VictorJuiz/thesis huggingface dataset:
Automated Image Analysis for Systematic and Quantitative Comparison of Protein Expression within Cell Populations
Keywords: Cell cycle
Image analysis
Protein expression
Segmentation
Subcellular localization
Yeast

Protein subcellular localization is a major indicator of protein function, and efforts have been made to systematically determine the localization of each protein in budding yeast using fluorescent tags. Based on the fluorescence microscopy images, subcellular localization of many proteins can be classified automatically using supervised machine learning approaches. Budding yeast has a stereotypical reproduction mode, such that cell-stage is related to the presence and size of a growing bud. In this work, I investigate the benefits of a cell recognition method and image features that utilize prior biological knowledge of budding yeast shape and its cell-stage dependent changes.I show that modeling cell-stage dependency of protein abundance and spatial distribution (expression pattern) within a continuous model for cell growth allows the identification of most previously identified localization patterns in a cluster analysis. Further, I show that similarities between the inferred protein expression patterns explain similarities in protein function better than previous manual categorization of subcellular localization. These results suggest that incorporating prior information about yeast morphology in automated image analysis will yield unprecedented power for pattern discovery in high-resolution, high-throughput microscopy images.Finally, using these new computational methods, I explore cell-to-cell variability in protein abundance and subcellular localization. I define a mean to quantify deviations in subcellular localizations, and find that the method defined is in agreement with previous measurements of cell-to-cell variability in the case of protein abundance. Hence, I show that cell-to-cell spatial variability is a protein expression property, whose measurement is only possible from microscopy images. This measure allows the systematic detection of many classes of such variability, without the use of any prior knowledge about subcellular localization.
Uncertain Dignity: Judging Human Dignity as a Constitutional Value
Keywords: Arendt
constitution
dignity
Kant
Reflective Judgment
respect

This dissertation examines what is the practical meaning of the idea of human dignity in the context of constitutional judgment. Against the commonly held view in political theory and legal scholarship that applying the idea of human dignity in law involves applying a single conception determinatively, my argument is that the way we think about the limit human dignity places on constitutional arrangements, involves a process of reflective judgment that oscillates between two conceptions. The first conception of human dignity is a deontological abstract idea that posits dignity as an inviolable, universal, formal property of all human beings. Most clearly associated with Immanuel Kant's writings, this conception plays a constitutive role in the constitutional sphere by underpinning the notion of legal subjectivity. The second conception of human dignity is intersubjective. Articulated originally by G.W.F Hegel and developed by contemporary exponents (most notably Axel Honneth), this conception underscores human vulnerability for recognition as an equal. It therefore plays a regulative role function in constitutional adjudication. This conception reveals contextual sensitivity towards what counts for particular individual in a particular time as respect. Together, these two conceptions form the normative syntax of the liberal conception of human dignity. Through conceptual inquiry and comparative constitutional analysis I reveal the process of illuminating tension between the universal (thin) perspective of human dignity and its particular (thick) enmeshments in the political community. Importantly, the relation between the two conceptions is non-transcendent. There cannot be a unified comprehensive definition of human dignity. Rather, the constitutional meaning of human dignity is a result of an on-going reflective judgment and continuous restatement at the level of the political community.
Statistical Methodologies for Genetic Association Studies with Rare Variants
Keywords: Linear statistic
Quadratic statistic
Rare variants
Response dependent sampling
Testing

In the search for genetic factors that are associated with complex heritable human traits, considerable attention has been focussed on rare variants that individually have small effects. Many recent papers have proposed testing strategies to detect association between traits and groups of rare variants with competing claims about the performance of various tests. The power of a given test in fact depends on the nature of any association and on the rareness of the variants in question.In this thesis we review such tests within a unified framework that covers a whole range of genetic models. We divide tests into linear and quadratic classes. We study performance of both classes through exact and asymptotic power calculations and novel simulation studies. We show that test statistics from both classes are complementary and they are powerful under limited settings. To achieve robustness, we propose to combine the evidence of association from two or more complementary tests. We consider the minimum-p and Fisher's methods of combining p-values from linear and quadratic statistics. Our extensive simulation studies show that both methods are robust across wide range of genetic models and have comparable or better power than alternative methods such as weighted kernel-based association tests. Our results also show that power to detect association in plausible genetic scenarios is low for studies of medium size unless a high proportion of the chosen variants are causal. To increase power, we also consider response-dependent sampling in association studies with rare variants. We also show that, under a broad range of generalized likelihoods and sampling plans, score statistic for testing association between a response Y and genetic variants are identical for two main likelihood approaches, and are of the same form as for ordinary random sampling on Y. Lastly, we evaluate proposed methodology and various sampling strategies with extensive simulations.
Calcium-sensing Receptor and Integrin Protein Complexes in Cerebellar Development and Cancer Cell Migration
Keywords: Brain
Calcium-sensing Receptor
Cancer
Development
Integrin
Migration

The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G protein-coupled receptor that senses changes in extracellular divalent cations and maintains systemic calcium homeostasis. Recent studies suggest that CaSR activation can promote cellular migration. In the present study, we initially sought to identify novel CaSR interacting proteins that might be associated with cellular migration. Using a metastatic tumour model consisting of medullary thyroid carcinoma cells (MTCs), and a brain developmental neuronal migration model comprised of highly motile cerebellar granule-cell precursor neurons (GCPs), we established that the CaSR couples to the integrin family of extracellular matrix (ECM) binding proteins to promote cell adhesion and migration. Integrins are single transmembrane spanning heterodimeric adhesion receptors that mediate cell migration by binding to ECM proteins. Co-immunoprecipitation and co-localization studies established that the CaSR and 1-containing integrins were present in a macromolecular complex in MTC cells and GCP neurons. In the tumour cells, CaSR-mediated activation of phospholipase C and rise in intracellular calcium was essential for integrin activation and potentiation of cell adhesion and migration. Conversely, CaSR mediated phosphorylation of ERK2 and AKT signaling, and the subsequent promotion of 1 integrin plasma membrane expression was crucial for cerebellar GCP migration. These
Examining the Effects of Dementia on the Postoperative Outcomes of Older Adults with Hip Fractures
Keywords: cohort study
dementia
health services
hip fractures
outcomes

This dissertation comprises three research studies related to the outcomes of older adults with dementia who sustained hip fractures in Ontario. The first dissertation study demonstrated that individuals with dementia accounted for 23.9% and 83.5% of all hip fractures from community and long-term care (LTC) settings, respectively. Among community-dwelling older adults, dementia was associated with an increased risk of LTC admission (hazard ratio (HR) = 2.49, 95% confidence interval (CI): 2.38-2.61, P
Lewis Acid Activated Olefin Metathesis Catalysts
Keywords: Alkylidene
Catalysis
Metathesis
Olefin Metathesis
Organometallic
Ruthenium

Since its discovery, catalytic olefin metathesis has been used as a powerful tool for the synthesis of a variety of molecules. Over the last 20 years research in this area has received enormous attention in the development of new catalysts and applications. The vast majority of the ruthenium based catalysts developed have been modifications to the Grubbs Catalyst type architecture. The research presented herein focuses on the development of new olefin metathesis catalysts bearing tridentate, dianionic ligands and their activation with Lewis acids. Complexes [(PPh
Essays on Digitization and the Market for Intangibles: Evidence from Creative and Technology Settings
Keywords: Competition
Copyright
Innovation
Intellectual Property
Strategy
Technology

This thesis examines the impact of intellectual property (IP) on firm-level performance outcomes in the market for intangibles. While the market for intangibles plays an expanding role in economic growth, it is often susceptible to market failure. In particular, digitization adds additional challenges to how firms shape their IP strategies by significantly lowering the cost of copying and sharing digital content, and thereby impacting firm appropriability in many settings. The first chapter analyzes the impact of a firm-level IP strategy commonly used by media industries to combat piracy - digital rights management (DRM) - on music sales. To do this, I exploit a natural experiment, where different record labels remove DRM from their entire catalogue of music at different times, to examine whether relaxing an album's sharing restrictions increases sales. Specifically, I compare sales of similar albums with and without DRM before and after DRM removal, and I find that removing DRM increases digital music sales. However, relaxing sharing restrictions does not impact all albums equally; it increases the sales of lower-selling albums (i.e., the ``long tail'') significantly but does not benefit top-selling albums. My results are consistent with theory that shows lowering search costs can facilitate the discovery of niche products, and suggest that the optimal strength of IP in creative industries depend on the distribution of products (e.g., mainstream vs. niche) within the firms' portfolio. My second and third chapters examine whether structural features of the market for intangibles, impact firm-level outcomes in technology-oriented industries. My second chapter reports the first empirical evidence linking the three main sources of failure emphasized in the market design literature (lack of market thickness, congestion, lack of market safety) to deal outcomes using novel survey data on technology licensing. This chapter disaggregates the licensing process into three stages and finds variation in the salience of market features. In the final chapter, I document the rated importance of different forms of IP and explore the extent to which firm and industry factors influence organizations' motivations for developing IP assets.
The Organization of Online Outsourcing: Observational and Field Experimental Studies
Keywords: Contract Labor
Economic Development
Economics of Digitization
International Labor Markets
Team Diversity

