Yes / Conference abstract

The effects of smoking cigarettes on sensory gating, P50 and stimulus-bound gamma band (32-48 Hz) oscillations were examined in two paradigms: paired-tone and oddball. During a paired-tone paradigm, our previous work (Crawford, McClain-Furmanski, Castagnoli, & Castagnoli, Neuroscience Letters 317(2002) 151-155) found heavy smokers exhibited chronic (rather than acute) effects in the frontal region: (1) larger P50 and GBO responses; (2) greater P50 and GBO sensory gating suppression, as well as earlier GBO sensory gating suppression. During an oddball paradigm, we (McClain-Furmanski, Crawford, Castagnoli & Castagnoli, in prep.) found an acute effect between 0 and 20 ms post-stimulus in the GBO, however we were unable to determine whether this effect was due to nicotine or the act of smoking. In the present study, participants were 24 heavy cigarette (20+/day) right-handed, non-depressed smokers with no known medical or psychiatric problems, and no known familial history of psychiatric problems. In the morning, they were tested after abstaining overnight and after smoking a cigarette containing either 1.1 mg of nicotine, or a denicotinized cigarette (< 0.04 mg). In study 1 (oddball paradigm), although some effects were found related to nicotine and/or smoking, observed as condition by group interactions with the groups changing differently across conditions, they differed in temporal and spatial localization from those hypothesized. Thus, the present study was unable to differentiate between nicotine effects and effects due to the act of smoking. In study 2 (paired-pulse paradigm), in traditional evoked potential analysis, we observed signficant chronic sensory gating, as measured by the ratio of N40-P50 amplitude in response to the second tone (S2) as compared to the response to the first tone (S1). The effect was greatest at the hypothesized location (FCZ). In time series analysis of the underlying GBO, we replicated our earlier findings in that S2/S1 effects could be detected across 60 msec of the response. These results are discussed in relation to the neurochemistry and neural processes underlying sensory gating at GBO production, as well as in relation to the known and hypothesized psychpharmacological effects of smoking tobacco. Furthermore, these results are related to the theorized basis of addiction. / Ph. D.

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Casting as a manufacturing process to make complex shapes of metal materials in mass production may experience many different defects such as porosity and incomplete filling. How to improve the casting quality becomes important. Gating/riser system design is critical to improving casting quality. The objective of the research presented in this thesis is to optimize gating/riser systems based on CAD and simulation technology with the goal of improving casting quality such as reducing incomplete filling area, decreasing large porosity and increasing yield. Therefore in the thesis, an optimization framework is presented based on CAD and simulation technology. Given a CAD model of part design and after converted to a casting model, it is the first step to evaluate castability of the casting design. Then the runner and risers are represented parametrically, and CAD models generated by varying parameters can be used in the simulation. After analyzing simulation results, the gating/riser system design is optimized to improve casting quality. In the thesis, one engine block is used to verify the effectiveness of the optimization method. Compared with the initial design, it is found that the optimized casting design can decrease porosity around 18% while the yield increases 16%.

