Characterization of ALDH1A1 as a novel tumorigenic target mediating TAZ-induced lung tumorigenesis and stem cell phenotypes

Recent studies suggest that lung cancer stem cells (CSCs) may play major roles in lung cancer development, metastasis and drug resistance. Therefore, identification of lung CSC drivers may provide promising targets for lung cancer. TAZ (transcriptional co-activator with PDZ-binding motif) is a transcriptional co-activator and key downstream effector of the Hippo pathway, which plays critical roles in various biological processes. TAZ has been shown to be overexpressed in non-small cell lung cancer (NSCLC) and involved in tumorigenicity of lung epithelial cells. However, whether TAZ is a driver for lung CSCs and tumor formation in vivo is unknown. In addition, the molecular mechanism underlying TAZ-induced lung tumorigenesis remains to be determined. In this study, we provided evidence that constitutively active TAZ (TAZ-S89A) is a driver for lung tumorigenesis in vivo in mice and formation of lung CSC. Oncogenes upregulated in TAZ-overexpressing cells were identified with further validation. The most dramatically activated gene, Aldh1a1 (Aldehyde dehydrogenase 1 family member a1), a well-established CSC marker, showed that TAZ induces Aldh1a1 transcription by activating its promoter activity through interaction with the transcription factor TEA domain (TEAD) family member. Most significantly, inhibition of ALDH1A1 with its inhibitor A37 or CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene knockout in lung cancer cells suppressed lung tumorigenic and CSC phenotypes in vitro, and tumor formation in mice in vivo. In conclusion, this study identified TAZ as a novel inducer of lung CSCs and the first transcriptional activator of the stem cell marker ALDH1A1. Most significantly, we identified ALDH1A1 as a critical meditator of TAZ-induced tumorigenic and CSC phenotypes in lung cancer. Our studies provided preclinical data for targeting of TAZ-TEAD-ALDH1A1 signaling to inhibit CSC-induced lung tumorigenesis and drug resistance in the future.

"Can you ask her to help?" An examination of the factors that promote and discourage prosocial intervention in preschool children

Previous research has examined young children’s ability to detect who would be most likely to provide help to others in a given situation, but little is known about their ability to intervene based on this knowledge in a real-life setting. In the current study, 48 three-year-old children chose between two actors to retrieve an out-of-reach object for the Experimenter; one actor was physically incapable of providing the object (blocked by a tall barrier), and one was capable. Participants’ looking behaviour between the two actors during the study was also recorded and analyzed as an additional, nonverbal measure of their prediction about who would help. Approximately half of the participants in the sample actively intervened on behalf of the Experimenter, but only after a direct request for help was made. Though the other participants did not engage in this helping behaviour, they chose the unblocked actor to help the Experimenter in a subsequent interview. Children also spent more time looking at the unblocked actor. Secondary analyses indicated that shyness prevented many children in the study from asking for help on behalf of the Experimenter from one of the actors. Finally, an unexpected side bias for looking behaviour toward the actors was found that has implications for how the study design could be improved for future research.

Design of Transparent Conducting Electrodes and Surface Relief Gratings for Plasmonic Polymer Solar Cells

As the concept of renewable energy becomes increasingly important in the modern society, a considerable amount of research has been conducted in the field of organic photovoltaics in recent years. Although organic solar cells generally have had lower efficiencies compared to silicon solar cells, they have the potential to be mass produced via solution processing. A common polymer solar cell architecture relies on the usage of P3HT (electron donor) and PCBM (electron acceptor) bulk heterojunction. One of the main issues with this configuration is that in order to compensate for the high exciton recombination rate, the photoactive layer is often made very thin (on the order of 100 $%). This results in low solar cell photocurrents due to low absorption. This thesis investigates a novel method of light trapping by coupling surface plasmons at the electrode interface via surface relief gratings, leading to EM field enhancements and increased photo absorption. Experimental work was first conducted on developing and optimizing a transparent electrode of the form &'()/+,/&'() to replace the traditional ITO electrode since the azopolymer gratings cannot withstand the high temperature processing of ITO films. It was determined that given the right thickness profiles and deposition conditions, the MAM stack can achieve transmittance and conductivity similar to ITO films. Experimental work was also conducted on the fabrication and characterization of surface relief gratings, as well as verification of the surface plasmon generation. Surface relief gratings were fabricated easily and accurately via laser interference lithography on photosensitive azopolymer films. Laser diffraction studies confirmed the grating pitch, which is dependent on the incident angle and wavelength of the writing beam. AFM experiments were conducted to determine the surface morphology of the gratings, before and after metallic film deposition. It was concluded that metallic film deposition does not significantly alter the grating morphologies.

