High surface area tungsten oxynitride samples have been prepared by the temperature programmed reaction (TPR) of W0₃ with NH₃. All samples were characterized by X-ray diffraction (XRD), nitrogen physisorption, and CO chemisorption. In addition, some sample compositions were determined by elemental analysis. Samples were prepared at various heating rates (β), allowing a Redhead analysis to be carried out giving an activation energy of nitridation of 109 kJ mol⁻¹. A heating rate of 0.016 K S⁻¹ gave optimum synthesis conditions. Solid state intermediates were studied by interruption of the temperature program at various stages. No distinct suboxide phases formed along the synthesis path were found using XRD. An increase in surface area, CO uptake and nitrogen weight content, were found to occur as the reaction progressed. Reactivity experiments showed reasonable hydro deoxygenation (HDO) and hydrodenitrogenation (HDN) activities, but little hydrogenation (HYD) or hydrodesulfurization (HDS) activities. / Master of Science

Reactivity ratios for the homogeneous free radical initiated copolymerization of acrylonitrile and methyl acrylate were measured by NMR on isolated, low conversion copolymers and by real time in situ FTIR. The system utilized azobisisobutyronitrile (AIBN) initiator in dimethyl formamide (DMF) at 62°. The FTIR technique allowed rapid generation of extensive copolymer compositions, which permitted application of nonlinear least squares methodology for the first time to this copolymer system. Thus, reactivity ratios at the 95% confidence level were determined to be 1.29 ± 0.2 and 0.96 ± 0.2 for acrylonitrile and methyl acrylate, respectively. The results are useful for the development of acrylonitrile (<90%) melt processable copolymer fibers and films, which could include precursors for carbon fibers. / Master of Science

Various nucleophiles were subjected to SRNl (nucleophilic substitution via a radical chain mechanism) conditions with representative carboaromatic and heteroaromatic substrates. Upon 5-25 min of near-UV irradiation, the carbanions of 2-benzyl-4,4-dimethyl-2-oxazoline, ethyl phenylacetate, t-butyl acetate, N,N-dimethylacetamide and dimethyl methylphosphonate underwent reactions with both 2-bromopyridine and iodobenzene in an S_R_N1 manner to give yields of good substitution products. The S_R_N1 reaction between N,N-dimethylacetamide enolate ion and 2-chloroquinoline occurred even without photostimulation. Due to incomplete ionization and the lack of homogeneity of the reaction mixture, potassio-2,4,4-trimethyl-2-oxazoline reacted with 2-bromopyridine to give low yield of the substitution product through a photostimulated S_R_N1 pathway. However, the reaction of this carbanion with iodobenzene afforded moderate yield of the substitution product, which was found to be formed via both S_R_N1 and AE mechanisms. The dimethyl phosphite anion reacted slowly with 2-bromopyridine and failed to react with 2-chloroquinoline and chloropyrazine under the influence of near-UV light. This unusual trend of reactivity was attributed to the inability of the product radical anion to restore an electron to the aromatic substrate, a necessary step in the propagation of the S_R_N1 cycle. Treatment of t-butyl α-trimethylsilylacetate with KNH₂ caused cleavage of the C-Si bond. t-butyl acetate and hexamethyldisiloxane were obtained upon quenching. Methylene triphenylphosphorane, sulfur and selenium stabilized carbanions of 1,3-dithiane, 2-phenyl-1,3-dithiane, dimethyl sulfone, t-butyl α-phenylthioacetate, bisphenylthiomethane and t-butyl α-phenylselenoacetate, failed to react with 2-bromopyridine and iodobenzene. The carbanion of dimethyl sulfone remained unreactive towards iodobenzene even upon attempted entrainment by a catalytic amount of acetone enolate. The dianion of phenylacetic acid reacted with iodobenzene to give biphenylacetic acid and benzene upon irradiation. Similar results were obtained with p-bromotoluene as substrate where substitution occurred only at the para position of the dianion. A non-chain mechanism was proposed to described both of these reactions. The dianion of phenylacetic acid also reacted with 2-bromopyridine to give a complex mixture under photostimulated conditions. 2-Benzylpyridine, bis(2-pyridyl)phenylmethane, p-(2-pyridyl)phenylacetic acid, potassio α-bis(2-pyridyl)phenylacetate, and 2-aminopyridine were found as products. Based on experiments performed with several probable intermediates of this reaction, and S_R_N1 mechanism can account for formation of all products. Preliminary results showed that the reaction of phenylacetamide dianion with iodobenzene also gave rise to the para substituted product. The dianion of 1,3-phenylacetone was found to react with iodobenzene to give 1,1,3-triphenylacetone via a mechanism other than an S_R_N1 pathway. / Ph. D.

