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

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

A Corpus-Based, Pilot Study of Lexical Stress Variation in American English

Phonological free variation describes the phenomenon of there being more than one pronunciation for a word without any change in meaning (e.g. because, schedule, vehicle). The term also applies to words that exhibit different stress patterns (e.g. academic, resources, comparable) with no change in meaning or grammatical category. A corpus-based analysis of free variation is a useful tool for testing the validity of surveys of speakers' pronunciation preferences for certain variants. The current paper presents the results of a corpus-based pilot study of American English, in an attempt to replicate Mompéan's 2009 study of British English

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

Consumption of submerged aquatic macrophytes by rudd (scardinius erythrophthalmus L.) in New Zealand

In experiments in New Zealand, rudd (Scardinius erythrophthalmus L.) of 108–277mm fork length (FL) ate a wide range of native and introduced submerged aquatic macrophytes in captivity and in the field. Rudd consumed the native charophytes Chara globularis Thuill., Chara fibrosa Ag. ex Bruz., and Nitella spp., the native macrophytes Potamogeton ochreatus Raoul. and Myriophyllum propinquum A. Cunn., and the introduced macrophytes Elodea canadensis Michx., Egeria densa Planch., Lagarosiphon major L., and Ceratophyllum demersum L. Rudd consistently consumed the Nitella spp. and Potamogeton ochreatus before Ceratophyllum demersum. From the results of experiments in tanks and in the field, we found the order of highest to lowest palatability was: Nitella spp. > Potamogeton ochreatus > Elodea canadensis> Chara globularis = Chara fibrosa> Egeria densa = Lagarosiphon major > Myriophyllum propinquum > Ceratophyllum demersum. The order of consumption was subject to some variation with season, especially for Egeria densa, Lagarosiphon major, and Myriophyllum propinquum. Rudd consumed up to 20% of their body weight per day of Egeria densa in spring, and 22% of their body weight per day of Nitella spp. in summer. Consumption rates were considerably lower in winter than in summer. The results of our field trial suggested that the order of consumption also applies in the field and that rudd are having a profound impact on vulnerable native aquatic plant communities in New Zealand. Nitella spp. and Potamogeton ochreatus are likely to be selectively eaten, and herbivory by rudd might prevent the re-establishment of these species in restoration efforts