Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

The innovative design of flat panel volume computed tomography (CT) systems has recently led to the emergence of a wide spectrum of new applications for both diagnostic and interventional purposes, such as ultra-high resolution bone imaging, image guided interventions, dynamic CT angiography, and interventional neuroradiology. Most of these applications require low X-ray dose to limit potential harm to the patient. One of the main challenges of low dose imaging is to maintain a quantum noise limited system to achieve the highest possible signal to noise ratio (SNR) at a given dose. One potential method to achieve a quantum noise limited system is to employ a high gain detector. Current flat panel CT technology is based on indirect conversion detectors that contain a scintillator and hydrogenated amorphous silicon (a-Si:H) p-i-n photodetectors which have a gain below unity and require a specialized p-layer. In this thesis, an alternative detector to the p-i-n photodetector, which can achieve gain above unity and thus aid in achieving quantum noise limited systems is investigated for large area flat panel imaging. The proposed detector is based on amorphous selenium (a-Se). Amorphous selenium is the most highly developed photoconductor for large area direct conversion X-ray imaging and is still the only commercially available large area direct conversion flat panel X-ray detector. However, the use of a-Se for indirect conversion imaging has not been significantly explored. Amorphous selenium has field dependent mobility and conversion efficiency, which increase with increasing electric field. It is also the only large area compatible avalanche-capable material; a property that was discovered more than 30 years ago. This unique property could be leveraged to provide the gain necessary for low dose medical imaging applications. The only current commercial avalanche capable a-Se optical detector uses electron beam readout in vacuum, which is not large area compatible and makes integration with pixelated readout electronics challenging. The detector structure proposed in this research seeks to address the challenges associated with integration of an avalanche capable a-Se detector with large area X-ray imager. One important aspect in the development of a-Se avalanche detectors is reducing the dark current and preventing a-Se breakdown as the electric field across the device is increased. A high dark current reduces the dynamic range of the detector, it increases the noise level, and it can lead to crystallization of the detector due to joule heating. To overcome the dark current problem, different blocking layers that allow for integration with large area flat panel imagers were investigated. Experimental results from fabricated devices provided the basis for the choice of the most suitable blocking layer. Two device structures are proposed using the selected blocking layer, a vertical structure and a lateral structure, each having associated benefits and drawbacks. It was shown that introducing a polyimide blocking layer brought down the dark current more than four orders of magnitude at high electric fields and does not deteriorate the charge transport properties of the detectors. The polyimide blocking layer also greatly minimizes physical stress related crystallization in a-Se improving reliability. Gain above unity was observed in the vertical structure and the initiation of impact ionization was verified by performing time-of-flight experiments. Although impact ionization was not verified in the lateral structure, this device structure was found to be highly sensitive to ultraviolet light due to the absence of a top contact layer. Devices were fabricated on several different substrates, including a CMOS substrate, to demonstrate their integration compatibility with large area readout electronics. The exhibited performance of the vertical device structure demonstrates that it is a suitable alternative to the p-i-n photodetector for low dose imaging applications.

