VictorJuiz/thesis huggingface dataset:
The Role of the ITAM-containing CEACAM3 Receptor in the Neutrophil Response to Infection by Neisseria gonorrhoeae
Keywords: Neutrophil
Neisseria
CEACAM

Bacterial species of the genus Neisseria include pathogens that are responsible for diseases of humans including bacterial meningitis (Neisseria meningitidis) and the sexually transmitted disease gonorrhea (Neisseria gonorrhoeae). These diseases are often characterized by a massive influx and activation of neutrophils, white blood cells involved in the early/innate immune response to pathogens, at the infection site. Neisseria spp. bind to and activate neutrophils via their Opacity-associated (Opa) outer membrane proteins, which interact with some members of the human carcinoembryonic antigen-related cellular adhesion molecule (CEACAM) family. One of these CEACAMs, CEACAM3 (CD66d), is unique in its restriction to neutrophils and its expression of a cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM; YxxL/Ix6-8YxxL/I). In the course of my thesis work, I have shown that this motif is critically dependent for the activation of the neutrophil response to Neisseria, through the coupling of neisserial binding to activation of the tyrosine kinase, Syk, which initiates downstream signaling responsible for the antimicrobial responses of neutrophils. These data contribute to the knowledge of how seemingly unrelated receptors of neutrophils (such as the IgG-binding Fcγ receptors, the fungal receptor Dectin-1, and the bacterial-binding CEACAM3) converge functionally on the presence of the ITAM.
Formal Methods in Automated Design Debugging
Keywords: Computer Engineering

The relentless growth in size and complexity of semiconductor devices over the last decades continues to present new challenges to the electronic design community. Today, functional debugging is a bottleneck that jeopardizes the future growth of the industry as it can account for up to 30% of the overall design eﬀort. To alleviate the manual debugging burden for industrial problems, scalable, practical and robust automated debugging solutions are required. This dissertation presents novel techniques and methodologies to bridge the gap between current capabilities of automated debuggers and the strict industry requirements. The contributions proposed leverage powerful advancements made in the formal method community, such as model checking and reasoning engines, to signiﬁcantly ease the debugging eﬀort. The ﬁrst contribution, abstraction and reﬁnement, is a systematic methodology that reduces the complexity of debugging problems by abstracting irrelevant sections of the circuits under analysis. Powerful abstraction techniques are developed for netlists as well as hierarchical and modular designs. Experiments demonstrate that an abstraction and reﬁnement methodology requires up to 200 times less run-time and 27 times less memory than a state-of-the-art debugger. The second contribution, Bounded Model Debugging (BMD), is a debugging methodology based on the observation that erroneous behaviour is more likely caused by errors excited temporally close to observation points. BMD systematically generates a series of consecutively larger yet more complete debugging problems to be solved. Experiments show the eﬀectiveness of BMD as 93% of the large problems are solved with BMD versus 34% without BMD. A third contribution is an automated debugging formulation based on maximum satisﬁability. The formulation is used to build a powerful two step, coarse and ﬁne grained debugging framework providing up to 980 times performance improvements. The ﬁnal contribution of this thesis is a trace reduction technique that uses reachability analysis to identify the observed failure with fewer simulation events. Experiments demonstrate that many redundant state transitions can be removed resulting in traces with up to 100 times fewer events than the original.
Theory of Constraints for Publicly Funded Health Systems
Keywords: theory of constraints
publicly funded health systems
system dynamics
performance measure
discrete event simulation
quality adjusted life year
resource allocation

