Luminous Infrared Starbursts in a Cluster of Galaxies

Analysing mid--infrared ISOCAM images of the cluster of galaxies J1888.16CL, we identified among its members several particularly active galaxies with total infrared luminosities well above 10^{11} Lsun. If powered by dust enshrouded starbursts, as suggested by their optical spectra, these Luminous Infrared Galaxies would exhibit star formation rates surprisingly high in the cluster environment. The triggering mechanism is unclear but could be tidal collisions within sub-structures or infalling groups.Comment: 5 pages, 2 figures, proceedings of the IAU Colloquium 195, "Outskirts of Galaxy Clusters: intense life in the suburbs", A. Diafero, e

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g

Translational Regulation of Utrophin by miRNAs

Background Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified. Methodology/Principal Findings Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ~99% in C2C12 cells and is mediated by both the 5′- and 3′-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR-206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells. Conclusions/Significance The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA-mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of superenhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods: An international collaboration, exome sequencing, molecular modeling, yeast twohybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability

Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening

Background: Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings: We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance: We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics an

Neuronal characterisation of syncoilin

Syncoilin is a member of the intermediate filament protein family. It is highly expressed in skeletal and cardiac muscle, where it binds to the dystrophin associated protein complex, via a-dystrobrevin. Syncoilin is increased in the muscles ofpatients with muscular dystrophies. Previous data from this laboratory indicated that syncoilin is also expressed in neurons, but its function in the nervous system is unknown. The aim ofthis thesis was to determine the neuronal function of syncoilin, by the identification of its binding partners. This is an important question because cytoskeletal dynamics are critical in the development and regeneration of neurons, and moreover, mutations in other intermediate filament proteins can cause amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. In this thesis, a co-immunoprecipitation and mass spectrometry strategy was used to identify binding partners for syncoilin in neurons. Two novel binding partners were identified, namely a-tubulin and the chaperone CCT, and verified using other methods. Additionally, the interaction of syncoilin with the neuronal intermediate filament peripherin was confirmed and investigated further. Finally, three syncoilin gene variants identified in a dHPLC screen ofpatients with motor neuropathies were characterised in terms of their predicted effects on the structure and binding properties ofsyncoilin and their subcellular localisation in the NSC-34 motor neuron cell line. The identification ofnovel binding partners for syncoilin in neurons gives important insights into the architecture and dynamic organisation ofthe neuronal cytoskeleton, and may also contribute to the understanding of syncoilin in skeletal muscle. Furthermore, the identification of syncoilin variants in patients with motor neuropathies suggests that syncoilin may be involved in the pathogenesis of motor neuron disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo