Target selection for antisense oligonucleotide induced exon skipping in the dystrophin gene

Duchene Muscular Dystrophy (DMD), and the milder allelic Becker muscular dystrophy (EMD), are X-linked recessive muscle wasting disorders characterised by mutations in the dystrophin gene. DMD occurs at a frequency of approximately 1 in 3500 male newborns and life expectancy is typically less than 30 years. Due to progressive muscle wasting, affected boys are restricted to a wheelchair by the age of 12 years. The most common cause of death is pneumonia, compounded by cardiac involvement. Mutations that disrupt the dystrophin reading frame, or prevent the synthesis of either terminus, preclude the synthesis of a fully functional dystrophin. The subsequent Joss of membrane integrity results in a severe DMD phenotype, as these weakened but still functional muscle fibres are subject to continuous cycles of damage and regeneration. Conversely, BMD mutations are generally found to be in-frame deletions where a shorter but semi-functional protein with intact amino and carboxyl tennini has been synthesised. BMD has an incidence almost ten times less than DMD. While the distribution of myopathy parallels DMD, the onset and progression of BMD is variable and generally less severe and some affected individuals are virtually asymptomatic

A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

A model describing the response of the growth of single human cells in the absence and presence of the anti-cancer agent topotecan (TPT) is presented. The model includes a novel coupling of both the kinetics of TPT and cell cycle responses to the agent. By linking the models in this way, rather than using separate (disjoint) approaches, it is possible to illustrate how the drug perturbs the cell cycle. The model is compared to experimental in vitro cell cycle response data (comprising single cell descriptors for molecular and behavioural events), showing good qualitative agreement for a range of TPT dose levels

Cofinement, entropy, and single-particle dynamics of equilibrium hard-sphere mixtures

We use discontinuous molecular dynamics and grand-canonical transition-matrix Monte Carlo simulations to explore how confinement between parallel hard walls modifies the relationships between packing fraction, self-diffusivity, partial molar excess entropy, and total excess entropy for binary hard-sphere mixtures. To accomplish this, we introduce an efficient algorithm to calculate partial molar excess entropies from the transition-matrix Monte Carlo simulation data. We find that the species-dependent self-diffusivities of confined fluids are very similar to those of the bulk mixture if compared at the same, appropriately defined, packing fraction up to intermediate values, but then deviate negatively from the bulk behavior at higher packing fractions. On the other hand, the relationships between self-diffusivity and partial molar excess entropy (or total excess entropy) observed in the bulk fluid are preserved under confinement even at relatively high packing fractions and for different mixture compositions. This suggests that the partial molar excess entropy, calculable from classical density functional theories of inhomogeneous fluids, can be used to predict some of the nontrivial dynamical behaviors of fluid mixtures in confined environments.Comment: submitted to JC

Five-dimensional Nernst branes from special geometry

We construct Nernst brane solutions, that is black branes with zero entropy density in the extremal limit, of FI-gauged minimal five-dimensional supergravity coupled to an arbitrary number of vector multiplets. While the scalars take specific constant values and dynamically determine the value of the cosmological constant in terms of the FI-parameters, the metric takes the form of a boosted AdS Schwarzschild black brane. This metric can be brought to the Carter-Novotny-Horsky form that has previously been observed to occur in certain limits of boosted D3-branes. By dimensional reduction to four dimensions we recover the four-dimensional Nernst branes of arXiv:1501.07863 and show how the five-dimensional lift resolves all their UV singularities. The dynamics of the compactification circle, which expands both in the UV and in the IR, plays a crucial role. At asymptotic infinity, the curvature singularity of the four-dimensional metric and the run-away behaviour of the four-dimensional scalar combine in such a way that the lifted solution becomes asymptotic to AdS5. Moreover, the existence of a finite chemical potential in four dimensions is related to fact that the compactification circle has a finite minimal value. While it is not clear immediately how to embed our solutions into string theory, we argue that the same type of dictionary as proposed for boosted D3-branes should apply, although with a lower amount of supersymmetry.Comment: 59 pages, 1 figure. Revised version: references added, typos corrected. Final version, accepted by JHEP: two references adde

Language, Religion, and Identity in Indonesia

Social, political, and economic turmoil now make it easy to forget that just two years ago Indonesia stood out amongst ethno-linguistically plural nations for its successful nationalist and developmentalist dynamic. And as recently as the mid-1990s, I ndonesian modernization seemed to be unimpeded by religious tension

Impact of surface roughness on diffusion of confined fluids

Using event-driven molecular dynamics simulations, we quantify how the self diffusivity of confined hard-sphere fluids depends on the nature of the confining boundaries. We explore systems with featureless confining boundaries that treat particle-boundary collisions in different ways and also various types of physically (i.e., geometrically) rough boundaries. We show that, for moderately dense fluids, the ratio of the self diffusivity of a rough wall system to that of an appropriate smooth-wall reference system is a linear function of the reciprocal wall separation, with the slope depending on the nature of the roughness. We also discuss some simple practical ways to use this information to predict confined hard-sphere fluid behavior in different rough-wall systems