Cancer, the second leading cause of death worldwide, is characterized by uncontrolled and abnormal cell growth. Even though researchers have made significant progress in its treatment over the past several decades, innovative therapeutic approaches that both improve patient survival and lessen the many debilitating side effects of conventional cancer treatments are vital. Accordingly, we first investigated the mechanism of interaction of a bimetallic complex, Ru(II)-Rh(III), with DNA. Non-covalent binding of Ru(II)-Rh(III) is strong and involves electrostatic and, potentially, groove binding interactions. Ru(II)-Rh(III) photobinds and photocleaves DNA through an O2-independent, metal-center mediated mechanism that could be beneficial in hypoxic tumors. Furthermore, the extent of covalent binding and cleavage of DNA, which inhibit PCR amplification, is dependent upon the strength of the non-covalent interactions. These results suggest that the toxicity of Ru(II)-Rh(III) could be selectively generated in tissues irradiated with light (e.g., a tumor). Secondly, we identified protein combinations selectively present in melanoma, which could be utilized in heteromultivalency. Heteromultivalent scaffolds display higher affinity towards cells that express a protein combination in comparison to those with only one of the proteins, which facilitates cell discrimination. Using an empirically-optimized threshold-based screening method and expression profiles of melanoma patients and normal tissues, we identified surface proteins and protein combinations that are selectively found in melanoma patients and not in normal tissues. After a preliminary validation process using the scientific literature, we used immunofluorescence to confirm differential expression of some of these combinations in established melanoma cell lines in comparison to immortalized keratinocytes controls. Finally, we investigated the resazurin assay, a method used for the evaluation of proliferation and cytotoxicity in more than 2,000 publications. We found that only ~14% of these utilized validated assay conditions, while ~40% failed to report essential analytical parameters needed for their replication. We evaluated assay parameters needed for accurate estimation of cell number in eight cell lines, and found that these are highly variable and independent of tissue type, growth kinetics, and energetic parameters. Furthermore, we obtained some insights into the biochemical reduction of resazurin and proposed minimum reporting standards, along with a sample protocol for assay validation. / PHD / Cancer, a group of diseases characterized by uncontrolled and abnormal cell growth, is the second-leading cause of death worldwide. Even though researchers have made significant progress in its treatment over the past several decades, innovative therapeutic approaches that both improve survival outcome and lessen the many debilitating side-effects of conventional cancer treatments are vital. First, we investigated the mechanism of interaction of a particular molecule, Ru(II)- Rh(III), with DNA. We found that Ru(II)-Rh(III) is strongly attracted to DNA due to its charge and an interaction with the indentations along its helix. Upon light activation only, Ru(II)-Rh(III) binds to and cleaves DNA without the need for molecular oxygen, which is scarce in tumors and can limit the activity of other drugs, and to an extent that is affected by the concentration of ions in the solution. Thus, the cytotoxic effect of Ru(II)-Rh(III) might be selectively activated in those tissues that are irradiated with light (e.g., a tumor). Secondly, we identified protein combinations selectively present in melanoma, which could be utilized in heteromultivalency. Heteromultivalent scaffolds bind strongly to cells that express a combination of proteins rather than one protein at a time, making them excellent candidates for delivering a payload in a selective manner. Using expression profiles of melanoma and normal tissues, we identified surface proteins and protein combinations that are selectively found in melanoma patients and not in normal tissues. After a preliminary validation process using the scientific literature, we used confirmed differences in the expression intensities of some of these combinations in melanoma cell lines in comparison to normal skin controls. Finally, we investigated the resazurin assay, a method used for the evaluation of cell growth and drug candidates in more than 2,000 publications. We found that only ~14% of these utilized validated assay conditions, while ~40% failed to report essential analytical parameters needed for their replication. We evaluated assay conditions for eight cell lines, and found that these are highly variable and independent of tissue type and some metabolic parameters. Furthermore, we obtained insights into the mechanism through which cells react with resazurin and proposed minimum reporting standards for publications, along with a protocol for assay validation.

