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The exploding foil initiator (EFI) is a high voltage detonator used to initiate explosions. It is designed to improvesafety standards by lowering the risk of accidental detonation and in doing so allows for in-line integration in, forexample, weapon systems that minimizes their complexity and thus reduces the number of possible failures. It ishighly reliable in terms of timing and avoids that functionality of the detonator deteriorates over time, which has beena problem in earlier designs of detonators. This thesis aims to develop an understanding of each part of the initiationprocess by means of computer simulations. The proportions of the electrically conducting bridge is varied in order tofind relations that optimize the design. Success depends on the simulated pressure generated inside a hexanitrostilbene(HNS) primer.The results showed that increasing the dimensions of the bridge greatly affects the pressure produced in the primer,but its proportions were still important. Unfortunately the simulations of the electrical explosion and the accelerationof the flyer suffered from convergence issues that rendered the flyer’s velocity graphs incomplete. But even with theseshortcomings, thanks to empirical data from earlier studies that analysed EFI prototypes, it was possible to makepredictions about the success of various set ups. The information gathered in this thesis should serve as a foundationfor future development of computer models of the EFI technology that will aid the production of prototypes that meetthe specific requirements.i / Den explosiva folieinitieraren (EFI) är en högspänningsdetonator som används för att initiera explosiva förlopp. Denär designad för att förbättra säkerheten genom att sänka risken för oavsiktlig detonering och till följd av detta möjligörför in-line integrering i, till exempel, vapensystem. Detta minimerar komplexiteten av sådanna system och sänker antaletmöjliga fel som kan uppstå. Denna teknolgi är högst pålitlig när det gäller timing och undviker att detonatorns funktionförsämras över tid, vilket har varit ett problem i tidigare konstruktioner av detonatorer. Denna avhandling syftar tillatt utveckla en förståelse för varje del av initieringsprocessen genom datorsimuleringar. Proportionerna av den elektrisktledande bryggan varierades för att hitta relationer som optimerar designen. Framgången beror på det simulerade trycketsom genereras inuti en primer av det explosiva materialet hexanitrostilben (HNS).Resultaten visade att ökade dimensioner på bryggan kraftigt påverkar trycket som produceras i primern, men dessproportioner var fortfarande viktiga. Tyvärr led simuleringarna av den elektriska explosionen och accelerationen avflyern av konvergensproblem som gjorde att flyerns hastighetsgrafer blev ofullständiga. Men även med dessa brister,tack vare empiriska data från tidigare studier som analyserade EFI-prototyper, var det möjligt att göra förutsägelserom framgången för olika uppsättningar. Informationen som samlats in i denna avhandling bör tjäna som en grund förframtida utveckling av dator modeller av EFI-teknologi som kommer att underlätta produktionen av prototyper somuppfyller specifika krav.ii

Non-coding RNAs (ncRNAs) account for a higher percent of the genome than coding mRNAs, and are implicated in human disease such as cancer, neurological, cardiac and many others. While the majority of ncRNAs involved in disease were originally attributed to a class of RNAs called micro RNAs (miRNAs) with a small size of only about 19 -24 base pairs, emerging research has now demonstrated a class of long non-coding RNAs (lncRNAs) that have a size of over 200 base pairs to be responsible for gene regulation and other functional roles and have also found to contribute to pathogenesis in humans. The increased size and structural complexity require novel tools to study their interactions beyond RNA interference. Synthetic antibodies are classic tools and therapeutics utilized to study and treat proteins involved in human disease. Likewise we hypothesize that structured RNAs can also take advantage of synthetic antibodies to probe their functions and be utilized as therapeutics. Currently, antibodies have been raised against microbial riboswitches and other structured RNAs of single-celled organisms, and only one human structured RNA to the best of our knowledge. However, no one has yet to create a synthetic antibody capable of behaving as a therapeutic against a structured RNA. We therefore sought to raise an antibody Fab against a structured RNA, human initiator tRNA, a model oncogenic non-coding RNA and demonstrate its efficacy in vitro. We then characterized the antibody and explored delivery options in cancer cells including the use of nanoparticle delivery systems. With the emerging transcriptome revealing new ncRNAs implicated in human disease, our research has begun to address a new therapeutic strategy, laying down the foundation for the future of structured RNA-targeted therapies.

