The control of oxygen delivery to cells in the body is the result of a small group of primary oxygen sensors, one of the most important of which is the hypoxia-inducible transcription factor-1 (HIF-1). Two alpha-ketoglutarate dependent non-heme iron dioxygenases are responsible for the regulation of HIF-1 through hydroxylation of residues on the HIF-1a subunit. One of these enzymes, known as the factor inhibiting HIF-1 (FIH-1) is responsible for hydroxylating residue Asn803 on HIF-1a, preventing the transcription of hypoxia related genes controlled by HIF-1. It was hypothesized that there would be a difference in inhibition of FIH-1 from the other HIF-1 regulating enzyme, the prolyl hydroxylase domain-2 (PHD2), when testing a series of ten small molecule inhibitors. The ten inhibitors chosen fell into three classes: pyrones, pyridines, and catechols. Of these inhibitors, it was found that catechols produced a significant inhibitory difference between PHD2 and FIH, and may provide useful in further inhibitor design and synthesis work.

Les tumeurs solides sont souvent confrontées à un environnement déficient en oxygène, dit hypoxique. Hypoxia-Inducible Factor 1 (HIF1) est le facteur de transcription clé de l’adaptation cellulaire à l’hypoxie, régulant de nombreux gènes impliqués dans l’angiogenèse, le métabolisme cellulaire ou la régulation du pH. Ma thèse s’articule en trois axes autour de HIF1 et de la reprogrammation métabolique hypoxique. J’ai d’abord étudié Factor-Inhibiting HIF1 (FIH), l’un des deux senseurs d’oxygène régulant HIF1. Nous avons montré que FIH est essentiel dans le développement tumoral en inhibant à la fois l’activité transcriptionnelle de HIF1 et la voie p53-p21. J’ai ensuite étudié le « shift » du métabolisme cellulaire vers la glycolyse induit par HIF1, générant une addiction pour le glucose. Nos travaux ont montré que paradoxalement, les cellules hypoxiques synthétisent du glycogène via HIF1 constituant ainsi une réserve de glucose intracellulaire. Le glycogène confère alors une résistance accrue des cellules tumorales suite à une carence en glucose. Enfin, j’ai pu montrer que l’AMPK, « gardien de la balance énergétique », n’est pas nécessaire au maintien d’un niveau viable d’ATP suite à l’inhibition de la glycolyse, via le blocage de l’export de lactate, mais exerce, un effet protecteur en absence de glucose. Cependant, l’inhibition conjointe du transporteur de lactate, MCT4, et de l’AMPK réduit fortement le développement tumoral dans un modèle de xénogreffes chez la souris, suggérant un rôle crucial de ces deux acteurs dans ce contexte. L’ensemble de ces travaux a permis d’identifier plusieurs cibles potentielles impliquées dans la plasticité métabolique en hypoxie. / Cells of solid tumors are often exposed to an environment deficient in oxygen, i.e. hypoxic. The Hypoxia-Inducible Factor-1 (HIF-1) is the major transcription factor involved in cellular adaptation to hypoxia. HIF-1 regulates a wide array of genes involved in angiogenesis, cellular metabolism or pH regulation. My thesis is organized into three axes around HIF-1 and metabolic reprogramming in hypoxia. I first studied Factor-Inhibiting HIF-1 (FIH), one of two oxygen sensors regulating HIF-1. We showed that FIH is essential for tumor development through inhibition of the HIF-1 transcriptional activity as well as through the suppression of the p53-p21 axis. I then studied the HIF-1-induced « shift » in cellular metabolism toward glycolysis, which generates a type of “glucose addiction”. We showed that paradoxically, tumor cells store glycogen in hypoxia through a HIF-1 dependant mechanism. Glycogen served as a reservoir of intracellular glucose, which allows hypoxic cells to survive periods of glucose starvation. Finally, I studied AMPK «the guardian of energy », and showed that surprisingly, this kinase is not necessary in maintaining a viable level of ATP when glycolysis is inhibited (by blockade of lactate export). However, as expected, AMPK protected cells during glucose starvation. Moreover, combined inhibition of the lactate transporter MCT4 and of AMPK reduced dramatically tumor development in a xenograft model, suggesting a crucial role for these two actors in the context of growth of tumor cells in a hostile environment. Taken together these results identified several potential drug targets involved in the metabolic plasticity of hypoxic cells.

A problem that has been the focus of much recent research in privacy preserving data-mining is the frequent itemset hiding (FIH) problem. Identifying itemsets that appear together frequently in customer transactions is a common task in association rule mining. Organizations that share data with business partners may consider some of the frequent itemsets sensitive and aim to hide such sensitive itemsets by removing items from certain transactions. Since such modifications adversely affect the utility of the database for data mining applications, the goal is to remove as few items as possible. Since the frequent itemset hiding problem is NP-hard and practical instances of this problem are too large to be solved optimally, there is a need for heuristic methods that provide good solutions. This dissertation developed a new method called Min_Items_Removed, using the Frequent Pattern Tree (FP-Tree) that outperforms extant methods for the FIH problem. The FP-Tree enables the compression of large databases into significantly smaller data structures. As a result of this compression, a search may be performed with increased speed and efficiency. To evaluate the effectiveness and performance of the Min_Items_Removed algorithm, eight experiments were conducted. The results showed that the Min_Items_Removed algorithm yields better quality solutions than extant methods in terms of minimizing the number of removed items. In addition, the results showed that the newly introduced metric (normalized number of leaves) is a very good indicator of the problem size or difficulty of the problem instance that is independent of the number of sensitive itemsets.

