http://bura.brunel.ac.uk/handle/2438/21 2013-05-21T22:02:35Z 2013-05-21T22:02:35Z Ojani, Maryam http://bura.brunel.ac.uk/handle/2438/7441 2013-05-20T15:11:26Z 2012-01-01T00:00:00Z

Title: Relationship between DNA damage response and telomere maintenance Authors: Ojani, Maryam Abstract: Telomeres are regions of repetitive DNA bound with a set of specialized proteins required to protect chromosomes from fusing with each other and from eliciting DNA damage response. Dysfunctional telomere maintenance can lead to premature cellular senescence, premature organismal aging and cancer predisposition. In the last few years the evidence has emerged indicating a link between dysfunctional maintenance of telomeres and defective DNA damage response. The objective of this project was to explore further this link by examining effects of some DNA damage response proteins on telomeres that have not been examined before and examining DNA damage response in cells in which telomeres are dysfunctional as a result of alterations in genes not directly involved in DNA damage response. We have developed a method, termed IQ-FISH, for accurate identification of average telomere length in interphase cells from individuals with defective DNA damage response. By applying IQ-FISH we could successfully measure telomere lengths in cell lines from patients that are heterozygous (+/-) and cell lines from patients or animals that are homozygous (-/-) with respect to mutations in these genes. We then analysed telomere length and function, as well as DNA damage response, in lymphoblastoid cell lines originating from BRCA1 and BRCA2 carriers (+/-) and also a single fibroblast cell line from a patient with bi-allelic mutations in BRCA2 (-/-). In addition we have analysed a mouse embryonic stem cell line in which Brca1 was deleted (Brca1-/-) by gene targeting. Our results show lack of correlation between DNA damage response and telomere maintenance in heterozygous cell lines (with the exception of one BRCA1+/- cell line) but a clear positive correlation in the case of cell lines with homozygous mutations. Finally, as a model for telomere dysfunction we have chosen cell lines from Dyskeratosis Congenita (DC) patients. DC is a rare progressive congenital disorder which results in premature aging. DC is primarily a disorder of dysfunctional telomere maintenance and we used cell lines from patients with mutations in DKC1, a gene encoding a protein termed Dyskerin which forms a part of the telomerase enzyme complex. Our results indicate that DC cells with dysfunctional DKC1 may have a dysfunctional DNA damage response. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

2012-01-01T00:00:00Z Ezzatizade, Vahid http://bura.brunel.ac.uk/handle/2438/7440 2013-05-20T14:59:14Z 2012-01-01T00:00:00Z

Title: Friedreich ataxia: Investigating the relationships between mismatch repair gene expression, FXN gene expression and GAA repeat instability in human and mouse cells and tissues Authors: Ezzatizade, Vahid Abstract: Friedreich ataxia (FRDA) is the most common inherited ataxia disorder, caused by a GAA repeat expansion mutation within the first intron of the FXN gene. The subsequent deficiency of frataxin protein leads to neurological disability, increased risk of diabetes mellitus, cardiomyopathy and premature death. The exact FRDA disease mechanism is not yet clear, despite some understanding of epigenetic, transcriptional and DNA repair system effects that lead to frataxin reduction. Previous studies have shown that mismatch repair (MMR) genes can affect other trinucleotide repeat disorders by destabilisation of the repeats. Furthermore, it has been proposed that frataxin deficiency might lead to cell malignancy by an as yet undefined mode of action. Therefore, the principle aim of this thesis was to use human and genetically altered mouse cells and tissues to understand the effects of MMR proteins on GAA repeat instability and FXN transcription, and also to identify potential changes in MMR transcription that might cause malignancy in FXN-defective human cells. Firstly, by using FXN and MMR genetically altered mice, MMR proteins were shown to be involved in both intergenerational and somatic GAA repeat instability, although their effects in the two systems were different. Thus, Msh2 or Msh3 were both found to protect against intergenerational transmission of GAA contractions, while loss of Msh2 or Msh3 reduced somatic GAA repeat expansions and increased levels of FXN transcription in brain and cerebellum tissues. Loss of Msh6 induced both intergenerational GAA repeat expansions and contractions, while the frequency of somatic GAA repeat expansions was reduced. Curiously, the level of FXN transcription was also reduced in Msh6-deficient brain and cerebellum tissues. On the other hand, Pms2 was found to protect against both intergenerational and somatic GAA repeat expansions, with loss of Pms2 causing increased GAA repeat expansions and decreased levels of FXN transcription in brain and cerebellum tissues. Finally, loss of Mlh1 led to a reduced frequency of both intergenerational and somatic GAA repeat expansions, but the level of FXN transcription was also reduced in brain and cerebellum tissues. Furthermore, upregulation of MMR mRNA expression was detected in human FRDA fibroblast cells, but downregulation was seen in FRDA cerebellum tissues, suggesting tissue-dependent control of FXN and MMR expression. In summary, these studies indicate that the MMR system can affect GAA repeat expansion instability and FXN transcription through different mechanisms of action. Furthermore, frataxin deficiency can also affect the levels of MMR mRNA expression in a tissue-dependent manner. These findings will assist future investigations aimed at identifying novel FRDA therapies. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

