VictorJuiz/thesis huggingface dataset:
Mechanism of cognitive impairment in a chronic model of atypical absence seizures

Chronic atypical absence seizures (CAAS) commonly exist as a component of the Leanox-Gastaut syndrome, a malignant epileptic disorder in children. CAAS are more severe and disabling than the benign condition of typical absence seizures. While typical absence seizures are easily controlled by medication and are not accompanied by significant neuropsychological problems, CAAS are refractory to medication, and, more importantly, are often associated with severe mental retardation. The reason for their striking difference in neurodevelopmental outcome is not clear, but will require a better understanding of the neuropathology underlying CAAS. Using a validated animal model of CAAS, rats treated with a cholesterol biosynthesis inhibitor, AY9944 (AY), reliably reproduce the electrographic, behavioural, pharmacological and cognitive features of clinical CAAS. This study has found that AY-treated animals exhibit a working memory deficit in the spatial task of radial arm maze and are impaired in synaptic plasticity (i.e. long-term potentiation), the putative cellular substrate for learning and memory. The specific gamma-aminobutyric acid B receptor (GABAB R) antagonist, CGP35348, reverses the memory impairment in the AY model and corrects for the attenuated long-term potentiation in face of their spontaneous CAAS. The data thus suggest that the GABABR plays an important role in the cognitive dysfunction of AY-treated rats, which appears to be independent of their seizure activity per se. As a proof of concept, the cognitive phenotype of GABABR subunit 1a overexpressing transgenic mice, that also display CAAS, was evaluated. These mutant animals consistently demonstrated impairments in spatial memory of the radial maze task and in synaptic plasticity, therefore confirming the involvement of GABABR in the learning and memory deficit associated with CAAS. This work has provided the first evidence of the therapeutic potential of GABABR antagonists for the treatment of mental retardation in epileptic syndromes where CAAS are a component.
A hybrid fuel cell-battery power supply for an electric forklift

A forklift is a motorized vehicle that is used for lifting heavy objects. Currently, battery powered electric forklifts are the preferred choice for indoor applications. The main problem with these forklifts is the time it takes to recharge the battery. A solution to this problem is to power the forklift using a hybrid fuel cell---battery power supply, where the fuel cell is used to continuously charge the battery. This thesis seeks to determine the factors that affect the sizing of the two power sources in the hybrid power supply and the fuel cell's fuel consumption rate through the development of a software simulation program. The program simulates the behaviour of a hybrid powered forklift as it operates through a full day of activities. The hardware required to link the fuel cell and battery together was studied with a small scale hardware implementation of the hybrid power supply.
Role of α4 integrins in early stages of leukocyte recruitment

Leukocyte emigration across endothelium is a key process in normal physiology and the inflammatory response. The current paradigm involves an initial tethering interaction of the leukocyte with the endothelium followed by rolling, arrest, firm adhesion accompanied by cell shape change, and ultimately transendothelial migration. α4 integrins expressed on leukocytes have been shown to play a key role in each of these processes. Under normal conditions, α4 integrins have minimal ligand-binding activity. However, upon receiving the appropriate stimuli, α4 integrins rapidly gain the capacity to bind ligands. Two mechanisms have been proposed to explain ligand binding. Conformational changes alter integrin affinity resulting in stable binding of ligand. Enhanced lateral movement of integrins in the plasma membrane, clustering, and multivalent binding to oligomeric ligand results in increased avidity. Affinity and avidity changes may not be mutually exclusive. The present work tested the hypothesis that rapid changes in α4 integrin affinity may be required for monocyte arrest via binding to VCAM-1 and that, once adherent, signaling via α4 integrins may activate other leukocyte adhesion pathways which may promote the subsequent steps of emigration. The data demonstrate that chemoattractants rapidly increase α4 integrin affinity. Increased α4 affinity occurs within seconds upon exposure to chemoattractant, peaking within 0.5 to 2 minutes, and returns to baseline by 10–20 minutes. Chemoattractant-induced monocyte arrest on VCAM-1-coated surfaces is inhibited by the presence of soluble ligand, indicating that high affinity α4 integrins mediate leukocyte arrest. Analysis of molecular signaling pathways suggests that up-regulation of α4 integrin affinity by chemoattractants is a G-protein dependent event and implicates a key role for both intracellular and extracellular calcium. Ligand binding to high affinity α4 integrins can activate the adhesive function of αLβ2 integrins. Taken together, these studies suggest that α4 integrin affinity regulation is a key mechanism for monocyte arrest and that α4 integrins are capable of activating other leukocyte adhesion molecules during emigration.
The development of biological markers for the identification of intrauterine alcohol exposure

