VictorJuiz/thesis huggingface dataset:
Trafficking and Function of the Lysosomal Transmembrane Protein LAPTM5

The lysosomal-associated protein transmembrane 5 (LAPTM5) is a protein preferentially expressed in the immune cells. LAPTM5 was isolated in our laboratory as an interacting partner of the ubiquitin ligase, Nedd4. The intracellular domains of LAPTM5 contain three PY (L/PPxY) motifs, which bind the WW domains of Nedd4, as well as a ubiquitin-interacting motif (UIM). Here, I show that sorting of LAPTM5 from the Golgi to the lysosomes requires its association with Nedd4 and the clathrin adaptor GGA3. Although the Nedd4-LAPTM5 interaction leads to the ubiquitination of LAPTM5, this event is not necessary for LAPTM5 sorting. Rather, the Nedd4-LAPTM5 complex recruits ubiquitinated GGA3, which binds the UIM of LAPTM5. Hence, I propose a novel mechanism by which the ubiquitin ligase Nedd4, via interactions with GGA3 and cargo (LAPTM5), regulates cargo trafficking to the lysosome without requiring cargo ubiquitination. Because nothing was known about the biological function of LAPTM5, at the beginning of my Ph.D. training, I set out to determine the role of LAPTM5 in the innate immune cells. I demonstrate that LAPTM5 interacts with kinesin, a motor protein previously implicated in the anterograde movement of the late endosomal/lysosomal compartments. In dendritic cells, I show that upon maturation LAPTM5 is present within endolysosomal tubules formed by class II MHC molecules. Although I find that LAPTM5 is dispensable for the translocation of peptide-loaded MHC II molecules to the cell surface, this study extends our knowledge of the repertoire of proteins present within tubules formed by the MHC II compartments in activated dendritic cells. In macrophages, I demonstrate that LAPTM5 acts as a positive regulator of NFκB and MAPK signaling cascades, and promotes efficient proinflammatory cytokine production in response to several inducers of macrophage activation. During TNFα stimulation, LAPTM5 is required for proper initiation of NFκB signaling by acting at the receptor-proximate level. Thus, my findings indicate that LAPTM5 is an important component of inflammatory signaling cascades in macrophages and highlight a role for the endosomal/lysosomal system in regulating these cascades. Collectively, the work presented in this thesis broadens our understanding of lysosomal membrane protein sorting and function.

Keywords: LAPTM5
lysosome
trafficking
NF-kB
innate immunity
Nedd4
Advisor: Rotin, Daniela
Improving Dependability for Internet-scale Services

The past 20 years have seen the Internet evolve from a network connecting academics, to a critical part of our daily lives. The Internet now supports extremely popular services, such as online social networks and user generated content, in addition to critical services such as electronic medical records and power grid control. With so many users depending on the Internet, ensuring that data is delivered dependably is paramount. However, dependability of the Internet is threatened by the dual challenges of ensuring (1) data in transit cannot be intercepted or dropped by a malicious entity and (2) services are not impacted by unreliability of network components. This thesis takes an end-to-end approach and addresses these challenges at both the core and edge of the network. We make the following two contributions: A strategy for securing the Internet's routing system. First, we consider the challenge of improving security of interdomain routing. In the core of the network, a key challenge is enticing multiple competing organizations to agree on, and adopt, new protocols. To address this challenge we present our three-step strategy that creates economic incentives for deploying a secure routing protocol (S*BGP). The cornerstone of our strategy is S*BGP's impact on network traffic, which we harness to drive revenue-generating traffic toward ISPs that deploy S*BGP, thus creating incentives for deployment. Empirical study of data center network reliability. Second, we consider the dual challenge of improving network reliability in data centers hosting popular content. The scale at which these networks are deployed presents challenges to building reliable networks, however, since they are administered by a single organization, they also provide opportunity to innovate. We take a first step towards designing a more reliable network infrastructure by characterizing failures in a data center network comprised of tens of data centers and thousands of devices. Through dialogue with relevant stakeholders on the Internet (e.g., standardization bodies and large content providers), these contributions have resulted in real world impact. This impact has included the creation of an FCC working group, and improved root cause analysis in a large content provider network.

