VictorJuiz/thesis huggingface dataset:
On the Diversity of Eukaryotic Transcription Factor Specificities

Transcription factor (TF) DNA-binding specificities (motifs) are often conserved between species, and many TFs have conserved functions over long evolutionary distances. As a consequence, changes in gene expression are largely attributed to evolution of cis-regulatory DNA sequences rather than changes to TF coding sequences. However, the number and diversity of TFs vary greatly between species, and there are numerous well-studied examples of TF diversification in DNA-binding and protein-interaction specificities. TF motif evolution has previously not been explored comprehensively, and its prevalence is largely unknown. In this thesis, I describe three studies that identify, measure, and predict the similarities between TFs and their motifs. I first describe an analysis of Caenorhabditis elegans TF specificities, and the discovery of novel motifs in expanded TF families. I then describe a novel method to better describe the similarity of two motifs. I conclude by estimating the degree of motif conservation between eukaryotic species at varying evolutionary distances using Similarity Regression (SR), which is an improved method to classify pairs of TFs as having similar or dissimilar motifs on the basis of their DNA-binding domain (DBD) sequences. Within major eukaryotic kingdoms (e.g. metazoans, plants, and fungi) it is typical that just over half of the TF motifs are conserved since the last common ancestor, indicating that diversification has occurred in multiple TF families. Even relatively small evolutionary distances (e.g. human to mouse) are associated with marked alterations in TF motifs, mainly in gene families with many duplications, like the C2H2 ZFs and Myb TFs. These studies indicate that TF motif evolution is prevalent, particularly in expanded TF families, and occurs in parallel with changes to cis-regulatory sequences.

Keywords: computational biology
evolutionary biology
gene regulation
transcription factors
Advisor: Hughes, Timothy R
Structural and Functional Characterization of Ubiquitin Variants and Ubiquitin Binding Proteins

The ubiquitin (Ub) system is an essential post-translational modification pathway found throughout eukaryotic cells and consists of proteins responsible for adding Ub to substrates (E1, E2, and E3 enzymes), removing Ub from substrates (deubiquitinases), and reading the Ub encoded signal found on substrates. The Ub system regulates cellular functions such as DNA repair and cell-cycle progression and as such, its dysregulation can contribute to disease states. Due to its prevalent nature in regulating critical cellular functions therapeutic modulation of the Ub system has become a promising area for therapeutic development. The first step towards modulating any cellular system is target identification, which requires a detailed understanding of the system’s components and how they function. Towards this end, Dr. Sidhu and his lab have developed a set of protein-based tools termed Ub variants (UbV). These reagents are engineered variants of Ub that contain substitutions that allow them to selectively and tightly bind to specific Ub binding proteins in the cell, leading to the inhibition of and in some cases activation of the targeted protein’s function. Consequently, researchers can use UbVs to understand the role of the targeted proteins in vivo and their potential as therapeutic targets. In this thesis, I aid our understanding of the Ub system through the use of biochemical and structural biology approaches by: (i) helping further the development of UbVs tools by identifying how they bind with high specificity and affinity to their target proteins and (ii) furthering our understanding of how the deubiquitinase USP37 uses a unique insertion containing Ub interacting motifs to cleave ubiquitin chains.

Keywords: Enzyme
Structural Biology
Ubiquitin
X-ray Crystallography
Advisor: Sicheri, Frank
Advancing Climate Change Adaptation

The impacts of climate change are vast and consequential. The years 2012 to 2016, using conservative estimates, revealed more than 1500 climate-related disaster events displacing over 3.2 million people and causing USD$450 billion in financial losses. Recent studies confirm that extreme weather events and the failure of climate change mitigation and adaptation are the leading risks to global stability. Climate change adaptation is advancing differently in nations across the world. Using pragmatism as a theoretical framework and applying a mixed methods approach, this dissertation seeks to identify determinants of adaptation. Grounded theory analysis of 403 national documents from 192 parties to the United Nations Framework Convention on Climate Change identified 35 themes of climate change adaptation. A mixed methods data transformation model was applied to study the influence of several relatively stable parameters on the level of climate change adaptation. Nineteen variables were suitable for Principal Component Analysis, which further categorized 15 as determinants. The top 5 determinants were identified using between groups multivariate analysis. The influence of geopolitical variables on climate change adaptation were analyzed, these included: GDP per capita, economic classification, system of government, level of democracy, land type, region, level of conflict, and refugees. The research resulted in several significant and unexpected findings. Countries with the highest levels of adaptation appear to have many key commonalities. This dissertation seeks to identify ways in which we can collectively advance climate change adaptation.