Confirmation of gestational ethanol exposure is required for the diagnosis of Fetal Alcohol Spectrum Disorder. The development of a novel neonatal screening test for fatty acid ethyl esters (FAEE) in meconium was investigated in this thesis. The potential application of meconium FAEE screening in the absence of maternal drinking history was investigated in a high-risk population. A substantial proportion of neonates (14%) suspected of intrauterine substance exposure were likely exposed to heavy maternal drinking, as identified by meconium screening. Baseline FAEE measurements in the meconium of neonates (n = 183) born to non-drinking mothers from Jerusalem and Toronto were investigated. Certain FAEE (ethyl laurate and myristate) were detected mostly at trace levels among non-exposed neonates. The presence of elevated levels of multiple FAEE (5--25 fold) and the presence of longer chain FAEE (ethyl palmitate, stearate, oleate, linoleate) were characteristic of neonates born to drinking mothers (n = 6). The use of cumulative FAEE measurements ge;2 nmol/g (excluding ethyl laurate and myristate) as a positive cut-off distinguished neonates with and without heavy prenatal alcohol exposure with the highest sensitivity (100%) and specificity (98%). The transfer and metabolic handling of FAEE by the human placenta was investigated to elucidate the origin of meconium FAEE. In vitro placental perfusion of 4 FAEE (ethyl palmitate, stearate, oleate, linoleate) at low and high concentrations (2--20 muM) in the absence and presence of a physiologic carrier, albumin, did not result in maternal-fetal transfer. Subsequent kinetic studies using subcellular preparations revealed that the majority of maternally derived FAEE were taken up and metabolized by enzymatic activities localized in the microsomal fraction of the human placenta (Mean Km 35--95 muM; Vmax 0.6--1.8 nmol/min/mg). Hence, FAEE detected in meconium were likely produced by the fetus from the ethanol that has been transferred to and metabolized by the fetus. These findings strongly support further validation of meconium FAEE as biomarkers of prenatal alcohol exposure. Future use of meconium FAEE screening as an objective and non-invasive method for the confirmation of intrauterine ethanol exposure can potentially facilitate earlier diagnosis and interventions in the affected children, leading to more favourable outcomes.
The roles of fgl2 in innate and acquired immunity: implications in chronic hepatitis B infection

Fgl2, also named as fibroleukin, is a member of the fibrinogen-related protein superfamily. The pivotal role of fgl2 in the pathogenesis of diseases (such as MHV-3-induced fulminant hepatitis, Th1 cytokine-induced fetal loss syndrome, and xenotransplantation) whose prominent feature involves fibrin deposition has been demonstrated. Several lines of evidence indicate that fgl2 exhibits a coagulation activity by being able to cleave prothrombin to thrombin; therefore, the induction of fgl2 during immune challenge may represent a novel mechanism whereby macrophages and endothelial cells activate the coagulation cascade. Here I expressed fgl2 protein in a baculovirus expression system and purified. The expressed protein exhibited similar biochemical property with the reported fgl2 protein detected previously in MHV-3 infected macrophages, verifying the efficacy of this expression system. The molecular basis of fgl2 prothrombinase activity was further explored. The kinetics of the enzymatic reaction of fgl2 to cleave human prothrombin to thrombin was examined. I found that the prothrombinase activity was detected only when fgl2 protein was reconstituted into negatively-charged phospholipids, and that Ser89 was critical for its activity. I also identified a novel immunomodulatory property of the soluble/non-membrane-associated fgl2, and further demonstrated that soluble fgl2 exerts immunosuppressive effects on T cell proliferation and LPS-induced DC maturation. The role of fgl2 and fibrosis in chronic hepatitis B infection were examined using an established HBV transgenic SCID mouse model. Collectively, my findings provide novel structural and functional insights into fgl2, which may play an important role in both innate and acquired immunity.
Pregnancy outcome and changes in smoking habits of women exposed to bupropion during pregnancy