A systematic study of the surface-initiated polymerisation kinetics of a relatively new type of atom transfer radical polymerisation (ATRP), activators regenerated by electron transfer (ARGET) ATRP, is first demonstrated in this report. Poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(methyl methacrylate) (PMMA) were successfully grown from silicon surfaces at room temperature by surface-initiated ARGET ATRP using a "3rd generation" cationic macroinitiator. The polymer films were analysed by ellipsometry, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). With the initial experiment showing that water accelerated conventional ATRP but made it less controlled, the effect of solvent on ARGET ATRP was also evaluated. The living character of ARGET ATRP was demonstrated by successfully reinitiating PHEMA-grafted silicon wafers to grow a second block of PHEMA. Initiator density was shown to have a great effect on the growth rate of PHEMA film thickness on silicon surfaces by comparing the ARGET ATRP growth of PHEMA films using two different initiators, "1st generation" and "3rd generation" cationic macroinitiators, which have different ratios of initiating groups to positive charge. Another type of initiator for ATRP systems, an amide silane, was then investigated as an alternative to polyelectrolyte macroinitiators to avoid degrafting. The effects of solvent, 2, 2′ bipyridyl (bpy) ligand concentration and different types of reducing agent on the growth of PHEMA film from amide-initiator coated silicon wafers by ARGET ATRP were then explored at room temperature. However, it was found that the swings in the uncontrolled laboratory ambient temperature caused inter-sample and inter-experiment variability and so could make the evaluations inaccurate or even wrong. An investigation of temperature on ARGET ATRP showed a dramatic effect on the polymerisation rate. The higher the temperature, the faster the polymerisation proceeded. Therefore, the effects of solvent, ratio of bpy to Cu and reducing agent on the ARGET ATRP growth of PHEMA brushes from amide initiator-coated silicon wafers were re-evaluated at a constant temperature, 30 °C. The development of a polydopamine-based initiator, which was designed to be able to be immobilised on a wide range of surfaces, is then presented in this report. Polydopamine was first shown to be able to deposit on various types of material surfaces by oxidative polymerisation in aqueous solution. Bromoester initiating groups for ATRP systems were incorporated into polydopamine coatings by reacting a fraction of the dopamine monomer with 2-bromoisobutyryl bromide (BIBB) before polymerisation. The modified polydopamine initiator film grew at a comparable rate to unmodified polydopamine, with a 45 nm being grown in 24 hours. Successful incorporation of initiator groups was confirmed by XPS and FTIR, and by the growth of PMMA and PHEMA polymer brushes by ARGET ATRP from the polydopamine initiator coatings. A PMMA brush with a thickness of 239 nm was grown in 72 hours, indicating that the grafting density is sufficiently high to be in the brush regime. This initiator was demonstrated to be able to deposit on a range of substrates, such as metals (steel) and polymers (polystyrene), and successfully initiate polymer growth, demonstrating its broad applicability. The assessment of ARGET ATRP as a simple and effective tool for interfacial shear strength improvement in cellulose-based fibre reinforced thermoplastic composites is finally presented. It was demonstrated by control experiments that grafting polystyrene on glass fibre surfaces via ARGET ATRP greatly improved the interfacial adhesion between glass fibres and a high-impact polystyrene (HIPS) matrix, although a specific value of interfacial strength was not obtained due to failure of the modified glass fibre composite samples in areas other than the interface. It was then demonstrated that PMMA was successfully grown from the surfaces of polydopamine initiator coated cotton fibre and BIBB-modified cotton fibre by ARGET ATRP. Polydopamine initiator was shown to be a better initiator for cotton fibre than BIBB, possibly since the adsorbed water on cotton fibres can react with BIBB. The improvement of interfacial adhesion between cotton fibres and a PMMA matrix by grafting PMMA on the cotton surface was assessed by peel testing of cotton fibres pressed into PMMA sheets. There is a clear trend in the relationship between the peeling force and growth time of PMMA on the cotton fibre by ARGET ATRP, although the inter-sample reproducibility is not good.

