VictorJuiz/thesis huggingface dataset:
Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery

Colloidal aggregation presents a significant nuisance in drug discovery programs; the self-assembly of hydrophobic compounds into colloidal particles leads to numerous artifactual results in screening assays. In biochemical enzyme inhibition assays colloids non-specifically adsorb proteins leading to partial unfolding and enzyme inactivation. In cell-based cytotoxicity assays colloids are unable to cross cell membranes leading to the drug being unable to bind to its intracellular target, resulting in apparent inactivity. Colloidal aggregation is not only common among drug screening candidates but also among clinically used drugs. Being composed entirely of active drug, colloidal drug aggregates have many properties that make them suitable as nanoparticle drug formulations. In this work, two methods to stabilize colloidal drug aggregates were developed to enable targeted delivery and in vivo utility. First, exploiting the ability of drug colloids to adsorb proteins, we formed controlled protein coronas to stabilize colloids in both buffered solutions and serum-containing media. Coronas comprising antibodies not only stabilized colloids but also enabled their specific internalization by target cells. Second, incorporation of amphiphilic surfactants during colloid formation resulted in a hydrophilic polymer layer that sterically stabilized drug colloids. Incorporation of surfactants significantly reduced protein adsorption, stabilizing drug colloids in serum-containing media. We designed methods to test colloid stability in high serum media in vitro based on co-aggregation with fluorescent FRET pairs. Finally, we investigated the influence of stable colloidal drug aggregates on the in vivo pharmacokinetics of chemotherapeutics. Stable colloidal formulations showed increased plasma circulation half-lives compared to solubilized, monomeric formulations. Overall, we demonstrate methods to stabilize, study and utilize colloidal drug aggregates, turning a nuisance into an opportunity for drug formulation.

Advisor: Shoichet, Molly S
Genetic Modifiers of Caffeine and Endurance Performance in Athletes

Background: Caffeine is used as an ergogenic aid by athletes to improve performance. However, the effects of caffeine differ between athletes. This may be due to genetic differences affecting caffeine metabolism and caffeine response during exercise. Objective: The aim was to determine whether variation in the CYP1A2 gene, which affects caffeine metabolism, and the HTR2A gene, which encodes serotonin receptors and may affect caffeine response, modify the ergogenic effects of caffeine during a 10-km cycling time trial. Methods: Competitive male athletes (n=101; age: 25 ± 4 years) completed the time trial under three conditions: 0, 2 or 4 mg of caffeine per kg body mass, using a split-plot randomized, double-blinded, placebo-controlled design. DNA was isolated from saliva and genotyped for polymorphisms in CYP1A2 (rs762551) and HTR2A (rs6313). Results: Overall, 4 mg/kg caffeine decreased cycling time by 3% versus placebo. A significant (p

Keywords: Athletes
Caffeine
Ergogenic Aids
Genetic Testing
Nutrigenomics
Sport Nutrition
Advisor: El-Sohemy, Ahmed
Large-scale Computational/Experimental Distributed Simulation Framework

Partitioned analysis methods have been mostly used in hybrid (experimental-numerical) simulations, multiphysics, and large-scale structure-media problems since they allow decomposition of a complex structural system into smaller subsystems. Although they have been considered to be superior to monolithic methods in terms of software reuse, difficulties still exist in the implementation process. This study addresses these difficulties and proposes a generalized integrated simulation framework to ease the coupling of the substructures analyzed with different Finite Element (FE) codes or tested with experimental specimens. This is enabled by the development of a generalized communication routine and the use of a staggered partitioned approach such that each involved program can act as a black box which is accessible only through standard model input and output, i.e. only boundary displacements and forces. In the simulation framework, the substructures to be integrated can be either quasi-statically or dynamically simulated which corresponds to the component-level and system-level decompositions of a system. The intent of the component-level and system-level decomposition methods are different. Specifically, the component-level decomposition method is aimed to capture the nonlinear hysteretic behaviour of critical structural components and consider their influence on the system’s response. The system-level decomposition method, on the other hand, equally treats the partitions as independent dynamic substructures and it focuses on the dynamic interactions among the substructures. The accuracy and stability of the two integrated simulation methods are evaluated and their implementations to different analysis software have been verified. The simulation framework has been successfully used in various industry and research projects. To illustrate the current development and demonstrate potential of the simulation framework, two application examples are presented. One application is made for the performance assessment of a high-rise building based on the component-level decomposition method. The other example is a nuclear power plant containment structure with soil-structure interaction based on the system-level decomposition method.

