How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model

Local Structure and It's Effect on The Ferromagnetic Properties of La0.5_{0.5}Sr0.5_{0.5}CoO3_3 thin films}

We have used high-resolution Extended X-ray Absorption Fine-Structure and diffraction techniques to measure the local structure of strained La$_{0.5}$Sr$_{0.5}$CoO$_3$ films under compression and tension. The lattice mismatch strain in these compounds affects both the bond lengths and the bond angles, though the larger effect on the bandwidth is due to the bond length changes. The popular double exchange model for ferromagnetism in these compounds provides a correct qualitative description of the changes in Curie temperature $T_C$, but quantitatively underestimates the changes. A microscopic model for ferromagnetism that provides a much stronger dependence on the structural distortions is needed.Comment: 4 pages, 4 figure

Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin protein, leading to progressive muscle weakness and premature death due to respiratory and/or cardiac complications. Cardiac involvement is characterized by progressive dilated cardiomyopathy, decreased fractional shortening and metabolic dysfunction involving reduced metabolism of fatty acids—the major cardiac metabolic substrate. Several mouse models have been developed to study molecular and pathological consequences of dystrophin deficiency, but do not recapitulate all aspects of human disease pathology and exhibit a mild cardiac phenotype. Here we demonstrate that Cmah (cytidine monophosphate-sialic acid hydroxylase)-deficient mdx mice (Cmah−/−;mdx) have an accelerated cardiac phenotype compared to the established mdx model. Cmah−/−;mdx mice display earlier functional deterioration, specifically a reduction in right ventricle (RV) ejection fraction and stroke volume (SV) at 12 weeks of age and decreased left ventricle diastolic volume with subsequent reduced SV compared to mdx mice by 24 weeks. They further show earlier elevation of cardiac damage markers for fibrosis (Ctgf), oxidative damage (Nox4) and haemodynamic load (Nppa). Cardiac metabolic substrate requirement was assessed using hyperpolarized magnetic resonance spectroscopy indicating increased in vivo glycolytic flux in Cmah−/−;mdx mice. Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic genes (Pdk1, Pdk4, Ppara), also denote disturbed cardiac metabolism and shift towards glucose utilization in Cmah−/−;mdx mice. Moreover, we show long-term treatment with peptide-conjugated exon skipping antisense oligonucleotides (20-week regimen), resulted in 20% cardiac dystrophin protein restoration and significantly improved RV cardiac function. Therefore, Cmah−/−;mdx mice represent an appropriate model for evaluating cardiac benefit of novel DMD therapeutics

Managing bereavement in the classroom: a conspiracy of silence?

The ways in which teachers in British schools manage bereaved children are under-reported. This article reports the impact of students' bereavement and their subsequent management in primary and secondary school classrooms in Southeast London. Thirteen school staff working in inner-city schools took part in in-depth interviews that focused on the impact of bereaved children on the school and how teachers responded to these children. All respondents had previously had contact with a local child bereavement service that aims to provide support, advice, and consultancy to children, their parents, and teachers. Interviews were audiotaped, transcribed verbatim, and analyzed using ATLAS-ti. Three main themes were identified from analysis of interview data. Firstly, British society, culture, local communities, and the family were significant influences in these teachers' involvement with bereaved students. Secondly, school staff managed bereaved students through contact with other adults and using practical classroom measures such as "time out" cards and contact books. Lastly, teachers felt they had to be strong, even when they were distressed. Surprise was expressed at the mature reaction of secondary school students to deaths of others. The article recommends that future research needs to concentrate on finding the most effective way of supporting routinely bereaved children, their families, and teachers

A light-fronts approach to electron-positron pair production in ultrarelativistic heavy-ion collisions

We perform a gauge-transformation on the time-dependent Dirac equation describing the evolution of an electron in a heavy-ion collision to remove the explicit dependence on the long-range part of the interaction. We solve, in an ultra-relativistic limit, the gauged-transformed Dirac equation using light-front variables and a light-fronts representation, obtaining non-perturbative results for the free pair-creation amplitudes in the collider frame. Our result reproduces the result of second-order perturbation theory in the small charge limit while non-perturbative effects arise for realistic charges of the ions.Comment: 39 pages, Revtex, 7 figures, submitted to PR

Intercalation and Staging Behavior in Super-Oxygenated La2CuO4+δLa_2CuO_{4 + \delta}

A high temperature electrochemical oxidation process has been used to produce large single crystals of $La_2CuO_{4 + \delta}$ suitable for neutron scattering experiments. Below room temperature the oxygen-rich phases have structural superlattice scattering peaks which indicate new periodicities ranging from 2 to 6.6 layers perpendicular to the copper oxide planes. A model structure originally proposed for $La_2NiO_{4 + \delta}$ can account for the superlattice peaks as a result of anti-phase domain boundaries between different tilt directions of the CuO$_6$ octahedra. Within this model, the changes in CuO$_6$ tilt directions are induced by segregated layers of interstitial oxygen which order in a manner similar to intercalants in graphite. This structural model thus clarifies previous work and establishes $La_2CuO_{4 + \delta}$ as a unique lamellar superconducting system with annealed disorder.Comment: 23 pages, latex, 6 figures (not including Figures 2 & 7 and Table 1 which were not submitted but are available upon request to the Authors at: [email protected]

Charged C-metric with conformally coupled scalar field

We present a generalisation of the charged C-metric conformally coupled with a scalar field in the presence of a cosmological constant. The solution is asymptotically flat or a constant curvature spacetime. The spacetime metric has the geometry of a usual charged C-metric with cosmological constant, where the mass and charge are equal. When the cosmological constant is absent it is found that the scalar field only blows up at the angular pole of the event horizon. The presence of the cosmological constant can generically render the scalar field regular where the metric is regular, pushing the singularity beyond the event horizon. For certain cases of enhanced acceleration with a negative cosmological constant, the conical singularity disappears all together and the scalar field is everywhere regular. The black hole is then rather a black string with its event horizon extending all the way to asymptotic infinity and providing itself the necessary acceleration.Comment: regular article, no figures, typos corrected, to appear in Classical and Quantum Gravit

CU and the CDC

Legionella is a gram-negative genus of bacteria that is the cause of Legionnaires disease. Currently, 50 species and 70 serogroups of Legionella have been identified. The Center for Disease Control (CDC) in Atlanta maintains a bank of identified and unidentified Legionella samples. The availability of sequencing technologies has increased since many samples were collected allowing for identification of many previously unidentifiable isolates. We received 68 unidentified samples from the CDC. A sequence based typing scheme was used for characterization. Genomic DNA was extracted from samples and polymerase chain reactionwas performed on the 16S and mip genes. These samples were then sequenced at Clemson University Genomics Institute. Currently, we have identified several samples which were previously undescribed. Once a sample is identified as novel, characterization through sequencing other genes along with morphological and biochemical assays will be conducted. As a collaborative project, regular meetings occur with scientists from the CDC. Characterization of novel strains expands this lab\u27s ability to conduct outbreak analysis and risk assessment along with expanding our knowledge of the pathogen