Human epithelium-specific ETS transcription factor-1 (ESE-1), which is also known as E74-like factor-3 (Elf3) in mice, is strongly expressed in lung during fetal development and in certain lung cancers. The primary goal of the work presented in this thesis was to investigate whether ESE-1 is involved in regeneration of the injured lung epithelium by administering naphthalene to both wild-type (Elf3 +/+) and Elf3-deficient (Elf3 -/-) mice. However, optimal conditions for proper utilization of the naphthalene-induced lung injury model must first be established. Therefore, dose-response studies were initially conducted by administering three different doses of naphthalene to both male and female mice, as described in chapter 2. Although it is shown that the extent of naphthalene-induced Clara cell injury is dose-dependent in both male and female mice, female mice are more sensitive to naphthalene-induced injury than male mice independent of the dose. Furthermore, it is also demonstrated that these gender-dependent differences in naphthalene injury can subsequently influence downstream lung repair kinetics. In light of these findings, lung regeneration was examined in both sexes of both Elf3 +/+ and Elf3 -/- mice. As reported in chapter 3, the kinetics of bronchiolar epithelial cell proliferation and differentiation is delayed considerably in Elf3 -/- mice following naphthalene injury. Moreover, expression of transforming growth factor-beta type II receptor, which is a well-known transcriptional target gene of ESE-1 and is involved in the induction of epithelial cell differentiation, is significantly lower in the bronchiolar airway epithelium of Elf3 -/- mice as compared to Elf3 +/+ mice under steady-state conditions and during repair of naphthalene-induced damage. Collectively, these findings occur to a similar extent in both sexes of both Elf3 +/+ and Elf3 -/- mice, and suggest that ESE-1 plays an important role in regulating the kinetics of airway epithelial regeneration after acute lung injury.

Respiratory virus infections are associated with asthma pathogenesis and exacerbations in children and adults. Unfortunately, it remains largely unknown whether innate and adaptive T cell anti-viral immunity differs in allergic disease versus health. Here, we established a short-term primary cell culture system using human peripheral blood mononuclear cells (PBMC) optimized for measuring immune responses to reovirus, respiratory syncytial virus (RSV) and metapneumovirus (MPV) based on virus-specific cytokine and chemokine production. The prevalence and intensity of innate and adaptive responses in children and adult populations was addressed. Using this in vitro model of human anti-viral immunity, we tested our global hypothesis that asthmatics mount anti-viral cytokine responses to respiratory viruses that differ from those of healthy individuals. MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Reovirus induced exceptionally strong IFN recall responses concomitant with intense IL-10 production, which were independent of viral replication in PBMC. Surprisingly, despite Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals, asthmatics exhibited significantly stronger pro-inflammatory IFNγ and IL-10 production towards virus stimulation than non-asthmatic children and adults. Moreover, children with current AHR, regardless of asthmatic status, exhibit a greater frequency and intensity of IFNγ responses towards pneumoviruses than do non-AHR counterparts. Conversely, expression of chemokine CCL5 was substantially weaker in asthmatics, and was further decreased in children with AHR and familial history of asthma. This pattern of enhanced pro-inflammatory and deficient anti-viral CCL5 responses towards pneumoviruses in children with markers of symptomatic asthma or AHR may underlie the enhanced sensitivity of these children to experience breathing difficulties following infection with respiratory viruses. Furthermore, we have clearly demonstrated a gene by environment interaction, whereby ETS exposure in children with familial asthma results in suppressed anti-viral IFNγ and IL-10 production. Therefore, we have attempted to determine whether genetic variation affects the intermediate phenotype of anti-viral immunity, in the population and dependent on clinical status. In summary, we have demonstrated that asthma, childhood exposures and genetics shape anti-viral cytokine responses in human. These findings have a substantial impact for physicians deciding the contextually appropriate treatment for asthma symptoms in their patients and could have implications for experimentation relating to mechanisms of disease, clinical practice and development of appropriate therapeutics. / October 2007

