VictorJuiz/thesis huggingface dataset:
Development of Small Molecule Activators of Caseinolytic Protease P

Caseinolytic protease (ClpP) is a cylindrical protease that degrades proteins in the presence of ATPase chaperones. On its own, bacterial ClpP can only degrade small peptides; however, the addition of a novel class of antibiotics, ADEPs, can cause unregulated proteolysis leading to bacterial cell death. Bacterial ClpP is an attractive target for antibiotic development. A high-throughput screen of small molecules identified a group of compounds which are termed Activators of Self-Compartmentalizing Proteases (ACP). A collection of ACP3 and ACP4/5 analogs was synthesized and investigated for biological activity. The project resulted in compounds with greater activity than the lead structures against isolated E. coli ClpP. Also, several analogs possessed bacteriostatic activity against N. meningitidis and S. aureus cell lines.

Keywords: Caseinolytic Protease P
ClpP, antibiotics
Advisor: Batey, Rob
Direct Steroidal Regulation and Inhibitory Mode of Action of Gonadotropin-inhibitory Hormone (GnIH or RFRP-3) in Immortalized Hypothalamic Cell Models

Fertility is dependent on the precisely orchestrated communication of an array of effectors within the reproductive axis, all of which impinge on gonadotropin-releasing hormone (GnRH) neurons. A novel reproductive inhibitor was identified in avian species and growing evidence suggests that the functional mammalian homologue, RFamide-related peptide-3 (RFRP-3 or GnIH) can inhibit GnRH neuronal activity and gonadotropin release. To date, the regulation and effects of RFRP-3 at the hypothalamic level are poorly understood. We established an Rfrp-expressing neuronal cell model to investigate the mechanisms of transcriptional regulation of the genes for RFRP and the RFRP receptor, GPR147 by dexamethasone and estradiol. We show that the RFRP system is a direct target for stress-associated transcriptional regulation. Further, employing a novel GnRH-secreting cell line, we report that GnRH neurons express Gpr147 and RFRP-3 represses the transcription of GnRH. These data further our understanding of the level and regulatory effects at which RFRP-3 modulates reproduction.

Keywords: Gonadotropin-Inhibitory Hormone
Reproduction
Hypothalamus
Gonadotropin-Releasing Hormone
Neurons
Cell line
RFamide-related peptide-3
Stress
Estrogen
Advisor: Belsham, Denise D.
The Effects of Fatty Acids on the Molecular Circadian Clock in Immortalized, Clonal Hypothalamic Neurons

Diets high in saturated fatty acids are associated with the development of circadian dysregulation, obesity, and type 2 diabetes mellitus. Conversely, unsaturated fatty acids are now known to improve insulin sensitivity, reduce weight gain, and alleviate obesity-induced inflammation. The aforementioned effects of saturated and unsaturated fatty acids have also been identified in the hypothalamus; however, there is a paucity of studies regarding the role of unsaturated fatty acids in circadian rhythms. Therefore, a novel cell model was established to examine the effects of omega-3 fatty acids on circadian rhythms in hypothalamic neurons. The mHypoE-37 cell line expresses Bmal1, Per2, and Rev-erbα in a circadian manner. The saturated fatty acid, palmitate, was found to induce circadian dysregulation of the mHypoE-37 neurons, whereas the unsaturated fatty acid, docosahexaenoic acid, protected against palmitate-induced circadian changes. These studies are the first to identify the potential for unsaturated fatty acids to protect the circadian system.

Keywords: Circadian
Physiology
Hypothalamus
Fatty acids
Palmitate
Omega-3
Neuron
Diabetes
Obesity
Cell line
Dysregulation
Advisor: Belsham, Denise
Identification of Disulfiram as a Potential Therapeutic for RB1 -proficient and -deficient Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) represents an aggressive subtype for which only chemotherapy is available. The RB1 tumour suppressor is frequently lost in human breast cancer, primarily in TNBC. Loss of RB1 deregulates the cell cycle and is thought to affect BC response to endocrine, radiation, and chemotherapy. However, the global chemosensitivity of Rb null BC is not known. Here I demonstrate that RB1-deficient TNBC cells are highly sensitive to radiation, and moderately sensitive to doxorubicin and methotrexate. However, loss of RB1 does not increase sensitivity to multiple other drugs. Moreover, a non-biased screen of 2 RB-deficient versus 2 RB-proficient lines with ~3500 drugs did not reveal any difference in sensitivity, but identified disulfiram as a potent drug, which compared favourably with current chemotherapeutics against TNBC. Disulfiram’s efficacy was validated against 13 human TNBC lines with an average IC50 of 300nM. IQGAP1 was identified as a potential target of disulfiram.