Keywords: computer science
networking
Advisor: Ganjali, Yashar
Killing the Beast: Animal Death in Canadian Literature, Hunting, Photography, Taxidermy, and Slaughterhouses, 1865-1920

This dissertation explores the ways in which practices of killing animals in late nineteenth and early twentieth century Canada shaped humans’ perceptions of self and place. Analyzing the multivalent meanings of animal death in wild animal stories, sport hunting, photography, taxidermy, and meat eating, I argue that killing animals was integral to the expansion of settler colonialism in the dominion, materially facilitating the extension of agriculture and industry, and rhetorically legitimizing claims to conquest over indigenous peoples and wild landscapes. But humans’ self-definitions through animal death were not straightforward tales of mastery. Increasingly aware of the disappearance of wildlife from the dominion’s forests, less dependent upon wildlife for subsistence, women and men attributed greater cultural, political, and economic value to the nation’s animals, empathizing with animals and condemning animal extinction. Expressing a sense of guilt over human culpability in the vanishing of wild species, then, humans sought ways of defeating the ravages of modernity by preserving traces of animals in material, representational forms, using encounters with animals as means of defining a sense of self and nation. Fictional stories of animals proliferated, sport hunting soared in popularity, and taxidermied animals adorned many walls. Contemporaries killed animals as a means of legitimizing colonial occupation of newly settled land and asserting mastery over nature, then, but they also regretted their role in precipitating the disappearance of animals from nature. In reconciling this paradox, human and animal engaged in an ongoing process of co-constitution, defining and redefining shifting boundaries of kinship and otherness in a myriad of ways. Such paradoxical meanings of animal death emerged when humans were no longer reliant upon wild animals for survival. As such, I conclude this study by analyzing an important counterpart to wild animal death—the slaughtering of domestic animals as meat. Eating commercially produced meat increasingly defined one’s status as a modern subject within a technologically advanced and civilized nation, the transition from eating wild animals to domestic animals symbolizing a sense of success in overcoming the challenges of settlement in a colonial landscape.

Keywords: Canadian history
hunting
literature
photography
museums
taxidermy
slaughterhouses
human-animal relations
Advisor: Radforth, Ian
The Role of Goal Congruence in Relationship Quality and Subjective Well-being

The goal of this dissertation was to examine how people pursue their personal goals in the context of an intimate relationship. Two studies were conducted; a daily diary study of dating partners’ joint activities and a longitudinal study of newly dating couples. In the daily diary study, people reported on their daily joint activities with their dating partners regarding whether their goals were met and how they were feeling during the given activity. The results showed that when people’s goals were met in an activity, their partners were able to accurately perceive that their goals were being met. However, when their goals were not met in the activity, their partners’ accuracy regarding their goals was only at chance levels. The partners’ overall levels of goal congruence did not predict the proportion of goal-congruent activities the partners participated in. However, the partners’ level of goal congruence predicted increases in life satisfaction, relationship commitment, and relationship satisfaction, as well as decreases in negative affect over time. In the longitudinal study, newly dating couples filled out measures of their goals, well-being, and relationship quality during their initial session. Three months later, the couples filled out measures of these same constructs again and answered questions about the goals that they reported pursuing during their initial session. Results showed that concurrently, the partners’ levels of goal congruence were associated with greater ability to make goal progress and higher relationship satisfaction, both of which, in turn, were associated with higher subjective well-being. Longitudinally, initial levels of goal congruence did not predict changes in goal progress and relationship quality over time. However, analysis of the individual goals indicated that people adjusted their goal pursuits based on the level of goal conflict between their own goals and their partners’ goals, such that people were more likely to stop pursuing or devalue goals that conflicted with their partners’ goals over time. Furthermore, the tendency to adjust goals over time was associated with increasing relationship commitment. The results of these studies show that conflict between relationship partners’ goals has important consequences for their relationship, goal progress, and personal well-being.

Keywords: well-being
close relationships
goal pursuit
relationship quality
Advisor: Schimmack, Ulrich
Optimization Models and Techniques for Radiation Treatment Planning Applied to Leksell Gamma Knife(R) Perfexion(TM)

Radiation treatment planning is a process through which a certain plan is devised in order to irradiate tumors or lesions to a prescribed dose without posing surrounding organs to the risk of receiving radiation. A plan comprises a series of shots at di erent positions with di erent shapes. The inverse planning approach which we propose utilizes certain optimization techniques and builds mathematical models to come up with the right location and shape, for each shot, automating the whole process. The models which we developed for PerfexionTM unit (Elekta, Stockholm, Sweden), in essence, have come to the assistance of oncologists in automatically locating isocentres and de ning sector durations. Sector duration optimization (SDO) and sector duration and isocentre location optimization (SDIO) are the two classes of these models. The SDO models, which are, in fact, variations of equivalent uniform dose optimization model, are solved by two nonlinear optimization techniques, namely Gradient Projection and our home-developed Interior Point Constraint Generation. In order to solve SDIO model, a commercial optimization solver has been employed. This study undertakes to solve the isocentre selection and sector duration optimization. Moreover, inverse planning is evaluated, using clinical data, throughout the study. The results show that automated inverse planning contributes to the quality of radiation treatment planning in an unprecedentedly optimal fashion, and signi cantly reduces computation time and treatment time.

