<p><font face="TimesNewRomanPSMT"> <p align="left">This thesis reports the synthesis of the imine ligands from Schiff base condensation reaction of aldehyde derivatives and equimolar quantities of aniline derivatives. The imine ligands spectrometry.</p> </font></p>

Cancer is a leading cause of death worldwide, accounting for around 13% of all death [1]. Traditional cancer therapeutics usually require careful selection of one or more intervention, such as surgery, radiotherapy, and chemotherapy, which have made momentous progress, but have ample limitations [2]. The next generation of cancer therapeutics will specifically target processes responsible for the growth and survival of cancer cells. Among the most promising of these molecularly-targeted therapeutics are short interfering RNAs (siRNAs). These siRNAs serve as the effectors of RNA interference, a naturally occurring and highly specific mechanism for regulating gene expression through sequence-specific degradation of messenger RNA. However, the native structure of RNA is plagued with undesirable chemical properties. For example, the sugar-phosphate backbone contains a negative charge which hinders its ability to cross the negatively charged lipid bilayer. Furthermore, the phosphodiester backbone is a substrate for nucleases, which catalytically cleaves the phosphate-oxygen bond, thus degrading the native RNA [3]. As such, there is widespread interest in chemically modifying the backbone of siRNAs in order to overcome some of the inherent problems with its native structure. There have been only two reports that have employed amide-bond linkages as phosphate replacements within siRNAs [4, 5]. In both of these studies, the amide bond containing monomer units were placed at the 3’-overhangs and not within the internal Watson-Crick region of the double stranded siRNA due to the limitation of standard solid-phase oligonucleotide synthesis. In this thesis, we proposed to utilize phosphoramidite chemistry to localize internal amide-bond modifications [6]. A practical synthesis of a peptide nucleic acid unit combined with an RNA nucleoside (PNA-RNA dimer, UaU) is reported [7]. Using this PNA-RNA dimer phosphoramidite allows us to control the site-specific location of the internal amide-bond modification throughout the desired RNA strand. Polyacrylamide gel (PAGE) and mass spectrometry analysis were performed to ensure the formation of full-length modified siRNA molecules. The effects of these modifications were explored with respect to the biophysical and biological properties of the modified siRNAs. The techniques used in this work included hybridization affinity assays (melting temperature), secondary structure determination (circular dichroism), cell-based luciferase assays, and nuclease stability assays. Melting temperature experiment reveals that localizing a UaU dimer unit within the RNA oligonucleotides has an overall destabilizing effect, whereas UaU modifications at the 3’-overhang positions show little change in thermal stability. Circular dichroism experimental results illustrate that all chemically modified siRNAs exhibit the standard A-form helix. In cell-based luciferase assays, we utilized two different target sequences and our results highlight the compatibility of utilizing a neutral amide-bond backbone within siRNAs. Specifically, the internal amide-bond modification is compatible within the RNAi machinery when placed at 3’-overhang position in the sense strand of the double-stranded siRNA. However, poor efficacy is observed when this unit is placed adjacent the Ago 2 cleavage site on the antisense strand. The nuclease stability assays reveal that the introduction of a PNA-RNA dimer at the 3’-end of the siRNA where the exonuclease cleaves the terminal nucleotide, increased markedly the resistance to serum-derived nucleases. To the best of our knowledge, this is the first report that involves amide-bonds as phosphate backbone replacements within the internal regions of siRNAs and thus opens the future possibility for examining and utilizing this modification in studying new structure-function relationships. / UOIT

Squaramides (3,4-diaminocyclobutene-1,2-diones) are known to be strong hydrogen bond donors, and recently have been demonstrated to show unusual responses to anions and the potential to adopt secondary structures. In the first part of the project, a small molecule version of a fluorene-based poly(squaramide) was synthesized to gain insights into the mechanism of the “turn-on” fluorescence response of the polymer in the presence of mono-basic phosphate anions. In the second part, mono and dipyridyl squaramides are examined. Pyridyl squaramides were discovered to form strong intramolecular hydrogen bonds, making the folding process more favorable than their urea counterparts. They are particularly interesting as their urea analogues are capable of taking up helical conformations when folded. The folding properties of these pyridyl squaramides in a range of solvents, and the influence of added anions on the folding process, are described herein.