Design of Transparent Conducting Electrodes and Surface Relief Gratings for Plasmonic Polymer Solar Cells

As the concept of renewable energy becomes increasingly important in the modern society, a considerable amount of research has been conducted in the field of organic photovoltaics in recent years. Although organic solar cells generally have had lower efficiencies compared to silicon solar cells, they have the potential to be mass produced via solution processing. A common polymer solar cell architecture relies on the usage of P3HT (electron donor) and PCBM (electron acceptor) bulk heterojunction. One of the main issues with this configuration is that in order to compensate for the high exciton recombination rate, the photoactive layer is often made very thin (on the order of 100 $%). This results in low solar cell photocurrents due to low absorption. This thesis investigates a novel method of light trapping by coupling surface plasmons at the electrode interface via surface relief gratings, leading to EM field enhancements and increased photo absorption. Experimental work was first conducted on developing and optimizing a transparent electrode of the form &'()/+,/&'() to replace the traditional ITO electrode since the azopolymer gratings cannot withstand the high temperature processing of ITO films. It was determined that given the right thickness profiles and deposition conditions, the MAM stack can achieve transmittance and conductivity similar to ITO films. Experimental work was also conducted on the fabrication and characterization of surface relief gratings, as well as verification of the surface plasmon generation. Surface relief gratings were fabricated easily and accurately via laser interference lithography on photosensitive azopolymer films. Laser diffraction studies confirmed the grating pitch, which is dependent on the incident angle and wavelength of the writing beam. AFM experiments were conducted to determine the surface morphology of the gratings, before and after metallic film deposition. It was concluded that metallic film deposition does not significantly alter the grating morphologies.

Shiftwork, sleep disturbance and the metabolic syndrome among female hospital workers

Background: Shiftwork is associated with increased sleep disturbance and cardiovascular and metabolic disease risk. This thesis will focus on shiftwork-related sleep disturbance and the potential mediating role of reduced sleep duration in the relationship between a current rotational shiftwork schedule and the metabolic syndrome among female hospital employees. Objectives: 1) To describe sleep patterns in relation to different shiftwork exposure metrics (current status, cumulative exposure, number of consecutive night shifts); 2) To assess the association between shiftwork metrics and sleep duration; 3) To determine whether sleep duration on work shifts mediates the relationship between a current rotational shiftwork pattern and the metabolic syndrome; and 4) To assess whether cumulative shiftwork exposure and the number of consecutive night shifts are associated with the metabolic syndrome. Methods: 294 female hospital employees (142 rotating shiftworkers, 152 dayworkers) participated in a cross-sectional study. Shiftwork parameters were determined through self-report. Sleep was measured for one week with the ActiGraph GT3X+, a tri-axial accelerometer. The metabolic syndrome was defined according to the Joint Interim Studies Consensus Statement. Sleep was described by shiftwork exposure parameters, and multivariable linear regression was used to determine associations between shiftwork variables and sleep duration. Regression path analysis was used to assess whether sleep duration was a mediator between a current shiftwork schedule and the metabolic syndrome, and the significance of the indirect (mediating) effect was tested with bootstrap confidence intervals. Logistic regression was used to determine associations between cumulative shiftwork exposure, number of consecutive night shifts, and the metabolic syndrome. Results: Current shiftworkers slept less on work shifts, more on free days, and were more likely to nap compared to dayworkers. Sleep duration on work shifts was a strong intermediate in the relationship between a current shiftwork pattern and the metabolic syndrome. Cumulative shiftwork exposure and the number of consecutive night shifts did not affect sleep or the metabolic syndrome. Conclusions: A current shiftwork pattern disrupts sleep, and reduced sleep duration is an important intermediate between shiftwork and the metabolic syndrome among female hospital employees.