This thesis aims to fill the gaps in the literature of the theory of constraints (TOC) in publicly funded health systems. While TOC seems to be a natural fit for this resource-constrained environment, there are still no reported application of TOC’s drum-buffer-rope tool and inadequate customizations with regards to defining system-wide goal and performance measures. The “Drum-Buffer-Rope for an Outpatient Cancer Facility” chapter is a real world case study exploring the usefulness of TOC’s drum-buffer-rope scheduling technique in a publicly funded outpatient cancer facility. With the use of a discrete event simulation model populated with historical data, the drum-buffer-rope scheduling policy is compared against “high constraint utilization” and “low wait time” scenarios. Drum-buffer-rope proved to be an effective mechanism in balancing the inherent tradeoff between the two performance measures of instances of delayed treatment and average patient wait time. To find the appropriate level of compromise in one performance measure in favor of the other, the linkage of these measures to system-wide performance measures are proposed. In the “Theory of Constraints’ Performance Measures for Publicly Funded Health Systems” chapter, a system dynamics representation of the classical TOC’s system-wide goal and performance measures for publicly traded for-profit companies is developed, which forms the basis for developing a similar model for publicly funded health systems. The model is then expanded to include some of the factors that affect system performance, providing a framework to apply TOC’s process of ongoing improvement in publicly funded health systems. The “Connecting Low-Level Performance Measures to the Goal” chapter attempts to provide a framework to link the low-level performance measures with system-wide performance measures. It is claimed that until such a linkage is adequately established, TOC has not been fully transferred to publicly funded health systems.
Electronic States of Heavy Fermion Metals in High Magnetic Fields
Keywords: physics
condensed matter
heavy fermion
high magnetic fields
Fermi surface
de Haas-van Alphen effect
dHvA
Lifshitz transition
spin-flop
electronic structure
YbRh2Si2
CePb3
UPt3
CeCoIn5
instrumentation
data acquisition
strongly-correlated
low temperature
electronic states
magnetoresistance
torque
itinerant
localized
4f-state

Heavy fermion metals often exhibit novel electronic states at low temperatures, due to competing interactions and energy scales. In order to characterize these states, precise determination of material electronic properties, such as the Fermi surface topology, is necessary. Magnetic field is a particularly powerful tool, since it can be used as both a tuning parameter and probe of the fundamental physics of heavy fermion compounds. In CePb3, I measured magnetoresistance and torque for 23 mK ≤ T ≤ 400 mK, 0 T ≤ H ≤ 18 T, and magnetic field rotated between the (100), (110), and (111) directions. For H||(111), my magnetoresistance results show a decreasing Fermi liquid temperature range near Hc, and a T^2 coefficient that diverges as A(H) ∝ |H −Hc|^−α, with Hc ~ 6 T and α ~ 1. The torque exhibits a complicated dependence on magnetic field strength and angle. By comparison to numerical spin models, I find that the “spin-flop” scenario previously thought to describe the physics of CePb3 does not provide a good explanation of the experimental results. Using novel data acquisition software that exceeds the capabilities of a traditional measurement set-up, I measured de Haas–van Alphen oscillations in YbRh2Si2 for 30 mK ≤ T ≤ 600 mK, 8 T ≤ H ≤ 16 T, and magnetic field rotated between the (100), (110), and (001) directions. The measured frequencies smoothly increase as the field is decreased through H0 ≈ 10 T. I compared my measurements to 4f-itinerant and 4f-localized electronic structure calculations, using a new algorithm for extracting quantum oscillation information from calculated band energies, and conclude that the Yb 4f quasi-hole remains itinerant over the entire measured field range, with the behaviour at H0 caused by a Fermi surface Lifshitz transition. My measurements are the first to directly track the Fermi surface of YbRh2Si2 across this field range, and rule out the 4f localization transition/crossover that was previously proposed to occur at H0.
When the "Twilight of Justice" Meets the "Dawn of Nanotechnology" : A Critique of Transhumanism and the Technological Imperative in the Light of George Grant's Moral Philosophy
Keywords: technology
ethics
nanotechnology
George Grant
moral philosophy
transhumanism
progress
technoscience
social and ethical implications of nanotechnology
technoprogressivism
technological imperative
nihilism
justice and love
tyranny

