VictorJuiz/thesis huggingface dataset:
Investigation of the role of reactive metabolites in anticonvulsant-induced idiosyncratic drug reactions

Lamotrigine, carbamazepine (CBZ), and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions (IDRs). Evidence suggests that such reactions are caused by reactive metabolites and are immune-mediated. One hypothesis that can link reactive metabolites with an immune-mediated reaction is the danger hypothesis, i.e. cell stress is important for the induction of an immune reaction. CBZ causes neutropenia suggesting that the reactive metabolite is formed by myeloperoxidase (MPO), which is the major oxidative enzyme in neutrophils. A major hepatic metabolite of CBZ is the 3-OH-CBZ and that of PHN is 4-OH-PHN. We found that 3-OH-CBZ and 4-OH-PHN are further oxidized by MPO/H2O2 to dimers, strong evidence for a free radical intermediate. Bioactivation of 3-OH-CBZ and 4-OH-PHN in the presence of model proteins lead to covalent binding, and MS/MS fragmentation revealed that the covalent binding site is tyrosine. Free radicals can generate ROS and other forms of cell stress consistent with the danger hypothesis, and we found that 3-OH-CBZ, but not 4-OH-PHN, generated reactive oxygen species (ROS) in a peroxidase-containing cell line. We found that CBZ and PHN treatment induced genes of protective enzymes related to the Keap-Nrfl-ARE signal pathway, such as glutathione transferase, and stress proteins, such as heat shock proteins. It also induced IL-6, a major mediator of the acute phase response, and increased urinary isoprostane levels, a marker of lipid peroxidation. We postulate that bioactivation of 3-OH-CBZ and 4-OH-PHN to free radicals by peroxidases may play an important role in CBZ- and PHN-induced IDRs. Although lamotrigine can cause agranulocytosis, the major IDR is skin rash. Lamotrigine is oxidized by MPO to a reactive N-chloro metabolite, which can be trapped with N-acetylhistidine; however, the amount of covalent binding in the presence of MPO was quite low. The amount of covalent binding to hepatic microsomes was even less. Despite testing other potential pathways mediated by enzymes present in the skin, such as sulfation of lamotrigine-N-oxide, no pathway was found that could reasonably be linked to reactive metabolite formation in the skin. It is possible that lamotrigine-induced skin rash is caused by the parent drug.
Conscientisation and the journey to self-advocacy: stories of students appropriating resilience and staying in school

This study critiques the deficit model of examining disengagement from secondary schools and the terminology of at-risk associated with early departure from school. Using the theoretical framework of Freirian critical analysis and the praxis of conscientisation, the research in this paper suggests that youth experiencing marginalization can participate in critical reflection and student empowerment. The model of self-advocacy and collaboration developed in this study explores resilience and autonomy as a precursor to a student's re-engagement in learning communities and more inclusive involvement in what I call a synergistic model of democratic education. Interviews were conducted with grade nine and ten students from an alternative secondary school who had chosen re-engagement despite various experiences of marginalization. In an effort to appropriate a more authentic exploration of the students' existing knowledge of themselves as learners, their Ontario School Records were used as a primary resource for the students to deconstruct their own academic, social and cultural histories. The voice of these students is examined through the lens of narrative inquiry within a contemporary participative action research framework. The critical dialogue that ensued became a scaffold where the students could negotiate individual and social changes (Freire, 1999; Ecclestone, 2004; Dei, 2003), face some moments of disequilibrium (Mikesch McKenzie, 2003) in their school stories, and become more competent as problem-solvers and contributors in the conversation about the difference between schooling and getting an education. The purposes of this study are to: (1) investigate the positive understanding of resilience in an educational context; (2) explore ways that students within supportive learning communities may come to appropriate the learning strategies they need for their own success; (3) strive to understand more deeply the connections between the protective factors associated with resilience and the decision to stay in school; (4) use the hermeneutic of Freirian critical conscientisation and dialogue to shift the conversation about individual and school related factors associated with early school leavers to a more critical social and cultural analysis; and (5) finally to access strategic mechanisms within communities of resilience that facilitate the process of pre-engagement, self-directed learning and self-advocacy (Ames, 1992; Garner, 1990).
On stable leader election in systems with reliable links