Different kinds of nanoparticles are widely used in optoelectronic and photovoltaic applications to harvest light to increase efficiency of devices. ETS-10, which is a synthetic microporous material consisting of &ndash / Ti-O-Ti-O-Ti- wires that run in the crystal in a and b directions, has been of interest in such applications due to its unique properties. In the current study, the synthesis conditions of ETS-10 were investigated in order to obtain pure ETS-10 crystals with the desired morphology. For this purpose, ETS-10 crystals were synthesized using different molar compositions. The effects of several synthesis parameters on the obtained products were investigated. Furthermore, ETS-10 thin films were prepared on ITO glass substrates using secondary growth of ETS-10 for the first time. The orientation of the -Ti-O-Ti-O-Ti- wires inside ETS-10 were explored by preparing several ETS-10 films on the ITO glass substrates using secondary growth of ETS-10 multilayers with a partial a(b)-out-of-plane preferred crystal orientation. This orientation can be desirable for the advanced applications of ETS-10 films. Afterwards, silver nanoparticle modified ETS-10 crystals were prepared and characterized in detail to understand the interaction of silver nanoparticles with the synthesized ETS-10 crystals. For this purpose, ETS-10 in the as-prepared and silver nanoparticle containing forms have been characterized using, XRD, ICP-OES, SEM, HR-TEM, N2 Adsorption, XPS, and UV/VIS spectroscopy. In order to investigate the optical properties of the silver modified ETS-10, transmittance-reflectance measurements were carried out. In general, it is believed that all steps necessary for the preparation of ETS-10 films and preliminary steps for investigating ETS-10 for future photovoltaic applications were determined.

This thesis examines the informational efficiency of the European carbon market based on the European Union Emissions Trading Scheme (EU ETS). The issue is approached from three different perspectives. I explore whether the volatility embedded in carbon options is a rational forecast of subsequently realized volatility. Then, I investigate if, and to what extent, new information about the structural and institutional set-up of the market impacts the carbon price dynamics. Lastly, I examine whether the European carbon market is relevant for the firm valuations of covered companies. First, perhaps because the market is new and derivatives’ trading on emission allowances has only started recently, carbon options have not yet been extensively studied. By using data on options traded on the European Climate Exchange, this thesis examines an aspect of market efficiency which has been previously overlooked. Market efficiency suggests that, conditional upon the accuracy of the option pricing model, implied volatility should be an unbiased and efficient forecast of future realized volatility (Campbell et al., 1997). Black (1976) implied volatility and implied volatility estimates directly surveyed from market participants are used in this thesis to study the information content of carbon options. Implied volatility is found to be highly informative and directionally accurate in forecasting future volatility. There is no evidence, however, that volatility embedded in carbon options is an unbiased and efficient forecast of future realized volatility. Instead, historical volatility-based forecasts are shown to contain incremental information to implied volatility, particularly for short-term forecasts. In addition, this thesis finds no evidence that directly surveyed implied volatility estimates perform better as a forecast of future volatility relative to Black’s (1976) estimates. Second, the market sensitivity to announcements about the organizational and institutional set-up of the EU ETS is re-examined. Despite their importance for the carbon price formation, demand-side announcements and announcements about the post-2012 framework have not yet been researched. By examining a very comprehensive and updated dataset of announcements, this thesis adds to the earlier works of Miclaus et al. (2008), Mansanet-Bataller and Pardo (2009) and Lepone et al. (2011). Market participants are found to rationally incorporate new information about the institutional and regulatory framework of the emissions trading scheme into the carbon price dynamics. However, they seem to be unable to accurately assess the implications of inter-temporal banking and borrowing on pricing futures contracts with different maturities. The impact of macroeconomic conditions on the market responsiveness is investigated by splitting the dataset into subsamples according to two alternative methods: 1) a simple split into pre-crisis and full-crisis time periods, and 2) according to a Bai-Perron structural break test. Evidence is found that in the context of economic slowdown and known allowances oversupply, the relationship between the carbon price and its fundamentals (institutional announcements, energy prices and extreme weather) breaks down. These findings are consistent with the arguments in Hintermann (2010), Keppler and Mansanet-Bataller (2010) and Koop and Tole (2011) that carbon price drivers change in response to the differing context of the individual trading periods. Third, the role of carbon performance in firm valuation is understudied. Since companies were not obliged to disclose their carbon emissions prior to the launch of the EU ETS, there exists little empirical evidence of the effect of carbon performance on market value. Earlier studies of the European carbon market have only focused on the impact of ETS compliance on the profitability and competitiveness of covered companies (e.g. Anger and Oberndorfer, 2008). There is also little research on how the newly available emissions data has altered the carbon performance of companies. This thesis addresses these gaps in the literature by examining the stock price reactions of British and German firms on the day of verified emissions release under the EU ETS over the period 2006 – 2011. An event study is conducted using a Seemingly Unrelated Regressions model to deal with the event clustering present in the dataset. Limited evidence is found that investors use information about the carbon performance of companies in their valuations. The information contained in the carbon emissions reports is shown to be somewhat more important for companies with high carbon-intensive operations. This thesis finds no conclusive evidence that the cap-and-trade programme has been able to provide regulated companies with enough incentives to de-carbonize their operations. The market does not punish companies which continue to emit carbon at increasing rates or reward companies which improve their carbon performance. In brief, the results of the thesis suggest that the market is not fully efficient yet. Inefficiently priced carbon options may allow for arbitrage trades in the market. The inability of investors to incorporate rules on inter-temporal banking and borrowing of allowances across the different trading periods leads to significant price reactions when there should be none. A recessionary economic environment and a known oversupply of emission allowances have led to a disconnect between the carbon price and its fundamental drivers. And, lastly, the signal embedded in the carbon price is not strong enough to invoke investor action and turn carbon performance into a standard component of investment analysis.

