Le processus visuel débute lorsque les photorécepteurs transforment la lumière en un signal biochimique qui est ensuite traité et transmis via la rétine. Notre groupe s'intéresse à élucider les défauts génétiques et les mécanismes à l'origine de pathologies rétiniennes comme la cécité nocturne congénitale stationnaire (CNCS), conséquence d'un défaut de transmission du signal entre les photorécepteurs et les cellules bipolaires. Cette thèse apporte de nouvelles connaissances sur la physiologie de cette première synapse visuelle. Nous avons identifié quatre nouvelles mutations dans SLC24A1, un échangeur ionique intervenant dans l'homéostasie du calcium dans les bâtonnets, à l'origine de la CNSC de type Riggs. Nous avons également identifié LRIT3 comme étant un nouveau gène impliqué dans la forme complète de CNCS. Nous avons décrit un modèle de souris invalidé pour Lrit3 avec un phénotype visuel similaire à celui des patients. Nous avons confirmé la localisation de LRIT3 aux extrémités dendritiques des cellules bipolaires ON, suggérant un rôle dans la cascade de signalisation mGluR6. Nous avons montré que LRIT3 était nécessaire à la localisation fonctionnelle de TRPM1. Nous avons de plus démontré un rôle additionnel de LRIT3 dans la formation de la synapse du cône n'impactant probablement que faiblement les voies OFF. Nous avons également réussi à détecter LRIT3 par spectrométrie de masse, ouvrant la voie à l'identification de ses partenaires. La meilleur connaissance de la physiologie et de la physiopathologie rétinienne doit mener non seulement à un meilleur diagnostic et conseil génétique des patients mais également au développement de nouvelles approches thérapeutiques. / The first steps in vision occur when rod and cone photoreceptors transform light into a biochemical signal, which gets processed through the retina. Our group investigates genetic causes and mechanisms involved in inherited retinal diseases as congenital stationary night blindness (CSNB), which reflects a signal transmission defect between photoreceptors and bipolar cells. This thesis gives several insights on the retinal physiology at this first visual synapse. We identified four novels mutations in SLC24A1 underlying the Riggs-type of CSNB, which has a role in calcium balance in rods. We subsequently identified a novel gene, LRIT3, which is mutated in the complete form of CSNB. We delivered a knock-out mouse model lacking Lrit3 which displays a phenotype similar to patients. We confirmed the localization of LRIT3 at the dendritic tips of ON-bipolar cells, suggesting a role of LRIT3 in the mGluR6 signaling cascade. We showed that LRIT3 is necessary for the functional localization of TRPM1. We also revealed that LRIT3 has an additional role in formation of the cone synapse but with probably only a minor effect on OFF-pathway functionality. We finally succeeded in immunoprecipitating and detecting LRIT3 by mass spectrometry, opening the way for the identification of LRIT3 partners. Improving knowledge about retinal physiology and physiopathology will lead to a better diagnosis and genetic counseling of the patients and to the development of novel therapeutic approaches.

O problema de controle de estoques com demanda não estacionária e lead-time positivo tem se tornado cada vez mais relevante em virtude da crescente tendência de redução do ciclo de vida dos produtos e internacionalização das cadeias de suprimentos. Embora haja uma solução exata para a minimização do custo esperado da política de estoques para este cenário, baseado no método de programação dinâmica, o custo computacional deste método ainda é considerado elevado. Este trabalho detalha e avalia através de simulação o método exato e duas aproximações para a minimização do custo esperado da política de estoques, em termos do desempenho em custo e eficiência computacional. Os resultados experimentais permitem a análise dos métodos disponíveis. Enquanto a abordagem heurística de Bollapragada e Morton, que utiliza o nivelamento da demanda não estacionária, perde desempenho de custo com o aumento do lead-time, a nova heurística proposta, que aproxima os parâmetros da política ótima por valores limitantes, produz resultados sucessivamente melhores com o aumento do lead-time. / The inventory control problem with nonstationary demand and positive lead-time has become increasingly important due to the growing trend of reduction in product life cycle and internationalization of the supply chain. Although there is an exact solution to the minimization of the expected cost of inventory policy on this environment, through the method of dynamic programming, the computational cost of this method is still considered high. This work details and evaluates through simulation the exact method and two heuristic solutions for the minimization of expected cost of inventory policy, in terms of cost performance and computational efficiency. The experimental results allow the analysis of the available methods. While the Bollapragada and Morton heuristic approach, which levels the non-stationary demand, decreases the cost performance when lead-time is increased, the new heuristic proposed, that approximates the optimal policy parameters by limiting values, successively produces better results with increasing lead-times.

Australia’s economy is heavily dependent on coal-based energy and greenhouse gas intensive natural resource extraction and processing industries. As part of an international climate change mitigation effort Australia will have to undergo a national transformation to a low emissions society by mid century. Federal and State Governments in Australia, like their counterparts in other major developed economies, have been persuaded that reliance on fossil fuels in stationary energy industries such as electricity generation and minerals processing will be able to continue with the deployment of a value chain of technologies fitted to these installations for capturing carbon dioxide, transporting it to a disposal site, and then injecting it into subsurface geological formations for permanent storage (carbon capture and storage, or CCS). Understanding the likely effectiveness of CCS for reducing greenhouse gas emissions from stationary energy industries is therefore critical to policy formulation for, and management of, Australia’s emissions mitigation effort and national transformation over the decades ahead. / This thesis aims to offer a clearer understanding of the practicalities, limitations and uncertainties surrounding future CCS use in Australia and of the contribution CCS can make to mitigating emissions from the Australian stationary energy sector in the period to 2050. It considers two central questions: Is CCS a realistic option for emissions mitigation in Australia? Are Australian climate policies formulated to facilitate CCS deployment and optimise its potential contribution? The criteria employed in this thesis for answering these questions are restricted to those having an ascertainable causal impact on the timing, pace and ultimate scale of CCS deployment within Australia. The methodology used for the research is grounded in critical approaches and integrated assessment within a holistic, trans-disciplinary paradigm. / This thesis finds that under Australia’s existing climate policy framework it is unrealistic to expect CCS can contribute more than 75 million tonnes of CO2 per annum to emissions mitigation by 2050. Australia does have sufficient potential geological storage resources to expect some environmentally safe CCS infrastructure could be engineered over time, but commencement of large scale build-out is not likely before 2025. When CCS will become a commercial mitigation option in Australia is unpredictable and dependent more on the political economy of climate change than on Australian research, development and demonstration activities. / The thesis also finds that the existing climate policy framework is increasing rather than decreasing the risks to timing and usefulness of CCS even to the level of 75 million tonnes of CO2 per annum by 2050. This thesis concludes that Australian Governments are not developing the institutional capability to oversee a holistic decarbonisation of the stationary energy sector. This capability is required not only to address the risks to CCS deployment but also to prevent market failures that foreclose an optimal contribution from all other potential mitigation technologies. The thesis proposes that an Australian national CCS company be created with responsibility for CCS integration, transport and storage services in order to develop Australian capability rather than that of international corporations.

<p>This thesis consists of three papers on the following topics in functional analysis and probability theory: Riesz bases and frames, weakly stationary stochastic processes and analysis of set-valued stochastic processes. In the first paper we investigate Uniformly Bounded Linearly Stationary stochastic processes from the point of view of the theory of Riesz bases. By regarding these stochastic processes as generalized Riesz bases we are able to gain some new insight into there structure. Special attention is paid to regular UBLS processes as well as perturbations of weakly stationary processes. An infinite sequence of subspaces of a Hilbert space is called regular if it is decreasing and zero is the only element in its intersection. In the second paper we ask for conditions under which the regularity of a sequence of subspaces is preserved when the sequence undergoes a deformation by a linear and bounded operator. Linear, bounded and surjective operators are closely linked with frames and we also investigate when a frame is a regular sequence of vectors. A multiprocess is a stochastic process whose values are compact sets. As generalizations of the class of subharmonic processes and the class of subholomorphic processesas introduced by Thomas Ransford, in the third paper of this thesis we introduce the general notions of a gauge of processes and a multigauge of multiprocesses. Compositions of multiprocesses with multifunctions are discussed and the boundary crossing property, related to the intermediate-value property, is investigated for general multiprocesses. Time changes of multiprocesses are investigated in the environment of multigauges and we give a multiprocess version of the Dambis-Dubins-Schwarz Theorem.</p>

This thesis focuses on the development of new stationary phases for use in hydrophilic interaction liquid chromatography using TRIS-based and phosphorylcholine typed monomers and porous silica particles as starting substrates. In this thesis, several ways of polymerizing highly hydrophilic mono­mers onto pore surfaces of silica supports are described, based on several “grafting from” schemes. “Controlled/living” radical polymerizations including atom transfer radical polymerization (ATRP) and iniferter-mediated polymerization in conjunction with conventional free radical polymerization are demonstrated to be successful tools for grafting different hydrophilic monomers (polyhydroxyl and phosphorylcholine [meth]acrylamide/acrylates) onto the silica surfaces. Reaction solvents are proven to play an essential role to achieve efficient graft polymerization of activated silica surfaces with these amphiphilic vinylic monomers, which is difficult because of their restricted access to the activated surface in solvents that can be used because of solubility constraints. Two tentacle TRIS-based polymer grafted silica, namely TRIS-WAX – TRIS functionality bonded to silica via a C–N–C imine bond and TRIS-Amide – TRIS bonded to silica via an amide bond, prove to be useful as stationary phases for hydrophilic interaction chromatography (HILIC).The TRIS-WAX exhibits a mixed mode hydrophilic partitioning and weak anion exchange (HILIC/WAX) retention mechanism while retention by hydrophilic partitioning is the dominant mechanism on the neutral TRIS-Amide phase which lacks weak anion exchange (WAX) properties. Interestingly, both these phases have selectivities that are radically different from most commercial HILIC stationary phases. Finally, a method is demonstrated for synthesizing a stratified (graft-copolymerized) silica material based on N,N′-methylenebisacrylamide and 2-methacryloyloxyethyl phosphorylcholine (MPC) using a “controlled/living” photoiniferter-mediated polymerization from the N,N-diethyldithiocarbamate iniferter moiety immobilized silica surfaces. This polymerization method proves to be successful for graft-blockcopolymerization of different highly hydrophilic monomers onto the activated surfaces of porous silica. In this way, silica surfaces are grafted with a cross-linked amide-based hydrogel, on top of which a tentacle zwitterionic phosphorylcholine-typed layer is synthesized. The resulted material proves to be useful for HILIC separations and possesses different selectivity for the tested organic acids compared to that of commercial ZIC-cHILIC stationary phase.

This thesis consists of three papers on the following topics in functional analysis and probability theory: Riesz bases and frames, weakly stationary stochastic processes and analysis of set-valued stochastic processes. In the first paper we investigate Uniformly Bounded Linearly Stationary stochastic processes from the point of view of the theory of Riesz bases. By regarding these stochastic processes as generalized Riesz bases we are able to gain some new insight into there structure. Special attention is paid to regular UBLS processes as well as perturbations of weakly stationary processes. An infinite sequence of subspaces of a Hilbert space is called regular if it is decreasing and zero is the only element in its intersection. In the second paper we ask for conditions under which the regularity of a sequence of subspaces is preserved when the sequence undergoes a deformation by a linear and bounded operator. Linear, bounded and surjective operators are closely linked with frames and we also investigate when a frame is a regular sequence of vectors. A multiprocess is a stochastic process whose values are compact sets. As generalizations of the class of subharmonic processes and the class of subholomorphic processesas introduced by Thomas Ransford, in the third paper of this thesis we introduce the general notions of a gauge of processes and a multigauge of multiprocesses. Compositions of multiprocesses with multifunctions are discussed and the boundary crossing property, related to the intermediate-value property, is investigated for general multiprocesses. Time changes of multiprocesses are investigated in the environment of multigauges and we give a multiprocess version of the Dambis-Dubins-Schwarz Theorem.

The research presented in this dissertation involves the development of chiral and achiral analysis using capillary electrochromatography (CEC) and CEC coupled to mass spectrometry (CEC-MS). Chapter 1 briefly reviews CEC fundamentals and latest development on chiral CEC and CEC-MS. The CEC-UV enantioseparations for several acidic compounds are described in Chapter 2. The optimum resolutions for these acidic enantiomers are achieved in ion-suppression mode, i.e. with an acidic mobile phase. One of major drawback in coupling CEC with MS is the bubble formation at the column outlet end, resulting in irreproducible retention time and erratic baseline, or even current breakdown. By introducing internal tapered columns, the aforementioned limitations of CEC-MS are successfully overcome in Chapter 3. The CEC-MS enantioseparation of warfarin and coumachlor is carefully investigated and applied to quantify R- and S-warfarin in human plasma. For individual enantiomers, a concentration of 25 ng/mL is detectable. To further improve the robustness of CEC-MS column, a new procedure of fabricating internal tapered columns is reported in Chapter 4. These internal tapered columns demonstrate excellent ruggedness, low background noise, and good compatibility in reversed-phase and polar organic modes of CEC-MS. In chapter 5, the feasibility of using internal tapered columns packed with vancomycin chiral stationary phase (CSP) is explored for simultaneous enantioseparation of eight â-blockers using CEC-MS. After a careful optimization of the mobile phase composition, sheath liquid and spray chamber parameter, 15 out of 16 enantiomers could be simultaneously resolved with excellent efficiency and detection sensitivity. The synthesis and characterization of sulfated and sulfonated cellulose phenylcarbamate CSPs is described in Chapter 6. The use of these CSPs, especially the sulfonated one, significantly enhances the EOF profile and sample throughput but maintain high enantiomeric resolving power under various modes of CEC and CEC-MS. By combining CEC and atmospheric pressure photo-ionization (APPI) MS, Chapter 7 demonstrates the separation and detection of mono-methylated benzo[a]pyrene (MBAP) isomers with ~100 times enhancement on detection sensitivity than CEC-UV. In Appedix 2, monolithic columns are synthesized through photopolymerized sol-gel approach and utilized for CEC and CEC-APPI-MS of polyaromatic hydrocarbons, and alkyl phenyl ketones.