A leader election algorithm is stable if it ensures that once a process is elected as the leader, it remains the leader as long as it continues to behave well, regardless of the behavior of other processes and links. We present three new leader election algorithms that exhibit stronger stability properties than currently known. Our algorithms are for systems with reliable links. The first two algorithms assume the existence of an eventual hub, i.e., a correct process whose incoming and outgoing links are eventually timely. The third algorithm is the first known stable algorithm that does not assume the existence of a hub: it requires only the existence of an eventual source, i.e., a correct process whose outgoing links are eventually timely. Our stable leader election algorithms are the first ones where the stabilization time does not depend on the rate at which processes send messages.
The anticonvulsant effects of progesterone and its metabolites

Introduction. Approximately one third of patients with epilepsy experience seizures that cannot be adequately controlled by currently available medications. Complex partial seizures are the most common type of seizure in adults and they are often drug-resistant. New drugs with novel mechanisms of action are needed to treat complex partial seizures. It has long been recognized that the steroid hormone progesterone has anticonvulsant effects. The anticonvulsant effects of progesterone are largely mediated by the actions of its metabolites. The present study was performed to determine if progesterone and four of its metabolites---5alpha-dihydroprogesterone (5alpha-DHP), allopregnanolone, 3alpha-dihydroprogesterone (3alpha-DHP), and 20alpha-dihydroprogesterone (20alpha-DHP)---have anticonvulsant effects against amygdala-kindled seizures in rats. The rat amygdala kindling model is an animal model of human complex partial seizures, secondarily generalized. The amygdala focal seizure models complex partial seizures, while the secondarily generalized component of the seizure models tonic-clonic seizures. Methods. Dose-response studies were conducted in the amygdala kindling model for progesterone and four of its metabolites in female rats. Time-response studies were performed for progesterone, 5alpha-DHP, and allopregnanolone. Dose-response studies were also conducted for progesterone, 5alpha-DHP, and allopregnanolone in male rats. In order to assess the anticonvulsant effects of progesterone, 5alpha-DHP, and allopregnanolone in male and female immature rats, dose-response studies were performed in the maximal pentylenetetrazol model. Results. Progesterone, 5alpha-DHP, allopregnanolone, and 3alpha-DHP were all anticonvulsant against amygdala-kindled seizures. 20alpha-DHP was not anticonvulsant at the doses tested. 5alpha-DHP was the most effective anticonvulsant, with low ED50's of 2.9 mg/kg against the secondarily generalized seizure and 4.3 mg/kg against the amygdala focal seizure in female rats. Similar results for 5alpha-DHP were seen in male rats. 3alpha-DHP and allopregnanolone suppressed the secondarily generalized component of the amygdala-kindled seizure, but they did not suppress the amygdala focal seizure. Progesterone, 5alpha-DHP, and allopregnanolone were all anticonvulsant against tonic seizures in immature rats. Conclusions. Only 5alpha-DHP suppressed the amygdala focal seizure, which models human complex partial seizures. 5alpha-DHP was also the only compound that did not produce sedation or ataxia. These results suggest that 5alpha-DHP might be an effective nontoxic anticonvulsant against drug-resistant human complex partial seizures.
Objective and subjective visual functions in Stargardt macular dystrophy

Conclusions. The mfERG, kinetic ERG and VA LV VFQ testing along with current visual function measurement tools might provide clearer perspective of visual dysfunction in patients with STGD. This in turn might help to understand the natural history of STGD. Purpose. To assess visual function measures, selected from knowledge of disease mechanism, in their abilities to detect vision dysfunction, in patients with Stargardt Macular Dystrophy (STGD). Results. The mfERG was more sensitive in detecting dysfunction than bfERG (p
Descriptive evaluation of the section 8 process for interferon treatment of patients with chronic hepatitis C in Ontario