Respiratory virus infections are associated with asthma pathogenesis and exacerbations in children and adults. Unfortunately, it remains largely unknown whether innate and adaptive T cell anti-viral immunity differs in allergic disease versus health. Here, we established a short-term primary cell culture system using human peripheral blood mononuclear cells (PBMC) optimized for measuring immune responses to reovirus, respiratory syncytial virus (RSV) and metapneumovirus (MPV) based on virus-specific cytokine and chemokine production. The prevalence and intensity of innate and adaptive responses in children and adult populations was addressed. Using this in vitro model of human anti-viral immunity, we tested our global hypothesis that asthmatics mount anti-viral cytokine responses to respiratory viruses that differ from those of healthy individuals. MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Reovirus induced exceptionally strong IFN recall responses concomitant with intense IL-10 production, which were independent of viral replication in PBMC. Surprisingly, despite Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals, asthmatics exhibited significantly stronger pro-inflammatory IFNγ and IL-10 production towards virus stimulation than non-asthmatic children and adults. Moreover, children with current AHR, regardless of asthmatic status, exhibit a greater frequency and intensity of IFNγ responses towards pneumoviruses than do non-AHR counterparts. Conversely, expression of chemokine CCL5 was substantially weaker in asthmatics, and was further decreased in children with AHR and familial history of asthma. This pattern of enhanced pro-inflammatory and deficient anti-viral CCL5 responses towards pneumoviruses in children with markers of symptomatic asthma or AHR may underlie the enhanced sensitivity of these children to experience breathing difficulties following infection with respiratory viruses. Furthermore, we have clearly demonstrated a gene by environment interaction, whereby ETS exposure in children with familial asthma results in suppressed anti-viral IFNγ and IL-10 production. Therefore, we have attempted to determine whether genetic variation affects the intermediate phenotype of anti-viral immunity, in the population and dependent on clinical status. In summary, we have demonstrated that asthma, childhood exposures and genetics shape anti-viral cytokine responses in human. These findings have a substantial impact for physicians deciding the contextually appropriate treatment for asthma symptoms in their patients and could have implications for experimentation relating to mechanisms of disease, clinical practice and development of appropriate therapeutics.