The purpose of this study was to examine and make explicit the relationships between commitment, rituals, and initiator tendency. Past research and theory suggests that these ideas are related. Two research questions guided the study: (1) How are initiator tendency and the number of rituals a couple participates in related to the commitment style?, and (2) How are initiator tendency and the meaningfulness of rituals related to commitment style? Data were obtained from 55 couples who completed a questionnaire to measure participation and meaningfulness of rituals, initiator tendency, and commitment. Final analyses were performed with only 39 of these couples as 16 newlywed couples were removed from the sample. Results suggested a significant relationship for meaningfulness of connection rituals with both personal commitment and moral commitment for the husbands in the study. A relationship was also found between initiator tendency and personal commitment for both husbands and wives, while only the wives showed a negative relationship between initiator tendency and constraint commitment. Implications for marriage and family therapy were presented and the limitations of the study were also discussed.

Increasing insensitivity demands on designing and producing munitions necessitates utilizing primarily insensitive initiation trains specifically in missile systems. Exploding Foil Initiator (EFI) is a high voltage detonator that is used as the initiation elementof rocket motor and warhead initiation trains of modern insensitive missile systems. In this thesis, EFI prototypes are designed and manufactured with the knowledge gained from detailed literature studies. An experimental setup is constructed including firing and testing means for EFI prototypes. That experimental setup is capable of firing EFI prototypes from 500 volts to 3000 volts voltage range. Besides, it allows measuring electrical characteristics like current and voltage traces and average velocity of the flyer plates of these prototypes.Using EFI prototypes,detonation tests of HNS &ndash / IV and PBXN &ndash / 5 explosive pellets are carried out.Function times and detonation outputs of the prototypesare measured with the same experimental setup. A numerical study which predicts electrical performance of EFI prototypes and impact characteristics of flyer plates are carried out. Numerical code is validated with the experimental results.

The essence of online group-buying is to lower the price by gathering orders However, the process is filled with uncertainty and risks, such as the number of joining members, the final price, the quality of products, and even the trustworthiness of the initiators. Generally speaking, consumers tend to reduce risks by searching more information. The more uncertainties there are, the more information seeking should be. Online feedback mechanism is often adopted as a strategy to lower risks and uncertainties. Both e-Bay and Yahoo provide such feedback mechanisms. In addition, the larger the number of accumulated orders is, the higher possibilities to lower the price and risk will be. Therefore, the purpose of this research is to explore how the online feedback mechanism and the number of accumulated orders impact consumers¡¦ perceived risk and trust in the initiator and furthermore, how the perceived risk and trust impact consumers¡¦ behavior in online group buying. The study shows that the content of the online feedback mechanism has significant impact on consumers¡¦ perceived financial risk, performance risk, total risk and the trust in initiator as well. The more negative the content is, the more risks the consumers perceive and the less trust in the initiators the consumers have. Furthermore, different contents will result in different kinds of risks perceived by consumers. With larger number of accumulated orders, consumers have more trust in initiators. Additionally, consumers have higher intentions to join group-buying when they perceive lower risk and more trust in initiators. Therefore, consumers¡¦ intentions to join group-buying have significant impact on their actual behavior.