Squaramides (3,4-diaminocyclobutene-1,2-diones) are known to be strong hydrogen bond donors, and recently have been demonstrated to show unusual responses to anions and the potential to adopt secondary structures. In the first part of the project, a small molecule version of a fluorene-based poly(squaramide) was synthesized to gain insights into the mechanism of the “turn-on” fluorescence response of the polymer in the presence of mono-basic phosphate anions. In the second part, mono and dipyridyl squaramides are examined. Pyridyl squaramides were discovered to form strong intramolecular hydrogen bonds, making the folding process more favorable than their urea counterparts. They are particularly interesting as their urea analogues are capable of taking up helical conformations when folded. The folding properties of these pyridyl squaramides in a range of solvents, and the influence of added anions on the folding process, are described herein.

Committee Chair: Dr. Shaun Wang Major Department: Risk Management and Insurance In this thesis I employ regime switching models on a unique dataset of bond downgrades to examine the information value of timely downgrades. I use ratings from a Nationally Recognized Statistical Rating Organization (NRSRO) and a non-NRSRO as proxies for the arrival of public and private information. Regime switching models allow us to identify the time at which a discrete shift in the underlying stock return process takes place, estimate the distribution of returns in each regime and also observe the duration of each regime associated with the day of the downgrade. The first contribution is proposing an alternative way to perform an event study. First I define a regime switching model with two regimes: one of low and high volatility. The probabilistic nature of regime switching models allows us to identify the exact day on which stock returns switch to a high volatility regime. This is directly observed through the estimated daily conditional probability of being in one of the two regimes. In summary, I find that stocks switch from a low-volatility regime (1.92%) to a high-volatility regime (6.10%) on the day of the downgrade. The high-volatility regime lasts for about three days and it is mainly driven by downgrades of the smaller bond rating company (non-NRSRO). The second contribution is to propose a method to quantify stock return distress costs associated with downgrades. This measure is based on the capital asset pricing model, uses the parameters of the regime switching model and the estimated daily conditional probabilities of being in each regime. I find that distress costs on stock returns range from 9.49% to 12.91% for the 10 days prior to the day of the downgrade when assuming unity for the market price of risk. The magnitude and direction (sign) of my estimates are consistent with prior literature on the information value of bond ratings. The third contribution is to propose an extension to regime switching models to the bivariate case with a common shock. I show through a state-contingent model how shocks to the economy may cause a one time loss that affects a portfolio of stocks. I derive the frequency and severity implications of such exogenous shocks on regime switching models.

In the last decade, reliability problems have become a critical subject in power modules. Understanding design weakness and failure mechanisms of thick wire bond are two critical steps in managing the risk of wire bond heel crack which is the topic of this thesis. Although this thesis does not target a specific type of power modules, we note that thick wire bond heel crack failures occur in Insulated Gate Bipolar Transistors (IGBTs). In fact, our aim is to understand failure mechanism in 300μm thick wire bonds with different geometries and materials. Since these wires experience harsh environmental conditions and high load transients, the wires undergo repetitive flexural movement which causes heel crack due to fatigue. For the purpose of understanding this failure mechanism, two experimental setups are built and utilized. The first experimental setup loads the wires using constant currents and observes the response using a scanning laser vibrometer to measure the displacement. The second experimental setup applies repetitive prescribed displacement to the first foot of the wire and detects fatigue failure using a Wheatstone bridge. It is realized that wires have different displacement property depending on their geometry and material. Maximum displacements are observed for Al-H11 instead of CuCorAl and PowerCu.