Natural and synthetic heterocyclic cations that bind to the DNA minor groove have demonstrated effectiveness as therapeutic agents for cancer, parasitic and viral diseases, as well as powerful probes for use to extend our fundamental understanding of DNA molecular recognition. Crystal and NMR structures with a variety of minor groove binding compounds have shed light on the structural varieties of these systems, the important solvent molecules in the complexes, and the induced fit effects for binding of both DNA and the bound small molecule. Topics of specific importance in DNA recognition are the development of a greater variety of cell-permeable minor groove agents that have increased DNA binding sequence selectivity. In this dissertation, the structural and energetic basis of the interaction between DNA and minor groove binders has been systematically investigated. A set of powerful and complementary biophysical methods have been used: gel electrophoresis with ligation ladder assay, circular dichroism, mass spectrometry, surface plasmon resonance and isothermal titration calorimetry have been applied to determine the binding stoichiometry, binding affinity, kinetics and thermodynamics, and also the structural influence that minor groove binders can have on DNA. The results of several minor groove complexes clearly show that based on DNA sequences, minor groove binders can have multiple binding modes and consequently affect the geometry of DNA minor groove and the overall DNA curvature in distinct manners. In addition, the binding enthalpy of a minor groove binder is essentially salt concentration and binding mode independent. Besides the investigation of DNA-minor groove binder complex, the binding and inhibition of transcription factor PU.1 has also been studied. The highly positive charged PU.1 targets DNA by inserting an α-helix in the major groove of the 5’-GGAA-3’ site, and displays a strong salt concentration dependency. A set of minor groove binders have been rationally designed based on the high-affinity DNA sequence for PU.1 to target the flanking sequences of the 5’-GGAA-3’ site. They display a structure-related PU.1 inhibition efficacy. This work demonstrates that minor groove binders are capable of modulating PU.1 by targeting the opposite groove and supports future efforts to develop agents for other transcription factors.

Respiratory virus infections are associated with asthma pathogenesis and exacerbations in children and adults. Unfortunately, it remains largely unknown whether innate and adaptive T cell anti-viral immunity differs in allergic disease versus health. Here, we established a short-term primary cell culture system using human peripheral blood mononuclear cells (PBMC) optimized for measuring immune responses to reovirus, respiratory syncytial virus (RSV) and metapneumovirus (MPV) based on virus-specific cytokine and chemokine production. The prevalence and intensity of innate and adaptive responses in children and adult populations was addressed. Using this in vitro model of human anti-viral immunity, we tested our global hypothesis that asthmatics mount anti-viral cytokine responses to respiratory viruses that differ from those of healthy individuals. MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Reovirus induced exceptionally strong IFN recall responses concomitant with intense IL-10 production, which were independent of viral replication in PBMC. Surprisingly, despite Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals, asthmatics exhibited significantly stronger pro-inflammatory IFNγ and IL-10 production towards virus stimulation than non-asthmatic children and adults. Moreover, children with current AHR, regardless of asthmatic status, exhibit a greater frequency and intensity of IFNγ responses towards pneumoviruses than do non-AHR counterparts. Conversely, expression of chemokine CCL5 was substantially weaker in asthmatics, and was further decreased in children with AHR and familial history of asthma. This pattern of enhanced pro-inflammatory and deficient anti-viral CCL5 responses towards pneumoviruses in children with markers of symptomatic asthma or AHR may underlie the enhanced sensitivity of these children to experience breathing difficulties following infection with respiratory viruses. Furthermore, we have clearly demonstrated a gene by environment interaction, whereby ETS exposure in children with familial asthma results in suppressed anti-viral IFNγ and IL-10 production. Therefore, we have attempted to determine whether genetic variation affects the intermediate phenotype of anti-viral immunity, in the population and dependent on clinical status. In summary, we have demonstrated that asthma, childhood exposures and genetics shape anti-viral cytokine responses in human. These findings have a substantial impact for physicians deciding the contextually appropriate treatment for asthma symptoms in their patients and could have implications for experimentation relating to mechanisms of disease, clinical practice and development of appropriate therapeutics.

