The human visual system gathers information about three-dimensional object shape from a wide range of sources. How effectively we can use these sources, and how they are combined to form a consistent and accurate percept of the 3D world is the focus of much research. In complex scenes inter-reflections of light between surfaces (mutual illumination) can occur, creating chromatic illumination gradients. These gradients provide a source of information about 3D object shape, but little research has been conducted into the capabilities of the visual system to use such information. The experiments described here were conducted with the aim of understanding the influence of chromatic gradients from mutual illumination on 3D shape perception. Psychophysical experiments are described that were designed to investigate: If the human visual system takes account of mutual illumination when estimating 3D object shape, and how this might occur; How colour shading cues are integrated with other shape cues; The relative influence on 3D shape perception of achromatic (luminance) shading and chromatic shading from mutual illumination. In addition, one chapter explores a selection of mathematical models of cue integration and their applicability in this case. The results of the experiments suggest that the human visual system is able to quickly assess and take account of colour mutual illuminations when estimating 3D object shape, and use chromatic gradients as an independent and effective cue. Finally, mathematical modelling reveals that the chromatic gradient cue is likely integrated with other shape cues in a way that is close to statistically optimal.

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Cancer therapy traditionally seeks to achieve complete tumor eradication via induction of cancer cell death by chemotherapeutic agents or radiation. An alternative strategy is to induce cytostasis, i.e. to arrest proliferation of cancer cells, perhaps in parallel with conventional chemotherapy. Such an alternative strategy could provide prolonged survival with less severe consequences of cytotoxic agents. To be truly effective, a chemotherapeutic drug should exert its action on biochemical targets specific for neoplastic cells while leaving the normal cells unaffected. Therefore, the knowledge of tumor cell-specific biochemical and signaling pathways is a pre-requisite for development of new, prospective anticancer drugs. In this study, we concentrated on the energy metabolism which is remarkably different in tumor and healthy cells. Cancer cells generate ATP mainly through the glycolytic pathway, and depend far less on oxidative phosphorylation (the Warburg effect). The way cancer cells generate energy reflects their need for energy as well as building blocks required for fast biosynthesis. Glycolysis, in contrast to oxidative phosphorylation, enhances biosynthetic pathways thus accelerating progression of tumor cells through the cell cycle. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) occupies a central position in the glycolytic pathway thus playing a critical role in the energy metabolism of cancer cells. Along with its enzymatic activity, GAPDH is a multifunctional protein which acts as a signaling and regulatory molecule in several cellular mechanisms. Based on the fact that glycolysis plays a pivotal role in survival of cancer cells, we hypothesized that down-regulation of GAPDH protein would alter the cancer cell proliferation, and cellular sensitivity of cancer cells to chemotherapy. The goal of this study was to evaluate GAPDH as a potential molecular target for treatment of cancer. In this project, our aims were: 1) To determine the effect of GAPDH level on cell proliferation and cell cycle progression of human carcinoma cells; 2) To elucidate the molecular mechanism(s) causing proliferation arrest in GAPDH-depleted cells; 3) To identify the chemotherapeutic agents exhibiting cytotoxic effect against non-dividing, senescent cells; 4) To analyze molecular dynamics of nuclear GAPDH and its mutant variants in the context of chemotherapy-induced stress. Towards these aims, we developed an experimental model where the level of GAPDH in human carcinoma cells was modulated by RNA interference (RNAi) technology. In vitro experiments were performed in this model system to evaluate the energy status, and signaling pathways in cancer cells after GAPDH depletion. Human carcinoma isogenic cell lines with different levels of GAPDH protein were analyzed for the sensitivity to various chemotherapeutic agents. Using site-mutagenesis, we prepared mutated variants of GAPDH and estimated their enzymatic activity. We also prepared constructs where GAPDH cDNA was fused with green fluorescent protein (EGFP) cDNA, and transiently expressed them in human cancer cells, to assess GAPDH localization and biological effects. We analyzed intranuclear localization and dynamic characteristics of GAPDH and its variants in the live cells using image confocal technologies (e.g. FRAP). In our study, we demonstrated that GAPDH is a molecular target with clinical potential for senescence-based tumor suppression. Our experiments revealed that depletion of GAPDH induces energy crisis and proliferation arrest in human carcinoma cells. We elucidated the molecular mechanisms initiated by GAPDH depletion, and demonstrated that GAPDH-depleted cells acquire the accelerated senescence phenotype. Moreover, we found chemotherapeutic agents cytotoxic to the senescent cells, a finding that opens a way to combination chemotherapy with therapy-induced senescence agents. Our results on dynamic characteristics of intranuclear GAPDH and its mutant forms indicate that in the nucleus, GAPDH interacts with biomolecules yet to be identified. The results of this study suggest a novel, prospective molecular target for pharmacotherapeutic intervention in cancer management. / Pharmaceutical Sciences