Keywords: triple negative breast cancer
chemotherapy
retinoblastoma protein
disulfiram
role of RB1 during chemotherapy
IQGAP1
disulfiram treats triple negative breast cancer
Advisor: Zacksenhaus, Eldad
A 'Phase Reset' Scheme for an 8-11Gb/s Bang-Bang CDR in 65nm CMOS

This thesis presents the design and implementation of a CDR with 'phase reset.' By continually 'resetting' the phase of the recovered clock to be aligned with data, cycle-slipping and bit errors during the lock process are reduced. This concept was demonstrated in a full-rate 8-11Gb/s Bang-Bang CDR in 65nm CMOS.

Keywords: Electronics and Electrical
Advisor: Sheikholeslami, Ali
Why Get Along? Dietary and Molecular Influences on Cooperation in an Ant-plant Symbiosis

In mutualisms, individuals exchange goods and services for net benefit. However, many sources of variation in these interactions remain unexplored. To examine why plantdwelling ants protect their host plants by killing herbivores, I shifted the macronutrient balance of their background diets. Providing ants with supplemental protein caused them to invest less in patrolling and defence activities, likely because the availability of lowcost protein made hunting for herbivores relatively less profitable. In contrast, supplemental sugar caused an increase in ant activity, possibly because carbohydrates serve as ‘fuel’ for patrolling. To examine a second source of variation in this interaction, I treated ants with an activator of PKG, a protein encoded by foraging, a gene with behavioural functions in other taxa. PKG activation caused ants to become more aggressive towards herbivores, causing their host plants to experience less herbivory. This suggests that an ortholog of foraging may influence cooperation in this system.

Keywords: ants
mutualism
Advisor: Frederickson, Megan
Characterization of Primary Esophageal/Gastro-esophageal Junction Cancer Xenograft Models and their Effectiveness in Studying Chemosensitivity

Primary esophageal (E) and gastro-esophageal junction (GEJ) cancer xenografts have the potential to become useful pre-clinical models of disease. In this study, we determined that p16 negative tumors that have not been exposed to neo-adjuvant chemo-radiation have higher engraftment chances. Morphological features and expression of certain molecular markers (p53, p16, Ki-67, EGFR, Her-2/neu) suggest that no major changes occur between primary tumors and xenografts or between early passage and late passage xenografts. Global gene expression data supported these results but revealed that approximately 2000 genes differed significantly between passage one xenografts and human tumors. Most of these genes, however, might coincide with stromal signals present in patient tumors but absent in xenografts. Primary E/GEJ cancer xenografts also showed a wide range of chemosensitivities to cisplatin-paclitaxel treatment, confirming the usefulness of these models in drug testing. These models also revealed potential ways to interrogate tumor initiating cell (TIC) dynamics after chemotherapy.

Keywords: primary tumour xenografts
esophageal cancer
gastro-esophageal junction cancer
engraftment
Advisor: Liu, Geoffrey
Ailles, Laurie
Influences of Gas Phase Movement on Contaminant Transport During Electrical Resistance Heating

This thesis examined the influence of relative permeability, constant concentration contaminant sources, multi-component gases, and latent heat effects on electrical resistance heating (ERH). An existing electro-thermal model coupled to a macroscopic invasion percolation model (ETM-MIP) was modified for the study. Simulations results showed that ERH may generate enough gas to significantly reduce aqueous phase relative permeability, thereby significantly reducing aqueous phase velocity and mass transport. When a constant concentration source zone is simulated, gas generation persists and gas bubbles travel much further with greater redistribution of contaminant. By including dissolved nitrogen and oxygen as background components, multi-component partitioning increases, resulting in more gas bubble generation. Finally, by taking into account latent heat, the model is able to simulate energy associated with vaporization, and constant co-boiling temperature plateaus are predicted in contaminant source zones.

Keywords: Environmental Engineering
Advisor: Sleep, Brent
CEO Duality In Listed Corporations: Is There An End To The Dichotomous Debate?

