VictorJuiz/thesis huggingface dataset:
From Education to Tumour Characteristics in Colorectal Cancer: An Analysis of the Pathways.
Keywords: Lifestyle
Diet
Alcohol
Physical activity
Smoking
Screening
Colorectal cancer
Tumour characteristics
Survival
MSI
Grade
Stage
Site

Background: Genetic and environmental factors have been associated with colorectal cancer (CRC) risk. However, their association with prognosis has been less studied. Methods: Path analysis was employed to examine causal pathways from education to environmental (diet, alcohol, smoking, physical activity) and personal factors (screening), and then to obesity and ultimately to tumour characteristics (stage, grade, microsatellite instability (MSI), and site) that are associated with CRC prognosis. Data came from the Ontario Familial Colon Cancer Registry. Pathways were evaluated for effect modification by sex and two indicators of CRC genetic susceptibility (Bethesda criteria and newly identified familial cancer clusters). Results: Four food patterns (healthy foods, high-fat foods, sweet and processed foods, and oriental foods) and four nutrient patterns (total macronutrient, fat vs. carbohydrate, and micronutrients from supplements and from foods) were identified. Education was associated positively with healthy lifestyle factors (e.g. healthy foods factor) and negatively with unhealthy factors (e.g. smoking). As expected, high body mass index (BMI) was associated with lower physical activity and higher fat vs. carbohydrate factor. Unexpectedly, BMI was positively associated with the healthy foods factor among Bethesda positive patients and men. An association between education and BMI was mediated by the healthy foods factor and by physical activity. Important poor prognostic factors, higher grade and stage, were associated with smoking and not being screened. However, unexpected associations included a positive association of physical activity with tumour grade among Bethesda positive patients and a positive association of healthy foods with stage among Bethesda negative patients. Patients with right-sided tumours were more likely to receive micronutrients from supplements, and screening and less likely to smoke, and for men, to have a high BMI, high fat diet and healthy food diet. Conclusion: Some unhealthy lifestyle factors, such as smoking and a high fat food dietary pattern, are associated with adverse CRC tumour characteristics and so may affect the prognosis. Family history may modify some associations though the findings require independent confirmation.
Mechanisms of Inhibitory Synaptic Plasticity: The Regulation of KCC2
Keywords: KCC2
chloride regulation

The mechanisms that regulate the activity of the neuron specific K+Cl- cotransporter (KCC2) remain poorly understood, despite the critical importance of this transporter in inhibitory synaptic transmission and plasticity. In this thesis I made three novel discoveries which reveal the cellular and molecular mechanisms of KCC2 regulation. First, I assayed the K+Cl- cotransport function of KCC2 under isotonic conditions and determined the molecular domain of the cotransporter required for constitutive Cl- transport in hippocampal neurons (Acton et al 2012). Specifically, I identified the 15 amino acid domain of the C-terminus in neurons that is responsible for the ability of KCC2 to cotransport K+Cl- under basal isotonic conditions, allowing it to remain constitutively active to create the steep Cl- gradient across the neuronal membrane required for synaptic inhibition. Secondly, I investigated a novel KCC2-interacting protein named Neto2 and determined its effect on the postsynaptic action of GABA (Ivakine et al 2013). I have found that Neto2, which is also an auxiliary protein of kainate-type ionotropic receptors, can also regulate the activity of the KCC2. Neto2 is required for neurons to maintain low [Cl-]i and strong synaptic inhibition. Third, I examined the functional relevance of the KCC2:Neto2:KAR multiprotein complex and found that this complex regulates the surface level membrane expression pattern of KCC2 and the stability of the cotransporter in the membrane. Moreover, I have provided the first evidence that the interactions of KCC2:Neto2:GluK2 regulate KCC2 via a PKC-mediated phosphorylation of the cotransporter. Taken together, these results resolve three novel mechanisms of KCC2 regulation: the identity of the key C-terminal domain of KCC2 required for isotonic transport, the functional significance of the KCC2:Neto2 interaction, and the mechanism by which the KCC2:Neto2:KAR complex regulates KCC2 expression and mobility in the neuronal membrane.
Epidemiologic Characterization of the Heterosexual Transmission of Human Immunodeficiency Virus and other Sexually Transmitted Infections in India
Keywords: HIV
India
AIDS
Epidemiology
Sexually transmitted infection
Public Health