Les applications d’électronique de spin telles les mémoires à accès aléatoire (MRAM), les capteurs (e.g.les têtes de lecture des disques durs d’ordinateurs) et les éléments de logique magnétique utilisent les interactionsd’échange ferromagnétique/antiferromagnétique (F/AF) dans le but de définir une direction de référence pour lespin des électrons de conduction. Les MRAM à écriture assistée thermiquement (TA-MRAM) utilisent mêmedeux bicouches F/AF : une pour le stockage de l’information et l’autre comme référence. Ces dernièresapplications technologiques impliquent des étapes de nanofabrication des couches minces continues pour formerune matrice de cellules mémoires individuelles. La qualification industrielle du produit final impose de sérieusescontraintes sur la largeur des distributions des propriétés magnétiques - y compris d’échange F/AF - de cellulemémoire à cellule mémoire. Des phases verres de spin réparties de manière aléatoire sur la couche continue, àl’interface F/AF ou dans le coeur de l’AF pourraient contribuer de manière significative à ces distributionsd’échange F/AF dans les dispositifs, après nanofabrication ; comme supposé il y a de cela quelques années. Lebut de cette thèse est d’étudier factuellement le possible lien entre verre de spin répartis dans des couches mincesF/AF et dispersions de propriétés d’échange de cellule mémoire à cellule mémoire dans les dispositifs TAMRAMcorrespondants. Avant cela, l’origine de ces régions verre de spin a été étudiée et une attention plusparticulière a été portée au rôle joué par les diffusions de Mn. Ces dernières ont été directement observées,comprises et l’utilisation de barrières complexes pour les réduire et par là même pour diminuer la quantité dephases verre de spin a été mise en oeuvre avec succès. En guise d’alternative pour varier la quantité de verres despin, l’utilisation d’AFs composites a été également étudiée dans le cadre de cette thèse. Ce type d’AF permet dumême coup de varier la stabilité thermique des grains AF et de répondre à un autre problème identifié pour lesTA-MRAM qui consiste à trouver des matériaux AF avec des propriétés de rétention et d’écriture intermédiairespar rapport aux matériaux actuellement utilisés. Finalement, ces AFs composites ont été utilisés comme moyende varier la quantité de verres de spin dans des dispositifs TA-MRAM réels et de prouver le lien direct avec ladispersion de propriétés de cellule mémoire à cellule mémoire. / Spintronics applications such as magnetic random access memories (MRAM), sensors (e.g.. hard diskdrive read head) and logic devices use ferromagnetic/antiferromagnetic (F/AF) exchange bias (EB) interactionsto set the reference direction required for the spin of conduction electrons. Thermally-assisted (TA-) MRAMapplications even use two F/AF exchange biased bilayers: one for reference and one for storage. Suchtechnological applications involve patterning full sheet wafers into matrix of individual bit-cells. Industrialproducts qualification imposes stringent requirements on the distributions of the magnetic properties from cell tocell, including those related to EB. It was supposed few years ago that randomly spread spin-glass like phases atthe F/AF interface or within the bulk of the AF layer significantly contribute to the distributions of EB propertiesin devices after processing. This thesis aimed at factually studying the link between spin-glasses spread overF/AF thin films and bit-cell dispersions of EB in corresponding TA-MRAM. Prior to that the origin of the spinglasslike regions and more specifically the role of Mn-diffusion was consolidated. Mn-diffusion was directlyobserved, understood and the use of complex barriers to reduce such diffusion and consequently to minimize theamount of spin-glass was successfully studied. Mixing AFs as another way to tune the amount of spin-glass likephases was also evidenced in the framework of this thesis. All at once, this last solution also tuned the AF grainsthermal stability and this solved another issue related to TA-MRAM, i.e. finding AF-materials with intermediateretention and write properties compared to the AFs presently used. Finally, those mixed antiferromagnets werethe mean chosen to tune the amount of spin-glass like phases in real TA-MRAM devices and to factually provetheir link with bit-cell distributions of EB properties.

Vaccines have saved more lives than any other medical intervention. Recombinant vaccines provide unmatched safety profiles, but at the expense of reduced immunogenicity. Virus-like particles (VLPs) resemble viruses in size, shape and repetitive arrangement but are devoid of pathogenic genetic material and therefore safe. Poor immunogens can be rendered immunogenic by display on VLPs. Successfully decorating VLPs is still a major challenge. Genetic fusion or chemical modification is often time-consuming and can lead to misassembly or misfolding, which obstructs generation of the desired immune response. SpyCatcher is a genetically encodable protein, previously engineered to form a covalent isopeptide bond to its peptide-partner SpyTag. Presented in this thesis are SpyCatcher-VLPs, based on the fusion of SpyCatcher to the bacteriophage VLP AP205. SpyCatcher- VLPs can be conveniently conjugated with SpyTag fused antigens, simply by mixing. I demonstrate the modularity of this approach by covalently linking several complex, cysteine-rich malarial antigens to SpyCatcher-VLPs, such as the transmission-blocking antigen Pfs25 and the blood-stage antigen CIDR. A single administration of Pfs25-SpyTag conjugated to SpyCatcher-VLPs induced potent antibody generation against Pfs25, even in the absence of adjuvant. Anti-Pfs25 antibodies induced by this platform conveyed potent transmission-blocking activity in the mosquito vector. The thesis further demonstrates the feasibility of more complex Catcher-nanoparticle architectures. The previously engineered SnoopCatcher covalently reacts with SnoopTag peptide and is orthogonal to the SpyCatcher / SpyTag pair. IMX313 is an engineered chimera of the multimerization domain of chicken complement inhibitor C4-binding protein. This work describes fusion of SnoopCatcher and SpyCatcher to IMX313, which yields independently addressable Catcher-moieties on a single IMX313 nanoparticle. Display of two antigens on one particle may enable single-particle, multi-disease vaccines as well as multi-stage vaccines to tackle immune evasion of parasites. The platforms presented should accelerate and enhance vaccine development and may create opportunities for imaging and metabolic engineering.