CEO duality has been the subject of debate for over twenty years and shows no signs of abating. With conflicting theoretical and empirical evidence underpinning the debate the practice has fluctuated, investor perception of board leadership structure has altered, international regulation has reacted, scholarly conceptualizations of duality have become overly complex, and the need to understand duality and conclude the debate has increased. This thesis explores duality in listed corporations and aims to form an appropriate solution to end the dichotomy. My solution requires one to confront misunderstandings which have led to a traditional insistence towards structural reform and prolonged the contentious debate, and recognize an underlying contention which needs to be resolved to bring finality to the debate. I argue finality is possible if a process oriented approach is adopted and corporations recognize the need to be technically equipped to deal with leadership structures in the modern corporate arena.

Keywords: Duality
Corporate governance
Board of directors
Board leadership
Advisor: MacIntosh, Jeffrey
Phylogeny and Molecular Evolution of the Voltage-gated Sodium Channel Gene scn4aa in the Electric Fish Genus Gymnotus

Analyses of the evolution and function of voltage-gated sodium channel proteins (Navs) have largely been limited to mutations from individual people with diagnosed neuromuscular disease. This project investigates the carboxyl-terminus of the Nav paralog (locus scn4aa 3’) that is preferentially expressed in electric organs of Neotropical weakly-electric fishes (Order Gymnotiformes). As a model system, I used the genus Gymnotus, a diverse clade of fishes that produce species-specific electric organ discharges (EODs). I clarified evolutionary relationships among Gymnotus species using mitochondrial (cytochrome b, and 16S ribosome) and nuclear (rag2, and scn4aa) gene sequences (3739 nucleotide positions from 28 Gymnotus species). I analyzed the molecular evolution of scn4aa 3’, and detected evidence for positive selection at eight amino acid sites in seven Gymnotus lineages. These eight amino acid sites are located in motifs that may be important for modulation of EOD frequencies.

Keywords: phylogeny
systematics
molecular evolution
evolution
voltage-gated sodium channel
scn4a
Nav1.4
sodium channel
gene
protein
fish
electric fish
knifefish
Neotropical fish
Gymnotiform
Gymnotus
electric organ discharge
electric field
electric organ
electric signal
cytochrome b
16S ribosome
phylogenetic reconstruction
phylogenetic tree
evolutionary history
positive selection
patterns of selection
neuromuscular disease
gene duplication
differential expression
maximum parsimony
parsimony
PAUP*
Bayesian inference
MrBayes
Bayesian
maximum likelihood
PAML
Advisor: Lovejoy, Nathan
Development of a Simple Rehabilitation Device for Hemiparetic Stroke Patients to Perform Reaching Exercises in the Transverse Plane

Upper-limb hemiparesis caused by stroke can severely limit a survivor's ability to perform activities of daily living. Treatment involves intensive, repetitive therapy that can strain limited resources. Rehabilitation devices have been developed to help reduce therapist burden and increase access to therapy. However, adoption is complicated due to their expense and use of complex actuators. A rehabilitation tool without actuators was developed to perform reaching under varying resistance in the transverse plane and measure the reaction force at the handle. Force measurements from the device were validated through comparison with a standard force plate. A new method to calculate the center of applied pressure on a spherical handle mounted on a load cell was developed and validated using 3D modeling. Finally, a study conducted on healthy subjects demonstrated directional effects on the trajectory length and straightness, while resistance effects were seen for the maximum force, time-to-peak velocity and time-to-peak force.

Keywords: stroke
rehabilitation
hemiparesis
biomechanics
Advisor: Mihailidis, Alex
ABO Genotype, “Blood-Type” Diet and Cardiometabolic Risk Factors

The ‘Blood-Type’ diet advises individuals to eat according to their ABO blood group to optimize health without the support of science evidence. The objective of this study was to determine whether consumption of a diet in accordance with an individual’s ABO genotype is associated with various biomarkers of cardiometabolic health. Study subjects (n=1,455) were participants of the Toronto Nutrigenomics and Health study. Dietary intake was assessed using a one-month, 196-item food frequency questionnaire and a diet score was calculated to determine relative adherence to each of the four blood type diets. ABO blood group was determined by genotyping rs8176719 and rs8176746 in the ABO gene. The results show that adherence to the Type-A, Type-AB, and Type-O diets were associated with favourable profile of certain cardiometabolic risk factors (P<0.05); however, these dietary effects were not dependent on someone’s ABO blood group. Therefore, the findings do not support the “Blood-Type” diet hypothesis

Keywords: ABO Genotype
"Blood-Type" Diet
Cardiovascular Health
Personalized Nutrition
Advisor: El-Sohemy, Ahmed
Novel Insights in Language Production Mechanisms in Autism Spectrum Disorder: A Magnetoencephalography Study.

