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Study of the post-translational modifications of histone H4 by Fourier transform ion cyclotron resonance mass spectrometryKarim, Muhammed January 2014 (has links)
Post-translational modification (PTM) of proteins is known to be a method by which protein function can be regulated. The addition of selected chemical groups at specific amino acid residues can act as a switch by which the function of a modified protein can be attenuated. Histones are a group of proteins which are found in the nucleus of eukaryotic cells and interact with DNA, providing it with a structural foundation upon which the chromosome is built. Histone proteins have numerous sequence variants and are known to be extensively post-translationally modified in a dynamic manner. These modifications have a direct effect on the interacting DNA resulting in increasing or decreasing levels of gene transcription. Advancements in analytical instrumentation, when coupled to high resolution separation techniques permit the analysis of increasingly complex biological mixtures. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) offers unrivalled mass resolving power and mass measurement accuracy, allowing the detailed study of mixtures of intact proteins and their post-translational modifications. These features have been exploited to provide a global view of the PTMs of histone proteins. The work contained within this thesis is a study, by FT-ICR MS, of the modifications of one of the most extensively modified histone proteins; histone H4. Firstly, the modifications of histone H4 were examined after treatment with a potent histone deacetylase inhibitor across several cell lines. The cell lines chosen showed a varying response to treatment with the inhibitor. From the cell lines tested, two which responded differently were further interrogated to elucidate the order in which acetylation occurs in the N-terminal region. Secondly, the modifications of histone H4 were analyzed after exposure to lactic acid over multiple treatment times. Lactic acid is a metabolic by-product, and is of interest when considering the Warburg effect and its role in tumorigenesis. Exposure of cells to levels of lactic acid which can be present under anaerobic conditions (i.e. during intense exercise) showed that lactate is able to inhibit histone de-acetylation. The resulting increase in hyper-acetylated forms of histone H4 could be potentially linked to increased gene expression, a typical observation in tumorigenic cells. Finally, using a mouse model for the neurological condition Rett Syndrome, the posttranslational modifications of histone H4 were investigated. The primary cause of Rett Syndrome is mutation of the DNA binding protein methyl CpG binding protein 2 (MeCP2). MeCP2 has been associated with multiple intracellular functions, one of which is chromatin remodelling. The work carried out showed a link between MeCP2 mutation and tri-methylation of histone H4. In addition, the tri-methylation was not solely identified through the presence of tri-methylated fragments in fragmentation mass spectra. Interestingly, the neutral loss of a methylene group was observed extensively during fragmentation of tri-methylated species. This unreported phenomenon made interpretation of spectra difficult; however, ultimately served as a useful marker for this modification.
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Pyrolysis studies of synthetic polymers by mass spectrometry and othermethodsChan, Kit-ha, 陳潔霞 January 1984 (has links)
published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy
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Electrospray ionization mass spectrometry analysis of covalent and non-covalent DNA complexesPierce, Sarah Elizabeth 01 September 2010 (has links)
The covalent and non-covalent interactions between DNA and external ligands and between DNA and itself are critical for cellular function. An increased knowledge of these interactions can be used for the development of disease-fighting agents, specifically anti-cancer drugs with improved sensitivity and specificity for tumor cells. Electrospray ionization mass spectrometry (ESI-MS) is useful in the screening and characterization of the interactions involving nucleic acids given the speed and small sample sizes that can be analyzed. In this dissertation, ESI-MS is used to characterize covalent and non-covalent interactions involving DNA to assist in determining how these interactions can lead to better therapeutics.
The non-covalent binding of ligands to quadruplex oligonucleotides is discussed first. Pyrrole inosine ligands, which bind to guanine bases, were found to interact with both quadruplexes and with guanine rich oligonucleotides without a quadruplex structure. While those interactions were specific with guanine, novel platinum complexes were found to form specific interactions with quadruplex structures themselves as the size of the ligands matched the size of a guanine quartet. This allowed the ligands to end-stack with quadruplexes with large thymine-rich loops between guanine-rich regions.
The non-covalent and covalent interactions between ligands and other DNA structures were also studied. The non-covalent binding of anthracycline ligands to mismatched DNA hairpins was probed. The analysis of solutions of approximately equimolar ligand and oligonucleotide indicated preferential binding to the mismatched sequences. Diazirdinyl benzoquinone crosslinkers, including the clinically studied RH1 and an analogue of RH1, were reacted with a variety of duplex oligonucleotides. The complexes were observed by LC-MS and dissociated using both CID and IRMPD to determine the sites of crosslinking. It was determined that both ligands could form interstrand crosslinks in DNA with 5’-GNC or 5’-GNNC sequences. The RH1 analogue, with a bulky phenyl group, formed fewer crosslinks than RH1.
In addition to studying DNA/ligand interactions, the interactions between oligonucleotides were also probed. Oligonucleotides containing non-standard isoguanine repeats were annealed in the presence of various cations to determine how those cations would affect the resulting secondary structures. In most cases, isoguanine containing strands formed pentaplexes rather than quadruplexes, which were observed for strands containing guanine bases. / text
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Microwave studies of the internal rotors Xâ†3CNOâ†2 (X=Cl,F) and Fâ†3SiN(CHâ†3)â†2 : rotational spectra and zero-point average structures of CFâ†3C#ident to#CX (X=F,H), CHâ†3C#ident to#CCl, CFâ†3CN and the asymmetric tops HNOâ†3 and HONOEllis, Mark Charles January 1993 (has links)
No description available.
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Studies of low-field nuclear magnetic resonance and Raman spectrometries for process analytical chemistryMcGill, Colin Adam January 2001 (has links)
No description available.
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PES studies of some short lived combustion intermediatesEllis, A. R. January 1985 (has links)
No description available.
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Synthesis and metal binding properties of novel Câ†2-symmetric tetraaza ligand systemsLawlor, Susan Elizabeth January 2001 (has links)
No description available.
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Photodouble ionisation studies of He and Dâ‚‚ using linearly and circularly polarised synchroton radiationCollins, Stephen Anthony January 2003 (has links)
No description available.
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Analytical and computational studies in ion trap mass spectroscopyClarke, Nigel J. January 1995 (has links)
No description available.
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Magnetic studies at low temperaturesLord, James Stanley January 1990 (has links)
No description available.
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