The political economy of industrial policy in Peru and Ecuador: 1980-2010

This dissertation focuses on industrial policy in two developing countries: Peru and Ecuador. Informed by comparative historical analysis, it explains how the Import-Substitution Industrialization policies promoted during the 1970s by military administration unravelled in the following 30 years under the guidance of Washington Consensus policies. Positioning political economy in time, the research objectives were two-fold: understanding long-term policy reform patterns, including the variables that conditioned cyclical versus path-dependent dynamics of change and; secondly, investigating the direction and leverage of state institutions supporting the manufacturing sector at the dawn, peak and consolidation of neoliberal discourse in both countries. Three interconnected causal mechanisms explain the divergence of trajectories: institutional legacies, coordination among actors and economic distribution of power. Peru’s long tradition of a minimal state contrasts with the embedded character of Ecuador long tradition of legal protectionism dating back to the Liberal Revolution. Peru’s close policy coordination among stakeholders –state technocrats and business elites- differs from Ecuador’s “winners-take-all” approach for policy-making. Peru’s economic dynamism concentrated in Lima sharply departs from Ecuador’s competitive regional economic leaderships. This dissertation paid particular attention to methodology to understand the intersection between structure and agency in policy change. Tracing primary and secondary sources, as well as key pieces of legislation, became critical to understand key turning points and long-term patterns of change. Open-ended interviews (N=58) with two stakeholder groups (business elites and bureaucrats) compounded the effort to knit motives, discourses, and interests behind this long transition. In order to understand this amount of data, this research build an index of policy intervention as a methodological contribution to assess long patterns of policy change. These findings contribute to the current literature on State-market relations and varieties of capitalism, institutional change, and policy reform.

The Effect of Foam Core Density on the Flexural and Axial Behaviour of Sandwich Panels of Varying Slenderness with Natural Flax-FRP and Glass-FRP Composite Skins

This study investigates the effect of foam core density and skin type on the behaviour of sandwich panels as structural beams tested in four-point bending and axially compressed columns of varying slenderness and skin thickness. Bio-composite unidirectional flax fibre-reinforced polymer (FFRP) is compared to conventional glass-FRP (GFRP) as the skin material used in conjunction with three polyisocyanurate (PIR) foam cores with densities of 32, 64 and 96 kg/m3. Eighteen 1000 mm long flexural specimens were fabricated and tested to failure comparing the effects of foam core density between three-layer FFRP skinned and single-layer GFRP skinned panels. A total of 132 columns with slenderness ratios (kLe/r) ranging from 22 to 62 were fabricated with single-layer GFRP skins, and one-, three-, and five-layer FFRP skins for each of the three foam core densities. The columns were tested to failure in concentric axial compression using pinned-end conditions to compare the effects of each material type and panel height. All specimens had a foam core cross-section of 100x50 mm with 100 mm wide skins of equal thickness. In both flexural and axial loading, panels with skins comprised of three FFRP layers showed equivalent strength to those with a single GFRP layer for all slenderness ratios and core densities examined. Doubling the core density from 32 to 64 kg/m3 and tripling the density to 96 kg/m3 led to flexural strength increases of 82 and 213%, respectively. Both FFRP and GFRP columns showed a similar variety of failure modes related to slenderness. Low slenderness of 22-25 failed largely due to localized single skin buckling, while those with high slenderness of 51-61 failed primarily by global buckling followed by secondary skin buckling. Columns with intermediate slenderness experienced both localized and global failure modes. High density foam cores more commonly exhibited core shear failure. Doubling the core density of the columns resulted in peak axial load increases, across all slenderness ratios, of 73, 56, 72 and 71% for skins with one, three and five FFRP layers, and one GFRP layer, respectively. Tripling the core density resulted in respective peak load increases of 116, 130, 176 and 170%.