Advisor: Kwon, Oh-Sung
Water Quality and Hydraulic Trade-offs in Drinking Water Distribution Networks

Historically, water distribution network design focused on providing water at the appropriate flow and pressure, particularly during high-demand and firefighting conditions. More recently, it was discovered that 18% of waterborne disease outbreaks in the U.S. could be linked to deficiencies in the distribution network (DN), shifting the distribution network research focus towards water quality. This thesis uses genetic algorithms to assess some of the tensions between providing high flows for firefighting and water quality in drinking water distribution networks. It is shown that relaxing the traditional design restrictions on minimum pipe diameters (i.e., that they be greater than 150 mm) can provide an improved balance of fire flow, water quality, and cost. Using genetic algorithms to generate a series of Pareto Fronts, it is shown that there are significant trade-offs between fire flow and achieving high flow velocities associated with establishing self-flushing pipes. Self-flushing pipes are believed to reduce high-turbidity water events, a major source of consumer complaints. A Monte Carlo simulation suggests that a velocity of 0.10 to 0.25 m/s is self-flushing. An additional benefit of high velocity networks may include better disinfectant mass transfer to the pipe wall, where opportunistic pathogens are likely to be found. To achieve these higher velocities, this work suggests a need to relax minimum pipe diameters, reduce redundant network loops, and reduce available fire flows. This approach is now used in several European countries but has yet to be adopted in North America. Finally, it is shown that health risks associated with intrusion remain relatively constant over time, even as the number of defects in the pipe and intrusion volume increase. It is suggested that health risks are a weak function of intrusion volume. Important risk factors for intrusion likely include the number of low-pressure events and the average pipe residence time.

Keywords: Distribution
Fire
Pareto
Water
Advisor: Karney, Bryan
Guo, Yiping
Systematic Analysis of Alternative Polyadenylation from High-throughput RNA Sequencing Data

Alternative polyadenylation (APA) of pre-messenger RNA (pre-mRNA) results in the formation of multiple mature mRNA transcripts from a single gene with distinct 3′ untranslated regions (3′ UTRs). It has been estimated that as many as 80% of mammalian protein-coding genes contain multiple polyadenylation (poly[A]) sites, thus contributing extensively to eukaryotic transcriptome diversity and complexity. In this thesis, I describe a new computational method, ‘Quantification of APA’ (QAPA), for profiling APA using conventional bulk RNA-seq data that accurately infers changes in APA by estimating differential 3′ UTR isoform expression. To demonstrate QAPA’s utility, I analyzed a longitudinal RNA-seq study of differentiation of mouse embryonic stem cells (ESCs) into glutamatergic neurons. By characterizing global changes of APA during this developmental process, I found a large number of genes with lengthening 3′ UTRs. These genes do not significantly overlap with those with steady-state gene expression or alternative splicing (AS) changes, indicating that APA represents a largely distinct regulatory layer. Modelling of poly(A) site usage using machine learning techniques further revealed cis-elements that are predictive of this process. I next used QAPA along with additional RNA-seq analysis tools that I helped develop to characterize the transcriptomes of different neuronal cell subtypes of the mouse hippocampus. This study revealed transcriptomic variation between different subtypes involving distinct programs of co-ordinated regulation between gene expression, AS, and APA. Among these programs, in comparing hippocampal neurons from the proximal and distal axis versus other regions, I identified a program of genes displaying differential expression of a subset of ribosomal proteins that are co-regulated with 3′ UTR lengthening of genes known to localize to the synapse. This observation suggests an important role for the coordination of local translation and mRNA localization in neurons. This also highlights the importance of profiling different post-transcriptional regulatory layers to begin to understand their contributions to cell type diversity. My thesis thus contributes new methods for profiling transcriptomes using RNA-seq data and demonstrates the utility of these methods in defining multilayered regulatory networks that underlie the development and specification of neuronal subtypes.