India houses the world&rsquo;s third largest population of people living with Human Immunodeficiency Virus (HIV) who constitute about 6% of the global HIV burden. In about 2008-9, an estimated 1.9 million [95%CI: 1.5 to 2.5] adults were living with HIV in India. The four southern Indian states of Andhra Pradesh, Karnataka, Maharashtra and Tamil Nadu account for about 60% of estimated HIV infections, although they house only 30% of the adult population. I report that most HIV infections in infected couples in the general population of India (85.4% (95%CI: 80.0, 90.7)) were introduced by the male partner. The per-partnership transmission probability of HIV in the general population was low 29.1% (95%CI: 22.5, 35.7) compared to what has been reported for other STIs. Important theoretical facilitating factors for HIV transmission were associated with HIV infection with nearly equal effect sizes in both genders and across HIV&ndash;risk settings (multiple partnerships (OR: 2.46 (95%CI: 1.98, 3.06) and STIs (ORHSV-2: 5.60 (95%CI: 3.37, 9.33); ORSyphilis: 4.12 (95%CI: 2.35, 7.25)). The strength of association of STIs with HIV was consistent. Intervention spending on, or coverage of, STI treatment-focused sex work interventions (per 1000 total district population) was associated with a reduced annual risk of either HIV (- 1.7%, 95%CI: -3.3, -0.10) or syphilis (-10.9%, 95%CI: -15.9, -5.8) infection in young pregnant women in the high-burden southern states. A decreased annual risk of syphilis iii among young pregnant women attending public prenatal clinics in the high-burden southern states was associated with a unit increase (per 1000 total district population) of intervention spending (-0.009%, 95%CI: -0.014, -0.004), number of STIs treated (-10.9%, 95%CI: -15.9, -5.8), FSWs reached (-3.0%, 95%CI: -5.2, -0.7) and condoms distributed (-0.034%, 95%CI: - 0.053, -0.015). Male sexual behaviour (non-regular partnerships and use of female sex work) is the dominant driver of HIV transmission in the general population of south India. Ulcerative STIs were strongly associated with HIV infection in south India and interventions aimed at treating STIs and promoting safer sex practices for FSWs and their clients have resulted in reductions in HIV and syphilis incidence and prevalence in the general population of south India.
Tragic Rhetoric: Sophocles and the Politics of Good Sense
Keywords: rhetoric
tragedy
prudence
good sense
democracy
judgment
Sophocles
Athens
inclusion
contingency
spectator
chance

This dissertation investigates rhetoric and prudence in Sophocles through close readings of Antigone, Ajax, Philoctetes, and Oedipus at Colonus. Central to the project is a reconstruc-tion of a uniquely Sophoclean conception of prudence as “good sense”; good sense is distinguished from traditional conceptions of prudence as an inter-subjective capacity for good judgment that is born of experience and chance. The study finds that while good sense and persuasive rhetoric are occasionally paired, they are frequently divorced from one another. Thus, in place of heroic conflicts and tragic failings, these readings present an alternative tragic tension between the persuasive yet often solipsistic speech of heroes and protagonists and the good sense of marginalized characters. This project is situated within the “turn to rhetoric” in contemporary democratic theory; in this context, it presents Sophocles as a novel and under-theorized resource in three overarching ways. First, his dramas were performed in a democratic context and gave voice to perspectives otherwise marginalized within the polis; in this respect he offers more inclusive democratic resources than his Athenian contemporaries. Second, these plays offer sobering insight into the impact of contingency in shaping rhetorical contexts. They reveal that overconfidence in rhetorical technē underestimates the extent to which successful persuasion is often aligned with chance and social advantage. Third, he draws attention to pervasive structural inequalities that work against and silence good sense. In this final respect the plays themselves are considered as didactic resources that cultivate reflective judgments and good sense in the spectator and reader.
Structural Insights into the Regulatory Mechanism of the Ryanodine Receptor and its Disease-associated Mutants
Keywords: Structural Biology
Ryanodine receptor
NMR
X-ray crystallography

Calcium is a ubiquitous second messenger in cells that plays a vital role in the control of cellular and physiological processes as diverse as cell division, memory and learning, fertilization and muscle contraction. Opening of the sarcoplasmic reticulum (SR) Ca2+-release channel, the ryanodine receptor (RyR), in response to mechanical or chemical stimuli via the dihydropyridine receptor (DHPR) is a crucial step in the process of muscle excitation-contraction coupling. I have determined the first high-resolution structure of a folded domain of RyR1 (RyR1A). The structure adopts a β-trefoil fold that is similar to the homologous suppressor domain of the inositol 1,4,5-trisphosphate receptor (IP3R). I identified a loop region in RyR1A concentrated with malignant hyperthermia (MH)- and central core disease (CCD)-associated mutations that have been implicated in perturbing inter-domain interactions with downstream regions of RyR. More recently I have used nuclear magnetic resonance (NMR) spectroscopy to study the structure and dynamics of the cardiac isoform (RyR2) A domain and its mutants. I detected a dynamic α-helix that undergoes an α-helix to β-strand switch in the catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated mutant, RyR2A Δ exon 3. This dynamic helix is localized at an interface with electron dense columns in the cryo-EM map of the tetrameric receptor that connect with the pore region, suggesting that this dynamic helix may also interact with downstream regions of RyR to gate the channel. My high-resolution structural studies in collaboration with others have shed light on the structural underpinnings of RyR function and dysfunction in human disease.
Engineering of TEV Protease for Manipulation of Biosystems
Keywords: protein engineering
TEV protease