Online shopping involves more uncertainty and risk than traditional shopping. These phenomena are even obvious in online group-buying. One of the main factors causing the uncertainty and risk is the role of the initiator. Since it is quite often that the initiators themselves are consumers, the initiators are not as huge and professional as the sellers. Clearly the trust in initiator becomes a major concern when joining the online group-buying. Based on the theory of planned behavior, the purpose of this research is to understand how initiator¡¦s reputation, interactions with initiator, consumers¡¦ perceived risk and personal characteristics impact consumers¡¦ trust in the initiators and then how the consumers¡¦ perceived trust in the initiators, subjective norm and familiarity with online group-buying together impact the consumers¡¦ behavior in group-buying. The study result indicates that the perceived initiator¡¦s reputation, interaction with initiator, perceived risks in online group-buying, and subjective norm impact the trust in initiator. Moreover, based on TPB, the trust has significant effects on consumer¡¦s intention to join online group-buying. Subjective norm has impacted the consumer¡¦s intention to join online group-buying not only directly but also through the trust in initiator indirectly. However, the familiarity with online group-buying has no significant effects on consumer¡¦s intention to join online group-buying.

The studies reported in this thesis address the aspects of initiator tRNA selection in Escherichia Coli. A summary of the relevant literature discussing the process of ptotein biosynthesis in general and initiator tRNA selection, in particular is presented in chapter 1. The next chapter (Chapter2) describes the ‘Materials and Methods’ used throughout the experimental work carried out in this thesis. It is followed by two chapters(Chapter 3 and Chapter 4) which describe the isolation and characterization of an E. coli mutant, to understand the mechanism of initiator tRNA selection. Chapter 5 comprises of some experimental work and future perspectives on the utility of the E.coli mutant. The last chapter (Chapter 6) summarizes the published work where I have contributed to besides the work described in Chapters 3 to 5. The summary of chapters 3-5 is as described below:- (i)Isolation and genetic mapping of extragenic suppressors of mutant initiator tRNA lacking the three consecutive G, C base pairs in the anticodon stem Initiator tRNA selection on the ribosomes is a result of several steps, some of which are unique to the prokaryotic world. Structure-function analyses of E.Coli tRNAfMet have revealed that the most important features of tRNAfMet, pertinent to its in vivo function as an initiator, are located in the acceptor stem and the anticodon arm regions. The three consecutive G-C base pairs in the anticodon stem of the tRNAfMet, conserved across all kingdoms of life, have been implicated in preferential binding to 30S ribosomal P-site. How the 3G-C base pairs are exploited by ribosomes in selecting the initiator tRNA, has been a long standing question. In the present work, a genetic screen was developed to isolate second site compensatory mutations of the mutant tRNAfMet, inactive in initiation because the 3G-C base pairs in it were changed to those found in the elongator tRNAMet(‘3G-C mutant’). Two extragenic suppressors were mapped to defined regions in the 12 min and 85 min locations in the E. Coli genome and three others were classified in these two broad groups. A super suppressor strain exhibiting synergistic suppression was generated. Further genetic mapping identified a G122D mutation in the folD gene encoding 5, 10 methylene tetrahydrofolate dehydrogenase/cyclohydrolase in one of the suppressor strains E. Coli A48. Complementation analysis using over expression of fold confirmed the results obtained by genetic mapping. (ii) Role of the intracellular S-adenosylmethionine flux in initiation with an initiator versus elongator tRNAs in Escherichia Coli How a defect in folD gene product (in E. Coli A48) leads to initiation with the ‘3G-C mutant’ initiator tRNA, has been addressed in this work. The FolD enzyme plays a key role in the one-carbon metabolism. The mutation in folD resulted in a lethal phenotype in minimal medium. The end-products of the pathway, 10 formyl-THF, methionine and S-adenosylmethionine(SAM) were analyzed for their possible role in initiation with the ‘3G-C mutant’ tRNAfMet, which