Mimicking natural evolution to solve hard optimization problems has played an important role in the artificial intelligence arena. Such techniques are broadly classified as Evolutionary Algorithms (EAs) and have been investigated for around four decades during which important contributions and advances have been made. One main evolutionary technique which has been widely investigated is the Genetic Algorithm (GA). GAs are stochastic search techniques that follow the Darwinian principle of evolution. Their application in the solution of hard optimization problems has been very successful. Indeed multi-dimensional problems presenting difficult search spaces with characteristics such as multi-modality, epistasis, non regularity, deceptiveness, etc., have all been effectively tackled by GAs. In this research, a competitive form of GAs known as fine or cellular GAs (cGAs) are investigated, because of their suitability for System on Chip (SoC) implementation when tackling real-time problems. Cellular GAs have also attracted the attention of researchers due to their high performance, ease of implementation and massive parallelism. In addition, cGAs inherently possess a number of structural configuration parameters which make them capable of sustaining diversity during evolution and therefore of promoting an adequate balance between exploitative and explorative stages of the search. The fast technological development of Integrated Circuits (ICs) has allowed a considerable increase in compactness and therefore in density. As a result, it is nowadays possible to have millions of gates and transistor based circuits in very small silicon areas. Operational complexity has also significantly increased and consequently other setbacks have emerged, such as the presence of faults that commonly appear in the form of single or multiple bit flips. Tough environmental or time dependent operating conditions can trigger faults in registers and memory allocations due to induced radiation, electron migration and dielectric breakdown. These kinds of faults are known as Single Event Effects (SEEs). Research has shown that an effective way of dealing with SEEs consists of a combination of hardware and software mitigation techniques to overcome faulty scenarios. Permanent faults known as Single Hard Errors (SHEs) and temporary faults known as Single Event Upsets (SEUs) are common SEEs. This thesis aims to investigate the inherent abilities of cellular GAs to deal with SHEs and SEUs at algorithmic level. A hard real-time application is targeted: calculating the attitude parameters for navigation in vehicles using Global Positioning System (GPS) technology. Faulty critical data, which can cause a system’s functionality to fail, are evaluated. The proposed mitigation techniques show cGAs ability to deal with up to 40% stuck at zero and 30% stuck at one faults in chromosomes bits and fitness score cells. Due to the non-deterministic nature of GAs, dynamic on-the-fly algorithmic and parametric configuration has also attracted the attention of researchers. In this respect, the structural properties of cellular GAs provide a valuable attribute to influence their selection pressure. This helps to maintain an adequate exploitation-exploration tradeoff, either from a pure topological perspective or through genetic operations that also make use of structural characteristics in cGAs. These properties, unique to cGAs, are further investigated in this thesis through a set of middle to high difficulty benchmark problems. Experimental results show that the proposed dynamic techniques enhance the overall performance of cGAs in most benchmark problems. Finally, being structurally attached, the dimensionality of cellular GAs is another line of investigation. 1D and 2D structures have normally been used to test cGAs at algorithm and implementation levels. Although 3D-cGAs are an immediate extension, not enough attention has been paid to them, and so a comparative study on the dimensionality of cGAs is carried out. Having shorter radii, 3D-cGAs present a faster dissemination of solutions and have denser neighbourhoods. Empirical results reported in this thesis show that 3D-cGAs achieve better efficiency when solving multi-modal and epistatic problems. In future, the performance improvements of 3D-cGAs will merge with the latest benefits that 3D integration technology has demonstrated, such as reductions in routing length, in interconnection delays and in power consumption.

Oxycodone is a semi-synthetic opioid originally developed as a safer alternative to morphine. It is commonly prescribed for its pain-relieving effects, but has recently been implicated as a major underlying cause of the current opioid epidemic due to its clinical limitations that include tolerance, dependence and a high abuse liability. Simultaneous consumption of opioids and ethanol has been shown to increase the risk of overdose and death from opioids in opioid-tolerant individuals. We hypothesized that ethanol reversed opioid tolerance and previous studies showed that ethanol reversed morphine tolerance. This dissertation investigated whether ethanol reversed tolerance to other opioids in mice, primarily oxycodone. We found that tolerance developed to the antinociceptive effects of both oxycodone and hydrocodone, and that the same dose of ethanol (1 g/kg i.p.) reversed that tolerance. Oral ethanol (2 g/kg) also effectively reversed oxycodone tolerance. Ethanol did not significantly alter either acute or chronic oxycodone brain concentrations, suggesting that the reversal effect was mediated by neuronal mechanisms. DRG neurons were isolated from adult mice and the effects of oxycodone were assessed using whole-cell patch clamp electrophysiology experiments. Oxycodone [3µM] acutely reduced neuronal excitability as measured by a shift in threshold potentials to a more positive value. DRG neurons incubated overnight with 10µM oxycodone did not respond to the 3µM oxycodone challenge, indicating tolerance developed within these neurons. To test if ethanol was reversing tolerance through neuronal mechanisms, we incubated DRG neurons overnight with 10µM oxycodone and applied 20mM ethanol to the media prior to recording. Tolerance was robustly reversed in these neurons, as indicated by a response to 3µM oxycodone. The PKC inhibitor, Bis XI, also reversed oxycodone tolerance. In these studies we have clearly shown that tolerance develops to oxycodone in both the whole animal in an isolated neuronal preparation. In addition we have shown that the tolerance produced in these two preparations was reversed by ethanol at blood levels similar to those seen in humans. Further we have also included preliminary data that suggest that this reversal of oxycodone tolerance by ethanol may well be due to its actions on PKC.

