Search for cosmic gamma radiation with a vidicon spark chamber Final report

Cosmic gamma radiation searched with vidicon spark chamber flown in high-altitude balloo

A Survey of the Northern Sky for TeV Point Sources

A search for steady TeV point sources anywhere in the northern sky has been made with data from the Milagrito air-shower-particle detector. Over 3 x 10**9 events collected from 1997 February to 1998 May have been used in this study. No statistically significant excess above the background from the isotropic flux of cosmic rays was found for any direction of the sky with declination between -5 degrees and 71.7 degrees. Upper limits are derived for the photon flux above 1 TeV from any steady point source in the northern sky.Comment: 2 Figure

Ribonucleoprotein Assembly Defects Correlate with Spinal Muscular Atrophy Severity and Preferentially Affect a Subset of Spliceosomal snRNPs

Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN) protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs) of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defective SMN complex function in snRNP assembly causes a significant decrease in the levels of a subset of snRNPs and preferentially affects the accumulation of U11 snRNP—a component of the minor spliceosome—in tissues of severe SMA mice. Thus, impairment of a ubiquitous function of SMN changes the snRNP profile of SMA tissues by unevenly altering the normal proportion of endogenous snRNPs. These findings are consistent with the hypothesis that SMN deficiency affects the splicing machinery and in particular the minor splicing pathway of a rare class of introns in SMA

Commonality amid diversity:multi-study proteomic identification of conserved disease mechanisms in spinal muscular atrophy

AbstractThe neuromuscular disease spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting from low levels of full-length survival motor neuron (SMN) protein. Despite having a good understanding of the underlying genetics of SMA, the molecular pathways downstream of SMN that regulate disease pathogenesis remain unclear. The identification of molecular perturbations downstream of SMN is required in order to fully understand the fundamental biological role(s) for SMN in cells and tissues of the body, as well as to develop a range of therapeutic targets for developing novel treatments for SMA. Recent developments in proteomic screening technologies have facilitated proteome-wide investigations of a range of SMA models and tissues, generating novel insights into disease mechanisms by highlighting conserved changes in a range of molecular pathways. Comparative analysis of distinct proteomic datasets reveals conserved changes in pathways converging on GAP43, GAPDH, NCAM, UBA1, LMNA, ANXA2 and COL6A3. Proteomic studies therefore represent a leading tool with which to dissect the molecular mechanisms of disease pathogenesis in SMA, serving to identify potentially attractive targets for the development of novel therapies