Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against <i>MYCN</i>-Amplified Neuroblastoma.

Targeted inhibition of proteins modulating epigenetic changes is an increasingly important priority in cancer therapeutics, and many small molecule inhibitors are currently being developed. In the case of neuroblastoma (NB), a pediatric solid tumor with a paucity of intragenic mutations, epigenetic deregulation may be especially important. In this study we validate the histone methyltransferase G9a/EHMT2 as being associated with indicators of poor prognosis in NB. Immunological analysis of G9a protein shows it to be more highly expressed in NB cell-lines with MYCN amplification, which is a primary determinant of dismal outcome in NB patients. Furthermore, G9a protein in primary tumors is expressed at higher levels in poorly differentiated/undifferentiated NB, and correlates with high EZH2 expression, a known co-operative oncoprotein in NB. Our functional analyses demonstrate that siRNA-mediated G9a depletion inhibits cell growth in all NB cell lines, but, strikingly, only triggers apoptosis in NB cells with MYCN amplification, suggesting a synthetic lethal relationship between G9a and MYCN. This pattern of sensitivity is also evident when using small molecule inhibitors of G9a, UNC0638, and UNC0642. The increased efficacy of G9a inhibition in the presence of MYCN-overexpression is also demonstrated in the SHEP-21N isogenic model with tet-regulatable MYCN. Finally, using RNA sequencing, we identify several potential tumor suppressor genes that are reactivated by G9a inhibition in NB, including the CLU, FLCN, AMHR2, and AKR1C1-3. Together, our study underlines the under-appreciated role of G9a in NB, especially in MYCN-amplified tumors

Near-IR spectroscopy of PKS1549-79: a proto-quasar revealed?

We present a near-IR spectrum of the nearby radio galaxy PKS1549-79 (z=0153). These data were taken with the aim of testing the idea that this object contains a quasar nucleus that is moderately extinguished, despite evidence that its radio jet points close to our line-of-sight. We detect broad Paschen Alpha emission (FWHM ~1745 km/s), relatively bright continuum emission, and a continuum slope consistent with a reddened quasar spectrum (3.1 < Av < 7.3), all emitted by an unresolved point source. Therefore we conclude that we have, indeed, detected a hidden quasar nucleus in PKS1549-79. Combined with previous results, these observations are consistent with the idea that PKS1549-79 is a young radio source in which the cocoon of debric left over from the triggering events has not yet been swept aside by circumnuclear outflows.Comment: 6 pages, 4 figures, accepted for publication in MNRA

Cognitive representations of disability behaviours in people with mobility limitations : consistency with theoretical constructs

Disability is conceptualised as behaviour by psychological theory and as a result of bodily impairment by medical models. However, how people with disabilities conceptualise those disabilities is unclear. The purpose of this study was to examine disability representations in people with mobility disabilities. Thirteen people with mobility disabilities completed personal repertory grids (using the method of triads) applied to activities used to measure disabilities. Ten judges with expertise in health psychology then examined the correspondence between the elicited disability constructs and psychological and medical models of disability. Participants with mobility disabilities generated 73 personal constructs ofdisability. These constructs were judged consistent with the content of two psychological models, namely the theory of planned behaviour and social cognitive theory and with the main medical model of disability, the International Classification of Functioning Disability and Health.Individuals with activity limitations conceptualise activities in a manner that is compatible with both psychological and medical models. This ensures adequate communication in contexts where the medical model is relevant, e.g. clinical contexts, as well as in everyday conversation about activities and behaviours. Finally, integrated models of disability may be of value for theory driven interdisciplinary approaches to disability and rehabilitation

Radiolytic mapping of solvent-contact surfaces in photosystem II of higher plants: Experimental identification of putative water channels within the photosystem

Background: Substrate water must reach the buried Mn4O 5Ca cluster in Photosystem II. Results: OH produced by radiolysis modified buried amino acid residues. These were mapped onto the PS II crystal structure. Conclusion: Two groups of oxidized residues were identified which form putative pathways to the Mn4O5Ca cluster. Significance: Identification of water and oxygen channels is crucial for our understanding of Photosystem II function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc

Cryptic diversity of the jewel beetles Agrilus viridis (Coleoptera: Buprestidae) hosted on hazelnut