Laboratory Investigation of Diluted Bitumen Trapping and Dissolution in Gravel

The Canadian economy is largely dependent on the distribution of large volumes of oil to domestic and international markets by a long network of pipelines. Unfortunately, accidents occur, and oil can leak or spill from these pipelines before it reaches its destination. Of particular concern are the long-term consequences of oil spills in freshwater, which include sinking of oil in water and the contamination of sensitive areas, such as where fish (e.g., salmon) deposit their eggs in gravel-dominated river sediments. There is a knowledge gap regarding the fate and behaviour of oil in river sediment. To this end, this study aimed at finding the potential for diluted bitumen (dilbit) oil to become trapped in gravel and to transfer hydrocarbons into water by dissolution, which are harmful to aquatic life. Two sets of laboratory experiments were conducted to simulate conditions of an oil spill on an exposed bank or in shallow water. In the first set, by conducting capillary pressure-saturation (Pc-Sw) experiments it was found that dilbit can enter gravel pores without much resistance and approximately 14% of the pore volume can be occupied by discontinuous single or multipore blobs of dilbit following imbibition of water. Air-water Pc-Sw experiments done in laboratory 1-D columns required gravity correction and could be successfully scaled to predict dilbit-water Pc-Sw curves, except for the trapped amount of dilbit. Trapped dilbit constituents can be dissolved into the water flowing through gravel pores (hyporheic flow) at different velocities. In the second set, dissolution experiments suggested that for the duration of the test, hydrocarbons that cause acute toxicity dissolve rapidly, likely resulting in a decrease in their effective solubility. However, dilbit saturation changed only <2% within that time. Chronically toxic PAH compounds were also detected in the effluent water. The total concentration of all detected PAHs and alkylPAHs exceeded the threshold literature value to protect early-life stage fish. Observations of decreased concentrations with increased aqueous velocities as well as less than equilibrium concentrations indicated that the mass transfer was rate-limited. A correlation was developed for the mass transfer rate coefficient to understand the mass transfer behaviour beyond the conditions used in the experiments, which had a Reynolds number exponent similar to the studies of NAPL dissolution in groundwater.

Sleep Quality as a Mediator of the Relationship Between Attachment Anxiety and Health Outcomes During Romantic Conflict

Attachment anxiety, or a fear of abandonment by those close to you, is an important predictor of many individual and interpersonal outcomes. Individuals high in attachment anxiety are more likely to experience physical illness due to disrupted immune functioning and deregulated stress responses. I was interested in examining potential mechanisms accounting for why individuals high in attachment anxiety are more likely to become ill. One variable that has been demonstrated to mediate the relationship between stress and health is sleep quality. As attachment anxiety is characterized by the experience of stress and worry over abandonment by romantic partners, I predicted sleep quality would mediate the relationship between attachment anxiety and health. Further, I predicted attachment anxiety would interact with romantic threat, in that individuals high in attachment anxiety who perceive threat to their relationships would have poor sleep quality (compared with individuals low in attachment anxiety and individuals high in anxiety who do not perceive threat) which would mediate the most unhealthy outcomes. I tested these hypotheses using three online diary studies. In the first two studies, participants completed a seven-night diary describing their sleep quality, health, and interaction with their partner. In Study 3, I surveyed participants once a week for eight weeks to examine longer-term health outcomes. Sleep quality did indeed mediate the relationship between attachment anxiety and various health outcomes over one week (Study 2), and showed a trend towards mediating effects over two months (Study 3). Interestingly, however, attachment anxiety did not interact with perceived romantic threat to predict health in the mediation analyses. Implications for sleep as a mediating variable are discussed, as well as the lack of attachment anxiety by romantic threat interaction.

Experimental and RANS-CFD Study of Nacelle Drag

The drag on a nacelle model was investigated experimentally and computationally to provide guidance and insight into the capabilities of RANS-based CFD. The research goal was to determine whether industry constrained CFD could participate in the aerodynamic design of nacelle bodies. Grid refinement level, turbulence model and near wall treatment settings, to predict drag to the highest accuracy, were key deliverables. Cold flow low-speed wind tunnel experiments were conducted at a Reynolds number of 6∙〖10〗^5, 293 K and a Mach number of 0.1. Total drag force was measured by a six-component force balance. Detailed wake analysis, using a seven-hole pressure probe traverse, allowed for drag decomposition via the far-field method. Drag decomposition was performed through a range of angles of attack between 0o and 45o. Both methods agreed on total drag within their respective uncertainties. Reversed flow at the measurement plane and saturation of the load cell caused discrepancies at high angles of attack. A parallel CFD study was conducted using commercial software, ICEM 15.0 and FLUENT 15.0. Simulating a similar nacelle geometry operating under inlet boundary conditions obtained through wind tunnel characterization allowed for direct comparisons with experiment. It was determined that the Realizable k-ϵ was best suited for drag prediction of this geometry. This model predicted the axial momentum loss and secondary flow in the wake, as well as the integrated surface forces, within experimental error up to 20o angle of attack. SST k-ω required additional surface grid resolution on the nacelle suction side, resulting in 15% more elements, due to separation point prediction sensitivity. It was further recommended to apply enhanced wall treatment to more accurately capture the viscous drag and separated flow structures. Overall, total drag was predicted within 5% at 0o angle of attack and 10% at 20o, each within experimental uncertainty. What is more, the form and induced drag predicted by CFD and measured by the wake traverse shared good agreement. Which indicated CFD captured the key flow features accurately despite simplification of the nacelle interior geometry.