Background. Chronic hepatitis C (HCV) is a significant cause of morbidity in Ontario. In 1996-1997, the only treatment available was interferon, an expensive, inefficacious therapy with significant side effects. Publicly funded interferon therapy was available through an individualized process requiring review of applications by expert hepatologists. Results. Reviewers approved 83% of 370 applicants during the study period. Kappa statistic for agreement with guidelines was 0.225. Only 22% of approved patients appeared to complete therapy. 56% of drug costs were paid for incomplete therapy. Conclusions. Reviewers adopt an overly permissive stance toward approval of interferon for HCV patients. Research questions. Do reviewers' approvals of therapy agree with clinical practice guidelines in effect during 1996-1997? What proportion of approved patients finishes prescribed therapy? What are the costs associated with successful and unsuccessful therapy?Methods. Descriptive analysis of clinical and administrative databases of the Ontario Drug Benefit Program.
An entity resolution framework for deduplicating proteins

This thesis describes the design and implementation of a new framework PERF for deduplicating protein mentions using of a wide range of protein attributes. A mention refers to any recorded information about a protein, whether it is derived from a database, a high-throughput study, or literature text mining, among others. This framework is easily extendable to the deduplication of protein-protein interactions (PPIs). PERF translates mentions into instances of a Framework XML schema to facilitate mention comparisons. This framework also uses "virtual attribute dependencies" to "enhance" mentions with additional attribute values. PERF computes a likelihood measure based upon the textual similarity of mention attributes, and the overlap between protein classes implied by each mention's non-sequence attributes. A prototype of the framework was implemented, and preliminary tests indicate that the framework can clearly separate duplicate mentions from non-duplicate mentions.
Development of appropriate technologies for double fortification of salt with iron and iodine

Ferrous fumarate was successfully agglomerated by an extruder to produce hard, dense, highly bioavailable, iron premixes with pellet-size of 0.5mm in diameter and length. These were then completely colour-masked with white TiO2, and microencapsulated with 10%-28%(w/w) of soy steatrine and 0.5%-5.0%(w/w) of Methocel in a pan coater. Double fortified salts (DFS) were prepared by blending iron premixes with Nigerian iodated salt and stored for 3 months at 40°C and 60% relative humidity (RH) to determine their stability. After three-month storage, no adverse colour change was observed in DFS. In addition, nearly 100% of ferrous iron and total iron were retained in all samples. 81%, 89% and 99% of iodine was retained in DFS respectively prepared by uncoated premixes, premixes coated with 21% of TiO2 and 5% methocel, as well as premixes coated with 21% of TiO2 and 21% of soy stearine.
Structure and function of the outer membrane phospholipid: lipid a palmitoyl transferase PagP from Escherichia coli

PagP is an outer membrane enzyme of Gram-negative bacteria that transfers a palmitate chain from phospholipids to lipid A in order to provide bacterial resistance against host immune defenses. Initial velocity experiments indicated a sequential kinetic mechanism for catalysis. This finding is consistent with our observation that PagP is insensitive to serine-modifying inhibitors, which target esterases utilizing a non-sequential mechanism. Site-directed mutagenesis implicated 7 residues in catalysis and one in lipid A binding. The active site was mapped to the extracellular surface by NMR spectroscopy. The crystal structure revealed an interior hydrophobic pocket that was implicated as an acyl-chain binding site because detergents that mimic acyl-chains reversibly inhibited PagP, while those with bulky substituents did not. Additionally, using mutagenesis to modulate the depth of the hydrophobic pocket, we constructed variants that utilized shorter acyl-chains. This is the first example of a hydrocarbon ruler in an integral membrane enzyme.
Characterization of lineage-specific expression and signaling function of mouse NKR-P1 (CD161)