Synthetic biology is a nascent discipline that aims to design and construct new biological systems beyond those found in nature, ultimately using them to probe, control, or even replace existing biological systems. The success of synthetic biology depends on the assembly of a set of well-defined and modular tools. These tools should ideally be mutually compatible, reusable in different contexts, and have minimum crosstalk with endogenous proteins of the subject. The tobacco etch virus protease (TEV protease, TEVp) is a suitable candidate for such a tool due to its unique substrate specificity and high efficiency. Importantly, TEVp is capable of imitating proteolysis, a ubiquitous mechanism in nature for post-translational modifications and signal propagation. Here, TEVp is employed as a self-contained proteolytic device capable of executing biological tasks that are otherwise governed by endogenous proteins and processes. Consequently, the goal of using TEVp for synthetic manipulation of biosystems is achieved. First, a single-vector multiple gene expression strategy utilizing TEVp self-cleavage was created. This approach was used for the robust expression of up to three genes in both bacterial and mammalian cells with consistent stoichiometry. The products can then be individually purified or targeted to distinct subcellular compartments respectively. Second, a temperature-inducible TEVp was created by incremental truncation of TEVp. The 18th truncation of TEVp (tsTEVp) resulted in negligible activity at 37 °C, but retained sufficient activity at 30 °C for rapid processing of its substrates in several mammalian cell cultures. Finally, tsTEVp was applied in the context of other synthetic modules to generate a variety of biological responses. Its versatility was demonstrated as cellular processes including protein localization, cellular blebbing, protein degradation, and cell death were rewired to respond to the physical stimulus of temperature.
Convex Solutions to the Power-of-mean Curvature Flow, Conformally Invariant Inequalities and Regularity Results in Some
Keywords: mean curvature
ancient solution
conformally invariant inequalities
optimal transportation

In this thesis we study three different problems: convex ancient solutions to the power-of-mean curvature flow; Sharp inequalities; regularity results in some applications of optimal transportation. The second chapter is devoted to the power-of-mean curvature flow; We prove some estimates for convex ancient solutions (the existence time for the solution starts from – ∞) to the power-of-mean curvature flow, when the power is strictly greater than ½. As an application, we prove that in two dimension, the blow-down of an entire convex translating solution, namely [special characters omitted], locally uniformly converges to [special characters omitted] as h → ∞. The second application is that for generalized curve shortening flow (convex curve evolving in its normal direction with speed equal to a power of its curvature), if the convex compact ancient solution sweeps the whole space R2, it must be a shrinking circle. Otherwise the solution must be defined in a strip region. In the first section of the third chapter, we prove a one-parameter family of sharp conformally invariant integral inequalities for functions on the n-dimensional unit ball. As a limiting case, we obtain an inequality that generalizes Carleman's inequality for harmonic functions in the plane to poly-harmonic functions in higher dimensions. The second section represents joint work with Tobias Weth and Rupert Frank; the main result is that, one can always put a sharp remainder term on the righthand side of the sharp fractional sobolev inequality. In the first section of the final chapter, under some suitable condition, we prove that the solution to the principal-agent problem must be C1. The proof is based on a perturbation argument. The second section represents joint work with Emanuel Indrei; the main result is that, under (A3S) condition on the cost and c-convexity condition on the domains, the free boundary in the optimal partial transport problem is C1,α.
Outcomes and Prospects for Collaboration in Two Aboriginal and Non-Aboriginal Forest Management Negotiations in Ontario
Keywords: collaborative natural resource management
intercultural collaboration
forest management
Aboriginal
Aboriginal-state relations
forest conflict
worldview
cross-cultural negotiation
negotiation
consensus building evaluation

