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

Rational representations and controller synthesis of L2 behaviors

This paper considers linear dynamical systems restricted to square integrable trajectories. Following the behavioral formalism, a number of relevant classes of linear and shift-invariant L2systems are defined. It is shown that rational functions, analytic in specific half-spaces of the complex plane, prove most useful for representing such systems. For various classes of L2 systems, this paper provides a complete characterization of system equivalence in terms of rational kernel representations of L2 systems. In addition, a complete solution is given for the problem when selected (non-manifest) variables of an L2 system can be completely eliminated from their behavior. This elimination theorem has considerable independent interest in general modeling problems. It is shown that the elimination result is key in the solution of the problem for realizing an arbitrary L2 system as the interconnection of a given L2 system and a to-be-synthesized L2 system. In the context of control, this problem amounts to characterizing the existence and parameterization of all controllers that, after interconnection with a given plant, constitute a desired controlled system

A model reduction scheme with preserved optimal performance

This paper addresses a problem in control relevant model reduction. More specifically, a model reduction scheme is proposed that preserves the disturbance decoupling property of the to-be-reduced plant. It is shown that optimal feedback laws designed for the reduced system will actually be optimal for the non-reduced system. Moreover, a characterization is given for the minimal reduction order for which this property can be established. This can be extended to the design of observers for complex systems. The results are illustrated by a simulation example