Furthermore, although it is known that the NK1.1 marker is encoded by the Nkrp1c gene, its transcriptional regulation has not been elucidated. The results presented in this thesis define the molecular basis of Nkrp1c expression in NK lineage cells. In particular, the location of the Nkrp1c transcriptional initiation site, a novel 5' untranslated exon, and the minimal functional core promoter have been identified. Furthermore, we describe the detection and analysis of a DNaseI hypersensitive site (HS1), located 9 kb upstream of the transcriptional initiation site, which exhibits NK cell-specific enhancer-like activity. Taken together, our findings identify the minimal elements necessary for conferring NK cell lineage-specific expression of the Nkrp1c gene. These findings set the stage for the further characterization of the DNA-binding factors responsible for the expression of this and other NK-specific genes, shedding light on our understanding of how NK cell functions are regulated. For over fifteen years, surface expression of the NK1.1 marker has been used to identify all cells belonging to a specific subset of lymphocytes, defining them as natural killer (NK) cells. NK1.1 epitope is shared by two closely related, but functionally opposing NK cell receptors, the stimulatory NKR-P1C and inhibitory NKR-P1B gene products. Thus, the molecular basis of NKR-P1B/C signaling in NK cells was investigated. In particular, the tyrosine kinase, Lck, was identified as the initiator of signaling for both the stimulatory and inhibitory NKR-P1 receptors. Furthermore, the amino acid motif (CxCP) was shown to mediate Lck association to the receptors, as well as the inhibitory motif (LxYxxL) responsible for their divergent functions. Most strikingly, the Lck tyrosine kinase is required for NKR-P1 activation, as NK cells from Lck-deficient mice cannot mediate NKR-P1-directed killing. Importantly, this discovery represents the first NK cell defect reported in these mice. These findings provide the foundation for a sequential model to explain the opposing functional outcomes induced by these two NKR-P1 receptors, shedding light on our understanding of how NK cell functions are regulated.
Application of photothermal radiometry to hardness testing and case hardening monitoring in AISI 1018 steel

The focus of the presented research is the application of photothermal radiometry to hardness testing and case hardening monitoring of steel. 3-D frequency scan results along the end quenched Jominy bar AISI 8620 and 1018 are presented. The hardness profiles from mechanical hardness testing are compared with thermal diffusivity depth profiles, which are obtained by numerical fitting frequency responses, and the responses of several identical frequencies along the bar. 1-D frequency scans are performed on carbonitrided and quenched AISI 1018 samples. Radial line scan and 2-D lateral surface mapping are presented as techniques to select homogeneous samples. The comparisons of thermal diffusivity depth profiles with microhardness depth profiles show that there is a general anticorrelation between thermal diffusivity and hardness, but not perfect anticorrelation. The possibility of the industrial application of PTR case hardening testing and heat treatment monitoring without thermal diffusivity depth profile reconstruction is discussed.
Identifying genes affecting SAD-1 localization in Caenorhabditis elegans

SAD-1 is a neuron-specific Serine/Threonine protein kinase that regulates several aspects of neural development in Caenorhabditis elegans. Double immunostaining using antibodies against SAD-1 and other presynaptic proteins suggests that endogenous SAD-1 localizes to regions outside active zones at presynapses. I also observed that the synaptic subcellular localization pattern of endogenous SAD-1, as well as the SAD-1::RFP marker is partially altered in mutants for UNC-104, a kinesin motor that transports synaptic vesicles, suggesting that anterograde transport of SAD-1 is partially dependent on UNC-104. In a screen for mutations affecting the distribution pattern of hpIs1/SAD-1::GFP puncta, I recovered 25 phenotypically distinct mutants. Among them, unc-41(hp293), hp314(I), hp296(IV) may represent genes that function in general presynaptic differentiation because mutations in these genes also display defective morphology of other presynaptic markers. Another mutant, hp313, affects the SAD-1::GFP marker specifically, suggesting that it either regulates the transgene expression or represents a gene specifically affecting SAD-1.
Fountain codes over fading relay channels

This thesis designs and implements cooperative protocols based on fountain codes over fading relay channels. Unlike traditional fixed-rate codes, fountain codes are capable of adapting rate to the channel realization without knowledge of channel statistics at the transmitter, which makes then robust to severe variation of channel statistics in wireless channels. We first introduce several two-phase rateless cooperative protocols, and then simulate their performances by implementing Raptor codes with 16-QAM over a slow, deeply-interleaved fading relay channel. Given no delay constraints, the rate performances of these protocols are compared under different assumptions of network geometry. Furthermore, to reduce decoding complexity, we propose to use a soft-decision version of the adaptive demodulation (ADM) method recently introduced in the literature at each receiver. Finally, we analyze a more practical scenario when delay constraints are added, by focusing on a data streaming application.
Roles of blood flow, vascular binding, transporters and metabolic enzymes on drug processing in rat liver