Objectives. (1) determined whether bupropion increases the risk for major malformations or other perinatal complications. (2) determined the effectiveness of bupropion as a smoking cessation aid during pregnancy. Methods. A prospective, controlled study with three groups exposed to (1) bupropion, (2) other antidepressants and (3) non-teratogenic drugs. Participants were enrolled during their pregnancy and followed up postpartum. Results. 101 women exposed to bupropion, with 99 known pregnancy outcomes. There were 71 live births, 18 spontaneous abortions, 8 therapeutic abortions and no statistical differences between bupropion and comparison groups, except for spontaneous abortion. Rate of smoking cessation during pregnancy was greater in the bupropion group, 45% vs. 13.6% compared to controls (p = 0.047) Conclusions. Bupropion does not appear to be associated with increase risk for major malformation above 1–3% baseline, but spontaneous abortion rates were higher in the bupropion group. It appears to be effective for smoking cessation in pregnancy.
Modeling uncertainty with evolutionary improved "fuzzy functions"

Fuzzy system modeling (FSM)--meaning the construction of a representation of fuzzy systems models--is a difficult task. It demands an identification of many parameters. This thesis analyses fuzzy-modeling problems and different approaches to cope with it. It focuses on a novel evolutionary FSM approach--the design of "Improved Fuzzy Functions" system models with the use of evolutionary algorithms. In order to promote this analysis, local structures are identified with a new improved fuzzy clustering method and represented with novel "fuzzy functions". The central contribution of this work is the use of evolutionary algorithms--in particular, genetic algorithms--to find uncertainty interval of parameters to improve "Fuzzy Function" models. To replace the standard fuzzy rule bases (FRBs) with the new "Improved Fuzzy Functions" succeeds in capturing essential relationships in structure identification processes and overcomes limitations exhibited by earlier FRB methods because there are abundance of fuzzy operations and hence the difficulty of the choice of amongst the t-norms and co-norms.

Keywords: Industrial engineering
Artificial intelligence
Computer science
The effectiveness of the Heaviness of Smoking Index as a predictor of smoking cessation in Canada

Smoking is a serious problem in Canada and nicotine addiction is a major impediment for many people in quitting smoking. Using the National Population Health Survey, the relationship between Heaviness of Smoking Index (HSI) at baseline in Cycle 2 (1996--97) and successful smoking cessation two years later at Cycle 3 (1998--99) was examined in 2938 Canadian adult smokers. A logistic regression model was developed for HSI as a predictor of smoking cessation, and then tested for effect modification and confounding. Individuals with low HSI scores had significantly greater odds of quitting than those with moderate or high scores; however, individuals with high HSI scores exhibited higher odds of quitting than individuals with moderate scores, particularly when the period of follow-up was extended. When considering nicotine dependence in a population, other models, such as the effect of cognitive and affective factors, should be considered when approaching smoking cessation.
Hypothalamic control of circadian rhythms in aortic smooth muscle cells

The hypothalamic master clock coordinates circadian rhythms in peripheral tissues, including the vasculature. Evidence suggests peripheral clocks act to integrate time-of-day information from neural or hormonal signals, regulating gene expression, and subsequently organ physiology. Using the vascular smooth muscle cell line Movas-1, we investigated three potential hormonal signals, and the effect of the circadian clock on vascular gene transcription. Norepinephrine and forskolin treatment synchronized bmal1 mRNA expression. Whereas the potential hormonal signals arginine-vasopressin, vasoactive-intestinal peptide and gastrin-releasing peptide did not alter or synchronize bmal1 or per1 expression. Serum synchronization of Movas-1 induced cycling of timp1, timp3, col3a1, sm22alpha and cnn1 mRNA. Microarray and real-time RT-PCR analysis of mouse aortic tissue revealed ultradian rhythms in these genes similar to the cycling observed in Movas-1. This work provides insight into the hormonal regulation of the vascular clock, and implicates the circadian machinery as an important regulator of gene expression in this tissue.
Tunable RF bandpass delta-sigma digital receivers with millimetre-wave sampling clocks

This thesis presents the design and implementation of direct digitizing analog-to-digital converters for software-defined radio receivers. A new design methodology in the s-domain for continuous-tithe DeltaSigma ADCs is presented. The system level design is carried out entirely in continuous-time by appropriately linearizing the digital components of the loop. A new circuit topology is introduced in the loop filter, which provides higher linearity and lower noise than previously reported filters. The filter is based on the combination of a MOSFET and HBT transistor, which also allows for low power operation. The feasibility of mm-wave sampling is investigated in both SiGe BiCMOS and nanoscale CMOS technologies. The critical building blocks of the mm-wave analog-to-digital converter are implemented in SiGe BiCMOS and nanoscale CMOS. New topologies for the single-bit quantizer and clock distribution network are proposed in CMOS. The CMOS transitnpeclance amplifier proves the best solution for broadband ainplifieatioa in nanoscale technologies, where the power supply must be kept lower than 1.2 V.A novel latch topology employing devices with low and high VT allows for operation at 40-Gb/s from 1.2 V with a record low power dissipation per latch. The design techniques presented in this work lead to the first analog-to-digital converter operating at mm-wave frequencies in any semiconductor technology. The 40-GHz continuous-time SigmaDelta ADC centered at 2 GHz achieves 59.8 dB of SNR over 60 MHz of signal bandwidth. The integration of the ADC with a 40-GHz PLL results in the world's first direct sampling mm-wave receiver. A comparison of measured receiver performance when external and on-chip clock source is employed shows no significant degradatioil for SNR of 60 dB. Furthermore, experimental results on a tunable digital receiver centered at 5 GHz and clocked at 40 GHz prove that the resolution of a continuous-time bandpass DeltaSigma modulator is a strong function of the filter quality factor.
Biological functions of commissureless and dNedd4 in axon guidance at the midline and in muscle synaptogenesis in Drosophila melanogaster

Ectopic expression of Comm(WT) in the muscles revealed a punctate, vesicular pattern, whereas, mutant Comm(2PY rarr; AY and 10K rarr; R) localizes to the muscle wall. Accordingly, aberrant muscle innervation is observed for the Comm(2PY rarr; AY and 10K rarr; R) mutants and also when dNedd4 is knocked-down by RNA interference. In this study, Drosophila melanogaster was used as an in vivo model system to examine the biological function of Commissureless (Comm) and dNedd4 (n barbelow;euronal precursor cell-e barbelow;xpressed d barbelow;evelopmentally d barbelow;ownregulated 4) in the process of axon guidance and muscle synaptogenesis. I have generated UAS-comm (WT, 2PY rarr; AY and 10K rarr; R) transgenic flies as well as UAS-dNedd4RNAi flies to reduce endogenous dNedd4 protein. Panneural expression of Comm(10K rarr; R) revealed a robo-like phenotype. Biochemical analysis revealed that Robo protein is reduced in the presence of Comm(10K rarr; R), suggesting that Robo is unstable. Similarly, panneural expression of dNedd4RNAi also produces a phenotype, resembling the Comm(2PY rarr; AY) mutant, with interruptions occurring along the longitudinal axons.
Communication of musical closure in performance: An investigation of non-pitch cues

The role of performance expression in the communication of tonal closure was examined. In Experiment 1, musicians hummed two versions of Silent Night, one ending that was tonally closed and another that was unclosed. All pitches were then set to a constant value using ProTools, so that the phrases only varied in the use of performance expression. Participants judged whether each sequence was closed or unclosed. The proportion of "closed" judgments was not higher for closed or unclosed sequences; however, some performers more capably communicate tonal closure than others. In Experiment 2, video recordings of the same hummed sequences were presented (no sound). Participants judged whether the (imagined) melody was closed or unclosed. The proportion of closed judgments was higher for closed than unclosed sequences. The results confirm that musicians express tonal closure and listeners decode such visual cues. The implications for models of musical performance are discussed.
The evolution of transitions between pollination modes in Penstemon