Keywords: Optimization
Semi-infinit
Perfexion
Radiosurgery
Advisor: Aleman, Dionne
Strategies of Defending Astrology: A Continuing Tradition

Astrology is a science which has had an uncertain status throughout its history, from its beginnings in Greco-Roman Antiquity to the medieval Islamic world and Christian Europe which led to frequent debates about its validity and what kind of a place it should have, if any, in various cultures. Written in the second century A.D., Ptolemy’s Tetrabiblos is not the earliest surviving text on astrology. However, the complex defense given in the Tetrabiblos will be treated as an important starting point because it changed the way astrology would be justified in Christian and Muslim works and the influence Ptolemy’s presentation had on later works represents a continuation of the method introduced in the Tetrabiblos. Abū Ma‘shar’s Kitāb al-Madkhal al-kabīr ilā ‘ilm akām al-nujūm, written in the ninth century, was the most thorough surviving defense from the Islamic world. Roger Bacon’s Opus maius, although not focused solely on advocating astrology, nevertheless, does contain a significant defense which has definite links to the works of both Abū Ma‘shar and Ptolemy. As such, he demonstrates another stage in the development of astrology. These three works together reveal the threads of a trend of a rationalized astrology separated from its mythical origins which began with Ptolemy and survived through both medieval Islam and medieval Europe. In the two examples of defending astrology I have used, Abū Ma‘shar and Roger Bacon, Ptolemy’s influence can be seen to have persisted from the second century through to the thirteenth, and the nature of the differences in their defenses illustrates the continuation and evolution of the tradition of defending astrology.

Keywords: astrology
medieval Islam
medieval Europe
ancient Greece
Ptolemy
Abu Ma'shar
Roger Bacon
transmission of science
Advisor: Jones, Alexander
Interactions between the Actin Cytoskeleton and Anthrax Toxin Receptor 1 (ANTXR1)

Interactions Between the Actin Cytoskeleton and Anthrax Toxin Receptor 1 (ANTXR1) Kristopher M. Garlick, Doctor of Philosophy, 2012, Department of Laboratory Medicine and Pathobiology, University of Toronto ABSTRACT Anthrax is caused by the bacterium Bacillus anthracis, which secretes three proteins that assemble to form a toxic complex at the host cell surface. These proteins are known as protective antigen (PA), lethal factor (LF), and edema factor (EF), and together constitute the major virulence factor of the bacterium. PA binds to one of two cell surface receptors, ANTXR1 or ANTXR2, and facilitates the entry of LF and EF into the cell where they exert various toxic activities. Studying anthrax toxin receptor interactions with PA is thus important for understanding anthrax pathogenesis as well as discerning their natural functions in cells. In this thesis I sought to investigate how interactions with intracellular proteins regulate ligand binding by ANTXR1. Previously it was demonstrated that ANTXR1 associates with the actin cytoskeleton, and this association correlated with low levels of PA binding. It was suggested that this interaction is most likely mediated by adaptor proteins. However, in this thesis I demonstrate that the cytoplasmic domain of ANTXR1 binds directly to actin. Further, I provide evidence that this direct link is sufficient to regulate interactions of the receptor with PA ligands. Finally, I demonstrate that it is the interaction with actin filaments, rather than monomers that accounts for the lower PA binding properties of ANTXR1 compared with receptors that do not associate with actin.

Keywords: anthrax
cytoskeleton
Advisor: Mogridge, Jeremy
Deciding How to Get By: Subsistence Choices among Homeless Youth in Toronto

This dissertation develops insights into subsistence related decision-making from the perspective of homeless and street involved young people themselves through 39 in-depth and life story interviews. The interviews provide insight into two important and underexplored questions: how the social organization of street spaces shapes street life and subsistence; and how the self is implicated in subsistence related decision-making. To address these questions the analysis develops a conceptual model based on field theory (Bourdieu 1984; Green 2008; Martin 2003) that conceptualizes “the street” as a collection of interlocking subfields—unique social terrains structured at the intersection of various social forces that position actors relative to one another and that orient actors towards particular approaches to street life. The core concepts of field theory—field, capital, and habitus—provide insight into how the unique social spaces of homelessness distribute resources, stratify actors, and provide discourses that frame practice. The analysis demonstrates the strength of this approach through case studies of three such subfields in Toronto. Further, the analysis extends the field framework, and contributes to research on the role of the self in street life, by examining how narratives influence the navigation of street spaces. Actors use narratives to make sense of their circumstances and to invest lines of action with a sense of personal meaning. This narrative perspective is integrated with a dual process approach to action (Vaisey 2009) that states that action is influenced by internalized dispositions formed through experience and upbringing (habitus), as well as through available cultural resources that underwrite and legitimize courses of practice. I extend this approach by considering how these two processes interact within narratives, and how the resulting interplay shapes how the homeless navigate the social spaces of homelessness.

