VictorJuiz/thesis huggingface dataset:
Specificity in PI3K-PKB/AKT-PTEN Signaling: Subcellular Locus-specific Functions of Pathway Targets

The PI3K-PKB/Akt-PTEN signal transduction pathway orchestrates a variety of fundamental cell processes and its deregulation is implicated in several human diseases, including cancer. While the importance of this pathway to many cellular functions is well established, the mechanisms leading to context-specific physiological outcomes in response to a variety of stimuli remain largely unknown. Spatial restriction of signaling events is one of the means to coordinate specific cellular responses. To investigate the subcellular locus-specific roles of the major PI3K effector PKB/Akt in various cell processes, I have devised a novel experimental system employing cellular compartment-directed PKB/Akt pseudosubstrate inhibitors. The work herein describes the development and characterization of the localized PKB/Akt pseudosubstrate inhibitor system and its application to investigate potential locus-specific functions in established PKB/Akt-regulated cellular processes. Subcellular compartment-restricted PKB/Akt inhibition in the 3T3L1 adipocyte differentiation model revealed that nuclear and plasma membrane, but not cytoplasmic, PKB/Akt activity is required for terminal adipocyte differentiation. Nuclear and plasma membrane pools of PKB/Akt were found to contribute to distinct stages of adipocyte differentiation, revealing that PKB/Akt activity impacts multiple points of this program. The localized PKB/Akt pseudosubstrate inhibitor system was also utilized to investigate the importance of distinct subcellular pools of PKB/Akt in breast epithelial cells. MCF-10A human breast epithelial cells can be grown in three-dimensional culture to form acinar structures that recapitulate in vivo mammary glandular architecture. Expression of the plasma membrane PKB/Akt inhibitor during cell growth in three-dimensional culture severely impaired acinar formation. On the other hand, expression of the nuclear PKB/Akt inhibitor during acinar development resulted in the formation of large, misshapen, multi-acinar structures. Assessment of the migratory capacity of MCF-10A cells upon localized PKB/Akt inhibition revealed that nuclear PKB/Akt inhibition promoted, while plasma membrane PKB/Akt inhibition impaired, MCF-10A cell migration. The development of locus-specific PKB/Akt inhibitors represents the first attempt to prioritize the targets of this kinase based on their subcellular localization. This work and its immediate extensions will further our understanding of the biology of PKB/Akt, a multi-tasking kinase with profound roles in development, cellular and organismal homeostasis and disease.

Keywords: Subcellular
PKB
AKT
Kinase inhibitor
adipocyte
localization
breast epithelial
migration
Advisor: Stambolic, Vuk
Informativeness of Value-at-risk Disclosure in the Banking Industry

Following the Basel Committee’s advocacy of value-at-risk (VaR) disclosure in external reports of financial institutions, the U.S. Securities and Exchange Commission issued Financial Reporting Release No. 48 to permit VaR disclosure as one of the most important disclosure approaches for market-risk quantitative information in 1997. This study is the first to empirically examine both economic determinants and consequences of VaR disclosure informativeness in the banking industry. First, this study finds that more informative VaR disclosure is associated with more effective corporate governance characteristics, including better shareholder protection, a larger and more independent board, the presence of a separate risk committee under the board of directors, a more independent risk committee, higher institutional ownership and a better overall governance environment. These results suggest that corporate governance mechanisms are important determinants of the informativeness of VaR disclosure. Second, the evidence shows that the cost of equity capital is negatively associated with the informativeness of VaR disclosure, consistent with informative VaR disclosure effectively communicating private information to investors about a bank’s market risk exposure and its risk management system. Additional evidence during the recent crisis further suggests the importance of VaR disclosure informativeness to the capital market as a strong signal reflecting the efficacy of risk management practices and the quality of risk governance mechanisms. However, I still find that a large proportion of the sample banks choose not to disclose information with respect to some important disclosure items (e.g., quantitative stress-test results, and non-trading portfolio VaR). It is necessary for government regulators to re-consider the current regulation on VaR disclosure in the external reports of the banking industry.