Keywords: adaptation
climate change
climate finance
determinants
environmental policy
vulnerability
Advisor: Gough, William
Characterization of CEACAM1 Spatial Distribution, Self-association and Dynamics using High-resolution Microscopy Techniques

CEACAMs are cell surface glycoproteins involved in homo- and heterophilic intercellular interactions that control cellular growth, differentiation, tumourigenesis, inflammation and infection. There is growing evidence that CEACAM1 isoforms regulate the cellular response to CEACAM1-mediated interactions between various cell types. Reinforcing this point, given its potential as a tumour suppressor and immunomodulator, CEACAM1 is being targeted for clinical development. However, there remain clear challenges owing to the observation that different CEACAM1 isoforms display cell-type specific expression patterns under different physiological conditions. Moreover, the ability of CEACAMs to form dimers and higher-order oligomers, which are thought to impact regulation of intercellular signals, add considerable complexity to our understanding of its functional role(s). Super resolution microscopy has enabled the quantitative characterization of the nanoscale distribution of several membrane proteins, revealing cluster hierarchies at the micro- and nano-scale. However, clustering and self-association are not necessarily the same piece of information and may have very different effects on the cellular response, so mapping the preferential nanoscale distribution of the various self-association states is of particular interest to many. This thesis reports on the development and application of a correlative STORM/homoFRET strategy to study CEACAM1 isoforms and mutants. We have further explored the use of single particle tracking (SPT) and mean square displacement analysis to characterize CEACAM1 dynamics as a function of oligomeric state and location. Building on these datasets, we have applied co-localization and co-occurrence approaches to measure CEACAM1 association to lipid-ordered regions, ezrin and actin. Finally, we present a set of preliminary methods and results that will serve to further the study of membrane protein clustering and self-association and their link to function. Together, this thesis aims to develop a more fulsome perspective on structure, association and dynamics of the CEACAM1 membrane protein while providing methodological approaches to tackle similar questions.

Keywords: CEACAM1
Cell signaling
FRET
Microscopy
Single particle tracking
Super resolution
Advisor: Yip, Christopher M
Kainate Receptor-mediated Regulation of Chloride Homeostasis

A balance between excitatory and inhibitory activity is needed to maintain proper brain function. At inhibitory synapses, potassium-chloride cotransporter 2 (KCC2) has long been known to be a critical regulator of inhibition through its ability to maintain a low intracellular chloride level. Surprisingly, KCC2 has recently been found to play an important role at the excitatory synapse, where it interacts with several proteins involved in excitatory neurotransmission, including the kainate receptor subunit GluK2. It is known that independent of kainate receptor activation, the physical interaction between KCC2 and GluK2 is important for KCC2 surface expression, oligomerization and recycling. However, it is unknown whether the activity of kainate receptors can directly influence KCC2 function. My thesis research has revealed a novel functional role for kainate receptors in CA3 pyramidal cells. I show that activating KARs in the hippocampus hyperpolarizes EGABA and increases the driving force for Cl-. This hyperpolarization occurs through both ionotropic and metabotropic KAR signaling. The metabotropic signaling mechanism is dependent on KCC2, but the ionotropic signaling mechanism produces a hyperpolarization of EGABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR: KCC2 interaction may play an important role in excitatory: inhibitory (E:I) balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signaling can regulate inhibition in multiple ways that may involve other chloride transporters. Activation of kainate-type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during period of strong glutamatergic activity and a potential target for developing strategies to treat diseases characterized by an imbalance in excitation and inhibition.

Keywords: electrophysiology
excitation
inhibition
kainate receptor
kcc2
synaptic transmission
Advisor: Woodin, Melanie A
Essays in Financial Economics: Empirical Corporate Finance

In this thesis, I study important firm events and their interactions with the market. Chapter 1 is a joint work with Kose John, Xu Tian, and Yihan Liu. In this chapter, we analyze the market reaction to CEO turnover announcements in the presence of information frictions. We find that the market reaction to forced CEO turnover announcements is negatively related to the level of asymmetric information between a firm and its investors. No such relation exists for voluntary turnovers. We also find that in cases where information frictions are high, companies attempt to present forced turnover as voluntary and this behavior leads to a less negative market response. Overall, our results suggest that firms act strategically when disclosing information about CEO turnover to avoid a negative market reaction. Chapter 2 shows that firms in highly competitive industries can benefit from good corporate governance. I analyze the stock market reaction to CEO/chairman consolidation announcements, and find that the market reacts positively to these events if the announcing firm has strong governance within an industry of high product market competition. The benefit of CEO duality comes from efficiency gains by management, and is positively related to market competition. Only firms with strong governance can capture this benefit. Overall, my results suggest that product market competition and corporate governance are complements for firms desiring to gain managerial efficiency through granting its CEO additional power. This chapter also provides evidence against potential one-size-fits-all policies aiming to mandate the separation of CEO and chairman roles. Chapter 3 provides novel evidence of how product market competition affects firm CEO turnover decisions through unexpected tariff cuts. I find that the likelihood of CEO turnover increases with the unexpected surge in industry competitiveness. Moreover, I find that this CEO turnover effect due to tariff cuts tends to be concentrated amongst firms with weak governance, and only affects non-exporting firms. Exporting firms, on the other hand, can benefit from increased export sales due to tariff cuts and so do not generally experience a fall in CEO-firm match quality as with non-exporting firms.

