDS 456 (2014)
    Oxford University Press
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    Publication Date: 2014-11-14
    Description: Ultrafast outflows (UFOs) are seen in many AGN, giving a possible mode for AGN feedback on to the host galaxy. However, the mechanism(s) for the launch and acceleration of these outflows are currently unknown, with UV line driving apparently strongly disfavoured as the material along the line of sight is so highly ionized that it has no UV transitions. We revisit this issue using the Suzaku X-ray data from PDS 456, an AGN with the most powerful UFO seen in the local Universe. We explore conditions in the wind by developing a new 3D Monte Carlo code for radiation transport. The code only handles highly ionized ions, but the data show the ionization state of the wind is high enough that this is appropriate, and this restriction makes it fast enough to explore parameter space. We reproduce the results of earlier work, confirming that the mass-loss rate in the wind is around 30 per cent of the inferred inflow rate through the outer disc. We show for the first time that UV line driving is likely to be a major contribution to the wind acceleration. The mass-loss rate in the wind matches that predicted from a purely line driven system, and this UV absorption can take place out of the line of sight. Continuum driving should also play a role as the source is close to Eddington. This predicts that the most extreme outflows will be produced from the highest mass accretion rate flows on to high-mass black holes, as observed.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents (2013)
    Oxford University Press
    Details
    Publication Date: 2013-04-20
    Description: DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O 6 -alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation-induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the F' prolac from strain CC102 (F'CC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O 6 -alkylguanine. The results showed the repair of O 6 -methylguanine to be performed by AGT 〉〉 MMR 〉 NER in order of importance, whereas the repair of O 6 -ethylguanine followed the order NER 〉 AGT 〉 MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation-induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N -alkyl- N -nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1 (2014)
    Oxford University Press
    Details
    Publication Date: 2014-02-08
    Description: Over 170 mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS), a lethal motor neuron disease. Although the molecular properties of SOD1 mutants differ considerably, we have recently shown that intracellular copper dyshomeostasis is a common pathogenic feature of different SOD1 mutants. Thus, the potentiation of endogenous copper regulation could be a therapeutic strategy. In this study, we investigated the effects of the overexpression of metallothionein-I (MT-I), a major copper-regulating protein, on the disease course of a mouse model of ALS (SOD1 G93A ). Using double transgenic techniques, we found that the overexpression of MT-I in SOD1 G93A mice significantly extended the lifespan and slowed disease progression, but the effects on disease onset were modest. Genetically induced MT-I normalized copper dyshomeostasis in the spinal cord without influencing SOD1 enzymatic activity. The overexpression of MT-I in SOD1 G93A mice markedly attenuated the pathological features of the mice, including the death of motor neurons, the degeneration of ventral root axons, the atrophy of skeletal muscles, and the activation of glial cells. Double transgenic mice also showed a decreased level of SOD1 aggregates within the glial cells of the spinal cord. Furthermore, the overexpression of MT-I in SOD1 G93A mice reduced the number of spheroid-shaped astrocytes cleaved by active caspase-3. We concluded that therapeutic strategies aimed at the potentiation of copper regulation by MT-I could be of benefit in cases of ALS caused by SOD1 mutations.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion (2017)
    Oxford University Press
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    Publication Date: 2017-01-10
    Description: The 2-methylthio (ms 2 ) modification at A37 of tRNAs is critical for accurate decoding, and contributes to metabolic homeostasis in mammals. However, the regulatory mechanism of ms 2 modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms 2 modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms 2 modification, which was rescued by the application of an exogenous CysSSH donor. Using a unique and stable isotope-labeled CysSSH donor, we show that CysSSH was capable of specifically transferring its reactive sulfur atom to the cysteine residues of ms 2 -modifying enzymes as well as ms 2 modification. Furthermore, the suppression of CysSSH production impaired insulin secretion and caused glucose intolerance in both a pancreatic β-cell line and mouse model. These results demonstrate that intracellular CysSSH is a novel sulfur source for ms 2 modification, and that it contributes to insulin secretion.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    CyanoBase: a large-scale update on its 20th anniversary (2017)
    Oxford University Press
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    Publication Date: 2017-01-05
    Description: The first ever cyanobacterial genome sequence was determined two decades ago and CyanoBase ( http://genome.microbedb.jp/cyanobase ), the first database for cyanobacteria was simultaneously developed to allow this genomic information to be used more efficiently. Since then, CyanoBase has constantly been extended and has received several updates. Here, we describe a new large-scale update of the database, which coincides with its 20th anniversary. We have expanded the number of cyanobacterial genomic sequences from 39 to 376 species, which consists of 86 complete and 290 draft genomes. We have also optimized the user interface for large genomic data to include the use of semantic web technologies and JBrowse and have extended community-based reannotation resources through the re-annotation of Synechocystis sp. PCC 6803 by the cyanobacterial research community. These updates have markedly improved CyanoBase, providing cyanobacterial genome annotations as references for cyanobacterial research.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Accelerated Proliferation and Abnormal Differentiation of Epidermal Keratinocytes in Endo- -Galactosidase C Transgenic Mice (2007)
    Oxford University Press
    Details
    Publication Date: 2007-10-27
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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