Factor inhibiting HIF (FIH) negatively regulates hypoxia inducible factor-1 (HIF-1) transcriptional activity, selectively controlling certain HIF-1 target genes, such as vascular endothelial growth factor (VEGF) and prolyl hydroxylase domain 3 (PHD3), but not others. PHD3 and VEGF are important for placental development and function and are overexpressed in preeclampsia (PE). The purpose of this study was to examine FIH in both normal and pathological human placentae. I hypothesized that FIH regulates VEGF and PHD3 in the placenta and that this rheostat is altered in PE. Results show that FIH suppresses PHD3 and VEGF in JEG-3 cells; this effect was abrogated by FIH gene silencing. Moreover, my data indicate that seven in absentia homologue-1 (Siah-1) targets FIH for degradation in the placenta; this degradation is enhanced in PE and likely contributes to aberrant VEGF and PHD3 expression. Overall, my data suggest an important role for FIH in the pathogenesis of PE.

Factor inhibiting HIF (FIH) negatively regulates hypoxia inducible factor-1 (HIF-1) transcriptional activity, selectively controlling certain HIF-1 target genes, such as vascular endothelial growth factor (VEGF) and prolyl hydroxylase domain 3 (PHD3), but not others. PHD3 and VEGF are important for placental development and function and are overexpressed in preeclampsia (PE). The purpose of this study was to examine FIH in both normal and pathological human placentae. I hypothesized that FIH regulates VEGF and PHD3 in the placenta and that this rheostat is altered in PE. Results show that FIH suppresses PHD3 and VEGF in JEG-3 cells; this effect was abrogated by FIH gene silencing. Moreover, my data indicate that seven in absentia homologue-1 (Siah-1) targets FIH for degradation in the placenta; this degradation is enhanced in PE and likely contributes to aberrant VEGF and PHD3 expression. Overall, my data suggest an important role for FIH in the pathogenesis of PE.

The goal of this thesis is to evaluate travelers' experience with Highway Advisory Radio (HAR) and Citizens' Band Radio Advisory System (CBRAS) technologies on both Florida Interstate Highway system (FIH) and the Florida Turnpike Enterprise (FTE) toll roads. To achieve this goal, two different survey tools were used. The first tool is a random digit dialing phone survey known as CATI (Computer-Assisted Telephone Interviewing). The second tool is a field survey that intercepts travelers at the Florida Turnpike Enterprise (FTE) service plazas and the Florida Interstate Highway (FIH) rest areas. HAR and CBRAS are traditional components of the Advanced Traveler Information Systems (ATIS). This thesis pays special attention to the effectiveness of HAR and CBRAS in improving travelers' experience. Feedback to analyze these two technologies was collected via a telephonic survey and a field survey. Two different field surveys (one for HAR and one for CBRAS) were designed and implemented to obtain feedback on these technologies. The field survey for CBRAS is unique and has never been done before for this purpose. A sample size of 1000 HAR surveys was collected through the CATI phone survey. Field surveys were collected at five locations across the state, including central, southeast, and southwest regions of Florida. The HAR field survey sample size was 1610 and the CBRAS field survey sample size was 613. All field surveys were conducted by UCF students at each of the five locations, over a 13-week data collection period. The HAR messages were designed to alert drivers of any adverse roadway traffic or weather conditions. The CBRAS is limited to truck drivers with the closed system radio pre-installed in their vehicles. However, truck drivers were also asked some questions on HAR if they do not use CBRAS. Basic statistical analysis was used to determine a number of performance indicators which include system's use and awareness, usability of provided information, route diversion, and travelers' demographics. In addition, the two HAR phone and field samples were combined together and examined using a decision tree model. Target questions were selected from the survey to build the tree network. The tree model aimed at identifying trends between categorical differences of travelers with respect to specific questions. Understanding travelers' satisfaction with HAR is critical to knowing its benefits. The ending results indicated that both basic statistical analysis and the decision tree model are in agreement. A comparison between HAR phone and field surveys indicates the following. Travelers interviewed for the HAR field survey were more aware of the HAR than travelers surveyed by phone. A small portion of the surveyed samples used HAR (22% and this was consistent between the phone and the field surveys). Also, 80% or more were satisfied with HAR for both phone and field samples and the majority (85% or more) supported its continuation as an indication of willingness to use it in the future, especially in emergency conditions. In terms of the types of messages they want to hear from HAR, traffic congestion was the most common. Dynamic Message Signs (DMS) were the most preferred source of travel information and were the alternative for HAR, if HAR gets terminated. This was followed by smartphone applications which received twice as much support from field surveyed travelers (28%) when compared to phone surveyed travelers (15%). The CATI Phone Survey was biased towards elderly people (60% of the sample) and mainly females (58%) that use the FTE roadway system. Users satisfied with the system are those who only use these roadways once per week or less. The survey ultimately shows that travelers rely on modern modes of obtaining traffic information than traditional ones, such as HAR. DMS, and smart phone applications are leading communication tools among all type of travelers. The HAR field survey was less biased with respect to age and gender distribution (56% were under 50 and 62% were males). Both surveys indicate that the sample is well educated (about 60% have an associate degree or higher). CBRAS serves a small segment of commercial truck drivers (only 12% out of 613 used CBRAS). However, this small segment used it heavily (84% used it sometimes, often, or always). And 92% of CBRAS users were satisfied or strongly satisfied with it. CBRAS was used mostly for route divergence, with 72% of the drivers relying on it for this purpose. Truck drivers who never used CBRAS (88% of the sample) were asked questions about HAR. Only 27% of them used HAR and 57% of these used it sometimes, often, or always with 72% of the truck users being satisfied with HAR compared to the 92% satisfied with CBRAS. The most common complaint about HAR by truck drivers was that it is not easy to access or understand. Based on responses of truck drivers for both HAR and CBRAS field surveys above, it seems that GPS navigation was the most preferred source of travel information (28%). In addition to the basic statistics, a decision tree model, using SAS Enterprise Miner was performed. The statistical analysis results indicated satisfaction of travelers. The decision tree model was used to predict and profile responses to all answered questions that each survey shared. Training data was included in the model and the model was able to leverage the questions. Results of the decision tree model predicted high user satisfaction rates. Analyses of the three implemented surveys show that HAR and CBRAS technologies are not used by a large proportion of travelers, but their users are typically satisfied with these technologies. A small portion of the surveyed sample of truck drivers uses CBRAS but they use it heavily and were very satisfied with it. The travelers' satisfaction level with HAR was high. The HAR and CBRAS systems are in the middle of a heated competition lead by digital communication, it may be a sign of the time to create HAR/CBRAS smart phone applications for the longevity of these traditional technologies.