QC 351 A7 no. 61 / In an attempt to design a three -mirror aspheric camera, a procedure was developed to arrive at a design with a minimum obscuration ratio. It was found that, in some cases, the sky baffling became the diffracting obscuration rather than the obscuration caused by the secondary. The procedure allowed for this and was able to select a system with the smallest diffracting obscuration in the pupil. Initially, two designs were selected and optimized through the use of aspheric surfaces. The designs represented two extremes in that one had much faster surfaces than the other. The fast mirror system was easier to optimize, performed better, and had the shorter over -all length. Further, evaluation of manufacturing errors on the fast mirror design showed that an acceptable level of performance could be expected if the errors were kept small. The maximum errors are spacing errors ±0.0005 in. tilt of surface errors ±0.001 /D in. radii of curvature errors ±0.125 in. where D is the diameter of the mirror surface.

Recent advances in synthetic biology have enabled the construction of non-native metabolic pathways for production of next-generation biofuels in microbes. One such biofuel is the jet-fuel precursor α-pinene, which can be processed into high-energy pinene dimers. However, accumulation of toxic biofuels in the growth medium limits the possible fuel yield. Overexpression of transporter proteins such as efflux pumps can increase tolerance to biofuels by pumping them out of the cell, thus improving fuel yields. However, too many efflux pumps can compromise the cell as well, creating a trade-off between biofuel toxicity and pump toxicity. In this work we improve the conditions of this trade-off in order to increase pinene tolerance in E. coli. We do so by constructing strains incorporating multiple efflux pumps from a variety of organisms and then testing them for tolerance in growth assay experiments. Previous research has suggested that certain combinations of efflux pumps can confer additional tolerance compared to the individual pumps themselves. However, the functional form of the combination of the tolerance provided by each pump and the toxicity due to their simultaneous activity is unknown. Using differential equations, we developed a growth model incorporating the trade-offs between toxicity of α-pinene and efflux pump activity to describe the dynamics of bacterial growth under these conditions. By analyzing biofuel toxicity and the effects of each efflux pump independently through a series of experiments and mathematical models, we propose a functional form for their combined effect on growth rate. We model the mean exponential growth rate as a function of pump induction and biofuel concentration and compare these results to experimental data. We also apply this technique to modeling toxicity of ionic liquids, a class of corrosive salts that has emerged as and effective chemical for pretreatment of biofuel production feedstock. We compare a model for a variety of ionic liquid responsive efflux pump controllers to that of an IPTG inducible controller and show agreement with experimental data, supporting the model's utility to test control schemes before conducting experiments. The overall goal of this project is to use modeling to guide design of tolerance mechanisms to improve overall biofuel yield.

BACKGROUND: It is well known that those taking chronic opioid pain medications often become tolerant to the medications and require escalating doses over time (Drewes, 2017). No objective method to identify tolerance currently exists. OBJECTIVE: The objective of this study is to determine the usability and feasibility of a wearable biosensor technology to determine a transition point between opioid naivety and tolerance. METHODS: Participant’s were recruited in the Emergency Department setting and were being admitted with a treatment plan that includes opioid analgesics. Participants were instructed to wear the sensor at all times and to ‘tag’ the sensor when opioid pain medications were administered. This data was analyzed for trends and changes in sensor data before and after opioid administration. Research staff also conducted formative interviews during and after hospital admission to gather information on the participants’ perception of the wearable biosensor and of opioid tolerance. RESULTS: The sample included 17 participants who received, on average, 21.2 morphine equivalents per day during admission. Over 90% of participants stated that they would wear the sensor again, and 70% would even wear two. Data analysis from the E4 biosensor indicated a difference between baseline physiological signaling and post-opioid administration. CONCLUSIONS: In this study, feasibility of wearable mHealth technology was assured, and the preliminary findings of the biosensor data suggest that the features from activity data at different axes can predict opioid use. Future studies will evaluate the development of tolerance among these participants. / 2021-06-17T00:00:00Z

Leung Siu Wai. / Bibliography: leaves 135-150 / Thesis (M.Ph.)--Chinese University of Hong Kong, 1984

