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Thesis advisor: Jianmin Gao / Thesis advisor: Eranthie Weerapana / Cyclic peptides provide a privileged scaffold when optimizing interactions with various biological targets. Their rigidified structure decreases the entropic cost of binding by preorganizing residues in a fixed conformation, which may enhance binding affinity. These molecules occupy a larger chemical space than typical small molecule drugs and may provide good candidates for inhibiting protein-protein interactions or being able to interact with previously undruggable targets. Given the benefits of these structures we aim to develop a one-bead-one-compound peptide library for screening against relevant biological targets. Herein we describe several routes to achieving cyclic peptides through side chain interactions and head-to tail amide bond linkages. Additional considerations for the development of the on resin library such as linker strategies and sequencing methods will be discussed. / Thesis (MS) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The thesis is divided in three parts based largely on published articles or on manuscripts submitted for publication. First we propose a new method which is called the shooting-bead method. This method is a fast and easy experimental technique for evaluating cantilever stiffness and flexural rigidity of semi-flexible to semi-rigid rod-like biological and nano-filaments based on the measurement of just two distances. The method is based on applying a force normal to the filament with a microsphere bead trapped in the laser tweezer followed by its sudden release. Through a simple measurement of the distances that the bead moves, the flexural rigidity of the filament can be found from the formula derived in this paper. Then we take into account the effects of the viscous drag force exerted on the filament itself. To this end, we have defined a key variable, called the filament energy-loss factor (or filament drag factor) that accounts for all the energy-loss effects. It has been shown that the effect due to the consideration of filament energy-loss factor on calculation of the flexural rigidity increases with increasing the flexibility of the filament. Finally, in the third part we discuss the effect of ultrasound on the microtubules. Here we have analytically solved equations of motion for the vibrational dynamics of an MT that is attached at its two ends. This is especially relevant for MTs during mitosis when they attach to chromosomes and centrosomes. Our analysis applies to MTs present inside a viscous solution and when driven by an ultrasound plane wave. We have shown that with using ultrasound plane waves the resonance condition for the MT treated as a rigid rod cannot be provided, and in order to achieve resonance we should excite a single mode of the MT with a harmonic number larger than a threshold value introduced in this thesis. Single mode excitation not only helps to transfer the minimum amount of energy to the surrounding medium compared with multi-mode excitation but it also allows for a simultaneous high-amplitude and high-quality factor which is impossible when using plane waves.

ANALYSIS OF WELDING PARAMETERS IN GAS METAL ARC WELDING BY A WELDING ROBOT Erener, Yavuz M.S., Department of Mechanical Engineering Supervisor : Prof. Dr. R. Tuna Balkan Co-Supervisor : Prof. Dr. M. A. Sahir Arikan September 2006, 130 pages In Robotic Gas Metal Arc Welding process, the welding parameters controlled by the welder (travel speed of the welding torch, wire feed speed, current, voltage, wire diameter, etc.) should be considered to obtain a desired welding quality. To design an appropriate welding model for the used equipment, the effects of each parameter should be studied by carrying out an adequate number of experiments. The welding process is described by analyzing the experimental data to define the relationships between the welding parameters and process variables. Various regressional models can be suggested to establish the analytical relationships. In this study, the relationship between bead geometry and voltage, current, travel speed and wire feed speed is established by using a specific computer program developed for this purpose.

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Chemotherapeutics are potent molecules capable of systematically treating cancer. As healthy tissues contain features also inherent to cancer cells, treatment often results in unwanted sideeffect. As chemotherapeutic side-effect produces significant harm and often limits optimal drug dosing, new strategies must be developed to improve treatment selectivity. A prodrug strategy provides one option to improve the selectivity of an established chemotherapeutic. By modifying a pharmaceutically active drug, interaction with biology may be functionally masked. Subsequent ‘un-masking’ the prodrug exclusively at the intended treatment site may direct treatment only to where the anticancer effect is required. This thesis progresses the novel approach of bioorthogonal organometallic (BOOM) prodrug activation. A metal catalyst and masked chemotherapeutic constitute reaction partners to provide a new strategy for intratumoural prodrug activation. Whereby the prodrug and metal catalyst are independently non-cytotoxic, in combination the prodrug undergoes catalytic activation to deliver an anticancer affect. By positioning the metal catalyst within a tumour (i.e. by microsurgery), an administered masked prodrug sensitive to catalyst-mediated activation could allow for ‘targeted’ chemotherapy localised to the tumour site. The design, synthesis and study of new BOOM prodrug candidates are reported herein. Novel protecting groups are developed to enhance drug masking to biology and subsequent catalyst-mediated activation. Prodrug screening studies are carried out in cancer cell culture models, with zebrafish and in ex vivo rodent model tumour explants. The catalyst, a palladium (Pd0) functionalised bead system, is optimised for enhanced activation, drug release and in vivo implantation. The potentially infinite generation of active chemotherapeutics exclusively in tumour would increase the efficacy of treatment whilst reducing harmful effect on healthy tissue.

