Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs efect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profle. Furthermore, we show co-expression of specifc DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration

The environment of Low Surface Brightness Galaxies

Using the Early Data Release of the Sloan Digital Sky Survey (SDSS) we investigated the clustering properties of Low Surface Brightness (LSB) galaxies in comparison to normal, High Surface Brightness (HSB) galaxies. We selected LSB galaxies and HSB galaxies with well measured redshifts from the SDSS data base and performed three-dimensional neighbour counting analysis within spheres of radii between 0.8 Mpc and 8.0 Mpc. As a second analysis method we used an N-th neighbour analysis with N varying from one to ten galaxies. Our results show significant differences between the galaxy densities of LSB galaxies and HSB galaxies on scales from 2 to 5 Mpc. At scales larger than 5 Mpc LSB and HSB galaxies share the same clustering properties. In the pie-slice diagrams the LSB galaxies appear to favour the inner rims of filaments as defined by the HSB galaxies, with a couple of LSB galaxies even being located inside the voids. Our results support the idea of gas-rich LSB galaxies forming and developing in low density regions without many galaxy interactions and just now reaching the filaments of the large scale structure.Comment: 4 pages, 5 figures, Astronomy & Astrophysics Letters in pres

On the nature of the X-ray source in GK Per

We report XMM-Newton observations of the intermediate polar (IP) GK Per on the rise to the 2002 outburst and compare them to Chandra observations during quiescence. We find an asymmetric spin light curve implying an asymmetric shape of a semi-transparent accretion curtain. A low Fe xvii (15.01/15.26 A) line flux ratio confirms the need for an asymmetric geometry and significant effects of resonant line scattering. Medium resolution spectra in outburst and quiescence are both fitted with a leaky absorber model for the post shock hard X-ray emission, a black body (outburst) for the thermalized X-ray emission from the white dwarf and an optically thin spectrum. The difference between high and low spin as well as QPO/flares states can be explained by a variation in the absorbing column density. The Fe fluorescence at 6.4 keV (equivalent width of 447 eV) is not significantly variable during spin cycle or on QPO periods. High-resolution RGS spectra reveal a number of emission lines from H-like and He-like elements. The lines are broader than the instrumental response with a roughly constant velocity dispersion for different lines, indicating identical origin. He-like emission lines are used to give values for the electron densities of log n_e ~ 12. We do not detect any variation in the emission lines during the spin cycle, implying that the lines are not noticeably obscured or absorbed. We conclude that they originate in the accretion curtains and propose a model for their shape.Comment: 14 pages, 22 figures, accepted by A&A; text re quiescent data changed slightly, references adde

Elementary Forms of the Metaphorical Life : Tropes at Work in Durkheim’s Theory of the Religious

Peer reviewedPostprin

Elucidating the selenium and arsenic metabolic pathways following exposure to the non-hyperaccumulating Chlorophytum comosum, spider plant

Although many studies have investigated the metabolism of selenium and arsenic in hyperaccumulating plants for phytoremediation purposes, few have explored non-hyperaccumulating plants as a model for general contaminant exposure to plants. In addition, the result of simultaneous supplementation with selenium and arsenic has not been investigated in plants. In this study, Chlorophytum comosum, commonly known as the spider plant, was used to investigate the metabolism of selenium and arsenic after single and simultaneous supplementation. Size exclusion and ion-pairing reversed phase liquid chromatography were coupled to an inductively coupled plasma mass spectrometer to obtain putative metabolic information of the selenium and arsenic species in C. comosum after a mild aqueous extraction. The chromatographic results depict that selenium and arsenic species were sequestered in the roots and generally conserved upon translocation to the leaves. The data suggest that selenium was directly absorbed by C. comosum roots when supplemented with SeVI, but a combination of passive and direct absorption occurred when supplemented with SeIV due to the partial oxidation of SeIV to SeVI in the rhizosphere. Higher molecular weight selenium species were more prevalent in the roots of plants supplemented with SeIV, but in the leaves of plants supplemented with SeVI due to an increased translocation rate. When supplemented as AsIII, arsenic is proposed to be passively absorbed as AsIII and partially oxidized to AsV in the plant root. Although total elemental analysis demonstrates a selenium and arsenic antagonism, a compound containing selenium and arsenic was not present in the general aqueous extract of the plant

The Spectra of T Dwarfs I: Near-Infrared Data and Spectral Classification

We present near-infrared spectra for a sample of T dwarfs, including eleven new discoveries made using the Two Micron All Sky Survey. These objects are distinguished from warmer (L-type) brown dwarfs by the presence of methane absorption bands in the 1--2.5 \micron spectral region. A first attempt at a near-infrared classification scheme for T dwarfs is made, based on the strengths of CH$_4$ and H$_2$O bands and the shapes of the 1.25, 1.6, and 2.1 \micron flux peaks. Subtypes T1 V through T8 V are defined, and spectral indices useful for classification are presented. The subclasses appear to follow a decreasing T$_{eff}$ scale, based on the evolution of CH$_4$ and H$_2$O bands and the properties of L and T dwarfs with known distances. However, we speculate that this scale is not linear with spectral type for cool dwarfs, due to the settling of dust layers below the photosphere and subsequent rapid evolution of spectral morphology around T$_{eff}$ $\sim$ 1300--1500 K. Similarities in near-infrared colors and continuity of spectral features suggest that the gap between the latest L dwarfs and earliest T dwarfs has been nearly bridged. This argument is strengthened by the possible role of CH$_4$ as a minor absorber shaping the K-band spectra of the latest L dwarfs. Finally, we discuss one peculiar T dwarf, 2MASS 0937+2931, which has very blue near-infrared colors (J-K$_s$ = $-0.89\pm$0.24) due to suppression of the 2.1 \micron peak. The feature is likely caused by enhanced collision-induced H$_2$ absorption in a high pressure or low metallicity photosphere.Comment: 74 pages including 26 figures, accepted by ApJ v563 December 2001; full paper including all of Table 3 may be downloaded from http://www.gps.caltech.edu/~pa/adam/classification ;also see submission 010844

Atomoxetine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with ADHD and dyslexia

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).</p> <p>Methods</p> <p>Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.</p> <p>Results</p> <p>Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.</p> <p>Conclusions</p> <p>Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.</p> <p>Trial Registration</p> <p>Clinical Trial Registry: ClinicalTrials.gov: NCT00191048</p