The genus Agrilus (Coleoptera: Buprestidae) represents a taxonomic puzzle, since the boundaries between species, subspecies and morphotypes tied to different host plants are sometimes difficult to establish on morphological characteristics alone. Some Agrilus species can cause severe agricultural damage; this makes correct distinctions of the taxon and knowing whether the insects switch from one host plant to another important. This study of mtDNA examined the genetic characteristics of lineages of A. viridis, a jewel beetle recently found causing damage to the hazelnut Corylus avellana in NW Italy. Three mitochondrial markers (a portion of the 12S rDNA and a DNA-fragment including partial NADH dehydrogenase subunit I gene, the tRNA Leucine gene and partial 16S rDNA, and partial  Cytochrome c oxidase) were compared between individuals collected on birch Betula sp., beech Fagus sp., willow Salix sp., alder Alnus sp. and hazelnut. We found a high genetic distance between A. viridis sampled on different host plants, while individuals sampled on the same host plant were similar despite a considerable geographic gap between sampled areas. Our study supports the general pattern for strong ecological separation between populations living on different host plants

Variability of M giant stars based on Kepler photometry: general characteristics

M giants are among the longest-period pulsating stars which is why their studies were traditionally restricted to analyses of low-precision visual observations, and more recently, accurate ground-based data. Here we present an overview of M giant variability on a wide range of time-scales (hours to years), based on analysis of thirteen quarters of Kepler long-cadence observations (one point per every 29.4 minutes), with a total time-span of over 1000 days. About two-thirds of the sample stars have been selected from the ASAS-North survey of the Kepler field, with the rest supplemented from a randomly chosen M giant control sample. We first describe the correction of the light curves from different quarters, which was found to be essential. We use Fourier analysis to calculate multiple frequencies for all stars in the sample. Over 50 stars show a relatively strong signal with a period equal to the Kepler-year and a characteristic phase dependence across the whole field-of-view. We interpret this as a so far unidentified systematic effect in the Kepler data. We discuss the presence of regular patterns in the distribution of multiple periodicities and amplitudes. In the period-amplitude plane we find that it is possible to distinguish between solar-like oscillations and larger amplitude pulsations which are characteristic for Mira/SR stars. This may indicate the region of the transition between two types of oscillations as we move upward along the giant branch.Comment: 12 pages, 13 figures, accepted for publication in MNRAS. The normalized light curves are available upon reques

Label-free electrochemical monitoring of DNA ligase activity

This study presents a simple, label-free electrochemical technique for the monitoring of DNA ligase activity. DNA ligases are enzymes that catalyze joining of breaks in the backbone of DNA and are of significant scientific interest due to their essential nature in DNA metabolism and their importance to a range of molecular biological methodologies. The electrochemical behavior of DNA at mercury and some amalgam electrodes is strongly influenced by its backbone structure, allowing a perfect discrimination between DNA molecules containing or lacking free ends. This variation in electrochemical behavior has been utilized previously for a sensitive detection of DNA damage involving the sugar-phosphate backbone breakage. Here we show that the same principle can be utilized for monitoring of a reverse process, i.e., the repair of strand breaks by action of the DNA ligases. We demonstrate applications of the electrochemical technique for a distinction between ligatable and unligatable breaks in plasmid DNA using T4 DNA ligase, as well as for studies of the DNA backbone-joining activity in recombinant fragments of E. coli DNA ligase

Hip disability and osteoarthritis outcome score (HOOS) – validity and responsiveness in total hip replacement

BACKGROUND: The aim of the study was to evaluate if physical functions usually associated with a younger population were of importance for an older population, and to construct an outcome measure for hip osteoarthritis with improved responsiveness compared to the Western Ontario McMaster osteoarthritis score (WOMAC LK 3.0). METHODS: A 40 item questionnaire (hip disability and osteoarthritis outcome score, HOOS) was constructed to assess patient-relevant outcomes in five separate subscales (pain, symptoms, activity of daily living, sport and recreation function and hip related quality of life). The HOOS contains all WOMAC LK 3.0 questions in unchanged form. The HOOS was distributed to 90 patients with primary hip osteoarthritis (mean age 71.5, range 49–85, 41 females) assigned for total hip replacement for osteoarthritis preoperatively and at six months follow-up. RESULTS: The HOOS met set criteria of validity and responsiveness. It was more responsive than WOMAC regarding the subscales pain (SRM 2.11 vs. 1.83) and other symptoms (SRM 1.83 vs. 1.28). The responsiveness (SRM) for the two added subscales sport and recreation and quality of life were 1.29 and 1.65, respectively. Patients ≤ 66 years of age (range 49–66) reported higher responsiveness in all five subscales than patients >66 years of age (range 67–85) (Pain SRM 2.60 vs. 1.97, other symptoms SRM 3.0 vs. 1.60, activity of daily living SRM 2.51 vs. 1.52, sport and recreation function SRM 1.53 vs. 1.21 and hip related quality of life SRM 1.95 vs. 1.57). CONCLUSION: The HOOS 2.0 appears to be useful for the evaluation of patient-relevant outcome after THR and is more responsive than the WOMAC LK 3.0. The added subscales sport and recreation function and hip related quality of life were highly responsive for this group of patients, with the responsiveness being highest for those younger than 66

Europe as a multilevel federation

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