Prostate cancer is a clinically heterogeneous disease, with manifestations ranging from a rapid and often fatal progression, to indolent disease. Unfortunately, current clinicopathological criteria cannot differentiate men whose tumours require immediate and aggressive therapy from those in which active surveillance may be more appropriate. Both PTEN deletion and ETS gene fusions are biomarkers with potential to aid in prostate cancer clinical management. In this thesis, I postulate that PTEN and fusion gene rearrangements may be associated with specific genomic changes, and might also have general impact on the genomic landscape of prostate cancer. A meta-analysis of somatic copy number alterations (CNAs) examined 662 unique prostate cancer patient samples consisting of 546 primary and 116 advanced tumours derived from eleven publications. Normalization, segmentation and identification of corresponding CNAs for meta-analysis were achieved using established commercial software. The CNA distribution in primary disease was characterized by losses at 2q, 3p, 5q, 6q, 8p, 12p, 13q, 16q, 17p, 18q and 10q (PTEN), and acquisition of 21q deletions associated with the TMPRSS2:ERG fusion rearrangement. Unsupervised analysis identified five genomic subgroups. Parallel analysis of advanced and primary tumours indicated that PTEN genomic deletions and the gene fusion were enriched in advanced disease. A supervised analysis of PTEN deletions and gene fusions demonstrated that PTEN deletion was sufficient to impose higher levels of CNA. Moreover, the overall percentage of the genome altered was significantly higher when PTEN was deleted, suggesting that this important genomic subgroup was likely characterized by intrinsic chromosomal instability. Candidate genes in each of the recurrent CNA regions characteristic of each subgroup showed that signalling networks associated with cancer progression and genome stability were likely to be perturbed at the highest level in the PTEN deleted genomic subgroup. Therefore classification of primary prostate cancer according to PTEN deletions, but not the gene fusion, was associated with greatly increased levels of CNA. Collectively, the impact of PTEN loss resulted in a significantly greater frequency and extent of alteration, and heightened genomic instability with concomitant pathway disruptions. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2014-04-29 14:20:06.02

Les interactions sociales se trouvent au cœur des activités économiques. Pourtant en sciences économiques, elles ne sont traitées que d'une manière limitée en se concentrant uniquement aux rapports de qu'elles entretiennent avec le marché (Mankiw and Reis, 2002). Le rôle que jouent les interactions sociales vis-à-vis des comportements des agents, ainsi que la formation de leurs attentes sont souvent négligé. Cette négligence reste d'actualité malgré que les premières contributions dans la littérature économique les ont depuis longtemps déjà identifiées comme étant de déterminants importants pour la prise des décisions des agents économiques, comme par exemple Sherif (l936), Hyman (1942), Asch (1951), Jahoda (1959) ou Merlon (1968). En revanche, dans les études de consommation (une spécialité au croisement entre les sciences économiques, de la sociologie et de la psychologie), les interactions sociales (influences sociales) sont con­sidérées comme les " ... déterminants dominants[ ... ] du comportement de l'individu ... " (Burnkrant and Cousineau, 1975). Le but de cette thèse est de construire un pont entre les interactions sociales et leur influence sur la formation des anticipations et le comportement des agents. / Social interactions are in the core of economic activities. Their treatment in Economies is however often limited to a focus on the market (Manski, 2000). The role social interactions themselves play for the behavior of agents as well as the formation of their attitudes is often neglected. This is despite the fact that already early contributions in economic literature have identified them as important determinants for the decision making of economic agents as for example Sherif (I936), Hyman (1942), Asch (1951 ), Jahoda (I 959) or Merton (1968). ln consumer research, a field on the intersection between Economies, Sociology and Psychology, on the other hand social interactions (social influences) are considered to be the" ... most pervasive determinants [ ... ] of individual 's behaviour. .. " (Bumkrant and Cousineau, 1975). The thesis at hand bridges the gap between social interactions and their influence on agents expectation formation and behavior.

The main aim of this thesis is to show how emission allowances for carbon dioxide work in the emission control system of the European Union. The first and second chapters explain global warming, give a summary of views on how to solve environmental pollution using economic instruments and inform about the first summit climate changes in 1992 in Rio de Janeiro. The third and fourth chapters discuss the origin and development of the European Union Emissions Trading Scheme (EU ETS) and other climate summits that were held between 2007 - 2015. The analytical part of my thesis deals with the third trading period of the EU ETS, the factors affecting the price of allowance and the measures resulting from global climate conferences. In this part I verify whether it is possible for climate conferences to be considered trend that moves the entire demand curve. This premise was tested with the aid of hypothesis: "In the period of the climate conference increases price of allowance." This hypothesis was examined on the basis of the condition ceteris paribus and the result of this thesis is the fact that conferences don't influence price of allowance. The results indicate that the price of allowance is probably influenced by other factors that were not the subject of my analysis.