Keywords: Homelessness
Youth
Subsistence
Field theory
Advisor: Hannah-Moffat, Kelly
Covering Arrays with Row Limit

Covering arrays with row limit, CARLs, are a new family of combinatorial objects which we introduce as a generalization of group divisible designs and covering arrays. In the same manner as their predecessors, CARLs have a natural application as combinatorial models for interaction test suites. A CARL(N;t,k,v:w), is an N×k array with some empty cells. A component, which is represented by a column, takes values from a v-set called the alphabet. In each row, there are exactly w non-empty cells, that is the corresponding components have an assigned value from the alphabet. The parameter w is called the row limit. Moreover, any N×t subarray contains every of v^t distinct t-tuples of alphabet symbols at least once. This thesis is concerned with the bounds on the size and with the construction of CARLs when the row limit w(k) is a positive integer valued function of the number of columns, k. Here we give a lower bound, and probabilistic and algorithmic upper bounds for any CARL. Further, we find improvements on the upper bounds when w(k)ln(w(k)) = o(k) and when w(k) is a constant function. We also determine the asymptotic size of CARLs when w(k) = Θ(k) and when w(k) is constant. Next, we study constructions of CARLs. We provide two combinatorial constructions of CARLs, which we apply to construct families of CARLs with w(k)=ck, where c<1. Also, we construct optimal CARLs when t=2 and w=4, and prove that there exists a constant δ, such that for any v and k≥4, an optimal CARL(2,k,v:4) differs from the lower bound by at most δ rows, with some possible exceptions. Finally, we define a packing array with row limit, PARL(N;t,k,v:w), in the same way as a CARL(N;t,k,v:w) with the difference that any t-tuple is contained at most once in any N×t subarray. We find that when w(k) is a constant function, the results on the asymptotic size of CARLs imply the results on the asymptotic size of PARLs. Also, when t=2, we consider a transformation of optimal CARLs with row limit w=3 to optimal PARLs with w=3.

Keywords: group divisible designs
covering arrays
group divisible covering desings
graph covering problem
packing arrays
group divisible packing designs
Advisor: Mendelsohn, Eric
Maternal Parenting and Individual Differences in Young Children’s Prosocial Abilities: Risk and Resilience

The purpose of these studies was to examine moderation processes for the influence of early maternal parenting practices on young children’s prosocial outcomes. Data for both studies were drawn from the Kids, Families, and Places study. Observational measures of mothers’ parenting practices and children’s cooperation outcomes were collected in the home, and both mothers and fathers reported on their children’s prosocial conduct. Study 1 was a longitudinal analysis of the interaction between maternal sensitivity after birth (Time 1) and children’s joint attention (JA) skills (Time 2, 18 months later) on children’s cooperation skills at 18 months. Findings indicated that children’s concurrent Responding to JA (RJA) was associated with cooperation and early maternal sensitivity moderated this relationship. Children high in RJA showed good cooperation irrespective of maternal sensitivity. However, low RJA was associated with high cooperation in the presence of high maternal sensitivity. Study 2 used person-oriented analyses to examine patterns of maternal parenting associated with young children’s concurrent prosocial behaviour across socioeconomic contexts. Latent Profile Analysis identified 3 profiles of parenting: Positive (14%), Negative (36%), and Combined (moderate levels of both positive and negative practices; 50%). Mothers from low-income families and those living in disadvantaged neighbourhoods were more likely to  belong to the Negative or the Combined profiles.  Moderation analyses indicated the protective influence of the Combined profile of parenting for children residing in impoverished socioeconomic contexts. In the context of low family SES and high neighbourhood disadvantage, children were rated as more prosocial if mothers use a combined style of parenting. A protective-enhancing effect was found, in which these high-risk children were actually rated better than those children who did not live in such adversity. Together, results highlight the importance of studying the association between parenting and prosocial outcomes within an ecological and contextual framework, with interactions amongst both child-level and distal factors, for understanding individual differences in prosocial development.

Keywords: Prosocial Development
Maternal Parenting
Risk and Resilience
Advisor: Jenkins, Jennifer M.