Thesis advisor: Harold Petersen / Using insights from Hyman Minsky’s Financial Instability Hypothesis (FIH), we develop a theoretical framework for how speculative bubbles may materialize in securities markets. Our model and empirical analysis show that agents place undue emphasis on recent experience of risk and returns when developing future expectations. We use the aggregate investor allocation to equities (aggregate total market capitalization of equities divided by the price of all real liabilities outstanding), Tobin’s Q (the aggregate market price of equities divided by the replacement cost of nonfinancial firms’ assets), Shiller Total Return Cyclically Adjusted Price to Earnings Ratio (TR CAPE), and Shiller Cyclically Adjusted Price to Earnings Ratio (CAPE) as proxy variables for bubbles. We find statistically significant, negative relationships between all four of these proxy variables and two dependent variables, Subsequent Ten-Year Annualized Cumulative Equity Market Returns (Nominal and Real), and also Subsequent 10-year Average Losses, thereby providing evidence against the Efficient Market Hypothesis and suggesting the possibility of speculative bubbles. / Thesis (BS) — Boston College, 2019. / Submitted to: Boston College. Carroll School of Management. / Discipline: Departmental Honors. / Discipline: Economics.

Les tumeurs solides sont souvent confrontées à un environnement déficient en oxygène, dit hypoxique. Hypoxia-Inducible Factor 1 (HIF1) est le facteur de transcription clé de l'adaptation cellulaire à l'hypoxie, régulant de nombreux gènes impliqués dans l'angiogenèse, le métabolisme cellulaire ou la régulation du pH. Ma thèse s'articule en trois axes autour de HIF1 et de la reprogrammation métabolique hypoxique. J'ai d'abord étudié Factor-Inhibiting HIF1 (FIH), l'un des deux senseurs d'oxygène régulant HIF1. Nous avons montré que FIH est essentiel dans le développement tumoral en inhibant à la fois l'activité transcriptionnelle de HIF1 et la voie p53-p21. J'ai ensuite étudié le " shift " du métabolisme cellulaire vers la glycolyse induit par HIF1, générant une addiction pour le glucose. Nos travaux ont montré que paradoxalement, les cellules hypoxiques synthétisent du glycogène via HIF1 constituant ainsi une réserve de glucose intracellulaire. Le glycogène confère alors une résistance accrue des cellules tumorales suite à une carence en glucose. Enfin, j'ai pu montrer que l'AMPK, " gardien de la balance énergétique ", n'est pas nécessaire au maintien d'un niveau viable d'ATP suite à l'inhibition de la glycolyse, via le blocage de l'export de lactate, mais exerce, un effet protecteur en absence de glucose. Cependant, l'inhibition conjointe du transporteur de lactate, MCT4, et de l'AMPK réduit fortement le développement tumoral dans un modèle de xénogreffes chez la souris, suggérant un rôle crucial de ces deux acteurs dans ce contexte. L'ensemble de ces travaux a permis d'identifier plusieurs cibles potentielles impliquées dans la plasticité métabolique en hypoxie.