DNA methylation and trinucleotide repeat expansion diseases

Copyright @ 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

DNA methylation and trinucleotide repeat expansion diseases

Copyright @ 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

Homogeneous and locally homogeneous solutions to symplectic curvature flow

J. Streets and G. Tian recently introduced symplectic curvature flow, a geometric flow on almost K\"ahler manifolds generalising K\"ahler-Ricci flow. The present article gives examples of explicit solutions to this flow of non-K\"ahler structures on several nilmanifolds and on twistor fibrations over hyperbolic space studied by J. Fine and D. Panov. The latter lead to examples of non-K\"ahler static solutions of symplectic curvature flow which can be seen as analogues of K\"ahler-Einstein manifolds in K\"ahler-Ricci flow.Comment: 15 page

Epigenetics in Friedreich's ataxia: Challenges and opportunities for therapy

Copyright © 2013 Chiranjeevi Sandi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies.This study is supported by funding from the European Union Seventh Framework Programme (FP7/2007–2013) under Grant agreement no. 242193/EFACTS; and by funding from theWellcome Trust (089757)

The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases

Copyright © 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)

Comparative (computational) analysis of the DNA methylation status of trinucleotide repeat expansion diseases

Copyright © 2013 Mohammadmersad Ghorbani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Previous studies have examined DNA methylation in different trinucleotide repeat diseases. We have combined this data and used a pattern searching algorithm to identify motifs in the DNA surrounding aberrantly methylated CpGs found in the DNA of patients with one of the three trinucleotide repeat (TNR) expansion diseases: fragile X syndrome (FRAXA), myotonic dystrophy type I (DM1), or Friedreich’s ataxia (FRDA). We examined sequences surrounding both the variably methylated (VM) CpGs, which are hypermethylated in patients compared with unaffected controls, and the nonvariably methylated CpGs which remain either always methylated (AM) or never methylated (NM) in both patients and controls. Using the J48 algorithm of WEKA analysis, we identified that two patterns are all that is necessary to classify our three regions CCGG* which is found in VM and not in AM regions and AATT* which distinguished between NM and VM + AM using proportional frequency. Furthermore, comparing our software with MEME software, we have demonstrated that our software identifies more patterns than MEME in these short DNA sequences. Thus, we present evidence that the DNA sequence surrounding CpG can influence its susceptibility to be de novo methylated in a disease state associated with a trinucleotide repeat.European Union Seventh Framework Programme and The Brunel University Graduate Program

Self-intersecting marginally outer trapped surfaces

We have shown previously that a merger of marginally outer trapped surfaces (MOTSs) occurs in a binary black hole merger and that there is a continuous sequence of MOTSs which connects the initial two black holes to the final one. In this paper, we confirm this scenario numerically and we detail further improvements in the numerical methods for locating MOTSs. With these improvements, we confirm the merger scenario and demonstrate the existence of self-intersecting MOTSs formed in the immediate aftermath of the merger. These results will allow us to track physical quantities across the non-linear merger process and to potentially infer properties of the merger from gravitational wave observations

A Small Acoustic Goniometer for General Purpose Research

Understanding acoustic events and monitoring their occurrence is a useful aspect of many research projects. In particular, acoustic goniometry allows researchers to determine the source of an event based solely on the sound it produces. The vast majority of the acoustic goniometry research projects used custom hardware targeted to the specific application under test. Unfortunately, due to the wide range of sensing applications, a flexible general purpose hardware/firmware system does not exist for this research. This dissertation focuses on the development of such a system which encourages the continued exploration of general purpose hardware/firmware and lowers barriers to research in projects requiring the use of acoustic goniometry. Simulations have been employed to verify system feasibility, and a complete hardware implementation of the acoustic goniometer has been designed and field tested. The results are reported, and suggested areas for improvement and further exploration are discussed

Kunstlike ja rakuvälise maatriksi valkudega kaetud pindade osa rakkude kasvu ja diferentseerumise reguleerimises