Effects of introspection on meta and structural attitude bases

Introspection is the process by which individuals question their attitudes; either questioning why they hold their attitudes (Why introspection), or how they feel about a particular attitude object (How introspection). Previous research has suggested that Why-introspection induces attitude change, and that Why and How introspection influence attitude-behaviour consistency,persuasion, and other effects. Generally, psychologists have assumed that affective and cognitive attitude bases are the mechanism by which introspection leads to these effects. Leading perspectives originating from these findings suggest that either Why introspection changes the content of cognitive attitude bases (the skewness hypothesis), or increases the salience of cognitive attitude bases (the dominance hypothesis); whereas How introspection may increase the salience of affective attitude bases (another part of the dominance hypothesis). However, direct evidence for these mechanisms is lacking, and the distinction between structural and meta bases has not been considered. Two studies investigated this gap in the existing literature. Both studies measured undergraduate students’ attitudes and attitude bases (both structural and meta, affective and cognitive) before and after engaging in an introspection manipulation (Why introspection / How introspection / control), and after reading a (affective / cognitive) persuasive passage about the attitude object. No evidence was found supporting either the skewness or dominance hypotheses. Furthermore, previous introspection effects were not replicated in the present data. Possible reasons for these null findings are proposed, and several unexpected effects are examined.

The Comparative Effectiveness of EEG Biomarkers in Antidepressant Response and Illness Prediction in Major Depressive Disorder

Background: There is growing evidence that individual EEG differences may aid in classifying patients with major depressive disorder (MDD) and also help predict clinical response to antidepressant treatment. This study aims to compare the effectiveness of EEG frequency band power, alpha asymmetry and prefrontal theta cordance towards escitalopram response prediction and MDD diagnosis, in a multi-site initiative. Methods: Resting EEG (eyes open and closed) was recorded from 64 electrodes in 44 depressed patients and 20 healthy controls at baseline, 2 weeks post-treatment and 8 weeks post-treatment. Clinical response was measured as change from baseline MADRS of 50% or more. EEG measures were analyzed (1) at baseline (2) at 2 weeks post-treatment and (3) as an ‘‘early change” variable defined as change in EEG from baseline to 2 weeks post-treatment. Results: At baseline, responders exhibited greater absolute alpha power in the left hemisphere versus the right while non-responders showed the opposite. Responders further exhibited a cortical asymmetry of greater right relative to left activity in parietal areas. Groups also differed in baseline relative delta power with responders showing greater power in the right hemisphere versus the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to right and the opposite was noted for non-responders. The opposite pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reduction in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance. Absolute delta power helped distinguish MDD patients from healthy controls. Conclusions: Hemispheric asymmetries in the alpha and delta bands at pre-treatment baseline and at 2 weeks post-treatment have moderate to moderately strong predictive utility towards antidepressant treatment response. These findings have significant potential for improving clinical practice in psychiatry by eventually guiding clinical choice of treatments. This would greatly benefit patients awaiting relief from depressive symptoms as treatment optimization would help overcome problems associated with delayed recovery. Our results also indicate that resting EEG activity may have clinical utility in predicting MDD diagnosis.

Analysis of Cosmogenic Impurities in Tellurium and Development of Tellurium Loading for the SNO+ Experiment

For the SNO+ neutrinoless double beta decay search, various backgrounds, ranging from impurities present naturally to those produced cosmogenically, must be understood and reduced. Cosmogenic backgrounds are particularly difficult to reduce as they are continually regenerated while exposed to high energy cosmic rays. To reduce these cosmogenics as much as possible the tellurium used for the neutrinoless double beta decay search will be purified underground. An analysis of the purification factors achievable for insoluble cosmogenic impurities found a reduction factor of $>$20.4 at 50\% C.L.. During the purification process the tellurium will come into contact with ultra pure water and nitric acid. These liquids both carry some cosmogenic impurities with them that could be potentially transferred to the tellurium. A conservative limit is set at $<$18 events in the SNO+ region of interest (ROI) per year as a result of contaminants from these liquids. In addition to cosmogenics brought underground, muons can produce radioactive isotopes while the tellurium is stored underground. A study on the rate at which muons produce these backgrounds finds an additional 1 event per year. In order to load the tellurium into the detector, it will be combined with 1,2-butanediol to form an organometallic complex. The complex was found to have minimal effect on the SNO+ acrylic vessel for 154 years.