O estudo das Relações Quantitativas entre Estrutura química e Atividade biológica (QSAR/QSAR-3D) utilizando diferentes estratégias metodológicas complementares, aplicadas iterativamente, se estende a diferentes áreas de aplicação. Dentre elas destaca-se o planejamento racional de novos fármacos e o estudo de seus mecanismos de ação. Moléculas candidatas a fármacos, geradas em estudos de QSAR-3D, freqüentemente, não se tomam fármacos por apresentarem inadequadas propriedades farmacocinéticas, ou seja, ADME (absorção, distribuição, metabolismo e excreção). Nota-se assim que o conhecimento das propriedades farmacocinéticas de ligantes deve ser uma preocupação presente, em qualquer nível de desenvolvimento de um novo fármaco e ressalta-se a importância do QSAR como uma ferramenta de grande valor, principalmente na compreensão da contribuição das propriedades físico-químicas, identificadas como sendo responsáveis pela atividade. A aplicação do QSAR permite elucidar a natureza e a grandeza das propriedades físico-químicas e estruturais nas interações entre o composto e o seu alvo biológico nos processos farmacocinéticos de ADME (TESTA, 2001; MALVEZZI et al.,, 2001; GAVIRAGHI et al., 2001). Recentemente, em trabalhos realizados em nosso laboratório (SIQUEIRA, 2001), envolvendo a análise de QSAR aplicada aos valores do bloqueio da transmissão neuromuscular determinados para uma série de onze brometos de [2-(4-X-benzamido)etil]benzildimetilamônio substituídos, demonstrou-se tanto a importância da presença de um grupo catiônico terminal como da lipofilicidade para o bloqueio da transmissão neuromuscular. No presente trabalho, visando descrever as interações hidrofóbicas determinantes da potencial atividade bloqueadora neuromuscular, para uma série de dez derivados da procaína, sendo eles: cloretos de 3-(dimetilamino)propiofenona (composto 1); de 3-(dietilamino)propiofenona (composto 2); de 3-(1-pirrolidino)propiofenona (composto 3); de 3-(1-piperidino)propiofenona (composto 4); de 3-(1-morfolino)propiofenona (composto 5); de 3-[1-(4-metilpiperazino)] propiofenona (composto 6); de 3-(c-hexilamino)propiofenona (composto 7); de N-[(N,N-dimetilamino)etil]benzamida (composto 8); de N-[(N,N-dimetilamino )metil]benzamida (composto 9) e, de N-[(N,N-dimetilamino)etil]benzoato (composto 10), por nós sintetizados, determinaram-se os respectivos parâmetros hidrofóbicos e relacionados à ionização (logPappSF; logPnSF; logPiSF; (pKaaq)SF; (pKaoct)SF; logPappHPLC; IogPnPot; IogPiPot; (pKaaq)Pot; logPcalc) obtidos por três métodos experimentais (por Shake-flask; por HPLC e potenciométrico) e por cálculo (programa CLOGP), como modelos de partição. Através da análise comparativa dos valores dos parâmetros hidrofóbicos e relacionados à ionização para a série de dez derivados da procaína (compostos 1-10) sintetizados neste trabalho foi possível constatar que: (i) os valores de IogPcalc modelam, apenas, parcialmente as interações hidrofóbicas refletidas nos valores de logPappSF e de logPappHPLC em valores de pH 3,0 e 10,0, enquanto que as interações hidrofóbicas refletidas nos valores de logPnPot são idealmente modeladas pelos valores de logPcalc; (ii) nas mesmas condições experimentais, os métodos Shake-flask, HPLC e potenciométrico revelam interações hidrofóbicas proporcionais, entretanto, correlações não ideais foram observadas quanto comparados entre si; (iii) os valores de pKaSF , determinados indiretamente por Shake-flask, foram validados pela determinação direta de pKaPot, por potenciometria. Embora o sistema de avaliação da bloqueadora da transmissão neuromuscular tenha sido adequado, a série de compostos estudada não