We develop a theoretical framework for a priori estimation of catalytic activity of metal nanoparticles using geometry-based reactivity descriptors of surface atoms and kinetic analysis of reaction pathways at various types of active sites. We show that orbitalwise coordination numbers 𝐶𝑁^α (α = 𝑠 or 𝑑) can be used to predict chemical reactivity of a metal site (e.g., adsorption energies of critical reaction intermediates) by being aware of the neighboring chemical environment, outperforming their regular (𝐶𝑁) and generalized (𝐶̅𝑁̅) counterparts with little added computational cost. Here we include two examples to illustrate this method: CO oxidation on Au (5𝑑¹⁰6𝑠¹) and O₂ reduction on Pt (5𝑑⁹6𝑠¹). We also employ Bayesian learning and the Newns-Anderson model to advance the fundamental understanding of adsorbate-surface interactions on metal nanocatalysts, paving the path toward adsorbate-specific tuning of catalysis. / Doctor of Philosophy / The interactions between reaction intermediates and catalysts should be neither too strong nor too weak for catalytic optimization. This Sabatiers principle arising from the scaling relations among the energetics of reacting species at geometrically similar sites, provides the conceptual basis for designing improved catalysts, but imposes volcano-type limitations on the attainable catalytic activity and selectivity. One of the greatest challenges faced by the catalysis community today is how to develop design strategies and ultimately predictive models of catalytic systems that could circumvent energy scaling relations. This work brings the quantum-chemical modeling and machine learning technique together and develops a novel stochastic modeling approach to rationally design the catalysts with desired properties and bridges our knowledge gap between the empirical kinetics and atomistic mechanisms of catalytic reactions.

Yes / The use of methylmalonyl-CoA epimerase (MCEE) to improve stereoselectivity in crotonase-mediated biocatalysis is exemplified by the coupling of MCEE, crotonyl-CoA carboxylase reductase and carboxymethylproline synthase in a three-enzyme one-pot sequential synthesis of functionalised C-5 carboxyalkylprolines starting from crotonyl-CoA and carbon dioxide. / Biotechnology and Biological Sciences Research Council, The Wellcome Trust, and CONACyT and FIDERH (Mexico, RGC) The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust (092809/Z/10/Z).