Keywords: value-at-risk disclosure
banking industry
Advisor: Richardson, Gordon
Callen, Jeffrey
Tropospheric Ozone over the Middle East and Its Interannual Variability: An Integrated Analysis with Satellite Observations and a Global Chemical Transport Model

Tropospheric ozone is a major atmospheric pollutant and a greenhouse gas. Nevertheless, many processes influencing its spatio-temporal distribution are still poorly understood, mainly due to the lack of adequate observations. One such region is the Middle East, where ozone measurements are scant. In this study, the GEOS-Chem chemical transport model is used to interpret newly available tropospheric ozone data from the Tropospheric Emission Spectrometer (TES) satellite instrument. TES reveals elevated ozone in the mid-troposphere (500-300 hPa) over the Middle East in summer 2005. This study demonstrates that the Arabian anticyclone in the mid-troposphere over the Middle East plays a critical role in facilitating the buildup of ozone. Additionally, the South Asian High in the upper troposphere helps transport ozone from the Asian monsoon region. Transport from Asia and local production are predominantly responsible for the ozone buildup, each contributing 30-35% to the ozone abundance in the region. Ozone transported from the boundary layer accounts for about 25% of local production. TES retrievals of water vapour and deuterated water are used for the first time to provide an independent assessment of the ozone transport pathways. Using a GEOS-Chem simulation from 1987 to 2006, it is found that this ozone buildup fluctuates interannually by about ±7% (or ±6 ppbv). The major contributors, ozone transported from Asia and ozone produced locally, vary by ±30% (±7 ppbv) and ±15% (±3 ppbv), respectively. The variations of Asian and local sources are related to the strengths of the South Asian High and the Arabian anticyclone, respectively. It is found that in years when the Asian influence is weaker in the region, transport from other areas, such as North America, is enhanced. This tradeoff between transport from Asia and other regions is found to be linked to the position and strength of the subtropical westerly jet over central Asia. These results suggest that climate-related changes in the general circulation of the atmosphere will have implications for the transport of pollution into the Middle East. Such changes in pollution in the region could have feedbacks on the climate through changes in the radiative forcing associated with tropospheric ozone.

Keywords: 0725
0608
Advisor: Jones, Dylan
Grobner Basis and Structural Equation Modeling

Structural equation models are systems of simultaneous linear equations that are generalizations of linear regression, and have many applications in the social, behavioural and biological sciences. A serious barrier to applications is that it is easy to specify models for which the parameter vector is not identifiable from the distribution of the observable data, and it is often difficult to tell whether a model is identified or not. In this thesis, we study the most straightforward method to check for identification – solving a system of simultaneous equations. However, the calculations can easily get very complex. Grobner basis is introduced to simplify the process. The main idea of checking identification is to solve a set of finitely many simultaneous equations, called identifying equations, which can be transformed into polynomials. If a unique solution is found, the model is identified. Grobner basis reduces the polynomials into simpler forms making them easier to solve. Also, it allows us to investigate the model-induced constraints on the covariances, even when the model is not identified. With the explicit solution to the identifying equations, including the constraints on the covariances, we can (1) locate points in the parameter space where the model is not identified, (2) find the maximum likelihood estimators, (3) study the effects of mis-specified models, (4) obtain a set of method of moments estimators, and (5) build customized parametric and distribution free tests, including inference for non-identified models.

Keywords: structural equation model
Grobner basis
model identification
constraints on covariances
Advisor: Brunner, Jerry
Classical Lie Algebra Weight Systems of Arrow Diagrams

The notion of finite type invariants of virtual knots, introduced by Goussarov, Polyak and Viro, leads to the study of the space of diagrams with directed chords mod 6T (also known as the space of arrow diagrams), and weight systems on it. It is well known that given a Manin triple together with a representation we can construct a weight system. In the first part of this thesis we develop combinatorial formulae for weight systems coming from standard Manin triple structures on the classical Lie algebras and these structures' defining representations. These formulae reduce the problem of finding weight systems in the defining representations to certain counting problems. We then use these formulae to verify that such weight systems, composed with the averaging map, give us the weight systems found by Bar-Natan on (undirected) chord diagrams mod 4T. In the second half of the thesis we present results from computations done jointly with Bar-Natan. We compute, up to degree 4, the dimensions of the spaces of arrow diagrams whose skeleton is a line, and the ranks of all classical Lie algebra weight systems in all representations. The computations give us a measure of how well classical Lie algebras capture the spaces of arrow diagrams up to degree 4, and our results suggest that in degree 4 there are already weight systems which do not come from the standard Manin triple structures on classical Lie algebras.