Keywords: alternative polyadenylation
high-throughput RNA sequencing
post-transcriptional regulation
Advisor: Blencowe, Benjamin J
Morris, Quaid
The Relationship Between Surgeon Technical Skill and Healthcare Costs in Partial Nephrectomy

Introduction: There has been increasing interest in assessing the surgical performance of practicing surgeons. There is a growing body of literature linking a surgeon’s technical skill to short-term post-operative complications. However, little research has been performed examining technical skill and patient safety, and no research has examined the relationship between technical performance and hospital cost. The primary purpose of this thesis is to determine the relationship between direct, 30-day hospital costs and surgeon technical skill in open and robotic partial nephrectomy. Methods: We performed four studies: a systematic review examining the literature on intraoperative adverse events and costs, a prospective, multicenter, multi-surgeon study examining the relationship between direct, 30-day hospital costs and surgeon technical skill, and a prospective, multicenter, multi-surgeon study comparing the rates of intraoperative events between open and robotic partial nephrectomy. Finally, we performed a cost utility analysis to compare the cost effectiveness of open partial nephrectomy to robotic partial nephrectomy. Results: Four research studies were completed. Our systematic review found that while the overall quality of the current literature was poor, intraoperative events increase the cost of abdominal surgery. For our surgical safety study, open partial nephrectomy has a greater number of severe intraoperative events than robotic partial nephrectomy. When comparing the costs between surgeons of differing skill levels, surgeons with higher levels of technical skill cost less than surgeons with lower levels of skill. Finally, at a Willingness to Pay (WTP) of $200,000/QALY, open partial nephrectomy is the most cost effective option, although robotic partial nephrectomy becomes cost effective when the fixed robotic costs are below $3,330 per case. Conclusion: We are the first to study the relationship between surgeon performance and short-term hospital costs. While future studies need to confirm our findings, our results highlight the possibility of financial benefit from improving surgeon performance. Furthermore, we conclude that the robotic platform may improve intraoperative patient safety and intraoperative event assessment may be useful in providing individualized feedback.

Advisor: Grantcharov, Teodor
Voter-buying, Electoral Reform, and Public Good Provision in Brazil

Electoral fraud is often a problem for new democracies. I study the consequences of voter-buying, defined as the act of inducing outsiders to fraudulently transfer their voter registration across jurisdictions in exchange for private benefits. Specifically, I explore the effects of Brazil's 2007 voter re-registration reform which was intended to curb voter-buying. Exploiting a fuzzy regression discontinuity design in the targeting of municipalities assigned to the reform, I examine the response of mayoral elections, public expenditures and socioeconomic outcomes to the imposition of exogenous barriers to voter-buying. The reform led to an increase in political competition and a rise in healthcare expenditures, a programmatic public good salient to poor voters. The increased investments in health are reflected in greater utilization of health services and better health outcomes: a 6.6 % increase in prenatal visits, a 15 % decrease in the incidence of low birth-weight, and 5.3 % reduction in the infant mortality rate. Consistent with imported voters being more pivotal in less populous municipalities, I find the impacts are larger in targeted municipalities that are small, and provide additional evidence that restrictions on voter-buying are the main driver of my results. I also provide evidence for more positive selection of politicians, and show that unintended disenfranchisement and incumbent reputation effects are not driving my results.