DIGITAL HISTORY: DESIGNING VIRTUAL ENVIRONMENTS THAT SUPPORT CRITICAL THINKING AND IDEA EXCHANGE, MOTIVATE AND ENGAGE USERS

In my thesis I argue for the use of system designs that: a) open access to a variety of users and allow for collaboration and idea exchange, while at the same time, b) are designed to motivate and engage users. To exemplify my proposed systems design, I created an interactive and open digital history project focused on Romanian culture and identity during Communism, from 1947, when the Communist Party took power by forcing the King to abdicate, until the revolution in 1989, which marked the end of Communism in Romania (Gilberg, 1990, Boia, 2014). In my project, I present the possibility to recreate Habermas’ notion of public sphere and “the unforced force of the better argument” (Habermas, 1989) and Dewey’s (2004) understanding of democracy as a mode of associated living imbued of the spirit of inquiry within contemporary digital history projects. Second, I outline system designs that motivate and engage users, by satisfying the basic psychological needs outlined in Ryan and Deci’s (2000) self-determination theory: autonomy, competence, and relatedness. Two more concepts are included to complete the proposed digital history project design: presence (Ryan, Rigby, & Przybylski, 2006) and learner hero (Rigby & Przybylski, 2009).

EXAMINATION OF VALPROIC ACID-INDUCED PERTURBATIONS TO DNA REPAIR, NF-ΚB SIGNALING AND CBP/P300 TRANSCRIPTIONAL CO-ACTIVATORS

Exposure to the antiepileptic drug valproic acid (VPA) is associated with an increased risk of congenital malformations including heart, skeletal and most frequently neural tube defects. Although the mechanisms contributing to its teratogenesis are not well understood, VPA was previously shown to increase homologous recombination (HR)-mediated DNA repair and decrease protein expression of the transcription factor NF-κB/p65. The studies in this thesis utilized in vivo and in vitro models to evaluate the expression of HR mediators, investigate the implications of decreased p65 including DNA binding and transcriptional activation, and the expression and histone acetyltransferase activity of Cbp/p300 with an aim to provide mechanistic insight into VPA-mediated alterations. The first study demonstrated that following maternal administration of VPA, mouse embryonic mRNA expression of HR mediators Rad51, Brca1 and Brca2 exhibited temporal and tissue-specific alterations. Protein expression of Rad51 was similarly altered and preceded increased cleavage of caspase-3 and PARP; indicative of apoptosis. The second study confirms previous findings of decreased total cellular p65 protein using P19 cells, but is the first to demonstrate that nuclear p65 protein is unchanged. NF-κB DNA binding was decreased following VPA exposure and maybe mediated by decreased p50 protein, which dimerizes with p65 prior to DNA binding. Transcriptional activity of NF-κB was also increased with VPA exposure which was not due to increased p65 phosphorylation at Ser276. Furthermore, the transcriptional activation capacity was unaffected by VPA exposure as combined exposure to VPA and TNFα additively increased NF-κB activity. The third study demonstrated that VPA exposure in P19 cells decreased Cbp/p300 total cellular and nuclear protein attributed primarily to ubiquitin proteasome-mediated degradation. Histone acetyltransferase (HAT) activity of p300 was decreased proportionately to nuclear protein following VPA exposure. Inhibition of Cbp/p300 HAT activity decreased p65 total cellular protein, increased caspase-3 cleavage and ROS similar to VPA exposures. Furthermore, pre-treatment with the antioxidant enzyme catalase attenuated the increase in caspase-3 cleavage, but not p65 protein. Overall, this thesis demonstrates that VPA exposure impacts the expression and activity of the transcription factor NF-κB and transcriptional co-activators/HATs Cbp/p300, which has implications for downstream VPA targets including Rad51, Brca1 and Brca2.