Keywords: knot theory
virtual knots
weight systems
Advisor: Bar-Natan, Dror
Roles of Passively and Actively Targeted Block Copolymer Micelles in Cancer Therapy

Nanoparticle-based drug delivery systems (NDDS) have emerged as a promising strategy for formulation of anticancer drugs due to their ability to passively target solid tumors via exploitation of the enhanced permeation and retention effect. In particular, nano-sized block copolymer micelles (BCMs) have proven to be a viable delivery vehicle for hydrophobic anticancer drugs. To further enhance the specificity of BCMs towards cancer cells, extensive research has been focused on the formulation of actively targeted BCMs with tumor cell binding antigens conjugated to their surface. However, the in vivo transport of passively and actively targeted BCMs has only been studied to a limited extent. This thesis explores the potential and limitations of passively and actively targeted BCMs, as NDDS for delivery to solid tumors. The in vivo transport of BCMs at the whole body, tumor, and cellular levels is investigated in human breast cancer xenografts. Overall, active targeting of BCMs with epidermal growth factor (EGF) as the tumor cell binding antigen was not found to alter the whole body clearance of the vehicles; however, particle size had a profound effect on their pharmacokinetics and biodistribution profiles. Both passively and actively targeted BCMs exhibited heterogeneous distribution throughout solid tumors, with preferential localization in the tumor periphery and/or highly vascularized regions. In addition, the BCMs were found to exhibit impaired tumor penetration due to limited mobility and/or the binding site barrier. Although active targeting increases the in vivo BCM cellular uptake, the BCMs largely remained in the extracellular compartment, indicating that incomplete BCM delivery to all tumor cells remains as a major biological barrier. Interestingly, EGF-conjugated BCMs induced a potent bystander effect in vitro as a result of the paradoxical apoptotic effect of EGF, which has the potential to treat nearby tumor cells that do not respond directly to BCM treatment in vivo. In this way, EGF-BCMs may be beneficial for rendering the aforementioned in vivo barriers such as limited tumor penetration, as well as heterogeneity in tumor vascularization and receptor expression.

Keywords: Drug Delivery
Cancer
Polymeric Micelles
Nanoparticles
Advisor: Allen, Christine
Proteomic and Molecular Genetic Investigation of Deubiquitinating Enzymes in the Budding Yeast Saccharomyces cerevisiae

Protein ubiquitination is essential for the proper functioning of many eukaryotic cellular processes. The cleavage of ubiquitin chains from ubiquitinated proteins is performed by deubiquitinating enzymes, of which there are 16 in the Ubp (ubiquitin specific protease) group in the budding yeast Saccharomyces cerevisiae. The goal of my thesis has been to examine the biological roles and molecular functions of these enzymes using a combination of proteomic and molecular genetic approaches. As part of a large collaborative effort, interacting protein partners of the Ubps were isolated through affinity purification of tagged proteins, followed by protein identification by mass spectrometry. Purification of tagged Ubp6 led to the identification of the 19S proteasome complex, along with a novel subunit, Sem1. As the human homologue of Sem1 was previously identified as being associated with a protein involved in the repair of DNA double-strand breaks, I examined the possible role of Sem1 in DNA damage repair. A deletion of Sem1 and other 19S subunits resulted in hypersensitivity to various DNA damaging drugs, implicating the 19S complex in the process of DNA repair. iii I also found that purified Ubp2 interacted stably with the ubiquitin ligase Rsp5 and the protein Rup1. UBP2 interacts genetically with RSP5, indicating a functional relationship, while Rup1 facilitates the physical tethering of Ubp2 to Rsp5. Using the uracil permease Fur4, a Rsp5 substrate, as a model reporter, I found that ubp2Δ cells exhibited a temporal stabilization of Fur4 at the plasma membrane following the induction of endocytosis, implicating Ubp2 in protein sorting, specifically at the multivesicular body. In order to understand the role of Ubp2, I examined the effect of Ubp2 on Rsp5 function. I found that Rsp5, similar to its mammalian homologues, is auto-ubiquitinated in vivo, and that Ubp2 is able to directly deubiquitinate Rsp5 in vitro. Moreover, the presence of a substrate or Rup1 both resulted in increased autoubiquitination, implying an auto-inhibitory mechanism of Rsp5 regulation. Taken together, the data presented in this thesis implicate deubiquitinating enzymes in interesting and varied roles in the cell, and suggest a novel mechanism for the modulation of Rsp5-dependent trafficking processes.

Keywords: molecular biology
ubiquitination
yeast
proteomics
genomics
protein trafficking
deubiquitination
Advisor: Emili, Andrew
The Edictum Theoderici: A Study of a Roman Legal Document from Ostrogothic Italy

This is a study of a Roman legal document of unknown date and debated origin conventionally known as the Edictum Theoderici (ET). Comprised of 154 edicta, or provisions, in addition to a prologue and epilogue, the ET is a significant but largely overlooked document for understanding the institutions of Roman law, legal administration and society in the West from the fourth to early sixth century. The purpose is to situate the text within its proper historical and legal context, to understand better the processes involved in the creation of new law in the post-Roman world, as well as to appreciate how the various social, political and cultural changes associated with the end of the classical world and the beginning of the Middle Ages manifested themselves in the domain of Roman law. It is argued here that the ET was produced by a group of unknown Roman jurisprudents working under the instructions of the Ostrogothic king Theoderic the Great (493-526), and was intended as a guide for settling disputes between the Roman and Ostrogothic inhabitants of Italy. A study of its contents in relation to earlier Roman law and legal custom preserved in imperial decrees and juristic commentaries offers a revealing glimpse into how, and to what extent, Roman law survived and evolved in Italy following the decline and eventual collapse of imperial authority in the region. Such an examination also challenges long-held assumptions as to just how peaceful, prosperous and Roman-like Theoderic’s Italy really was.