gerou valores válidos para a construção das correspondentes curvas dose-resposta. Os valores obtidos de lC50 para os compostos 3, 4 e 8 da série estudada foram insuficientes, em número, para serem utilizados em uma análise de QSAR. Estudos futuros podem ser realizados com o objetivo de verificar a atividade anestésica local para os compostos da série estudada, avaliando-se a perda da sensibilidade à estimulação sensorial, em cobaias, ou em estudos mais sofisticados de eletrofisiologia (patch clamp). Poder-se-á, assim, fornecer subsídios para elucidar as contribuições relativas da forma catiônica e da forma neutra, respectivamente de compostos ionizáveis com atividade anestésica local. / The scope of Quantitative Structure and Biological Activity Relationships (QSAR/QSAR-3D) studies, using distinct complementary methods, spreads over multiple areas of applicability. Among those, striking are the rational design of new drugs and the enlightenment of their mechanism of action. Candidate molecules, shaped by QSAR-3D analysis, frequently fail to become drugs, and hit the market, due to insufficient pharmacokinetic properties (i.e. absorption, distribution, metabolism and excretion; ADME). Hence, the awareness of pharmacokinetic properties of molecules should be a concern at any leveI of development of new drug candidates. Noteworthy is the use of QSAR as a tool of great value, specially, in the comprehension of the contribution of the physical-chemical properties, responsible for the biological activity. (TESTA, 2001; MALVEZZl et ai., 2001; GAVlRAGHl et ai., 2001). ln this work, aiming to describe the hydrophobic interactions determining the neuromuscular blocking activity of a series of ten procaine derivatives: the hydrochlorides of 3-(dimethylamine)propiophenone (compound 1); of 3-(diethylamine)propiophenone (compound 2); of 3-(1-pirrolidine)propiophenone (compound 3); of 3-(1-piperidine)propiophenone (compound 4); of 3-(1-morfoline)propiophenone (compound 5); of 3-[1-(4-methylpiperazine)]propiophenone (compound 6); de 3-(c-hexilamine)propiophenone (compound 7); de N-[(N,N-dimethylamine)ethyl]benzamide (compound 8); de N-[(N,N-dimethylamine)methyl]benzamide (compound 9) and, of N-[(N,N-dimethylamine)ethyl]benzoate (compound 10), prepared by us, the corresponding hydrophobic parameters (logPappSF; logPnSF; logPiSF; (pKaaq)SF; (pKaoct)SF; logPappHPLC; IogPnPot; IogPiPot; (pKaaq)Pot; logPcalc) were obtained by three experimental methods (Shake-flask; HPLC and potenciometric) and by calculus (CLOGP) as models of partition and distribution. Following the comparative analysis of the values of the hydrophobic parameters determined for the ten compounds of the series of procaine analogs, it was possible to conclude that: (i) the values of IogPcalc reflect only partially, the hydrophobic interactions encoded in the values of logPappSF and logPappHPLC determined in pH values of 3,0 and 10,0; (ii) the values of logPcalc reflect the hydrophobic interactions encoded in the values of logPnPot; (iii) in the same experimental conditions, the methods Shake-flask, HPLC and potenciometric, reflect proportional hydrophobic interactions, although the observed correlations were not ideal when the methods were compared between each other; (iv) the values of pKaSF, determined indirectly by Shake-flask, were validated by the direct measurement of pKaPot, by potentiometry. Even though the system used to measure the neuromuscular blocking actions was adequate, the series of procaine derivatives failed to provide sufficient values to prepare dose-effect curves and proceed with the quantitative structure activity relationships.