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Sensory gating helps prevent incoming irrelevant sensory information from entering into the higher cortex and ensures normal information processing. Sensory gating is seen as the ability of the nervous system to modulate its sensitivity to incoming stimuli (Braff & Geyer, 1990; Adler, Olincy, Waldo, Harris & Griffith, et al., 1998). Smoking tobacco can facilitate early sensory gating in schizophrenics, and enhance prepulse inhibition asymmetry (right greater than left) in individuals with schizotypal personality. The purpose of this study was to test the following hypotheses: 1) Individuals with schizotypal personalities have poorer sensory gating than those without them. 2) Among individuals with schizotypy (high schizotypy), those who smoke have better sensory gating than those who do not smoke; among those without schizotypy (low schizotypy), smokers will demonstrate better sensory gating. 3) After abstaining, schizotypal smokers will show increased sensory gating due to smoking. 4) Individuals with schizotypy will show greater P50 deficits in the left hemisphere, and smoking can enhance this asymmetry (left greater than right). From 613 online-surveyed participants, 39 (18 men) right-handed undergraduates (Mean age = 18.87) were selected to represent four groups: High and Low Schizotypy, half of which were smokers, and half were non-smokers. Smokers were tested while abstaining and after smoking. Non-smokers were tested twice in the same manner without smoking. P50 sensory gating, P50 amplitude and P50 latency were analyzed separately at frontal (F3, F4, Fz), fronto-central (FC3, FC4, FCz), central (C3, C4, Cz), centro-parietal (CP3, CP4, Cpz) and parietal (P3, P4, Pz) regions. With respect to the hypotheses of the study, it was found that: 1) Sensory gating, as assessed by S2 (P50-N40)/S1 (P50-N40), was greater at frontal-central and central regions in comparison to mid-frontal and parietal regions. 2) Furthermore, sensory gating was significantly greater at midline than left or right hemispheres. 3) Condition 1 showed better sensory gating than Condition 2. 4) The High Schizotypy group showed poorer sensory gating than the Low Schizotypy group among non-smokers. 5) Smokers showed poorer sensory gating than non-smokers in the Low Schizotypy group. In terms of P50 amplitude, it was found that: 1) FCz and Cz showed the highest P50 amplitude, greater than all other sites. 2) S1 had higher P50 amplitude than S2. 3) The low schizotypy individuals had significantly greater P50 amplitude in the left than in the right fronto-central region, but the high schizotypy individuals showed more P50 amplitude in the right hemisphere than did the low schizotypy individuals. 4) Smokers showed a greater left than right P50 amplitude in centro-parietal region, whereas the non-smokers showed the opposite asymmetry with a greater right than left P50 amplitude in central, centro-parietal and parietal regions. In terms of P50 latency, it was found that: 1) The P50 latency became significantly slower from posterior to anterior sites. 2) In HiS/S and LoS/NS groups, Condition1 was faster than Condition 2. In LoS/S and HiS/NS groups, Condition1 was slower than Condition 2. 3) Among smokers, left hemisphere latency was shorter than right hemisphere for S1, but for S2, left hemisphere was slower than right hemisphere. Among non-smokers, left and right hemisphere latencies were almost the same for S1 and S2. / Master of Science

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Ligand-gated ion channels couple intra- and extracellular chemical signals to cellular excitability. In response to a specific ligand, these channels change their permeability to certain ions by opening or closing their ion conductive pathway, a controlling mechanism known as channel gating. Although recent studies with X-ray crystallography and site-directed mutagenesis have revealed several structures potentially important for channel gating, the gating mechanism is still elusive. Ligand-dependent channel gating involves a series of transient events and asymmetric movements of individual subunits. Understanding of these events appears to be a challenge to current approaches in gating studies by using the homomeric wild-type or mutant channels. I therefore took an alternative approach by constructing heteromeric channels. Subunit stoichiometric studies of the Kir1.1 channel showed that a minimum of one functional subunit was required for the pH-dependent gating of the channel. Four subunits in this channel were coordinated as dynamic functional dimers. In Kir6.2 channel, stoichiometry for proton-binding was almost identical to that for channel gating in the M2 helix, suggesting a one-to-one direct coupling of proton binding in C-terminus to channel gating in M2 helix. Positive cooperativity was suggested among subunits in both the proton binding and channel gating. Ligand binding can be differentiated from channel gating by studying the ATP-dependent gating of Kir6.2 channel. Disruptions in ATP binding were found to change both the potency and efficacy of the concentration-dependent curves, while the baseline activity instead of maximum inhibition was affected by disruptions of channel gating. Four subunits in the Kir6.2 channel undergo negative cooperativity in ATP binding and positive cooperativity in channel gating. The ligand binding was coupled to the gating mechanism in the same subunit and neighboring subunits, although the intrasubunit coupling was more effective. These results are well described with the operational model which we have applied to ion channel studies for the first time. By manipulating the relative distance and the interaction of two transmembrane helices, the inner helix bundle of crossing was found to not only serve as a gate but also determine the consequence of ligand binding.

Voltage clamp fluorometry (VCF) was first developed in the mid 1990s by Isacoff and his colleagues. In this approach fluorophores are attached to substituted cysteine residues that are engineered by site-directed mutagenesis. Changes in the dielectric environment of the fluorophore report local transitions that are associated with electrically-related and electrically-silent transitions. VCF provides a powerful technique to observe real time reports of ion channel gating conformations. It has proven to be a useful technique because it adds insight that is not available using other techniques. X-ray crystallography studies give a predominantly static picture of the channel, while patch clamping of channels gives information only about residues that effect ionic current flow. Similarly, gating current provides insight only about residues that are charged and move across the membrane electric field. In this thesis we examined the structural rearrangements of the Shaker channel and the effect of 4-AP on channel gating. We also examined for the first time the structural rearrangements of the Kv1.5 gating and the how the channel responds to depolarization pulses. This work is instrumental in the examination of the potassium channel gating.