Fear is an adaptive emotion that typically increases across infancy to help keep infant exploration in check. Too much fear, however, can become maladaptive and lead to psychopathology later in childhood. Thus, it is important to understand how both fear reactivity and regulation develop early in life in order to identify at-risk children early on. Maternal factors, such as parenting behaviors and personality, are associated with both fear reactivity and regulation, but results have been mixed, possibly due to a trait-based approach to assessing maternal personality. The goal of my dissertation was to examine the growth trajectories of fear reactivity and regulation across infancy and toddlerhood both unconditionally and within the contexts of maternal parenting and personality functioning. Infants and mothers were assessed when infants were 10-months (n = 48), 14-months (n = 42), and 18-months (n = 34) old. At each age, infant fear reactivity was assessed using behavioral coding during the Laboratory Temperament Assessment Battery fear tasks and infant fear regulation was examined via respiratory sinus arrhythmia reactivity during the fear tasks. At 10- and 14-months, maternal parenting behaviors were coded during an interaction task and maternal personality functioning was assessed via maternal self-report. Hierarchical linear modeling demonstrated that maternal personality functioning moderated the association between maternal affect and infant fear reactivity growth and maternal personality functioning moderated the association between maternal directiveness and infant fear regulation growth. These results aid in the understanding of how maternal factors relate to infant fear development. / Doctor of Philosophy / Fear is an adaptive emotion that increases across infancy to help keep infants safe as they gain the ability to explore their environments independently. Some infants, however, exhibit heightened levels of fear that set them on a path for negative consequences, like anxiety disorders, in childhood. This typically occurs when infants have high levels of fear without appropriate regulation strategies to manage such. Maternal factors, like parenting behaviors and personality, have both been shown to affect the development of fear and the regulation of fear, but results are not consistent. Given this, the goal of my dissertation was to examine how level of fear (fear reactivity) and management of fear (fear regulation) develop across infancy and toddlerhood under the context of maternal parenting and personality. Infants and mothers were assessed when infants were 10-months (n = 48), 14-months (n = 42), and 18-months (n = 34) old. At each age, infant fear reactivity was assessed using behavioral coding during the Laboratory Temperament Assessment Battery fear tasks and infant fear regulation was examined via physiological means based on heart rate. At 10- and 14-months, maternal parenting behaviors were coded during an interaction task and maternal personality functioning was assessed via maternal self-report. Results demonstrated that maternal personality functioning moderated the association between maternal affect and infant fear reactivity development and maternal personality functioning moderated the association between maternal directiveness and infant fear regulation development. These results aid in the understanding of how maternal factors relate to infant fear development.

No / Cocrystal monohydrate of nitrofurantoin (NF) with melamine (MELA) has been studied as NF is an antibacterial drug used for the treatment of urinary tract infections. The structure of nitrofurantoin-melamine-monohydrate (NF-MELA-H2O) is characterized by FT-IR and FT-Raman spectroscopy. The energies and vibrational frequencies of the optimized structures calculated using quantum chemical calculations. Supported by normal coordinate analyses and potential energy distributions (PEDs), the complete vibrational assignments recommended for the observed fundamentals of cocrystal hydrate. With the aim of inclusion of all the H-bond interactions, dimer of NF-MELA-H2O has been studied as only two molecules of cocrystal hydrate are present in the unit cell. By the study of dimeric model consistent assignment of the FT-IR and FT-Raman spectrum obtained. H-bonds are of essential importance in an extensive range of molecular sciences. The vibrational analyses depict existence of H-bonding (O-H⋯N) between water O-H and pyridyl N atom of MELA in both monomer and dimer. To probe the strength and nature of H-bonding in monomer and dimer, topological parameters such as electron density (ρBCP), Laplacian of electron density (∇2ρBCP), total electron energy density (HBCP) and H-bond energy (EHB) at bond critical points (BCP) are evaluated by quantum theory of atoms in molecules (QTAIM). Natural bond orbitals (NBOs) analyses are carried out to study especially the intra and intermolecular H-bonding and their second order stabilization energy (E(2)). The value of HOMO-LUMO energy band gap for NF-MELA-H2O (monomer and dimer both) is less than NF, showing more chemical reactivity for NF-MELA-H2O. Chemical reactivity has been described with the assistance of electronic descriptors. Global electrophilicity index (ω = 7.3992 eV) shows that NF-MELA-H2O behaves as a strong electrophile than NF. The local reactivity descriptors analyses such as Fukui functions, local softnesses and electrophilicity indices performed to determine the reactive sites within NF-MELA-H2O. In MEP map of NF-MELA (monomer and dimer) electronegative regions are about NO2 and C=O group of NF, although the electropositive regions are around NH2, N-H group and H2O molecule. Molar refractivity (MR) value of NF-MELA-H2O (monomer and dimer) lies within the range set by Lipinski's modified rules. This study could set as an example to study the H-bond interactions in pharmaceutical cocrystals.