This research presents advancements in the coupling of capillary electrochromatography (CEC) to mass spectrometry (MS) for the analysis of different chemical classes of surfactants. Chapter 1 provides a brief introduction that summarizes the mechanics and fundamentals of CEC, including instrumentation and applications for CEC-MS. Chapter 2 describes the on-line hyphenation of a packed CEC column with an internally tapered tip coupled to electrospray ionization-mass spectrometry (ESI-MS) and atmospheric pressure chemical ionization-mass spectrometry (APCI-MS) for the analysis of betaine-type amphoteric or zwitterionic surfactants (Zwittergent®). The interesting aspects include CEC-MS column manufacture and charaterization, as well as a comparison between the CEC-ACPI-MS and CEC-ESI-MS ionization pattern of zwittergents. In Chapter 3, the CEC-MS of alkyltrimethyl-ammonium ions (ATMA+) with chain length ranging from C1-C18 is optimized using an internally tapered CEC-MS column packed with mixed mode C6/strong cation exchange stationary phase and coupled to an ESI source. In addition, the optimized CEC-ESI-MS protocol is applied for the challenging analysis of commercial sample Arquad S-50 ATMA+ containing cis-trans unsaturated and saturated soyabean fatty acid derivatives. In Chapter 4, a novel CEC-UV method for separation of the various Triton X-100 oligomers is presented. A systematic mobile phase tuning and comparison of monomeric vs. polymeric stationary phases was conducted. In Chapter 5, we present the first application of CEC coupled to MS for analysis of Triton X (TX-) series surfactants. A characterization from the viewpoint of the ion and adduct formation for TX-series nonionic surfactants with a variable number of ethoxy units (n=1.5-16) in the scan mode are first discussed. Next, utilizing the TX-series as model alkylphenolpolyethoxylates (APEOs), a detailed investigation of the chromatographic separation and MS detection are performed followed by analysis of very long chain TX series with n=30-70. In Chapter 6, CEC-MS utilizing full scan positive ion mode of ESI was employed to study the effect of fragmentor voltage on the in-source collision induced dissociation (IS-CID) of several APEO nonionic surfactants. Finally, in Chapter 7, the preparation and characterization of a novel liquid crystalline stationary phase suitable for separation of neutral and charged compounds in packed column CEC is evaluated.

This thesis consists of three chapters, covering topics in both the design and modeling aspects of computer experiments as well as their engineering applications. The first chapter systematically develops a new class of space-filling designs for computer experiments by splitting two-level factorial designs into multiple layers. The new design is easy to generate, and our numerical study shows that it can have better space-filling properties than the optimal Latin hypercube design. The second chapter proposes a novel modeling approach for approximating computationally expensive functions that are not second-order stationary. The new model is a composite of two Gaussian processes, where the first one captures the smooth global trend and the second one models local details. The new predictor also incorporates a flexible variance model, which makes it more capable of approximating surfaces with varying volatility. The third chapter is devoted to a two-stage sequential strategy which integrates analytical models with finite element simulations for a micromachining process.

This thesis is concerned with simulation output analysis. In particular, we are inter- ested in estimating the variance parameter of a steady-state output process. The estimation of the variance parameter has immediate applications in problems involving (i) the precision of the sample mean as a point estimator for the steady-state mean and #956;X, and (ii) confidence intervals for and #956;X. The thesis focuses on new variance estimators arising from Schrubens method of standardized time series (STS). The main idea behind STS is to let such series converge to Brownian bridge processes; then their properties are used to derive estimators for the variance parameter. Following an idea from Shorack and Wellner, we study different levels of folded Brownian bridges. A folded Brownian bridge is obtained from the standard Brownian bridge process by folding it down the middle and then stretching it so that it spans the interval [0,1]. We formulate the folded STS, and deduce a simplified expression for it. Similarly, we define the weighted area under the folded Brownian bridge, and we obtain its asymptotic properties and distribution. We study the square of the weighted area under the folded STS (known as the folded area estimator ) and the weighted area under the square of the folded STS (known as the folded Cram??von Mises, or CvM, estimator) as estimators of the variance parameter of a stationary time series. In order to obtain results on the bias of the estimators, we provide a complete finite-sample analysis based on the mean-square error of the given estimators. Weights yielding first-order unbiased estimators are found in the area and CvM cases. Finally, we perform Monte Carlo simulations to test the efficacy of the new estimators on a test bed of stationary stochastic processes, including the first-order moving average and autoregressive processes and the waiting time process in a single-server Markovian queuing system.