Keywords: Roman Law, Ostrogothic Italy, Edictum Theoderici, Transition, Decline, Late Antiquity
Advisor: Everett, Nicholas
Multi-cohort Stand Structural Classification: Ground and LiDAR-based Approaches for Boreal Mixedwood and Black Spruce Forest Types of Northeastern Ontario

Natural fire return intervals are relatively long in eastern Canadian boreal forests and often allow for the development of stands with multiple, successive cohorts of trees. Multi-cohort forest management (MCM) provides a strategy to maintain such multi-cohort stands that focuses on three broad phases of increasingly complex, post-fire stand development, termed “cohorts”, and recommends different silvicultural approaches be applied to emulate different cohort types. Previous research on structural cohort typing has relied upon primarily subjective classification methods; in this thesis, I develop more comprehensive and objective methods for three common boreal mixedwood and black spruce forest types in northeastern Ontario. Additionally, I examine relationships between cohort types and stand age, productivity, and disturbance history and the utility of airborne LiDAR to retrieve ground based classifications and to extend structural cohort typing from plot to stand-levels. In both mixedwood and black spruce forest types, stand age and age related deadwood features varied systematically with cohort classes in support of an age-based interpretation of increasing cohort complexity. However, correlations of stand age with cohort classes were surprisingly weak. Differences in site productivity had a significant effect on the accrual of increasingly complex multi-cohort stand structure in both forest types, especially in black spruce stands. The effects of past harvesting in predictive models of class membership were only significant when considered in isolation of age. As an age emulation strategy, the three cohort model appeared to be poorly suited to black spruce forests where the accrual of structural complexity appeared to be more a function of site productivity than age. Airborne LiDAR data appear to be particularly useful in recovering plot-based cohort types and extending them to the stand-level. The main gradients of structural variability detected using LiDAR were similar between boreal mixedwood and black spruce forest types; the best LiDAR-based models of cohort type relied upon combinations of tree size, size heterogeneity, and tree density related variables. The methods described here to measure, classify, and predict cohort-related structural complexity assist in translating the conceptual three cohort model to a more precise, measurement based management system. In addition, the approaches presented here to measure and classify stand structural complexity promise to significantly enhance the detail of structural information in operational forest inventories in support of a wide array of forest management and conservation applications.

Keywords: Boreal Forest
Forest Structure
Stand structural classification
LiDAR
Advisor: Malcolm, Jay R.
Smith, Sandy
PGE Anion Production from the Sputtering of Natural Insulating Samples

The goal of this research was to devise a new analytical technique, using Accelerator Mass Spectrometry (AMS), to measure Platinum Group Element (PGE) concentrations to the sup-ppb levels in natural, insulating, samples. The challenges were threefold. First, a method of sputtering an insulating sample to successfully produce a stable beam of anions needed to be devised. Second, a suitable standard of known PGE concentrations had to be found and third, spectral analysis of the beam had to verify any claims of PGE abundance. The first challenge was met by employing a modified high intensity negative ion source flooded with neutral caesium that successfully sputtered insulators to produce a beam of negative ions. The second challenge, that of finding a suitable standard, was fraught with difficulties, as no synthesized standards available were found to be appropriate for this work. As a result, direction is provided for future production of standards by ion implantation. The third challenge, successful spectral analysis, was accomplished using a newly designed gas ionization detector which allowed for resolution of the interfering molecular fragment from the PGE ions. Coupled with the use of the SRIM computer programme, positive identification of all peaks in the spectra of the analyzed samples was accomplished. The success of the first and third challenges lead to the qualitative analyses of geological samples for sub-ppb levels of PGE by AMS. Quantitative analyses await only for the appropriate standards and with those will come a whole new range of research possibilities for measuring sub-ppb levels of PGE in insulating samples by AMS.

Keywords: Platinum Group Elements
trace element analysis
Accelerator Mass Spectrometry
Sputtering of Insulators
Advisor: Gorton, Mike