This dissertation describes the design, development and results of a simple, inexpensive, rugged, pyroelectric heat-of-reaction detector that can be made in many configurations. The measured heat of reaction results from the reaction of a substrate on an enzyme. The enzyme is immobilized in a flow channel with a pyroelectric polymer film, poly(vinylidene fluoride) or PVDF. The sample is introduced into the flow channel using flow injection analysis technology. The heat from the reaction causes the pyroelectric material to produce an electrical potential proportional to the change in temperature which, in turn, is proportional to the substrate concentration. This potential is amplified and recorded. A differential instrument amplifier produces a difference signal from a sample and reference PVDF film. This removes noise caused by stray electromagnetic radiation and piezoelectric pressure responses. A conventional Flow Injection Analysis unit was employed. The FIA flow rate was four ml/min and the time from injection to peak maximum was less than three seconds, with a return to baseline of less than thirty seconds. This gives a quick analysis time and a reasonable number of analyses per unit time. Data interpretation is straight forward, peak height is proportional to the concentration. A 70 μl sample gives a good response. Larger samples do not improve the signal. The system showed minimum detectable number of moles that is comparable to other methods, 7 x 10⁻⁸ moles. The detector showed good response for more than two orders of magnitude. The results show excellent correlation to the modeled system of heat trans+er through the PVDF sensor. / Ph. D.

The primary aim of this study was to investigate whether the joint action of the parasympathetic (PNS) and sympathetic nervous system (SNS) influenced three distinct indicators of child adjustment. Although evidence suggests that patterns of reactivity in the PNS and SNS each contribute to adjustment in youth, a paucity of work has examined the interaction between the two systems. Moreover, much of the research on children's autonomic reactivity has overly relied on variable-centered analytic approaches, which aim to predict variance and assume homogeneity in the relations between predictors and outcome. This project also incorporated a person-centered approach to systematically identify individual differences in the interrelation between PNS and SNS reactivity and to classify children into homogeneous autonomic reactivity groups. The person-centered results were then applied to variable-centered analyses to examine how adjustment varied across homogeneous autonomic reactivity groups. Thus, the goal of this study was to apply both variable-centered and person-centered analyses to investigate whether children's autonomic reactivity was related to child adjustment. Children (N = 64, 8-10 years, M = 9.06, SD = 0.81) and one parent completed a psychophysiological laboratory assessment at Wave 1 during which each child's respiratory sinus arrhythmia reactivity (RSAR; an index of PNS reactivity) and skin conductance level reactivity (SCLR; an index of SNS reactivity) was assessed in response to a mirror tracing challenge task. At both Wave 1 and Wave 2, each parent reported on their child's internalizing symptoms, externalizing symptoms, and social competence. The variable-centered analyses revealed that, consistent with hypotheses, the two-way RSAR x SCLR interaction was significant predicting internalizing symptoms at Time 1 and at Time 2. In both cases, RSA withdrawal was associated with fewer internalizing symptoms when coupled with low SCLR. When coupled with high SCLR, RSA withdrawal was associated with more internalizing symptoms at Time 1; however, RSAR was unrelated to Time 2 internalizing when coupled with high SCLR. In addition, SCLR was associated with more social competence and (marginally) fewer externalizing problems over time. The person-centered analyses (i.e., a model-based cluster analysis) identified two distinct clusters based on children's RSAR and SCLR. Children in Cluster 1 showed slight RSA withdrawal combined with SCL activation (modest reciprocal SNS activation) and exhibited marginally more internalizing and less social competence, as compared to children in Cluster 2 who, as a group, showed heightened RSAR (either withdrawal or augmentation) and SNS activation. When a 3-cluster model was examined, results indicated that children who showed modest reciprocal SNS activation (Cluster 1) showed marginally more internalizing symptoms then children who showed strong reciprocal SNS activation (Cluster 2A) and marginally less social competence then children who showed coactivation (Cluster 2B). This study offers important evidence that person-centered analyses can identify differences in autonomic reactivity that are relevant to children's adjustment. Cluster analysis identified only two (i.e., reciprocal SNS activation, coactivation) of the four autonomic profiles assumed to be represented in simple slope analyses in previous work. Thus, incorporating person-centered techniques in future research is an important and likely fruitful approach to investigating how autonomic reactivity contributes to child development.