Successful intercultural natural resource management collaboration is challenged by divergent worldviews and power disparities. Studies of non-intercultural collaboration efforts demonstrate that good outcomes emerge when procedural conditions are met, such as fostering open and high-quality deliberations, use of interest-based bargaining techniques and collective definition of the scope of the process. The applicability of these procedural conditions to intercultural collaboration efforts, such as negotiations between Aboriginal people, government resource managers and sustainable forest license holders, has not been explored. The aim of this thesis is to examine the outcomes and factors influencing two intercultural collaborations in the northeast region of Ontario. Semi-structured interviews with collaboration participants, negotiation meeting minutes and draft agreements are used as data sources. Following a general inductive coding approach and using QSR NVivo 2, the analysis of outcomes in both cases highlights improvements in relationships, increased understanding among the parties and the gradual definition of the scope of the negotiation. The findings also demonstrate that several barriers, including a lack of clear policy and legislative framework for collaboration and different definitions of the problem discourage intercultural collaboration. In one negotiation process, frequent and high quality deliberations, using an interest-based negotiation approach, and efforts to mutually define the scope of the negotiation prior to substantive negotiation do not overcome these systemic barriers to collaboration. However, in another negotiation process, the social and relational characteristics of the community and participants do contribute to the parties recognizing their interdependence, focusing on shared goals and undertaking joint action. This research demonstrates that the development of shared goals and acknowledgement of divergent problem definitions are more important to intercultural collaboration success than the development of improved relationships and establishing a mutually acceptable scope prior to collaboration. In the absence of a supportive legislative basis for the distribution of forest decision-making authority and responsibilities, this understanding of how Aboriginal, government and forest industry participants can collaborate is useful for developing more effective and equitable intercultural collaboration.
Self-compassion and Recovery from Sexual Assault
Keywords: self-compassion
sexual assault
trauma
mindfulness

Despite concerted efforts to eradicate violence against women and challenge victim-blaming attitudes towards survivors of sexual assault, women continue to be sexually victimized and encounter negative and accusatory reactions by family, friends, and society at large. For many survivors, the consequences are internalizing blame and feelings of shame, which has been shown to be related to increased psychological distress, self-destructive coping mechanisms, depression, generalized anxiety, and post-traumatic stress (Arata, 1999; Davis &amp; Breslau, 1994; Feiring, Taska, &amp; Lewis, 2002; Frazier, 1990, 2000; Frazier &amp; Schauben, 1994; Wyatt et al., 1990). New research in the area of self-compassion suggests that this way of self-relating can counter shame (Gilbert, 2005) and serve as a resiliency factor for coping with daily stressors (Leary, Tate, Adams, Allen, &amp; Hancock, 2007) and contribute to well-being (Neff, 2003a). No study has yet empirically evaluated self-compassion among survivors of trauma, nor more specifically, victims of sexual assault. The present study investigated the relationships between self-compassion and various indicators of psychological health that have been associated with posttrauma adjustment. One hundred and forty-one women in North America who experienced a sexual assault in the past 5 years (aged 18 to 61, M age = 27 years) completed measures assessing trauma history (sexual trauma history, childhood trauma and stressful life experiences), posttrauma adjustment (psychological distress, negative posttraumatic cognitions, and shame), self-compassion, self-criticism, and life satisfaction. The results of the study showed that self-compassion was significantly negatively related to psychological distress, negative posttraumatic cognitions, shame and self-criticism, and was positively related to life satisfaction. Hierarchical linear regressions revealed that when controlling for earlier childhood trauma and other stressful life experiences, self-compassion was a strong and significant predictor, explaining between 19 to 42% of the variance in psychological distress, negative posttraumatic cognitions, shame, and self-criticism. Comparing groups based on severity of sexual assault revealed that women who experienced attempted rape reported significantly higher levels of self-criticism compared with women who experienced sexual coercion. These findings bolster recent studies that equate self-compassion with psychological resilience. The negative relationships revealed between self-compassion and measures reflecting posttrauma adjustment and self-criticism, along with the positive association with life satisfaction clearly demonstrate validity in the pursuit of self-compassion as an important psychological construct that may help women recover from sexual trauma.
A Conceptual Analysis of Canadian Palliative Care Ethics
Keywords: palliative care
ethics
medical sociology

Introduction: In the palliative care literature there has been debate over the occurrence and the desirability of the rationalization of palliative care. The discussion is based mostly on opinion, anecdote and argument. Little discussion is based on research, or is specific to Canada. Considering this question of rationalization, this thesis asks whether Canadian palliative care ethics has changed, and if so in what regard. Methods: Discourse analysis was used to evaluate texts and interviews from early and late Canadian palliative care. Based on expression, influence and comprehensiveness, two key texts were identified from each of the early and late periods of palliative care. Ten interviews were conducted with Canadian palliative care pioneers practicing across these periods. These interviews were semi-structured, and were based on the background literature and the textual analysis. Results: Analysis of the textual data led to the descriptive themes of person, profession and well-being. These themes, when compared across the early and late periods, generated three themes of process. Analysis of the interview data generated three similar themes of process. The themes of process from the textual and interview data were similar enough to generate three overall themes of process – routinization, medicalization, and professionalization.