The roles of blood flow, vascular binding, transporters and metabolic enzymes on hepatic drug processing were investigated theoretically and experimentally. A simple, physiologically-based pharmacokinetic (PBPK) model was developed to illustrate the competing nature of transporters and metabolic enzymes in hepatic drug processing. This was further extended to the zonal, physiologically-based pharmacokinetic (ZPBPK) model to include transporter and enzyme heterogeneity. Digoxin was used as the model compound to integrate various in vitro data on zonal hepatocyte uptake, protein binding and red blood cell (rbc) distribution into the ex vivo liver perfusion data via fitting and simulation with the ZPBPK modes. For this poorly cleared compound, clearance was rate-limited to binding to protein and rbc and not to the flow rate, and was unaffected by transporter and enzyme heterogeneity. The ACE inhibitor, enalapril (EN) was transported by human OATP1B1, OATP1B3 and MRP2 in single- or double-transfected mammalian cells. EN was also shown to be a substrate of rat Mrp2 in the Eisai hyperbilirubinemic rat (EHBR). In tumour-bearing livers derived from colon carcinoma metastasis, EN transport and metabolism was unchanged in the tumor-bearing liver vs. sham-operated livers, when EN was delivered into the portal vein or hepatic artery in perfused liver preparations. This project demonstrates that the blood flow, vascular binding, transporters and metabolic enzymes are all important factors that affecting the hepatic drug processing. The conceptual framework on hepatic drug extraction developed under normal conditions was able to explain drug disposition in livers that develop metastasic tumours.
Modelling volatility in financial markets

In this thesis, I study the dynamics of the volatility process and focus on estimation and forecasting. Recent research uses high frequency intraday data to construct ex post measures of daily volatility including realized volatility (RV). Chapter 1 is the introduction. In Chapter 2, I use a Bayesian approach to investigate the evidence for structural breaks in reduced form time-series models of RV. I focus on the popular heterogeneous autoregressive (HAR) models of the logarithm of realized volatility. Using Monte Carlo simulations I demonstrate that the estimation approach is effective in identifying and dating structural breaks. Applied to daily S P 500 data, I find strong evidence of a single structural break in log(RV). The main effect of the break is on the long-run mean and variance of log-volatility. Chapter 3 uses a Bayesian model averaging approach to forecast realized volatility. Candidate models include HAR specifications based on the logarithm of realized volatility, realized power variation, realized bipower variation, a jump and leverage term. The Bayesian model averaging provides very competitive density forecasts and consistent but modest improvements in point forecasts over the benchmarks. Applied to equity and exchange rate volatility over several forecast horizons, the Bayesian model averaging provides the best performance compared to the benchmarks including HAR, AR and simple model averaging models. I discuss the reasons for this, including the importance of using realized power variation as a predictor. In the last chapter, I propose a new joint model of volatility and duration in high frequency framework using tick-by-tick data. This model decomposes the conditional variance into different volatility components associated with different transaction horizons. Using stock market data, I demonstrate its superiority over the traditional GARCH counterpart. In addition, I show that a fat-tailed t-distribution for return innovations and a Burr distribution for duration innovations improve density forecasts, compared with normal and exponential distribution, respectively.
Parameter estimation and data detection in OFDMA systems

In the estimation stage, three training schemes are proposed to estimate CFO, PHN and channel response in OFDMA. Our contribution is to extend a previously derived single user CFO, PHN and channel estimation algorithm into the multiuser environment by applying the EM algorithm. This thesis considers the issue of parameter estimation and data detection in OFDMA systems. Analysis in previous works have shown that carrier frequency offset (CFO) and phase noise (PHN) have a very damaging effect in OFDMA systems. In order to mitigate their effects, a two-stage receiver is proposed. In the detection stage, using the CFO and channel estimates from the estimation stage, a joint PHN estimation and data detection algorithm is proposed by applying the multi-stage interference cancelation technique.