This dissertation examines how contemporary Western ethical perspectives frame moral judgments about technologies intended to expand or enhance human abilities. Of particular interest are technological advances that involve nanotechnology, a realm of technoscience that seeks the precise control of matter through deliberately designing structures, devices, and processes with novel and useful properties at the molecular scale. In this thesis I analyze trends in the emerging dialogue about the social and ethical implications of nanotechnology. There is growing awareness that technological “progress” should not outpace critical reflection over the means and ends of those advances, but I argue that there is a tension between the role of ethics and the practice of technoscience. By ethics I mean ongoing public discussion that contemplates what it means to live a “good life” and that maintains limits to human actions. By contrast, the practice of technoscience appears to be guided by the “technological imperative” which holds that we can only know what is good by first figuring out what is possible. Despite concerted interdisciplinary efforts to address the broad range of ethical issues posed by nanotechnology’s proposed goals, the prevailing tone of the current discussion tends to reveal what I call a “technoprogressive” bias, or the belief that technological development is a primary way to improve the human estate and that it leads inevitably to cumulative progress. However, because technoprogressive commentary on nanotechnology focuses on concerns that are framed mainly in terms of risk assessment, cost-benefit analyses, and utilitarian principles, technoprogressive ethics overlooks crucial ethical questions of a different nature, questions that deal with the limits of human action, the nature of justice, and the meaning of being human. To analyze the implications of technoprogressive ethics, I employ the moral philosophy of Canadian thinker George Grant because he articulates an underrepresented yet valuable critique of Western society’s relationship with technology. Grant speaks for a type of transcendental moral realism that challenges the primacy of the technological imperative, insisting that justice ultimately must be grounded upon non-negotiable limits, and that there are objective norms to which human freedom and human self-assertion have to answer.
Investigation into Feline Leukemia Virus Subgroup C Interaction with its Host Receptor FLVCR1 and the Role of FLVCR1 in Diamond Blackfan Anemia
Keywords: 0379
0720

Retroviral infection requires an initial interaction between the host cell and the virion. This interaction is predominantly mediated by an envelope (env) protein exposed on the external face of the virion. For gammaretroviruses, such as feline leukemia virus (FeLV), the receptor-binding domain (RBD) is located in the N terminus of env. The RBD forms a distinct domain that is sufficient for binding to the host receptor, but is inefficient in the absence of the corresponding C terminal env, Cdomain, sequence in viral infection studies. I developed a series of hybrid constructs between subgroup C, A and T FeLVs that use distinct receptors for infection to determine the role of Cdom in FeLV binding and infection. Using this approach, I have shown that the C domain (Cdom) of FeLV-C env forms a second receptor-binding domain, distinct from its RBD, which is critical for efficient binding and infection of FeLV-C to host cells expressing FLVCR1. I propose that this mechanism of interaction is conserved for all gammaretroviruses. My results could have important implications for designing gammaretrovirus vectors that can efficiently infect specific target cells. Upon infection with FeLV-C virus, cats develop a disease known as pure red cell aplasia (PRCA). This disease is characterized by a defect in erythropoeisis that results in a decreased number of mature erythroid cells. PRCA has been suggested to be caused by the FeLV-C env binding to and disrupting the host receptor, FLVCR1. Interestingly, feline PRCA is clinically identical to Diamond Blackfan Anemia (DBA), a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cellular development. I show that erythroid cells from five DBA patients exhibit low levels of total FLVCR1 transcript expression. In addition, the DBA patients express unique alternatively spliced FLVCR1 transcripts. These alternatively spliced transcripts encode FLVCR1 proteins that are defective in their cellular expression, cell surface localization, and receptor function. Taken together, I propose that the specific anemia observed in DBA is caused by decreased levels of functional FLVCR1 protein due to lowered and alternative splicing of FLVCR1 transcript.
Influence of Invasive Species, Climate Change and Population Density on Life Histories and Mercury Dynamics of Two Coregonus Species
Keywords: Dreissena
Bythotrephes
multiple stressors
food web
bioaccumulation
contaminant
trophic disruptor
activity
bioenergetics
global warming