All reinforced concrete (RC) design theories are based on the assumption that concrete exhibits a perfect bond with the steel reinforcement. The bond between steel and concrete is essential to the transfer of the load applied from the concrete to the steel reinforcement. When steel bars are corroded, the concrete cracks, and the strength of the bond between the steel bars and the concrete is decreased. Structures such as bridges and marine structures are prone to corrosion. These structures are usually also subjected to repeated loading. Repeated loading can initiate cracks in the concrete surrounding the steel bars that propagate as the number of load cycles increases leading to the destruction of the concrete-steel interface and slip of the steel bars inside the concrete. The combined effect of corrosion and repeated loading reduces the service life of RC structures. This study investigated the effect of anchorage length and confinement from supports, stirrups and carbon fibre reinforced polymer (CFRP) on the bond behaviour of corroded and uncorroded reinforced concrete beams subjected to monotonic and repeated loading. Fifty-seven large-scale reinforced concrete beams (152*254*2000 mm) were tested for the purpose of this study. The variables were stirrup spacing (75 mm and 150 mm), anchorage length (200 mm, 350 mm and 650 mm), corrosion level (mild corrosion and high corrosion level), repair condition (wrapped or unwrapped with FRP sheets in the anchorage zone) and the fatigue load range. From this study, it was found that the resistance to bond stresses (forces) between the steel and concrete were provided mainly by the concrete keys. The bond stresses increased with the number of the concrete keys engaged. The factors that affected the number of concrete keys engaged were: confinement from the supports, confinement from the stirrups, confinement due to wrapping with FRP sheets and change in anchorage length. Decreasing the stirrup spacing from 150 mm to 75 mm increased the number of concrete keys engaged thus increasing the bond capacity and changed the mode of failure under monotonic loading from splitting to pullout. The beams with the first stirrup spacing (150 mm c/c) when tested under repeated loading failed by bond fatigue while the beams with the second stirrup spacing (75 mm c/c) failed by flexure at the end of a debonded region that started from the support. The failure mechanism is discussed for each case. The change in anchorage length from 200 mm to 350 mm increased the static and fatigue bond capacity of the beams by 60% and 12.5% respectively. The debonding for this group of beams (200 mm and 350 mm anchorage length) subjected to monotonic loading started from the pocket and propagated towards the support while the debonding for the 350 mm anchorage length beams subjected to repeated loading started at the location of a crack that widened while fatiguing the beam and propagated towards the support. The change in anchorage length from 350 mm to 650 mm did not affect the monotonic bond capacity of the beams since in this case, debonding was initiated from the supports and the change in anchorage length had little effect. The confinement with FRP sheets caused the concrete keys at both the top and bottom of the bar to be crushed and increased the bond stress of the wrapped beams. The bond strength of the beams repaired with CFRP sheet was governed by the strength of the FRP sheets for all anchorage lengths and corrosion levels. The CFRP repair of the 200 mm anchorage length set of beams increased the capacity of the uncorroded beams by 80% and the capacity of the corroded beams by about 25% under static and repeated loading compared to the control (uncorroded and unrepaired) beam. The CFRP repair of the 350 mm anchorage length set of beams changed the mode of failure from bond to flexure. The fatigue life for the beams varied linearly on a logarithmic scale with the load range applied with a shallow slope. Corroding the 200 mm anchorage length set of beams to a mild corrosion level decreased their fatigue strength by 34% compared to the control beams. Corroding the 350 mm anchorage length set of beams to a mild corrosion level did not affect the fatigue strength for the single beam that failed in bond. Finally a probabilistic approach was used to allow the design engineers to estimate the design fatigue life for similar beams with 95% probability for a given normalized stress ratio.

I denna uppsats har den musikaliska förändringen i James Bond-temat, sett över de 21 filmer som gjorts fram till denna uppsats genomförande, analyserats och tolkats. Syftet är att dela med mig av mina tankar och analyser om hur temat framförts och utvecklats, samt därmed också bidra till att utveckla kunskapen om James Bond-världen.Efter en litteraturbaserad del, där bakgrunden till James Bond-temats uppkomst behandlas, så analyseras sedan film för film i Bond-serien från Dr. No till Casino Royale. Analysen tar främst upp delarna synkronisering, instrumentering och influenser.Analyserna visar på att James Bond-temat i grund och botten bygger på samma melodi genom alla filmer, men också har förändrats i stor utsträckning i utförandet.

No description available.

Disulfide bonds are special covalent cross links between two cysteines in a protein. This kind of bonding state plays an important role in protein folding and stabilization. For connectivity pattern prediction, it is a very difficult problem because of the fast growth of possible patterns with respect to the number of cysteines. In this thesis, we propose a new approach to address this problem. The method is based on hybrid models with SVM. Via this strategy, we can improve the prediction accuracies by selecting appropriate models. In order to evaluate the performance of our method, we apply the method by 4-fold cross-validation on SP39 dataset, which contains 446 proteins. We achieve accuracies with 70.8% and 65.9% for pair-wise and pattern-wise prediction respectively, which is better than the previous works.