Keywords: Clientelism
Regression Discontinuity
Voter-Buying
Advisor: Bobonis, Gustavo J
Li, Nicholas
Natural Enemies of Wood-boring Beetles in Northeastern Temperate Forests and Implications for Biological Control of the Emerald Ash Borer (Coleoptera: Buprestidae) in North America

The emerald ash borer (hereafter EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), is a wood-boring beetle accidentally introduced into North America during the 1990s, and has since been killing millions of ash trees, Fraxinus spp. L. (Lamiales: Oleaceae), as it spreads across Canada and the USA. Native North American natural enemies, especially parasitoid wasps, are important mortality factors of EAB, but little information is available on their arrival and detection in EAB-infested regions, and their feasibility for augmentative biological control against EAB is uncertain. Two important native parasitoid groups, Phasgonophora sulcata Westwood (Hymenoptera: Chalcididae) and Atanycolus spp. Foerster (Hymenoptera: Braconidae), were investigated to determine (1) factors influencing their capacity to disperse, (2) vegetation and habitat characteristics influencing their local abundance and role in EAB mortality, (3) whether their populations can be augmented to increase parasitism of EAB, and (4) how best to detect and monitor their populations as EAB continues to spread. The weak dispersal capacity of P. sulcata suggests it should be released as pupae close to EAB if used in an augmentative biological control program. Forest vegetation and habitat structure determine local abundance of P. sulcata and Atanycolus spp., and tree biomass, tree condition, and floral resource availability are important predictors of high parasitism on EAB. Relocating parasitoid-infested ash logs to EAB-infested sites can significantly augment populations of native parasitoids to increase EAB parasitism by 64.8 ± 18.1 % three years after introduction. Purple prism traps can be used to detect and monitor changes in populations of relocated P. sulcata and Atanycolus spp. These findings improve our understanding of the role of native natural enemies in suppressing EAB population growth and slowing ash tree mortality in North America.

Keywords: Agrilus planipennis
Atanycolus spp.
Augmentative biological control
Conservation biological control
Invasive species
Phasgonophora sulcata
Advisor: Smith, Sandy M.
Thomas Hobbes and the Kingdom of Darkness: The Critique of the Catholic Tradition and the Modern Catholic Response

This project explores Thomas Hobbes’ critique of religion as a polemic against the Catholic tradition. I argue that Hobbes’ construction of political philosophy was motivated by his desire to create a stronger platform for absolute Sovereignty due to the need for greater political stability in England during the first half of the 17th century. In order to achieve this goal, Hobbes had to dismantle the foundation of rival forms of political authority in England; the strongest being the ethos of the Catholic Church that remained after the English Reformation. To accomplish the task of challenging the Catholic Church’s authority, Hobbes questioned the scholastic foundation upon which that authority relied. Drawing upon Leo Strauss’ unpublished work, Hobbes’ Critique of Religion, this project uses Strauss’ critique to draw out the elements specific to Hobbes’ attack upon Catholicism, and not just religion in general. Hobbes systematically challenged Catholic natural philosophy and Catholic institutions to call into question the efficacy and legitimacy of Catholic political authority. These attempts to undermine the foundation of Catholic political authority necessitated the construction of a replacement philosophy, which gave rise to a new and completely secular foundation for early modern political philosophy. Striving for greater political stability, Hobbes redefines political philosophy by relegating the role of religion and restructuring Catholic beliefs to limit the agency Catholicism had in directing the behaviour of its believers in their political and ethical choices. This project takes up this question from the vantage point of modern Catholic critics, like Elizabeth Anscombe and Alasdair MacIntyre, who lament the changes that occurred at the beginning of the Enlightenment. These Catholic critics argue that the current problem in ethics started in the Enlightenment. However, the seeds of the transformation of ethics can be traced further back to the beginnings of the early modern period and specifically to the construction of a secular foundation for political theory through the thought of Thomas Hobbes. Thus, this project demonstrates that this lamentable state of the modern condition as described by 20th century Catholic critics implicates the changes Hobbes initiated through his critique of the Catholic tradition in the 17th century. The nature of the changes Hobbes made to political philosophy in the 17th century become the very substance of the critique levelled against modernity by Catholic critics centuries later.