Adaptation to pollinators is considered a major force shaping floral form and function. One approach to studying the mechanisms behind floral diversification is to concentrate on pollinator shifts. A pollinator shift, or transition, is the change in a plant lineage, over evolutionary time, from being adapted to using one type of pollinator to adapting to another type. The purpose of this thesis was to investigate how mechanical aspects of pollination affect the evolution of transitions from insect-pollination to hummingbird-pollination, using the plant genus Penstemon as a model. Two discrete types of Penstemon flowers are distinguished, associated with either bee- or hummingbird-pollination. Convergent transitions to hummingbird-pollination have occurred at least 14 times independently within the group. The superior pollination efficiency of hummingbirds over bees might account for the repeated transitions to hummingbird-pollination. I compared the two pollinators visiting bee-adapted Penstemon strictus and bird-adapted P. barbatus. On P. strictus, bees and birds had similar pollen transfer efficiencies, but hummingbirds were more efficient on P. barbatus than on P. strictus. I propose that a change in nectar rewards that makes a Penstemon patch more attractive to hummingbirds can trigger a shift to more-efficient bird-pollination by simple floral changes. Such changes include characters that explicitly exclude bees. Shifts to hummingbird-pollination can be explained under such conditions, but unless the conditions are sustained, bee-pollination constitutes a stable strategy. Similar trade-offs probably contribute to the formation and maintenance of diversity in flower form across angiosperms. When specializing on hummingbird pollination, floral characters may change to improve the morphological fit between bird and flower, or to exclude the less efficient bees, or both. I experimentally modified floral traits in P. strictus to resemble bird-syndrome flowers, and found effects on pollen transfer, suggesting that restricting pollination by bees played an important role in the evolution of hummingbird-flowers. Additionally, I contrasted patterns of pollen presentation in the two types of flowers across penstemons. Previous models predicted less gradual pollen presentation by flowers with more efficient pollinators. After controlling for relatedness, I found less restricted presentation in hummingbird-pollinated penstemons, consistent with the finding that birds are more efficient than bees.
An examination of glial apoptosis and the death receptors FAS and P75 in the pathophysiology of spinal cord injury

Apoptosis and the programmed cell death pathways with which it is associated may represent new targets for therapeutic intervention in spinal cord injury and neurotrauma. Evidence from animal models is accumulating to suggest that these processes do occur following injury to the central nervous system. This thesis examined apoptosis and the FAS and P75 death receptor pathways after spinal cord injury in the rat and mouse. Evidence of apoptosis following rat spinal cord injury came from DNA agarose electrophoresis, TUNEL, and electron microscopy. TUNEL experiments with double labeling immunohistochemistry indicated that the majority of these cells were oligodendrocytes (the remainder being largely microglia). Post-traumatic apoptosis in the spinal cord peaked at 7 days and was temporally and spatially related to degenerating axons. Furthermore, both the FAS and P75 death receptors were expressed on oligodendrocytes, microglia and TUNEL positive cells after spinal cord injury. The timecourse of expression for these proteins together with the timecourse of caspase 8 and 3 activation were examined by western blotting. These experiments suggested that FAS expression, and downstream caspase activation, shared the same temporal distribution as TUNEL after spinal cord injury. In FAS deficient mice the pathology of spinal injury was ameliorated with evidence of decreased cell death and axonal preservation. In vitro organotypic spinal cord slices from these mice showed less cell death after injury and less caspase activation. These findings were associated with improved behavioral recovery, improved axonal integrity and sparing of white matter in chronically injured animals. These experiments are the first to demonstrate a neuroprotective effect by inhibition of a programmed cell death pathway in spinal cord injury. The data indicate that the time window for intervention after spinal cord injury is far longer than was previously held; that glial cell death is associated with posttraumatic axonal degeneration and is a key mechanism in the pathophysiology of this injury; and that the role of other programmed cell death pathways should be explored. More directly, this thesis indicates that the FAS death receptor pathway influences glial apoptosis and axonal integrity after spinal cord injury and thus represents a potential target for therapeutic intervention.