Non-indigenous species can profoundly alter the ecosystems they invade and impact local economies. Growth and body condition declines of commercially fished Great Lakes lake whitefish coincide with the establishment of non-native dreissenid mussels and the cladoceran Bythotrephes longimanus. Declines in lake herring abundance—a key prey item for other commercially important species—have also been reported. Though additional stressors such as climate change may have contributed to changes in coregonid populations, they have not been thoroughly evaluated. Here, I present data that condition and contaminant declines in coregonids are associated with increasing density or warming climate, but growth declines in lake whitefish are likely due to ecosystem changes associated with dreissenids and Bythotrephes. In South Bay, Lake Huron, changes in lake whitefish diet composition and stable isotope signatures were consistent with increased reliance on nearshore resources after dreissenid establishment; lake whitefish occupied shallower habitats and experienced declines in mean diet energy densities post-dreissenid invasion. Growth of South Bay lake whitefish declined after environmental effects were statistically removed, whereas condition declines were explained best by changes in lake whitefish density. Among four lake whitefish populations, growth declined after dreissenids established, but not in uninvaded reference populations. Growth also declined among four lake whitefish populations after the establishment of Bythotrephes relative to reference populations. In contrast with growth, condition of lake whitefish did not change as a result of dreissenid or Bythotrephes invasion. Bioenergetic models revealed that activity rates increased and conversion efficiencies decreased in lake whitefish populations exposed to dreissenids, despite higher consumption rates in populations with dreissenids present. Condition declines among many lake whitefish and lake herring populations (and declines in mercury among herring populations) reflected regional differences and were not related to the presence of Bythotrephes or Mysis relicta. Declines in condition were more pronounced in northwest Ontario populations where climate has changed more dramatically than in southern Ontario. This work suggests that projected range expansions of dreissenid mussels and Bythotrephes will likely affect native fisheries, and their effect on these fisheries may be exacerbated by declining fish condition associated with climate change.
Cu/Zn Superoxide Dismutase Misfolding in Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis
Protein Misfolding
Antibody Design

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration resulting in progressive paralysis and death. The only known cause of typical ALS is mutations in SOD1; these predominantly missense mutations produce a toxic gain-of-function in the enzyme Cu/Zn superoxide dismutase (SOD1). The prevailing hypotheses regarding the mechanism of toxicity were a) oxidative damage from aberrant SOD1 redox chemistry, and b) misfolding of the mutant protein. The goal of this thesis was to investigate the molecular mechanisms of the mutant SOD1 (mSOD1) misfolding and toxicity. We proposed that oxidative damage to SOD1 itself could cause its misfolding and aggregation. To investigate this hypothesis, we subjected purified SOD1 in vitro to metal catalyzed oxidation. Oxidation of SOD1 produced aggregates reminiscent of those observed in ALS pathology. Aggregation propensity of zinc-deficient SOD1 and several mSOD1s known to have lower zinc-binding affinity was proportional to partial unfolding. Oxidation of SOD1 caused conversion of several His residues to 2-oxo-histidine. Because oxidation of SOD1 primarily affected the metal-binding His residues, we hypothesized that oxidation of wild-type, holo-SOD1 should lead to aggregation. Increasing the concentration of wild-type SOD1 in oxidation reactions produced aggregates similar to those observed earlier. Both wild-type and mSOD1 aggregation kinetics revealed an initial decrease in particle size rather than a monotonic increase using dynamic light scattering. This was consistent with the conversion of SOD1, normally an obligate homodimer, into monomers prior to aggregation. This observation was confirmed using analytical ultracentrifugation. The common aggregation pathway for wild-type and mSOD1 suggested a mechanism for sporadic ALS caused by SOD1 misfolding. To interrogate the in vivo misfolding pathway of SOD1, we used its high-resolution structure to create an antibody that reacts with monomer/misfolded SOD1 but not the native dimer. Upon verifying the reactivity of this antibody, we showed that monomer/misfolded SOD1 is found in a human case of familial ALS and in transgenic animal models of ALS. Misfolded SOD1 is found primarily in affected cells, motor neurons. Misfolded SOD1 is also initially absent, but appears prior to symptom onset. These observations together suggest a causal role for SOD1 misfolding through a monomeric intermediate in ALS pathogenesis.
A Needs-based Approach for Health Human Resources Planning for Dentistry in Jeddah, Saudi Arabia
Keywords: dental public health
Health human resources
Saudi Arabia
Dentistry