O sequenciamento e a programação da produção trazem grandes benefícios financeiros às empresas se realizados de forma adequada. Atualmente, soluções generalizadas apresentam resultados aceitáveis, porém têm como consequência benefícios inferiores quando comparados a estudos específicos. O ramo da otimização de resultados possui dois tipos de soluções: as exatas para problemas de menores dimensões e não exatas, ou heurísticas, para problemas de médias e grandes dimensões. Este trabalho apresenta algoritmos exatos do tipo Branch & Bound e Modelos de Programação Linear Inteira Mista para solucionar quatro variações de problemas de scheduling: Fm|block|∑Cjm, Fm|block|∑Tj, Fm|block, Sijk|∑Cjm e Fm|block, Sijk|∑Tj. As abordagens utilizadas são inéditas na literatura e apresentaram resultados animadores para a maioria dos cenários. O limitante para o tempo total de fluxo obteve resposta ótima em 100% dos casos para problemas de até 20 tarefas e 4 máquinas em menos de uma hora. Para o tempo total de atraso, o limitante se mostrou mais eficiente quando os valores das due dates apresentam alta taxa de dispersão. Para os casos com setup, foram elaboradas três variações de limitantes para cada problema. O limitante com setup que apresentou o melhor desempenho foi o que obteve a melhor relação entre o seu valor numérico e seu custo computacional. Os modelos MILP solucionaram 100% dos problemas sem setup para até 20 tarefas e 4 máquinas e para os casos com setup, foram solucionados problemas de até 14 tarefas e 4 máquinas no tempo limite de uma hora. Os testes computacionais mostram a eficiência na redução do número de nós e, consequentemente, no tempo de execução. Portanto, o estudo realizado indica que, para problemas de pequeno porte e médio, os métodos em questão possuem grande potencial para aplicações práticas. / Job Sequence and Programming give benefits both financial and organizational to any company when performed properly. Nowadays, there is still a gap between theory and practice due to solutions that are short in specification. The analyzed problems differ in type and dimension thus modifying its complexity. The results optimization field is divided into two types of solution: the exact solution for minor problems and the non-exact solution for greater dimension problems. The present paper presents exact algorithms to solve the problems Fm|block|∑Cjm, Fm|block|∑Tj, Fm|block, Sijk|∑Cjm by the Branch & Bounds and Mixed Integer Linear Program models. The approaches are new and presented good results for most cases. Bounds for the no-setup total flow time scenario solved 100% of the 20 jobs and 4 machines cases. High dispersion range due dates contributed for the effectiveness of the no-setup total tardiness bound\'s effectiveness. Three different approaches were developed for the setup cases. The best approach aimed to optimize the value/effort factor for the B&B. The Mixed Integer Linear Program models solved 100% of the no-setup cases for 20 jobs and 4 machines. The MILPs setup cases solved optimally 14 jobs and 4 machines cases. Computational tests were executed and analyzed and they highlighted the node count reduction and, consequently, the execution time. The present study points out that the exact methods can be applied to small and medium scheduling problems in practice.

