Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event.

The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.

OBJECTIVE: Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions ΔE218 and ΔE224, resulting in a significant hypercontractile phenotype with congenital muscle stiffness, rather than weakness, and respiratory failure in one patient. METHODS: The effect of the Tpm3.12 deletions on the contractile properties in dissected patient myofibers was measured. We used quantitative in vitro motility assay to measure Ca(2+) sensitivity of thin filaments reconstituted with recombinant Tpm3.12 ΔE218 and ΔE224. RESULTS: Contractility studies on permeabilized myofibers demonstrated reduced maximal active tension from both patients with increased Ca(2+) sensitivity and altered cross-bridge cycling kinetics in ΔE224 fibers. In vitro motility studies showed a two-fold increase in Ca(2+) sensitivity of the fraction of filaments motile and the filament sliding velocity concentrations for both mutations. INTERPRETATION: These data indicate that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca(2+) sensitivity of the troponin-tropomyosin complex, resulting in abnormally active interaction of the actin and myosin complex. Both mutations are located in the charged motifs of the actin-binding residues of tropomyosin 3, thus disrupting the electrostatic interactions that facilitate accurate tropomyosin binding with actin necessary to prevent the on-state. The mutations destabilize the off-state and result in excessively sensitized excitation-contraction coupling of the contractile apparatus. This work expands the phenotypic spectrum of TPM3-related disease and provides insights into the pathophysiological mechanisms of the actin-tropomyosin complex.

Flow cytometry analysis: a quantitative method for collagen VI deficiency screening.

Mutations in COL6A1, COL6A2 and COL6A3 genes result in collagen VI myopathies: Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and intermediate phenotypes. At present, none of the existing diagnostic techniques for evaluating collagen VI expression is quantitative, and the detection of subtle changes in collagen VI expression remains challenging. We investigated flow cytometry analysis as a means of quantitatively measuring collagen VI in primary fibroblasts and compared this method with the standard method of fibroblast collagen VI immunohistochemical analysis. Eight UCMD and five BM molecularly confirmed patients were studied and compared to five controls. Flow cytometry analysis consistently detected a reduction of collagen VI of at least 60% in all UCMD cases. In BM cases the levels of collagen VI were variable but on average 20% less than controls. Flow cytometry analysis provides an alternative method for screening for collagen VI deficiency at the protein level in a quantitative, time and cost-effective manner.

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency.

The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (α-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function.