A intervenção por soldagem em dutos em operação adquiriu nos últimos anos extrema importância na indústria do petróleo, visto que por meio dela é possível instalar derivações bem como reparar trechos danificados na malha dutoviária sem a interrupção do fluxo dos produtos escoados, o que certamente impactaria em elevados custos nas operações. Os principais limitantes da técnica de soldagem em operação é o risco de perfuração do duto pelo arco durante a soldagem e principalmente, o elevado risco das juntas soldadas sofrerem fissurações induzidas pelo hidrogênio. Estas últimas surgem devido à ocorrência de três fatores em conjunto: alto nível de hidrogênio no processo de soldagem, tensão residual e, microestrutura susceptível. Neste trabalho, são feitas algumas considerações acerca dos métodos atualmente empregados para se contornar os limitantes da técnica da soldagem em operação aplicada pelo processo de eletrodo revestido (ER). Mais especificamente, estudou-se uma metodologia da técnica da dupla camada, amplamente empregado nos procedimentos de soldagem que visam evitar a formação de microestrutura susceptível à trincas por hidrogênio e, avaliação de dois softwares comumente empregados para avaliar o risco de perfuração do duto pelo arco durante a soldagem em operação. Paralelamente investigou-se equações para estimativas de durezas máxima da ZAC publicada por diversos autores. Ficou evidente que a metodologia avaliada para a prevenção da perfuração do duto durante a soldagem em operação é bastante confiável e pode ser aplicada com segurança. Quanto às estimativas de dureza máxima na ZAC, os resultados não foram unânimes dentre as equações dos autores investigados. A metodologia da técnica da dupla camada estudada se mostrou eficiente, porém com algumas limitações. / Welding interventions onto in-service pipe lines have acquired relevant importance in the last few years in petroleum industry, since with this technique it is possible to install derivations as well to repair damaged pipe lines portions without interrupt the flux of its products, which in turn would results in high costs. The in-service welding techniques limitations are mainly the risk of pipe wall burn through by the electric arc and, the hydrogen cold crack joint susceptibility. The last one is due to the action, at the same time, of three mainly factors: high hydrogen levels and, susceptible microstructure. In this work it is made some considerations about methods usually applied to work out the limitations of shielded metal arc welding technique applied to in-service welding. Specifically talking, it was studied a temper bead technique commonly used in procedures which the aim is to avoid the presence of hydrogen cold crack susceptible microstructure and, evaluate two commonly software used to prevent the wall pipe burn-through risk by the arc welding. Additionally, it was investigated some published equations to estimate the maximum HAZ hardness. It was clarified that the evaluated methodology to prevent the pipe wall burn-through risk during the welding process is very confident and safety to be applied in practice situations. The studies conducted about the maximum HAZ hardness showed that just a few of the investigated equations and authors, the results are reliable. The temper bead technique studied as presented as an efficiently method, although some limitations must be taken in account.

A intervenção por soldagem em dutos em operação adquiriu nos últimos anos extrema importância na indústria do petróleo, visto que por meio dela é possível instalar derivações bem como reparar trechos danificados na malha dutoviária sem a interrupção do fluxo dos produtos escoados, o que certamente impactaria em elevados custos nas operações. Os principais limitantes da técnica de soldagem em operação é o risco de perfuração do duto pelo arco durante a soldagem e principalmente, o elevado risco das juntas soldadas sofrerem fissurações induzidas pelo hidrogênio. Estas últimas surgem devido à ocorrência de três fatores em conjunto: alto nível de hidrogênio no processo de soldagem, tensão residual e, microestrutura susceptível. Neste trabalho, são feitas algumas considerações acerca dos métodos atualmente empregados para se contornar os limitantes da técnica da soldagem em operação aplicada pelo processo de eletrodo revestido (ER). Mais especificamente, estudou-se uma metodologia da técnica da dupla camada, amplamente empregado nos procedimentos de soldagem que visam evitar a formação de microestrutura susceptível à trincas por hidrogênio e, avaliação de dois softwares comumente empregados para avaliar o risco de perfuração do duto pelo arco durante a soldagem em operação. Paralelamente investigou-se equações para estimativas de durezas máxima da ZAC publicada por diversos autores. Ficou evidente que a metodologia avaliada para a prevenção da perfuração do duto durante a soldagem em operação é bastante confiável e pode ser aplicada com segurança. Quanto às estimativas de dureza máxima na ZAC, os resultados não foram unânimes dentre as equações dos autores investigados. A metodologia da técnica da dupla camada estudada se mostrou eficiente, porém com algumas limitações. / Welding interventions onto in-service pipe lines have acquired relevant importance in the last few years in petroleum industry, since with this technique it is possible to install derivations as well to repair damaged pipe lines portions without interrupt the flux of its products, which in turn would results in high costs. The in-service welding techniques limitations are mainly the risk of pipe wall burn through by the electric arc and, the hydrogen cold crack joint susceptibility. The last one is due to the action, at the same time, of three mainly factors: high hydrogen levels and, susceptible microstructure. In this work it is made some considerations about methods usually applied to work out the limitations of shielded metal arc welding technique applied to in-service welding. Specifically talking, it was studied a temper bead technique commonly used in procedures which the aim is to avoid the presence of hydrogen cold crack susceptible microstructure and, evaluate two commonly software used to prevent the wall pipe burn-through risk by the arc welding. Additionally, it was investigated some published equations to estimate the maximum HAZ hardness. It was clarified that the evaluated methodology to prevent the pipe wall burn-through risk during the welding process is very confident and safety to be applied in practice situations. The studies conducted about the maximum HAZ hardness showed that just a few of the investigated equations and authors, the results are reliable. The temper bead technique studied as presented as an efficiently method, although some limitations must be taken in account.