554 research outputs found
Fast Mesh Refinement in Pseudospectral Optimal Control
Mesh refinement in pseudospectral (PS) optimal control is embarrassingly easy
--- simply increase the order of the Lagrange interpolating polynomial and
the mathematics of convergence automates the distribution of the grid points.
Unfortunately, as increases, the condition number of the resulting linear
algebra increases as ; hence, spectral efficiency and accuracy are lost in
practice. In this paper, we advance Birkhoff interpolation concepts over an
arbitrary grid to generate well-conditioned PS optimal control discretizations.
We show that the condition number increases only as in general, but
is independent of for the special case of one of the boundary points being
fixed. Hence, spectral accuracy and efficiency are maintained as increases.
The effectiveness of the resulting fast mesh refinement strategy is
demonstrated by using \underline{polynomials of over a thousandth order} to
solve a low-thrust, long-duration orbit transfer problem.Comment: 27 pages, 12 figures, JGCD April 201
Detrended fluctuation analysis as a statistical tool to monitor the climate
Detrended fluctuation analysis is used to investigate power law relationship
between the monthly averages of the maximum daily temperatures for different
locations in the western US. On the map created by the power law exponents, we
can distinguish different geographical regions with different power law
exponents. When the power law exponents obtained from the detrended fluctuation
analysis are plotted versus the standard deviation of the temperature
fluctuations, we observe different data points belonging to the different
climates, hence indicating that by observing the long-time trends in the
fluctuations of temperature we can distinguish between different climates.Comment: 8 pages, 4 figures, submitted to JSTA
Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia
Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program
Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus
© 2013 Al-Mahdawi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, which induces epigenetic changes and FXN gene silencing. Bisulfite sequencing studies have identified 5-methylcytosine (5 mC) DNA methylation as one of the epigenetic changes that may be involved in this process. However, analysis of samples by bisulfite sequencing is a time-consuming procedure. In addition, it has recently been shown that 5-hydroxymethylcytosine (5 hmC) is also present in mammalian DNA, and bisulfite sequencing cannot distinguish between 5 hmC and 5 mC.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS (CS), the Wellcome Trust [089757] (SA) and Ataxia UK (RMP) to MAP
Intramedullary melanotic schwannoma
We present a case of an intramedullary melanotic schwannoma (IMS) of the thoracic spinal cord. To our knowledge, this is the seventh reported case of an IMS of the central nervous system. Schwannomas are benign nerve sheath tumors of neural crest origin composed entirely of well differentiated Schwann cells that typically occur in peripheral nerves. Both the intramedullary location and the melanotic component of the reported lesion make it exceedingly rare. We will present our case, theories as to the origin of these tumors, clues in radiographic identification, and current clinical follow-up recommendations
Friedreich's Ataxia Causes Redistribution of Iron, Copper, and Zinc in the Dentate Nucleus
MutLα heterodimers modify the molecular phenotype of Friedreich ataxia
This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. Methodology/Principal Findings: To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription. Conclusions/Significance: Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription. © 2014 Ezzatizadeh et al.This article has been made available through the Brunel Open Access Publishing Fund
A comparison of Kneipp hydrotherapy with conventional physiotherapy in the treatment of osteoarthritis of the hip or knee: protocol of a prospective randomised controlled clinical trial
Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models
This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. Methodology/Principal Findings: We have generated fibroblast cells and neural stem cells (NSCs) from control Y47R mice (9 GAA repeats) and GAA repeat expansion YG8R mice (190+120 GAA repeats). We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs) exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR) gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. Conclusions/Significance: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy, for gene therapy, and as a source of cells for cell therapy testing in FRDA mice. © 2014 Sandi et al
Star forming dwarf galaxies
Star forming dwarf galaxies (SFDGs) have a high gas content and low
metallicities, reminiscent of the basic entities in hierarchical galaxy
formation scenarios. In the young universe they probably also played a major
role in the cosmic reionization. Their abundant presence in the local volume
and their youthful character make them ideal objects for detailed studies of
the initial stellar mass function (IMF), fundamental star formation processes
and its feedback to the interstellar medium. Occasionally we witness SFDGs
involved in extreme starbursts, giving rise to strongly elevated production of
super star clusters and global superwinds, mechanisms yet to be explored in
more detail. SFDGs is the initial state of all dwarf galaxies and the relation
to the environment provides us with a key to how different types of dwarf
galaxies are emerging. In this review we will put the emphasis on the exotic
starburst phase, as it seems less important for present day galaxy evolution
but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy
Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon,
September 2010, Springer Verlag, in pres
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