538 research outputs found
The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases
No full textCopyright © 2014 Al-Mahdawi, Anjomani Virmouni and Pook. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.This article has been made available through the Brunel Open Access Publishing Fund.DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC) modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC), which is formed by oxidation of 5mC by ten-eleven translocation (TET) enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS). The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA), Huntington's disease (HD), and Parkinson's disease (PD).Sara Anjomani Virmouni was supported by funding to Mark A. Pook from the Friedreich’s Ataxia Research Alliance(FARA)
DNA methylation and trinucleotide repeat expansion diseases
No full textCopyright @ 2012 InTechThis article has been made available through the Brunel Open Access Publishing Fund.This article is made available through the Brunel Open Access Publishing Fund
Epigenetic-based therapies for Friedreich ataxia
No full textThis article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene silencing. Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy. Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option. In this review we summarize our current understanding of the epigenetic basis of FXN gene silencing and we discuss current epigenetic-based FRDA therapeutic strategies. © 2014 Sandi, Sandi, Anjomani Virmouni, Al-Mahdawi and Pook
A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment
No full textArticle first published online: 9 JUL 2014Abstract not availableStuart J Ellem, Renea A Taylor, Luc Furic, Ola Larsson, Mark Frydenberg, David Pook, John Pedersen, Bree Cawsey, Andrew Trotta, Eleanor Need, Grant Buchanan and Gail P Risbridge
Ang Tanawing Pangwika Bilang Pook-Lunan ng mga Usaping Pangwika sa Pilipinas
No full textAng negatibong pagtingin ng mga Pilipino sa kanilang mga sarili ay mababakas sa sitwasyon ng wikang Filipino at ng mga lokal at dayuhang wika sa bansa sa pamamagitan ng pagtingin at pag-usisa sa ating kapaligiran partikular ang wikang makikita rito na tinatawag na tanawing pangwika o linguistic landscape (LL). Ito ang sitwasyong nais suriin ng papel na ito, partikular ang ipinahihiwatig ng mga pag-aaral kaugnay sa tanawing pangwika sa iba’t ibang pook sa bansa na may tuon sa tinatawag na “top-down signs” o mga karatula o signages na ginawa o nagmula sa pamahalaan o mga ahensiyang pampamahalaan. Partikular na nais matugunan ng pag-aaral na ito ang sumusunod na mga kaugnay na katanungan: a.) Ano- ano ang kinalalabasan ng mga pag-aaral tungkol sa tanawing pangwika sa iba’t ibang pook sa bansa sa estado ng paggamit ng wikang Filipino at ng mga lokal na wika sa bansa? b.) Paano sinasalamin ng tanawing pangwika sa bansa ang tunguhin ng mga polisiyang pangwika mula nang maiakda ang Konstitusyong 1987 hanggang sa kasalukuyan? c.) Anong mga hakbang ang isinasagawa ng mga indibidwal at pangkat (nasa gobyerno man o nasa pribadong institusyon) bilang pagkontra sa pagsasakapangyarihan ng Ingles sa mga polisiyang pangwika? Ito ay isang deskriptibong pagsipat sa estado ng mga wika sa pook sa bansa partikular sa mga wikang ginagamit sa mga karatula o signs na nagmumula sa pamahalaan. Tuon lamang nito ang pagsusuri ng mga saliksik-papel tungkol sa tanawing pangwika sa Pilipinas
Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich Ataxia
No full textCopyright © 2014 Anjomani Virmouni 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.Background - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats).
Methodology/Principal Findings - We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.
Conclusions/Significance - Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.European Union, Ataxia UK and FARA
Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus
No full text© 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
Capitalism's transcendental time machine
No full textThis thesis seeks to establish a connection between abstract thought
and material practice. It does so by focusing on the relation between the
transcendental philosophy of time and the socio-technics of time-keeping
practices.
The thesis begins with a discussion of Kant's philosophy of time as
outlined in the Critique of Pure Reason. It argues that Kant's discovery of the
transcendental coincides with the development of an entirely new conception
of time. This new conception overturns classical thought by making a
distinction between the abstract form of time and the empirical phenomena of
movement and change.
The second chapter maps the transcendental philosophy of time on to
the history of capitalist time-keeping. This history includes: the invention and
development of the mechanical clock, temporal standardization and the
increasing importance of the equation 'time = money. The aim in bringing
these two spheres together is to show, both that Kant's philosophy of time
owes much to his empirical surroundings, and also that capitalist time can
only be understood through the temporal abstraction of transcendental
thought. This link between Kant and capitalism is blocked, however, by a
dividing line which separates the philosophical nature of time from the
empirical changes of history.
In order to surpass this problem the thesis turns to the work of Deleuze
and Guattari whose 'transcendental materialism' connects the abstract
production of time with empirical innovations. This is accomplished by
replacing the classical conception of a transcendent eternity with the
immanent materiality of an exterior plane. This plane - which they call Aeonis
composed of thresholds, or singular events which make no distinction
between time and that which occurs in time. The final chapter explores the
dawn of the third millennium - or Y2K - as constituting one such Aeonic event
Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life
No full textFriedreich ataxia (FRDA) patients are homozygous for expanded GAA triplet-repeat
alleles in the FXN gene. Primary neurodegeneration involving the dorsal root ganglia
(DRG) results in progressive ataxia. While it is known that DRG are inherently sensitive
to frataxin deficiency, recent observations also indicate that they show age-dependent,
further expansion of the GAA triplet-repeat mutation. Whether somatic instability is
progressive has not been systematically investigated in FRDA patients. Small pool PCR
analysis of ~2300 individual molecules from tissues of an 18-week fetus, homozygous
for expanded alleles, revealed very low levels of instability compared with adult-derived
tissues (4.2% versus 30.6%, P<0.0001). Mutation load in blood samples from multiple
patients and carriers increased significantly with age, ranging from 7.5% at 18-weeks
gestation to 78.7% at 49y (R=0.91; P=0.0001). Therefore, somatic instability in FRDA
occurs mostly after early embryonic development and progresses throughout life,
lending further support to the role of postnatal somatic instability in disease
pathogenesis
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