This thesis explores how digitized international labor markets affect hiring and the organization of production using experimental and observational data from the world's largest online contract labor market, oDesk. Team-based production in knowledge work is becoming increasingly important for firm success, and with the globalization of economic activities, teams of workers are increasingly diverse in their nationality and skill sets. In the first chapter of this thesis I test whether these differences have meaningful implications for performance by designing and conducting a natural field experiment to examine how national diversity affects the returns to team work. I find that team work improves outcomes when workers are from the same country, and worsens outcomes when workers are from different countries relative to groups independent workers. I also find that these results are most pronounced for groups of workers with specialized skills sets. These findings suggest that while technology is facilitating cross-border interactions with potentially large benefits such as knowledge transfer, market growth, and access to higher paying jobs, participants in international markets may benefit from investing in managing the costs associated with national diversity. Aside from the costs national diversity introduces into team work, international labor markets may also introduce informational costs for employers trying to hire from countries they know little about. Using observational data from the same market, oDesk, the second chapter of my dissertation considers how employers from developed countries and contract workers from developing countries overcome the information asymmetries associated with remote work. This chapter finds that workers from less developed countries are disadvantaged relative to those from developed countries in terms of their likelihood of being hired by employers from developed countries, but that verifiable information benefits them relatively more. This suggests that reliable and easily understood information can overcome some of the difficulties associated with hiring foreign workers. The final chapter of my thesis considers some of the broader implications of the digitization of contract labor for workers and firms by taking advantage of observational and survey data from oDesk.
Three Essays on the Impact of Knowledge Accumulation on the Process of Knowledge Creation with a Focus on Collaboration
Keywords: Collaboration
Innovation
Specialization

The cumulative nature of knowledge constantly alters the innovative landscape and thus the process of knowledge creation. In this dissertation, I explore the impact of cumulativeness on individual-level collaboration as it shapes the production of new ideas. I focus on two main influencing factors: conditions of access to knowledge and knowledge accumulation as it leads to increased specialization. This is important since the ability to build on knowledge influences the evolution of innovation trajectories.In the first study, I explore the composition of collaboration and the impact of a researcher level of expertise on the type of knowledge created. Leveraging a natural experiment, the launch of Microsoft Kinect, which triggered an unanticipated reduction in the cost of motion-sensing technology, I examine how individuals respond to opportunities for knowledge creation opened by a change in conditions of access to knowledge. Despite growing emphasis on the importance of specialists for knowledge creation, I identify generalists - researchers with broader exposure to knowledge - as playing a particularly important role in the process of innovation with implications for the type of knowledge created. Specifically, generalists have a higher propensity than specialists to respond to opportunities for knowledge creation that span knowledge areas and play a central role in coordinating collaboration between specialists required to execute on the opportunities. In the second study, I focus on the impact of increased specialization due to knowledge accumulation on the rate of collaboration. The knowledge burden hypothesis - that reaching the knowledge frontier is progressively costly due to knowledge accumulation and results in increasing specialization and collaboration - is one of several theories advanced to explain the widely documented observation that researcher team size is increasing over time. I exploit a natural experiment, the collapse of the USSR as an exogenous shock to the knowledge frontier in theoretical mathematics, to provide results of a first causal test in support of the knowledge burden hypothesis. This identification exercise is important since this hypothesis leads to policy implications that do not apply to other explanations of increases in team size. Lastly, in the third study, I discuss the influence of collaboration and individual-level breadth and depth of expertise in potentially influencing the rate and direction of a big science project. A narrative on commercial quantum computing innovation, a controversial contemporaneous endeavour, suggests the influential role of an entrepreneurial venture coordinating large-scale collaboration to exploit an opportunity at the intersection of knowledge areas.
Endoscopic Classification of Representations of GSp(2n) and GSO(2n)
Keywords: Arthur packet
automorphic representation
endoscopy
multiplicity
similitude group
trace formula