Advisor: DiCenso, James
Engrams, Neurogenesis, and Forgetting

In this thesis, three projects are described that add to our understanding of how forgetting is represented in the brain. In project 1, age-dependent changes in forgetting of spatial information is characterized in mice. Infant mice displayed significant forgetting when tested one month following training (i.e., infantile amnesia). Overtraining infant mice did not overcome the forgetting phenotype, indicating that the observed forgetting is not due to a deficit in memory encoding. Presentation of an environmental reminder one month following training led to memory recovery, suggesting that infantile forgetting is caused, at least in part, by a deficit in memory retrieval. Given the evidence that infantile amnesia is a deficit in memory retrieval, project 2 asked whether infantile forgetting can be overcome via a dentate gyrus engram ‘tag-and-activate’ strategy. Optogenetic stimulation of dentate gyrus encoding neural ensembles recovered ‘lost’ infant memories even 90 days following the initial learning event. In a process akin to pattern completion, memory recovery was associated with reinstatement of both hippocampal and cortical engram neurons. Recent work from our lab has shown that hippocampal neurogenesis promotes forgetting in both infants and adults. In project 3, the mechanism underlying neurogenesis-mediated forgetting was explored. Multiple transgenic mouse lines were used that granted bidirectionally control over the extent to which adult-generated dentate gyrus neurons remodel surrounding neural circuitry. Using this strategy, we found evidence that newborn neurons promote forgetting by reconfiguring the circuitry within which hippocampal memories are embedded. Importantly, neurogenesis-induced forgetting was negatively correlated with engram reinstatement in the hippocampus. Together, this thesis adds to the growing literature on the neural basis of forgetting.

Keywords: Engram
Forgetting
Infantile amnesia
Memory
Memory trace
Neurogenesis
Advisor: Frankland, Paul
Imaging Lactate Metabolism in Breast Cancer with Hyperpolarized 13C Magnetic Resonance Imaging

Breast cancer is a heterogeneous disease. Some patients attain prolonged control with first-line therapies, while others present with highly aggressive, treatment resistant malignancies. Second- and third-line treatments often carry the risk of severe, potentially life threatening side effects and only a minority patients ultimately live longer because of them. The difficulty of identifying which patients would be likely to benefit from which combination of drugs, as well as separating those whose disease is responding to their treatment from those whose is not, contributes to the provision of ineffective care. Hyperpolarized 13C magnetic resonance imaging is an emerging modality that can detect lactate production associated with reprogrammed metabolism in cancer. Changes in 13C lactate signal following treatment may be a valuable early indication of disease response and may help guide treatment decisions. While clinical translation of hyperpolarized 13C MRI has been steadily progressing, there are currently no published studies assessing the value of imaging lactate with hyperpolarized 13C MRI for better understanding and treating patients with breast cancer. In this dissertation, three technical works are presented to address the needs of robust 13C imaging for clinical translation. 13C MRI requires separate radio frequency transmit and receive hardware called RF coils that have been designed to operate at the 13C rather than 1H resonant frequency. RF coils must also conform to the anatomy under investigation. In order to perform 13C imaging in breast, a 13C breast coil system was devised and constructed. While the speed afforded by echo-planar imaging makes it an attractive technique for meeting the strict constraints of 13C MRI, off-resonance magnetization can lead to geometric distortion and spatial misregistration of imaging data. A dual-echo technique is proposed as an approach to account for sources of distortion. Volumetric encoding is highly desirable in order to allow comparison of 13C lactate signals from diseased and normal tissues, but larger regions require more time to encode and this can limit the temporal resolution of dynamic acquisitions. A pseudo-random undersampling scheme is proposed in order to reduce encoding time requirements and improve coverage.

Keywords: breast cancer
compressed sensing
hyperpolarized MRI
lactate
metabolism
MRI
Advisor: Cunningham, Charles H