Optimum filter-and-sum beamforming is useful for array systems that suffer from spatially correlated noise and interference over large bandwidth. The set of finite impulse response (FIR) filter coefficients used to implement the optimum filter-and-sum beamformer are selected to optimize signal-to-noise ratio (SNR) and reduce interference from the certain directions. However, these array systems may also be vulnerable to dispersion caused by physical components such as antennas and cables, especially when the dispersion is unequal between sensors. The unequal responses can be equalized by using FIR filters. Although the problems of optimum-SNR beamforming, interference mitigation, and per-sensor dispersion have previously been individually investigated, their combined effects and strategies for mitigating their combined effects do not seem to have been considered. In this dissertation, combination strategies for optimum filter-and-sum beamforming and sensor dispersion correction are investigated. Our objective is to simultaneously implement optimum filter-and-sum beamforming and per-sensor dispersion correction using a single FIR filter per sensor. A contribution is to reduce overall filter length, possibly also resulting in a significant reduction in implementation complexity, power consumption, and cost. Expressions for optimum filter-and-sum beamforming weights and per-sensor dedispersion filter coefficients are derived. One solution is found via minimax optimization. To assess feasibility, the cost is analyzed in terms of filter length. These designs are considered in the context of LWA1, the first ``station'' of the Long Wavelength Array (LWA) radio telescope, consisting of 512 bowtie-type antennas and operating at frequencies between 10 MHz and 88 MHz. However, this work is applicable to a variety of systems which suffer from non-white spatial noise and directional interference and are vulnerable to sensor dispersion; e.g., sonar arrays, HF/VHF-band riometers, radar arrays, and other radio telescopes. / Ph. D.

In asthma therapy, the use of theophylline to prevent bronchial spasm and glucocorticoids to decrease inflammation is widely indicated. Apart from the acute asthma attack oral theophylline is treated for chronic therapy in order to minimize inflammation and to enhance the efficiency of corticosteroids and recover steroids’ anti-inflammatory actions in COPD treatment. The preferred application route for respiratory disease treatment is by inhalation, such as dry powder inhalers (DPI) being the delivery systems of first choice. As shown recently, there is an advantageous effect if the drugs are given simultaneously which is caused by a synergistic effect at the same target cell in the lung epithelia. Therefore, it seems rational to combine both substances in one particle. This type of particle has the advantage over a combination product containing both drugs in a physical mixture which occurs rather randomly deposition leading to API segregation and non-dose-uniformity. Dry powder inhalers (DPIs) is a type of therapeutic pharmaceutical formulations usually present in the solid form. Due to the nature of the solid-state, an understanding of chemical and physical properties must be established for acquiring optimum performance of the active pharmaceutical ingredients (APIs). In recent year, generation of DPIs is a destructive procedure to meet the micron size. Such processes are inefficient and difficult to control. Moreover, according to current researches on combination APIs formulation, this type of DPIs performed a greater variability in does delivery of each active, leading to poor bioavailability and limit clinical efficient. This result suggest that combination formulations require advanced quality and functionality of particles with suitable physicochemical properties. Hence, in order to production of binary and combination DPIs products, the aim of this study was to develop the spray drying and ultrasonic process for engineering of combination drug particles that will be delivered more efficiently and independently of dose variations to the lung. Microparticles were produced by spray drying or/and ultrasonic technique. The processing parameters and addition of excipients (polymers) were optimized using a full factorial design such that microparticles were produced in a narrow size range suitable for inhalation. Employing excipients resulted in high saturation environment leading to minimized sphere particles when compared to conventional solvent. Solid state characterization of microparticles using powder x-ray diffraction and differential scanning calorimetry indicated that the particles contained crystalline but no cocrystal. The combination particles comparable to or better than micronized drug when formulated as a powder blended with lactose. It was concluded that the use of HPMC enhanced crystallinity suitable for inhalation; and combination particles improved uniform distribution on the stage of NGI.

With a rise in concern for animal welfare, the equine world has started using positive reinforcement (R+); as such, horses often experience a combination of negative reinforcement (R-) and R+. I compared the effects of R- to a combination of positive and negative reinforcement (R-/R+) training. Horses were trained to walk across two visually discriminable liverpools (striped, Experiment 1; colored water, Experiment 2), each associated with either R- or R-/R+, and training type alternating across six days. I measured highest training criteria reached, prevalence of undesirable behaviors, salivary cortisol (pre- and post-training), time spent by the trainer in motionless human tests (pre- and post-training), and horses' preference for the two liverpools using concurrent choice. Across both experiments, I found no significant difference in the proportions of criteria reached between training types; horses engaged in mugging for longer periods of time in R-/R+ than R-; no significant difference between training types for the pre- to post-change of cortisol; a greater proportion of horses increased time spent with R-/R+ trainer than the R- trainer; and no difference between first choice in the preference test or time horses spent in proximity to the liverpool, based on the training type with which the liverpool was associated. Overall, I found few differences between R-/R+ and R-, which could be due to horses only having 30 min total training contact with either training, or my use of relatively low intensities of R- and R+. / Master of Science / The equine world has started using positive reinforcement (R+), such as providing treats. Often horses experience a combination of negative reinforcement (R-) and R+, such as having rein pressure released and being given a treat. I compared effects of R- to a combination of positive and negative reinforcement (R-/R+) training. Horses were trained to walk across two visually distinct liverpools, a 1 m X 2.7 m shallow pool, (striped, Experiment 1; colored water, Experiment 2) each associated with either R- or R-/R+, and training type alternating across six days. I measured highest training level reached, occurrence of undesirable behaviors, salivary cortisol (a measure of stress), time spent by the trainer in motionless human tests, and horses' preference for the two liverpools. Across both experiments, I found no significant difference in the proportions of criteria reached between training types; horses investigated the trainer for treats for longer durations in R-/R+ than R-; no significant difference between training types for the pre- to post-change; a greater proportion of horses increased time spent with R-/R+ trainer than R- trainer; and no difference between first choice in the preference test or time horses spent in proximity to the liverpool, based on the training type with which the liverpool was associated. Overall, I found few differences between R-/R+ and R-, which could be due to horses only having 30 min total training contact with either training, or my use of relatively low intensities of R- and R+.

In the present paper, an attempt is made to obtain the potential distribution in the case of two such charges, a source-sink combination, located on the axis of a bore hole drilled through an infinite, homogeneous medium.