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Loomade kõik rakud puutuvad oma elu jooksul kokku neid ümbritseva rakuvälise maatriksiga. See on rakkude poolt sekreteeritud vaheaine, mis peamiselt koosneb valkudest ja polüsahhariididest. Koes annab rakuväline maatriks rakkudele mehhaanilise toe ja võimaldab üles ehitada keerukaid organeid. Lisaks mõjutab rakuväline maatriks rakkude kasvu, migreerumist ja diferentseerumist, kuivõrd maatriksi komponentidelt lähtuvad neid protsesse toetavad signaalid. Ühed enimuuritud rakuvälise maatriksi valgud on kollageenid ja laminiinid. Käesolevas doktoritöös uuriti rakk-maatriks kontaktide mõju rakkude kasvule ja diferentseerumisele. Esmalt uuriti kuidas rakkude kasvupinna topograafilised omadused mõjutavad inimese naha fibroblastide kasvu. Kasvupinnasena kasutati ränil põhinevat materjali (n.ö tehisklaasi), mis andis võimaluse tekitada pindu, mis oli kaetud erineva suurusega ümarate struktuuridega. Nende struktuuride keskmine diameeter oli 200 nm, 500nm, 1 µm ja 10 µm. Selgus, et mida suuremad olid struktuurid (diameeter 500 nm, 1 µm ja 10 µm), seda aeglasem oli rakkude kasv ning sellega kaasnes rakkude nn „vananemine”. Meie teine uuring näitas, et želatiini ja glükoosi elektrospinnimise teel on võimalik tekitada kasvupindasid, mis sobivad inimese naha fibroblastide kasvatamiseks. Lisaks ilmnes, et sellised kasvupinnad tõstavad rakuvälise maatriksi valkude, laminiinide, ekspressiooni taset fibroblastides. Kolmandas uuringus käsitlesime laminiinide paiknemist ja sekreteerimist inimese trombotsüütidest. Vastupidiselt varemarvatule selgus, et laminiinid ei paikne trombotsüütide α-graanulites. Kui trombotsüüte aktiveeriti trombiiniga, siis väljusid laminiinid rakkudest mikrovesiikulite, mitte aga eksosoomide koosseisus. Doktoritöö neljandas uurimuses iseloomustati laminiinide ekspressiooni inimese embrüonaalsetes tüvirakkudes. Selgus, et retinoolhappega mõjutatud tüvirakkude varajase diferentseerumise käigus suureneb neis laminiini 511 hulk, aga laminiini 521 hulk väheneb. Lisaks leiti, et inimese embrüonaalsetes tüvirakkudes ekspresseerub lisaks varemkirjeldatule veel mitmeid teisi laminiinide isovorme. Veel enam, selgus, et mitmed erinevad laminiinide isovormid ekspresseeruvad ka sellistes inimese embrüonaalsetes tüvirakkudes, mis ei ole läinud diferentseerumise teele.All animal cells interact with extracellular matrix (ECM) either continuously or during important phases of their life-time. ECM provides mechanical support for tissues and is thus necessary for building up organs with complex structures. The interactions between cells and ECM regulate cell growth, migration and differentiation. The major components of ECM are proteins and polysaccharides that are secreted by various cell types. Collagens and laminins are examples of widely-studied ECM proteins. The research presented in the current thesis was designed to study the ways in which cells interact with the surrounding extracellular matrix and how these bidirectional interactions affect cell growth and differentiation. Firstly, we studied how topographical properties of silica-based surfaces affect the growth of human dermal fibroblasts. Surfaces with four different sizes of round structural elements were produced (200 nm, 500nm, 1 µm ja 10 µm). It was found that increase in the size of these structural elements coincided with the decrease in cell growth and induced cell senescence. The second study demonstrated that electrospun gelatin-based scaffolds that contain glucose are suitable for growth of primary dermal fibroblasts. These scaffolds induced expression of ECM proteins such as laminins in fibroblasts. The third study investigated the localization and secretion of laminins in human platelets. Our investigation revealed that platelets do not store laminins in typical alpha granules as was shown previously, and that these proteins are secreted via microvesicles but not via exosomes when platelets become activated. The fourth study of this thesis characterized the expression of laminins in human embryonic stem cells. We observed that the relative amount of laminin-511 increases while the amount of laminin-521 decreases during early differentiation induced by retinoic acid. Additionally, we found that human embryonic stem cells express a wider range of different laminin chains than previously described, and that the laminin repertoire was independent of their differentiation status