Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age

INTRODUCTION: In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thin. The reasons for these differences in remyelination efficiency, the thinner remyelinated myelin sheaths compared to developmental myelin and the subsequent effect on the underlying axon are unclear. We studied CNS remyelination in the highly regenerative adult zebrafish (Danio rerio), to better understand mechanisms of what we hypothesised would be highly efficient remyelination, and to identify differences to mammalian CNS remyelination, as larval zebrafish are increasingly used for high throughput screens to identify potential drug targets to improve myelination and remyelination. RESULTS: We developed a novel method to induce a focal demyelinating lesion in adult zebrafish optic nerve with no discernible axonal damage, and describe the cellular changes over time. Remyelination is indeed efficient in both young and old adult zebrafish optic nerves, and at 4 weeks after demyelination, the number of myelinated axons is restored to normal, but internode lengths are short. However, unlike in rodents or in humans, in young zebrafish these regenerated myelin sheaths were of normal thickness, whereas in aged zebrafish, they were thin, and remained so even 3 months later. This inability to restore normal myelin thickness in remyelination with age was associated with a reduced macrophage/microglial response. CONCLUSION: Zebrafish are able to efficiently restore normal thickness myelin around optic nerve axons after demyelination, unlike in mammals. However, this fails with age, when only thin myelin is achieved. This gives us a novel model to try and dissect the mechanism for restoring myelin thickness in CNS remyelination. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0077-y) contains supplementary material, which is available to authorized users

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Genome Instability and Cance

Validation of the ICRF antenna coupling code RAPLICASOL against TOPICA and experiments

In this paper we validate the finite element code RAPLICASOL, which models radiofrequency wave propagation in edge plasmas near ICRF antennas, against calculations with the TOPICA code. We compare the output of both codes for the ASDEX Upgrade 2-strap antenna, and for a 4-strap WEST-like antenna. Although RAPLICASOL requires considerably fewer computational resources than TOPICA, we find that the predicted quantities of experimental interest (including reflection coefficients, coupling resistances, S- and Z-matrix entries, optimal matching settings, and even radiofrequency electric fields) are in good agreement provided we are careful to use the same geometry in both codes

Validation of a NTM model using databases of disruptive plasmas at JET

Pressure-driven instabilities such as the neoclassical tearing modes (NTMs) limit the maximum achievable plasma normalized beta (N) needed for a reliable and efficient tokamak device. For a better understanding of the involved phenomena an almost fully analytic, dynamic, interpretative, multi-mode model describing the evolution of the NTMs is presented. An explicitly derived final formula of the NTM perturbed flux function is provided having a clear time dependent expression. To obtain the latter, the equations the perturbations satisfy are basically solved in the whole space: the ideal plasma perturbed momentum equations, the magnetic island perturbed resistive equations, the perturbed circuit equations in the plasma surrounding resistive wall and coils and finally the perturbed equations in the vacuum between the plasma and the external structures. The external coils play the role of feedback coils and/or error field generating coils. The system of the perturbed equations is completed by all the existing boundary equations across boundaries and the jump equation across the magnetic island that takes into account a heuristic bootstrap term. The assumption of the small perturbations from the equilibrium state is used in order to track the problem analytically, therefore the system of the perturbed equations is a linear one. Obviously the real diagnostic data quantities are not static and cannot be treated as equilibrium quantities from a strict mathematical point of view. This would drive the perturbed system of equations profoundly nonlinear and basically impossible to be analytically treated. Based on the assumption that usually the perturbed quantities have a significantly higher growth rate compared to the diagnostic quantities growth rate, it has been used the approximation that the plasma quantities collected from the diagnostic data behave like equilibrium quantities on the perturbations time scale. This approximation allows us to keep our proposed model linear and to provide a clear, quasi-analytic NTM solution. This solution and therefore the entire model validity have been tested against various discharges at JET