Stateless model checking is a technique for testing and verifying concurrent programs, based on exploring the different ways in which operations executed by the processes of a concurrent program can be scheduled. The goal of the technique is to expose all behaviours that can be a result of scheduling non-determinism. As the number of possible schedulings is huge, however, techniques that reduce the number of schedulings that must be explored to achieve verification have been developed. Dynamic partial order reduction (DPOR) is a prominent such technique. This dissertation presents a number of improvements to dynamic partial order reduction that significantly increase the effectiveness of stateless model checking. Central among these improvements are the Source and Optimal DPOR algorithms (and the theoretical framework behind them) and a technique that allows the observability of the interference of operations to be used in dynamic partial order reduction. Each of these techniques can exponentially decrease the number of schedulings that need to be explored to verify a concurrent program. The dissertation also presents a simple bounding technique that is compatible with DPOR algorithms and effective for finding bugs in concurrent programs, if the number of schedulings is too big to make full verification possible in a reasonable amount of time, even when the improved algorithms are used. All improvements have been implemented in Concuerror, a tool for applying stateless model checking to Erlang programs. In order to increase the effectiveness of the tool, the interference of the high-level operations of the Erlang/OTP implementation is examined, classified and precisely characterized. Aspects of the implementation of the tool are also described. Finally, a use case is presented, showing how Concuerror was used to find bugs and verify key correctness properties in repair techniques for the CORFU chain replication protocol. / UPMARC / RELEASE

This thesis focuses on the connectivity problems of the new sources to the electrical network. The first part of the thesis deals with the description of the new source and the method of its connection to the electrical network. Furthermore, in work, there are elaborated the blocking conditions for substation TR Neratovice expanded distribution point. A distribution network operator must receive an attachment application for connecting before the actual connection. The attachments consist of study cases of conjunction that values the inverse influence on the distributional network and informs the operator about the required measures for the reliable service with the new source. PSS Sincal computer software was used to survey the inverse influences on the distributional network. Based on processed data, the evaluation of conjunction of the synchronous generator to the grid at TR Neratovice substation was reconsidered.

Biological activity of IL-2 and IL-7 in vivo is significantly increased when complexed with some of the respective anti-cytokine mAb. Different immune cell subsets can be preferentially stimulated depending on the anti-IL-2 mAb used to complex IL-2. IL-2/anti-IL-2 mAb S4B6 immunocomplexes (IL-2/S4B6) induce preferential expansion of CD122high cells whereas IL-2/anti-IL-2 mAb JES6-1 immunocomplexes (IL-2/JES6-1) highly selectively stimulate CD25high cells in mice. Similarly, IL-7/anti-IL-7 mAb M25 immunocomplexes (IL-7/M25) possess higher stimulatory activity for both naïve and memory CD8+ T cells in vivo in comparison to free IL-7. CTLA-4 and PD-1 molecules are inhibitory receptors which negatively regulate proliferation, survival and effector functions of T cells. Blocking antibodies against these molecules represent promising immunotherapeutic tool for treatment of malignant diseases. We examined possible synergism of IL-2/S4B6 and αCTLA-4 plus αPD-1 mAbs in tumor-bearing mice. We found that the expansion of recently activated CD8+ T cells driven by IL-2/S4B6 was further augmented by αCTLA-4 plus αPD-1 mAbs. However, these two immunotherapeutic approaches did not show synergistic antitumor activity in any mouse tumor model tested. Next, we showed that IL-7/M25 possessed higher biological activity...

In recent years, IP based end-to-end services have grown in popularity. Efficiently meeting the user demand for such services, different techniques for traffic engineering transport networks have been developed. One such technique, currently being developed for multilayered networks, is Generalized Multi-Protocol Label Switching (GMPLS). GMPLS is a necessary networking technique because provisioning end-to-end services will today, and in the foreseeable future, very likely require the co-operation of multiple network layers. Here, the readiness of GMPLS for optical networks is investigated by reviewing the current support for optical networking components in the GMPLS standard documents. Based on this investigation, a candidate solution for routing and constraint-based path computation in optical network segments has been derived. This candidate solution is shown to efficiently handle the additional attributes and constraints inherent in optical networking components. / De senaste åren har IP-baserade tjänster ökat i popularitet. För att effektivt möta de användarkrav som ställs på sådana tjänster har olika tekniker för att styra transportnätverk utvecklats. En sådan teknik, nu under utveckling för multi-lagrade nätverk, är GMPLS. GMPLS är en nödvändig nätverksteknik eftersom tillhandahållandet av sluttjänster mellan olika användare idag, och inom en överskådlig framtid, mycket sannolikt kommer att kräva samarbete mellan flera nätverkslager. Här undersöks GMPLS färdighet i optiska nätverk genom att se över det nuvarande stödet för optiska nätverkskomponenter i GMPLS standarddokument. Baserat på denna undersökning har en kandidatlösning för routing och begränsad vägberäkning i optiska nätverkssegment tagits fram. Denna kandidatlösning visas effektivt hantera de ytterligare attribut och restriktioner som existerar i optiska nätverkskomponenter.