2012-01-01T00:00:00Z Abdul Rahim, Suzari http://bura.brunel.ac.uk/handle/2438/7437 2013-05-17T13:34:20Z 2013-01-01T00:00:00Z

Title: Supplier selection in the Malaysian telecommunications industry Authors: Abdul Rahim, Suzari Abstract: Supplier selection plays an important role in any organisation. This study investigates and examines supplier selection criteria and the impacts on buying firm performance; specifically focusing on the telecommunications industry in Malaysia. Previous studies in this area have focussed on the criteria such as quality, price, delivery, supplier relationship management and decision making tools and techniques. However, little research has been undertaken to include government policies and business ethics as elements in the supplier selection criteria. After a literature review and interviews, the development of conceptual frameworks and a number of hypotheses were put forward. To achieve an in-depth study, four major telecommunications service provider companies in Malaysia were chosen as a case study. A questionnaire was used as the main instrument in gathering data. The questionnaire is principally concerned with the understanding of supplier selection and its criteria; based upon the variables that are used for the model and hypothesis testing. The study also investigates the relationship between supplier selection and the impact of supplier selection to the company performance. This model was tested using Structural Equation Modelling (SEM) technique with the AMOS software application. Results indicated all of the criteria include quality, price, delivery, supplier relationship management, decision making tools and techniques, government policy and business ethics as valid constructs. A good model fit was also established. The findings of this research conclude that the influencing criteria to supplier selection in the telecommunications industry in Malaysia are supplier delivery performance standards and supplier relationship management even when considering the remainder of the above mentioned elements.The price factors were found to be less important due to this factor possibly leading to unhealthy competition in the market in terms of price wars among the suppliers in order to win the business. Most of the criteria are also interrelated to each other and affect the supplier selection decision. This model has added new perspectives to the study of supplier selection in the supply chain management field. As for future research it is suggested that intangible elements such as political, cultural and social influences are included in the conceptual framework; as this would offer important insight for management bodies in organisation, academia and public policy fields alike. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

2013-01-01T00:00:00Z Gharib, Islam http://bura.brunel.ac.uk/handle/2438/7436 2013-05-21T13:05:40Z 2013-01-01T00:00:00Z

Title: Integration of sketch-based ideation and 3D modeling with CAD systems Authors: Gharib, Islam Abstract: This thesis is concerned with the study of how sketch-based systems can be improved to enhance idea generation process in conceptual design stage. It is also concerned with achieving a kind of integration between sketch-based systems and CAD systems to complete the digitization of the design process as sketching phase is still not integrated with other phases due to the different nature of it and the incomplete digitization of sketching phase itself. Previous studies identified three main related issues: sketching process, sketch-based modeling, and the integration between the digitized design phases. Here, the thesis is motivated from the desire to improve sketch-based modeling to support idea generation process but unlike previous studies that only focused on the technical or drawing part of sketching, this thesis attempts to concentrate more on the mental part of the sketching process which play a key role in developing ideas in design. Another motivation of this thesis is to produce a kind of integration between sketch-based systems and CAD systems to enable 3D models produced by sketching to be edited in detailed design stage. As such, there are two main contributions have been addressed in this thesis. The first contribution is the presenting of a new approach in designing sketch-based systems that enable more support for idea generation by separating thinking and developing ideas from the 3D modeling process. This kind of separation allows designers to think freely and concentrate more on their ideas rather than 3D modeling. the second contribution is achieving a kind of integration between gesture-based systems and CAD systems by using an IGES file in exchanging data between systems and a new method to organize data within the file in an order that make it more understood by feature recognition embedded in commercial CAD systems. Description: This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.

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