Four-week rapamycin treatment improves muscular dystrophy in a fukutin-deficient mouse model of dystroglycanopathy

Tissue mass-normalized values of cytochrome C reduced in vitro by succinate dehydrogenase from homogenized TAs of VEH- or RAPA-treated LC and KO mice. Two-way ANOVA. (PDF 291 kb

Improving estimation of glacier volume change: a GLIMS case study of Bering Glacier System, Alaska

International audienceThe Global Land Ice Measurements from Space (GLIMS) project has developed tools and methods that can be employed by analysts to create accurate glacier outlines and resultant measures of glacier extent. To illustrate the importance of accurate glacier outlines and the effectiveness of GLIMS standards we have conducted a case study on Bering Glacier System (BGS), Alaska. BGS is a complex glacier system aggregated from multiple drainage basins, numerous individual ice streams, and many accumulation areas. Published measurements of BGS surface area vary from 1740 to 6200 km2, depending on how the boundaries of this system have been defined. Utilizing GLIMS tools and standards we have completed a new outline and analysis of the area-altitude distribution (hypsometry) of BGS using Landsat images from 2000 and 2001. We compared this new outline (3632 km2) with three previous outlines to illustrate the errors that result from the widely varying estimates used in previous analysis of BGS area. The use of different BGS outlines results in highly variable measures of volume change and net balance (bn). Outline variability alone results in a net balance rate range of ?1.0 to ?3.2 m/yr water equivalent (W.E.), a volume change range of ?4.2 to ?8.2 km3/yr, and a near doubling in contributions to sea level equivalent (SLE), 0.0122 mm/yr to 0.0236 mm/yr. A study of three different models of BGS net balance leads us to favor estimates of bn of ?1.2 m/yr W.E. and total volume change of ?4.2 km3/yr for the period 1950?2004. These estimates result in a near doubling of contributions to sea level equivalent when compared with previous studies. While current inaccuracies in glacier outlines hinder our ability to fully understand glacier change, there is no reason why our understanding of glacier extents should not be comprehensive and accurate. Such accuracy is possible with the increasing volume of satellite imagery of glacierized regions, and recent advances in tools and standards

Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window