In 1989 Arthur conjectured a very precise description about the structure of automorphic representations of reductive groups using Arthur packets and endoscopy theory. In his recent monograph [Art13], he proved this conjecture for symplectic groups and orthogonal groups G. The results are conditional on the stabilization of twisted trace formula, which is a project in progress under Mœglin and Waldspurger (see [MW14], [Wal14a]-[Wal14e]). Our goal is to extend Arthur’s result to general symplectic groups and general even orthogonal groups Ge, by studying the restriction of representations from Ge to G. This idea goes back to Labesse and Langlands [LL79], where they considered G to be SL(2) and Ge to be GL(2). To extend Arthur’s result, there are two main problems that we have solved in this thesis. One is local and the other is global. Locally, we have determined the tempered Arthur packets for Ge, and shown they satisfy certain character relations under the endoscopic transfer. Globally, we have proven the functoriality of endoscopic transfer for a large family of tempered automorphic representations of Ge.
From the Hands of Quacks: Aural Surgery, Deafness, and the Making of a Surgical Specialty in 19th Century London
Keywords: Deafness
History of Medicine
Otology
Professionalization
Specialization
Surgery

This dissertation critically examines the social and medical perceptions of nineteenth-century British aural surgery, a subset of medical practice providing treatments for aural diseases. Tracing the efforts of a particular group of London-based aural practitioners ("aurists") and their visions of a specialist identity, this dissertation explores how medical legitimacy was founded within a field constantly battling accusations of charlatanry. As aurists fiercely competed with each other for positions, status, and patients, accusations of quackery weakened their attempts to forge authority as skilled experts. Questions of credibility grazed the boundaries between authority and legitimacy as aurists not only defended their speciality from the broader medical occupation, but also from a social prejudice that deemed deafness medically incurable. Aurists thus used the rhetoric of "medical science" to invoke particular representations on how they wanted to define their surgical authority and be perceived by the broader medical community. From an examination of various strategies aurists used to construct their surgical authority, this dissertation highlights the resonances between quackery, entrepreneurialism, and legitimatization; "quack" was a highly ambiguous term generally used to disqualify an adversary or competitor, or to dismiss a particular medical procedure or technology. This dissertation is divided into five chapters, with each chapter showcasing the varied ways in which aurists constructed their identity and shaped their claims to legitimacy: from publicly disputing rules against medical intervention at deaf asylums, creating specialty hospitals, increasing publications of aural treatises, and developing newer diagnostic, therapeutic, and assistive instruments.
Development of Novel Magnetic Resonance Imaging Techniques to Evaluate Plasticity in the Injured Human Cervical Spinal Cord
Keywords: cervical spinal cord
functional imaging
imaging biomarkers
plasticity
segmentation
Spinal cord injury

Traumatic injury to the human spinal cord is a devastating condition that results in motor and sensory impairment. The goal of this thesis is to develop magnetic resonance imaging techniques as a biomarker to evaluate the human spinal cord after injury. The specific aims are: 1a) to characterize the standard T1 and T2-weighted intramedullary spinal cord signal characteristics first used by clinicians treating spinal cord injury in order to classify patients along a spectrum of injury severity; 1b) to calculate the sensitivity and specificity of MRI biomarkers to determine neurological function and 1c) to determine whether standard T1 and T2-weighted imaging biomarkers offer an advantage over clinical examination to predict neurological outcomes. 2) To determine whether spinal functional MRI can be used to distinguish spinal cord injury patients from healthy controls by 2a) determining whether there is an abnormal neuro-vascular response to afferent stimulation in dermatomes of normal sensation, above the level of injury, in spinal cord injury (SCI) patients 2b) to determine whether the neuro-vascular response to afferent stimulation in dermatomes of altered sensory perception, below the level of injury, is correlated to the degree of sensory loss and 2c) to determine the functional connectivity between regions of the spinal cord that process an afferent stimulus and other regions of the brainstem-spinal cord axis. 3) To outline the diversity of segmental anatomy of the human spinal cord across a cohort of individuals by 3a) measuring the position of vertebral bodies and spinal cord segments relative to the ponto-medullary junction; 3b) to calculate the relative positions of vertebral bodies and spinal cord segments; and 3c) to predict the position of spinal cord segments. Results indicate that 1) standard T1 and T2-weighted intramedullary spinal cord signal characteristics offer no advantage over clinical examination to predict prognosis. 2) Spinal fMRI can be utilized to provide evidence of spinal cord plasticity after traumatic injury and 3) there is natural diversity of the position of vertebral and spinal cord segments relative to the ponto-medullary junction that should be taken into account for advanced imaging studies. Collectively, the new knowledge presented herein contributes to the advancement of imaging techniques to investigate the human spinal cord.