Keywords: CEO Duality
CEO Turnover
Corporate Governance
Empirical Corporate Finance
Information Friction
Product Market Competition
Advisor: Mondria, Jordi
Foreverdark

Foreverdark is a single movement, ten-minute concertino (short concerto) for amplified cello soloist with live electronic processing and chamber orchestra. The exact instrumentation consists of violoncello solo, flute, clarinet, oboe, bassoon, trumpet in Bb, horn in F, tenor trombone, percussion, piano, harp, violin 1, violin 2, viola, violoncello, and double bass; each part is played by a single player. The compositional style is a continuation and deeper exploration of the composer’s current compositional interests, namely the integration of quotation and popular music style signals within more broadly art music formats. By amplifying and separating the cello soloist from the ensemble, the player’s position alludes to that of a “lead guitarist;” subsequently, much of their melodic material (and that of the orchestra around them) is sourced from a variety of heavy metal riffs, most of them from bands the composer listened to as a teenager. The piece’s title, “Foreverdark,” both references the song with a similar name (Foreverdark Woods) by Viking metal artist Bathory as well as the composer’s long and somewhat nostalgic relationship to the metal genre itself. In addition to heavy metal-sourced melodic and rhythmic motifs, “Foreverdark” also contains some material bordering on a folk music aesthetic. Surprisingly, metal-turned-folk is a common stylistic shift in for some of the bands quoted within the work.

Keywords: cello
concerto
metal
Advisor: Kulesha, Gary
Beauty, Love and Justice

Beauty, Love and Justice Parisa Sabet Sarvestani Doctor of Musical Arts Faculty of Music University of Toronto 2019 Abstract “Beauty, love and Justice” is a five-movement orchestral composition approximately 16 minutes long. The orchestra consists of 2 flutes, 2 oboes, 2 clarinets, 2 bassoons, 4 horns, 3 trumpets, 2 trombone, 1 bass trombone, 1 tuba, percussion (4 players), 1 harp, 1 piano and strings. It is developed based on the basic musical elements that I found common among all cultures such as repetition of simple rhythmic pattern, harmonic series and natural sound effects such as breathing, humming, whispering, talking and air sounds. In addition, I explored various ways of incorporating unusual timbral effects and extended techniques to create an intriguing sonic environment. My ultimate goal was to create complexity by fusing simpler musical elements. The first movement begins with successive crescendos over repetition of simple rhythmic patterns; harmonic language derived from a harmonic series on “C”. As the grand opening leads into a calmer section, air sounds in combination with whispering percussive syllables “ta ka ta ka ta ka” express a longing to speak up. These sounds gradually become louder and thicker until the movement ends with shouting. The second movement starts mysteriously; the string section plays excerpts from a ‘fandom’ melodic line which is never presented in its entirety. In the meantime, a complex rhythmic pattern gradually reveals from the percussions section that leads to the ending that is similar to the first movement. The third movement is slow led by pitched percussion instruments while wind and brass sections play secondary roles. The fourth movement starts with percussion and winds on identical melodic material with that ending the third movement, but in a faster tempo. As it comes to the end, the same melodic materials is heard once again, faster this time, and builds up to a grand conclusion. Similar to the previous movements, the fifth movement starts exactly the same way as the first movement. However as the grand opening leads into the calm section, a well-known chant in the Baha’i tradition is leaping from one instrument to the next while the rest of the orchestra plays the original musical materials introduced in the first movement.

Keywords: CULTURE
EXTENDED TECHNIQUES
HARMONIC SERIES
PERSIAN MUSIC
TIMBRAL EFFECTS
Advisor: HATZIS, CHRISTOS
White Matter Microstructure and Emotional Functioning in Children Treated for Posterior Fossa Tumours