Objectives: Tolerance is a hyporesponsive state caused by repeated exposure to a stimulus. In the intestine, dysregulation of tolerance to luminal stimuli may lead to chronic and deleterious inflammation, such as characterizes Inflammatory Bowel Disease. The role of T-cells in immune tolerance is well known, but that of the epithelium requires investigation. Epithelial tolerance is gene-specific and differentially regulated, but the role of and involvement of epigenetics in tolerance regulation is unknown. We hypothesized that prior stimulation may cause epithelial cells to become hyporesponsive (tolerized) and that modification of histone methylation may alter the response to pro-inflammatory stimulation. The aim of this work was to examine if known inhibitors of histone methylation modifying enzymes affected the expression of CXCL8 in response to IL-1β. Methods: CXCL8 production of intestinal epithelial cells was measured by ELISA after stimulation with the pro-inflammatory stimuli P3CK and IL-1β and small molecule epigenetic inhibitors. The CXCL8 production of cells stimulated with a pro-inflammatory stimulus was compared to pre-stimulated cells after a second stimulus. CXCL8 production of IL-1β-pre-stimulated cells was also compared to CXCL8 production when these cells were incubated with epigenetic inhibitors. The effects of these inhibitors on histone methylation levels were examined by Western blotting for the global effect and by ChIP-qPCR for specific effects at the CXCL8 locus. Results: Intestinal epithelial cells stimulated with pro-inflammatory stimuli produced a large CXCL8 response. Pre-stimulation significantly decreased CXCL8 production after a second stimulus. The time-course of CXCL8 expression was measured to ensure that CXCL8 expression due to pre-stimulation was over before the second IL-1β-stimulation. In the presence of specific epigenetic inhibitors, pre-stimulation by IL-1β did not reduce CXCL8 production after a second IL-1β- stimulation. The specific effect of these inhibitors on the epigenetic signature at the CXCL8 locus was confirmed by ChIP. Thus, histone methylation modification disrupted tolerization of intestinal epithelial cells to a pro-inflammatory stimulus. Conclusion: The inflammatory response of the intestinal epithelium can be tolerized by prior stimulation with pro-inflammatory cytokines. Tolerization is lost after incubation with inhibitors known to modify histone methylation status, indicating for the first time, the involvement of histone methylation in this phenomenon.

The legacy of historical biogeography impacts many organisms and results in a wide range of character variation over a latitudinal gradient. The pitcher-plant mosquito Wyeomyia smithii is one such organism that demonstrates a wide range of phenotypic and genotypic variation over the entirety of its range from the Gulf Coast to Canada. A geographic cline established by the presence and recession of the Laurentide Ice Sheet is manifest in the narrow range of thermal tolerance exhibited by different populations and also in the differing propensity of bloodfeeding by these mosquitoes. These contemporary clines were analyzed by a variety of experimental methods ranging from year-long fitness assays, scanning electron microscopy, and RNA-sequencing to determine the patterns underlying the resulting evolutionary differences among established populations. This dissertation includes both unpublished and co-authored material.

Barely Visible Impact Damage (BVID) can occur when laminated composite material is subject to impact, i.e. from runway debris or dropped tools, and may result in a significant reduction in the compressive strength of composite structures. A component containing BVID subjected to compression may fail via a number of mechanisms. However, it is assumed that the impact damage problems to be modelled will fail by delamination buckling leading to propagation of damage away from the original site. This precludes problems where the initial mechanism of failure is via kink banding or buckling of the full laminate. An analytical model is presented, for application to various composite structures, which predicts the level of compressive strain below which growth of BVID following local buckling of a delaminated sublaminate will not occur. The model is capable of predicting the critical through-thickness level for delamination, the stability of delamination growth, the sensitivity to experimental error in geometric measurements of the damage area and additionally establishes properties desirable for laminates optimised for damage tolerance. Problems treated with the model are split into two impact categories; ‘face’ (i.e. an out-of-plane skin impact) and ‘free edge’ (i.e. an in-plane stiffener edge impact) and two compressive loading regimes; ‘static’ and ‘fatigue’. Analytical results for static and fatigue compression of face impacted plates show an agreement of threshold strain to within 4% and 17% of experimental values respectively. In particular, for impacts to the skin under a stiffener subject to static loading the model is accurate to within 5%. An optimised laminate stacking sequence has shown an experimental increase of up to 29% in static strength can be achieved in comparison to a baseline configuration. Finally, compression testing has been undertaken on three coupons in order to validate an analysis of static free edge problems. Analytical results are, on average, within 10% of experimental results. An optimised laminate is theoretically predicted to increase static compression after free edge impact strength by at least 35%.

This document presents the Centralized Energy Management System (CEMS), a dynamic fault-tolerant reclustering protocol for wireless sensor networks. CEMS reconfigures a homogeneous network both periodically and in response to critical events (e.g. cluster head death). A global TDMA schedule prevents costly retransmissions due to collision, and a genetic algorithm running on the base station computes cluster assignments in concert with a head selection algorithm. CEMS' performance is compared to the LEACH-C protocol in both normal and failure-prone conditions, with an emphasis on each protocol's ability to recover from unexpected loss of cluster heads.