Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery. METHODS: We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies. RESULTS: By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients. CONCLUSIONS: We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in samples of muscle and skin

Submillimeter Imaging of NGC 891 with SHARC

The advent of submillimeter wavelength array cameras operating on large ground-based telescopes is revolutionizing imaging at these wavelengths, enabling high-resolution submillimeter surveys of dust emission in star-forming regions and galaxies. Here we present a recent 350 micron image of the edge-on galaxy NGC 891, which was obtained with the Submillimeter High Angular Resolution Camera (SHARC) at the Caltech Submillimeter Observatory (CSO). We find that high resolution submillimeter data is a vital complement to shorter wavelength satellite data, which enables a reliable separation of the cold dust component seen at millimeter wavelengths from the warmer component which dominates the far-infrared (FIR) luminosity.Comment: 4 pages LaTeX, 2 EPS figures, with PASPconf.sty; to appear in "Astrophysics with Infrared Surveys: A Prelude to SIRTF

High-Frequency Measurements Of The Spectrum Of Sagittarius A*

We report near-simultaneous interferometric measurements of the spectrum of Sagittarius A* over the 5-354 GHz range and single-dish observations that have yielded the first detection of Sgr A* at 850 GHz. We confirm that Sgr A*'s spectrum rises more steeply at short millimeter wavelengths than at centimeter wavelengths, leading to a near-millimeter/submillimeter excess that dominates its luminosity. Below 900 GHz, Sgr A*'s observed luminosity is 70 +/- 30 L.. A new upper limit to Sgr A*'s 24.3 mu m flux, together with a compilation of other extant IR data, imply a far-infrared spectral turnover, which can result from either an intrinsic synchrotron cutoff or excess extinction near Sgr A*. If the former applies, Sgr A*'s total synchrotron luminosity is <10(3) L., while in the latter case it is <3 x 10(4) L. if spherical symmetry also applies.NSF AST96-15025, AST96-13717Astronom

Piloting a manualised weight management programme (Shape Up-LD) for overweight and obese persons with mild-moderate learning disabilities: study protocol for a pilot randomised controlled trial

National obesity rates have dramatically risen over the last decade. Being obese significantly reduces life expectancy, increases the risk of a range of diseases, and compromises quality of life. Costs to both the National Health Service and society are high. An increased prevalence of obesity in people with learning disabilities has been demonstrated. The consequences of obesity are particularly relevant to people with learning disabilities who are already confronted by health and social inequalities. In order to provide healthcare for all, and ensure equality of treatment for people with learning disabilities, services must be developed specifically with this population in mind. The aim of this project is to pilot the evaluation of a manualised weight management programme for overweight and obese persons with mild-moderate learning disabilities (Shape Up-LD)

Unstable Disk Galaxies. I. Modal Properties

I utilize the Petrov-Galerkin formulation and develop a new method for solving the unsteady collisionless Boltzmann equation in both the linear and nonlinear regimes. In the first order approximation, the method reduces to a linear eigenvalue problem which is solved using standard numerical methods. I apply the method to the dynamics of a model stellar disk which is embedded in the field of a soft-centered logarithmic potential. The outcome is the full spectrum of eigenfrequencies and their conjugate normal modes for prescribed azimuthal wavenumbers. The results show that the fundamental bar mode is isolated in the frequency space while spiral modes belong to discrete families that bifurcate from the continuous family of van Kampen modes. The population of spiral modes in the bifurcating family increases by cooling the disk and declines by increasing the fraction of dark to luminous matter. It is shown that the variety of unstable modes is controlled by the shape of the dark matter density profile.Comment: Accepted for publication in The Astrophysical Journa

A note on multi-dimensional Camassa-Holm type systems on the torus

We present a $2n$-component nonlinear evolutionary PDE which includes the $n$-dimensional versions of the Camassa-Holm and the Hunter-Saxton systems as well as their partially averaged variations. Our goal is to apply Arnold's [V.I. Arnold, Sur la g\'eom\'etrie diff\'erentielle des groupes de Lie de dimension infinie et ses applications \`a l'hydrodynamique des fluides parfaits. Ann. Inst. Fourier (Grenoble) 16 (1966) 319-361], [D.G. Ebin and J.E. Marsden, Groups of diffeomorphisms and the motion of an incompressible fluid. Ann. of Math. 92(2) (1970) 102-163] geometric formalism to this general equation in order to obtain results on well-posedness, conservation laws or stability of its solutions. Following the line of arguments of the paper [M. Kohlmann, The two-dimensional periodic $b$-equation on the diffeomorphism group of the torus. J. Phys. A.: Math. Theor. 44 (2011) 465205 (17 pp.)] we present geometric aspects of a two-dimensional periodic $\mu$-$b$-equation on the diffeomorphism group of the torus in this context.Comment: 14 page

Parallel pull flow: A new lean production design

This case study is #2 in a series of studies that relate specifically to the development and application of lean manufacturing techniques for the furniture and wood component supplying industries. Case study #2 is an example of how productivity can be increased in a furniture manufacturing organization by using a new lean production design termed Parallel Pull Flow (PPF). This case study provides information about lean manufacturing and how a lean manufacturing system can be implemented, followed by a detailed case study of a furniture manufacturing company’s adoption of a new final assembly PPF lean production system