Children treated for brain tumours that arise in the posterior fossa (PF) experience lifelong cognitive and emotional difficulties, and exhibit white matter (WM) damage. This thesis combined diffusion tensor imaging (DTI), eye-tracking and standardized measures of cognitive and emotional functioning in children treated for PF tumours and typically developing children, to: 1) characterize outcomes related to decreases in treatment intensity, 2) objectively evaluate emotional functioning, and 3) examine the associations between WM microstructure and emotional functioning. It was found that treatment with the lowest intensity craniospinal irradiation protocol spared WM in the temporal lobe of children treated for malignant PF tumours. In addition, patients treated on lower intensity protocols had largely preserved cognitive, social and affective functioning. However, novel eye-tracking tasks designed to evaluate emotional functioning uncovered some remaining deficits; children treated for PF tumours had difficulty recognizing facial emotions despite attending to the faces, and difficulty regulating their initial attention away from emotional faces. Notably, this eye-tracking measure of emotion regulation was associated with emotional control in daily life. The current work also revealed that relations between WM microstructure and emotional functioning can diverge in the injured and uninjured brain; WM predicted facial emotion recognition in typically developing children only, whereas WM was associated with emotion regulation in patients only. In a field dominated by findings that characterize negative sequelae, this work highlights the possibility of favourable outcomes for PF tumour patients who are eligible for treatment with lower intensity protocols. Despite these positive outcomes, subtle emotional functioning deficits not captured by standardized questionnaires persist. To better understand how emotional processes are altered in children treated for PF tumours, novel objective measures are required. This thesis detailed one such behavioural marker to evaluate emotion regulation, using eye-tracking technology, and characterized an oculomotor response that may warrant interventional follow-up.

Keywords: Diffusion tensor imaging
Eye-tracking
Neuropsychology
Paediatric brain tumours
White matter
Advisor: Mabbott, Donald J
Merchants of War: Mercenaries, Economy, and Society in the Late Sixteenth-century Baltic

The polities of the sixteenth-century Baltic competed and cooperated with one another and with local power groups in fluctuating patterns of rivalry and expedient partnership. Mercenarism thrived in this context, as early modern governments were seldom equipped with the fiscal and logistical tools or the domestic military resources needed to wholly meet the escalating challenges of warfare, while mercenaries themselves were drawn to a chaotic environment that afforded opportunities for monetary gain and promotion into the still-coalescing political elites of the region’s emerging powers. This study sits, like the mercenary himself, at the intersection of the military, the economic, the social, and the political. Broadly, it is an analysis of mercenaries in Livonian and Swedish service during the so-called Livonian War of 1558 to 1583. Mercenaries are examined as agents of the polities for whom they fought and as actors with goals of their own, ambiguously positioned figures whose outsider status and relative independence presented both opportunities and challenges as they navigated the shifting networks of conflict and allegiance that characterized their fractious world. The aims of this study are threefold. The military efficacy of Western and Central European professional soldiers is assessed in an Eastern European context, problematizing the notion of Western military superiority in a time of alleged military revolution. The effects of prolonged warfare on Estonian and Livonian society are examined with an eye on interactions between local communities and the foreign soldiery, as well as on the ramifications of increasing participation in military enterprise by segments of the Livonian population. Mercenarism is also analyzed as a key site of the early modern struggle for greater governmental control over the economy and legitimate violence, whether through the cooption of privileges traditionally enjoyed by non-state and local power groups or through partnership between these factions and centralizing governments.

Keywords: Estonia
Landsknecht
Livonia
Livonian War
mercenaries
Sweden
Advisor: Kivimäe, Jüri
Enhancing GPR Surveys By Utilizing Dispersive Properties and Phase Information

Ground-penetrating-radar (GPR) is a non-destructive testing method that utilizes the transmission or reflection of electromagnetic (EM) waves to locate anomalies beneath a surface. GPR is now widely used in mining, civil engineering, environmental sciences, and archaeology to survey the subsurface. In a conventional GPR survey, only the arrival time of the EM pulse is used to obtain an estimate for the depth of a target. There is much more information incorporated in GPR records that can be used to infer conditions below the surface. This thesis aims to enhance GPR surveys by utilizing material properties and signal processing. Large quantities of systematic data are necessary for completing the two projects; therefore, a numerical simulation tool is developed. A 2D finite-difference-time-domain (FDTD) simulation of EM wave propagation is established using MATLAB. Dispersive materials described by N-term Debye models can be simulated by the algorithm, which facilitates studies on dispersive materials. Contrary to common assumptions, some materials, especially those that are wet, have frequency-dependent relative permittivities. The dispersion in velocity changes the shape of the source pulse during propagation and poses a challenge for travel time estimation. Instead of treating dispersion as an obstacle to GPR applications, a novel method of distinguishing dispersive materials by estimating quality factor (Q*) is proposed in the thesis. Using a combination of laboratory measurements and modelling results, it is shown that GPR signals can be used to identify dispersive behaviours. On the signal processing side, a method of estimating radii of cylindrical objects from phase information is demonstrated. In contrast to previous studies, the phase information of reflected signals have better resolution and are closer to theoretical values compared to arrival time analysis. The method, with limitations investigated through uncertainty calculations, is applied to both numerical examples and real GPR data for testing.

Keywords: Dispersion
GPR
Phase
Radius estimation
Advisor: Ghent, Rebecca R