Improving translational studies: lessons from rare neuromuscular diseases

Animal models play a key role in the development of novel treatments for human disease. This is particularly true for rare diseases – defined as disorders that affect less than 1 in 2000 people in the human population – for which, very often, there are no effective methods of treatment. Pharmaceutical companies are increasingly focussing on the development of therapies for the more than 7000 rare diseases. Because the majority of these are the result of single gene disorders, the exceptional ability to manipulate the mouse genome means that many such studies will take place in the laboratory mouse. But how good are the mouse models and how useful are they in assessing the potential for translational medicine? In this Editorial, I will discuss current difficulties in translational research as well as examples of good laboratory practice and guidelines that are being implemented to improve the translational potential of animal studies in the field of neuromuscular rare diseases. This could represent a potentially useful approach for adoption by other disease fields to achieve a greater success rate in translational studies

Investigating synthetic oligonucleotide targeting of miR31 in Duchenne muscular dystrophy

Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block. This approach would act synergistically with exon skipping where possible, but by targeting the 3’UTR it would further be of benefit to the many DMD patients who express low levels of in-frame transcript. We here present investigations into the feasibility of combining exon skipping with several different strategies for miR31-modulation, using both in vitro models and the mdx mouse (the classical animal model of DMD), and monitoring effects on dystrophin at the transcriptional and translational level. We show that despite promising results from our cell culture model, our in vivo data failed to demonstrate similarly reproducible enhancement of dystrophin translation, suggesting that miR31-modulation may not be practical under current oligonucleotide approaches. Possible explanations for this disappointing outcome are discussed, along with suggestions for future investigations

The Invisible Higgs Decay Width in the Add Model at the LHC

Assuming flat universal extra dimensions, we demonstrate that for a light Higgs boson the process $pp\to W^*W^* +X \to Higgs,graviscalars +X \to invisible+X$ will be observable at the $5 \sigma$ level at the LHC for the portion of the Higgs-graviscalar mixing ($\xi$) and effective Planck mass ($M_D$) parameter space where channels relying on visible Higgs decays fail to achieve a $5 \sigma$ signal. Further, we show that even for very modest values of $\xi$ the invisible decay signal probes to higher $M_D$ than does the ($\xi$-independent) jets/\gam + missing energy signal from graviton radiation. We also discuss various effects, such as Higgs decay to two graviscalars, that could become important when $m_h/M_D$ is of order 1.Comment: 6 pages, 2 figures, To appear in the Proceedings of the Les Houches Workshop 2003: ``Physics at TeV Colliders'', ed. F. Boudjem

Wind and solar powered turbine

A power generating station having a generator driven by solar heat assisted ambient wind is described. A first plurality of radially extendng air passages direct ambient wind to a radial flow wind turbine disposed in a centrally located opening in a substantially disc-shaped structure. A solar radiation collecting surface having black bodies is disposed above the fist plurality of air passages and in communication with a second plurality of radial air passages. A cover plate enclosing the second plurality of radial air passages is transparent so as to permit solar radiation to effectively reach the black bodies. The second plurality of air passages direct ambient wind and thermal updrafts generated by the black bodies to an axial flow turbine. The rotating shaft of the turbines drive the generator. The solar and wind drien power generating system operates in electrical cogeneration mode with a fuel powered prime mover

Model-Independent Description and Large Hadron Collider Implications of Suppressed Two-Photon Decay of a Light Higgs Boson

For a Standard Model Higgs boson with mass between 115 GeV and 150 GeV, the two-photon decay mode is important for discovery at the Large Hadron Collider (LHC). We describe the interactions of a light Higgs boson in a more model-independent fashion, and consider the parameter space where there is no two-photon decay mode. We argue from generalities that analysis of the $t\bar t h$ discovery mode outside its normally thought of range of applicability is especially needed under these circumstances. We demonstrate the general conclusion with a specific example of parameters of a type I two-Higgs doublet theory, motivated by ideas in strongly coupled model building. We then specify a complete set of branching fractions and discuss the implications for the LHC.Comment: 4 pages, 4 figure

Holomorphic selection rules, the origin of the mu term, and thermal inflation

When an abelian gauge theory with integer charges is spontaneously broken by the expectation value of a charge Q field, there remains a Z_Q discrete symmetry. In a supersymmetric theory, holomorphy adds additional constraints on the operators that can appear in the effective superpotential. As a result, operators with the same mass dimension but opposite sign charges can have very different coupling strengths. In the present work we characterize the operator hierarchies in the effective theory due to holomorphy, and show that there exist simple relationships between the size of an operator and its mass dimension and charge. Using such holomorphy-induced operator hierarchies, we construct a simple model with a naturally small supersymmetric mu term. This model also provides a concrete realization of late-time thermal inflation, which has the ability to solve the gravitino and moduli problems of weak-scale supersymmetry.Comment: 18 pages, 1 figur