Absence or impairment of functional communication is a fundamental deficit in Autism Spectrum Disorder (ASD). The specific factors that contribute to a great variety of speech and language impairments are still unknown but have a neurobiological substratum. We investigated the brain control of speech production mechanism in children with ASD using Magnetoencephalography (MEG). MEG is a neuroimaging modality with high temporal resolution that records neural activation in real time. A group of children with ASD and age- and sex- matched controls performed simple oromotor (open and close mouth) and speech tasks (one-syllable and multi-syllable phoneme production). Atypical and significantly different brain neural activation in motor (BA 6 and BA 4) areas and speech control (BA 47, BA 22) areas were noted in children with ASD compared to typically developing controls. The present thesis provides new evidence contributing to the understanding of speech and language production in individuals with autism.

Keywords: Autism
ASD
Neuroimaging
Magnetoencephalography
Speech production
Advisor: Anagnostou, Evdokia
Pang, Elizabeth
Ryanodine Receptor Modulator, Dantrolene Sodium, Improves Survival Following Ventricular Fibrillation

Background: Ventricular fibrillation (VF) is associated with dysfunctional cardiac calcium cycling and poor survival. We hypothesized dantrolene improves survival following VF by stabilizing calcium dysregulation. Methods: VF was induced in 26 healthy Yorkshire pigs and left untreated for 4 min followed by 3 min of CPR and defibrillation. Dantrolene was infused during CPR. Rabbit hearts (n=14) were studied to evaluate the effect of dantrolene on VF-induced calcium cycling dysfunction. Results: Survival was higher in the dantrolene group. (85% vs. 39%, P=0.01) Dantrolene-treated pigs required significantly lower defibrillation energy level. (150J vs. 650J, P<0.05) Systolic pressure was significantly higher during the post-defibrillation period in the dantrolene group. (P=0.001) In rabbit hearts, dantrolene significantly mitigated the amplitude of VF-induced diastolic calcium elevations and increased the calcium alternans threshold. (P<0.05) Conclusion: Our findings suggest dantrolene facilitates successful defibrillation, prevents myocardial stunning and improves survival following VF. The effects are mediated through normalizing the VF-induced dysfunctional calcium cycling.

Keywords: Dantrolene
RyR2
Ventricular Fibrillation
CPR
Advisor: Nanthakumar, Kumaraswamy
smig-1(ev809) is a Novel Suppressor of Distal Tip Cell Migration Mutants in Caenorhabditis elegans

smig-1(ev809) is a novel suppressor of multiple distal tip cell (DTC) migration mutants in the nematode Caenorhabditis elegans. In the C. elegans hermaphrodite, the two U-shaped gonad arms develop and form as a result of the migration of two DTCs. smig-1(ev809) suppresses DTC migration defects of mutants encoding components of intracellular glycosylation pathways as well as extracellular basement membrane glycoproteins. The smig-1(ev809) mutation bypasses the requirement for a fully functional chondroitin pathway and MIG-17 metalloprotease in DTC pathfinding. I found that i) suppression of the hypomorphic chondroitin mutant mig-22(k141) is not completely dependent on MIG-17 activity; ii) the smig-1(ev809) mutant is likely to be a loss- of-function suppressor; and iii) SMIG-1 does not visibly affect the localization of poorly glycosylated MIG-17 on the gonad surface. Understanding SMIG-1 function will shed light on the role of glycosylation, the extracellular matrix and basement membranes in cell migration during development.

Keywords: cell migration
developmental genetics
ADAMTS metalloprotease
chondroitin
distal tip cell
mig-6
ev809
mig-17
mig-22
glycosylation
mig-23
tm4684
C50F2.4
basement membrane
Advisor: Culotti, Joseph
Mediation of Canadian Tax Disputes

This paper evaluates mediation as a potential alternative strategy for resolving Canadian tax disputes with the Canada Revenue Agency (CRA). It examines the current notice of objection procedure for resolving tax disputes and reviews its challenges to achieve timeliness and high quality communication and information exchange with Canadian taxpayers. It examines mediation as an alternative dispute resolution strategy and surveys its potential benefits in the tax context. Drawing upon the experiences of the United States, United Kingdom, and Australia with tax mediation, this paper resurrects the idea, last seriously considered by the CRA in 1997, that mediation has the potential to address the deficiencies in the Canadian notice of objection process. Finally, this paper examines the constraints under which the Canada Revenue Agency operates and discusses the types of Canadian tax disputes that are, as a result, both well and ill-suited to resolution by mediation.