revealed that lowering of the steady-state abundance of methionine and SAM had a direct role in initiation with the ‘3G-C mutant” tRNAfMet. Analysis of the 16S tRNA revealed that the methylations, as a result of reduced levels of SAM, were undetectable in the E.Coli A48. This prompted us to generate targeted mutations in the methyltransferase genes, which have highlighted the importance of methylations in initiator tRNA selection. Consistent with the growth retardation phenotype of methylase deficient strains at higher temperatures, the E. Coli A48 also displays temperature sensitivity. Further analysis of mycoplasma genomes, which do not follow the strong conservation of three G-C base pairs in the anicodon stem of initiator tRNA has uncovered an hitherto unknown evolutionary connection between methylations of 16S rRNA and initiator tRNA selection. We observed genetic interaction between infC(encoding IF3) and fold (encoding FolD). We also demonstrate initiation with tRNAfMet containing mutations in one, two or all the three G-C base pairs, as also with the elongator tRNA (tRNAGln). (iii) Utility of E. Coli A48 in investigation of biological processes: Some Preliminary studies and future perspectives. The availability of the E. Coli A48 strain is a valuable addition to the field of initiator tRNA selection and opens up further opportunities for its application. In this study, we have analyzed some of the properties of the E. Coli A48 strain viz. sensitivity to UV light and formylation independent initiation. E. Coli possess multiple copies of initiator tRNA, encoded by the metZVW operon and the metY gene. We reasoned that the abundance of cellular initiator tRNA might be a contributing factor in maintenance of specificity of initiation. Consistent with our prediction, we observed initiation with the ‘3G-C mutant’ tRNAfMet in E. Coli strains deficient in initiator tRNA genes. The various aspects of SAM limitation, biological functions of post-transcriptional modifications, incorporation of non-methionine amino acids in then-terminus of proteins and genetic approaches to system biology for the understanding of one-carbon metabolism are discussed.

>Magister Scientiae - MSc / Apoptosis or programmed cell death is vital to the development of organisms as they maintain the balance between cell death and cell growth. Failure to activate apoptosis has been implicated in carcinogenesis and often results from the over expression of anti–cancer proteins such as the X–linked inhibitor of apoptosis protein (XIAP). XIAP is over expresses in certain cancers and is a potent inhibitor of the initiator caspase 9 and effector caspases 3 and 7. The increased expression of XIAP in cancer cells result in the resistance to apoptosis. The control of XIAP is therefore considered as a target for anti–cancer drug development. Embelin or 2,5–dihydroxy–3–undecyl–1,4–benzoquinoine is a dihydroxyquinone compound that was previously shown to inhibit XIAP. This drug was discovered by structure based computational screening. The binding of embelin to XIAP displaces XIAP from caspases, consequently eliminating the inhibitory effect of XIAP on apoptosis. The objective of this study was to develop a gold nanoparticle that can be used for the targeted delivery of embelin to cancer cells thereby enhancing pro–apoptotic effects of the pro–apoptotic drug, ceramide. XIAP expression levels were investigated by Western blot analysis in a panel of human cancer cell lines available in the laboratory to identify two cell lines that can be used as low and high XIAP expression controls. Gold nanoparticles were synthesized and conjugated with embelin and a cancer targeting peptide with the amino acid sequence LTVSPWY. The biconjugated nanoparticles were used to co–treat MCF7 and HepG2 cells with ceramide. Apoptosis was quantified using flow cytometry. The uptake of gold nanoparticles was investigated using HR–TEM and ICP–OES. This study showed that gold nanoparticles conjugated with the LTVSPWY peptide is specifically targeted to and taken up by cancer cells. Gold nanoparticles conjugated with embelin promoted ceramide induced apoptotic cell death of cancer cells. However, it was observed that gold nanoparticles biconjugated with the LTVSPWY peptide and embelin failed to enhance the pro–apoptotic effects of ceramide. iii This study successfully demonstrated that gold nanoparticles conjugated with embelin could be used to enhance the effects of anti–cancer drugs using ceramide as an example.