This study aims to provide a human resource planning example to inform government bodies in Saudi Arabia to reallocate community resources towards better dental health. This was achieved by: conducting an inventory on government human and structural oral health care resources in Jeddah and Bahrah; assessing the oral health status and treatment needs for Saudi citizens following the WHO criteria for oral health surveys; exploring the potential differences between oral health supply and treatment needs; and providing 16 models of the number and mix of dentists and hygienists to balance requirements and supply. We conducted a population-based sample survey to collect data on dental status and service requirements through self-administered questionnaires and clinical examinations. We also conducted a census of dentists and assessed their total service output by means of self-administered questionnaires. The population’s treatment needs time was estimated using the clinically assessed treatment needs multiplied by time units contained in the 2001 ODA fee-guide. Dentists’ available time was calculated from dentists’ questionnaires and the activity assessment forms. The times for treatment needs and supply of services were compared to identify differences in treatment hours. Of the 2000 participants aged 6, 12, 16, 24-29 and 35-44, 76.8% rated their oral health as excellent and 29.2% reported visiting the dentist at least once a year. The prevalence of periodontal conditions as described by the CPITN was 86.1%. The caries prevalence for the permanent and deciduous dentitions was 71.3% (mean DMFT=4.92) and 85.5% (mean dmft=5.45) respectively. One hundred seventy-five government and university dentists (56.6% response rate) completed the total service output instruments. When the projected total FTE-dentists needed to treat the incidence of oral diseases/ conditions (11,214) is contrasted with the total available supply in Jeddah and Bahrah (289 dentists) the remaining FTEs needed to meet the needs becomes 10,925 FTE-dentists. Health promotion strategies and increased productive hours could reduce this to 2,729 dentists and 1,595 hygienists. The General Directory of Health Affairs of Jeddah will need to develop different approaches to oral health promotion and/or care provision to meet the population needs.
The Political Eeconomy of Dentistry in Canada
Keywords: Dentistry
Political economy
Sociology of professions
Survey

Publicly financed dental care has recently increased its profile as a health policy issue in Canada. The media have championed the challenges experienced by low-income groups in accessing dental care. Governments across the country have responded with targeted funds. Social concern has even promoted the Canadian Medical Association to call for the inclusion of dental care within Medicare, and in changing a policy position that is over one hundred years old, the Canadian Dental Association now recommends that governments establish a dental safety net for all disadvantaged Canadians. In this environment, important questions have emerged: Why did Canada never incorporate dental care into Medicare? How have governments been involved in dental care? What are governments doing now? What are the disparities in oral health and dental care? What gaps exist in the system? What does the profession think? What does the public think? Through a document review, administrative survey, expenditure trend analysis, and public and professional opinion surveys, this dissertation answered these questions with the aim of clarifying the many issues that surround publicly financed dental care in Canada. It appears that dental care was not included in Medicare due to material and ideological reasons; namely decreases in dental caries and human resource limitations, the belief in viable options to large-scale service delivery, and the belief that maintaining one’s oral health and the ability to seek out dental care are individual responsibilities, not social ones. As such, there has developed in policy and programming a predilection to support dental care for children, for social assistance recipients, for seniors, and for select marginalised groups, or those groups where personal responsibility is not totalising. There is also a bias, developed over the last thirty years, towards structuring publicly financed dental care in private ways. This has resulted in a system that has certain biases, inconsistencies, and gaps, such that it cannot clearly and fully respond to current disparities. It is in the conciliation of public and private approaches to care that publicly financed dental care can achieve a stable footing and a clear direction forward.