Advisor: Alarie, Benjamin
Rac Null Leukocytes Are Associated With Increased Inflammation-mediated Alveloar Bone Loss

Genetic and epigenetic factors that predispose to ineffective control of subgingival biofilm composition are incompletely understood. The objective of this study was to elucidate how leukocytes impact on the course of periodontitis in Rac-null mice. Models of acute gingivitis and periodontitis were used to assess the early inflammatory response and patterns of chronicity leading to alveolar bone loss. Leukocyte margination was differentially impaired during attachment in conditional Rac1-null and during rolling and attachment in Rac2-null mice. The inflammatory responses to subgingival ligatures were altered in Rac-null compared to WT mice. In response to persistent subgingival challenge Rac-null mice had increased alveolar bone loss with resorption patterns characteristic to aggressive periodontitis, partially explained by higher osteoclastic activity in Rac-null mice. This study demonstrates that migratory leukocyte defects are rate limiting steps in the periodontal inflammatory process that lead to more aggressive forms of periodontitis.

Keywords: Inflammation
Rac GTPases
Periodontitis
Advisor: Glogauer, Michael
The Acute and Residual Effects of Cannabis on Driving and the Risk of Collision for People who Drive after using Alcohol and Drive after using Cannabis

Although the impairing effects produced by alcohol and their direct effect on the driving task have been well defined for decades, similar information on the effects of Δ9-tetrahydrocannabinol (THC) following cannabis use in relation to driving skill is lacking. A combination of experimental and epidemiological studies is presented that examine the effects of THC on driving and collision risk. Preliminary data from a driving simulation study explores how THC impairs driving ability both acutely and residually and consideration is given to the challenges faced when conducting this type of research. Epidemiological data from a population-level survey demonstrate that the self-reported concurrent behaviours of driving under the influence of alcohol (DUIA) and driving under the influence of cannabis (DUIC) impart an increased risk of past-year collision more than 3 times greater than reporting driving after using a single substance, or not driving following substance use.

Keywords: cannabis
driving
Advisor: Brands, Bruna
Foll, Bernard Le
Drag on a Cylinder in a Viscoelastic Stokes Flow

This thesis reports on measurements of drag on an unbounded cylinder in a viscoelastic Stokes flow, and compares these values with a Newtonian equivalent. Cylinders of diameter 0.5 to 3.34 mm were submerged 10 to 36 mm into slowly rotating annular tanks with channel widths between 133 to 152 mm. Theoretical formulas and computer simulations were used to correct for the effects of ends and walls, yielding estimates of the unbounded drag. The methodology was verified by testing Newtonian fluids and comparing the results to Kaplun’s (1957) prediction for unbounded drag. The test fluids used were a silicone oil, a polybutene, and two Boger fluids. By comparing the Boger fluid results to equally viscous Newtonian results, the contributions of elasticity to the drag were determined. The Deborah number (De) was used to represent the magnitude of flow elasticity, and an onset of elastic effects was measured between 0.5 and 0.7.

Keywords: Fluid Mechanics
Stokes Flow
Non-Newtonian
Viscoelastic
Boger Fluids
Cylinder Drag
Advisor: James, David
Inhibition of TDP-43 Aggregation using Native State Binding Ligands

TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well understood. We postulate that the aggregation process plays a major role in pathogenesis, and we hypothesize that oligonucleotide ligands of TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation of this aggregation-prone protein. Using recombinant TDP-43 we were able to examine the extent to which various oligonucleotide molecules affects its aggregation in vitro. We have found that certain natural sequence and de novo designed oligonucleotides bind TDP-43 and prevent its natural tendency to aggregate. The clinical and therapeutic implications of these findings are discussed.

Keywords: TDP-43
protein aggregation
protein misfolding
native state stabilization
ALS
FTLD
aggregation inhibition
Advisor: Chakrabartty, Avi