Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

The mechanism of gamete fusion remains largely unknown on molecular level despite its indisputable significance. A few molecules requisite for membrane interaction are known, among them IZUMO1 on sperm and tetraspanin CD9 on egg. A concept of a large multitprotein complex on both membranes forming a fusion machinery is recently emerging. CD9 is expected to play a role in organizing egg membrane order and to interact laterally with other factors. On the other hand, IZUMO1 contains one immunoglobulin (Ig) domain, which is known for its interaction with various molecules and thus is expected to have a binding partner on the egg membrane. Ig domains are known for their involvement in interactions with Fc receptors and Fc receptor-like molecules, which makes these a potential partner for sperm in gamete binding and fusion. Recent experiments identified Fc receptor-like 3 as a candidate binding partner for sperm by one-bead one-compound assay. The aim of presented study was to assess the localization of FCRL3 in mouse eggs, together with its potential co-localization with IZUMO1 on complexes of zona-free eggs with bound sperm. In this study, FCRL3 molecule has been found across the cytoplasm, possibly in the intracytoplasmic membrane compartments of the cell, as well as on the egg membrane. Its presence...

Suture or bone anchors are used to reattach a tendon or ligament after it has been torn away from the bone. Anchors provide secure attachments to bone during trauma or reconstructive surgery, holding the ligament or tendon in place and potentially allowing greater mobility during recovery. Computer modelling techniques are used to investigate both established bone anchor technology, such as threaded implants, and emerging technologies such as cement augmentation or sonic-fusion. Sonic fusion is an ultrasound-assisted anchoring method which has recently been introduced in low load maxillofacial applications, and is expected to be used in other low load applications such as hallux valgus alignment procedures and suture attachment. Threaded anchors were examined using two Finite Element (FE) models of human cancellous bone, representing both “normal” and “weaker” bone. Simulation and analysis revealed the critical nature of modelling the microstructure of bone. Changing the direction of loading in the model leads to significant changes in the response of the construct, and this cannot be represented in continuum models, or in physical models using artificial cancellous bone. Rapid prototyping (RP) using 3d printing was used for validation of the FE models. While this method has previously been implemented to create physical bone models, testing an assembly model and comparing it to FE results for inclined loading had not been attempted. RP models were created of the threaded anchor in both “normal” and “weaker” bone, and a sonic fusion model in the normal bone was also created. These models were then subjected to mechanical testing. Results produced from the simulation correlated with the physical results. The importance of a cortical layer was re-confirmed. At the apparent densities simulated, engagement with the cortical layer increases pull-out force dramatically. Engaging the anchor even with a thin cortical layer can produce a significant improvement to pull-out strength. Novel sonic fusion FE models were created from a CT scan of animal bone, and the geometry for both the sonic-fusion pin and bone were taken from the CT scan. Computer generated geometry was used to build pin concepts of varying shapes. It was shown that if good engagement is made with bone, as in the case of all of the concepts created, then sonic fusion can produce a good holding power - comparable with that of a threaded anchor. The results showed that sonic-fusion requires less drill penetration into the bone, meaning less of the inherent bone structure is removed – vital for patients with poor bone quality. Bone cement models were investigated. Bone augmentation models were created, and the addition of cement demonstrated an improvement in anchor holding power. The research showed that there are benefits to using FEA as a tool to evaluate the mechanical aspects of cement distribution. The results proved the hypothesis that augmentation will likely increase the holding power of anchor, and its distribution will affect pull-out significantly. This work has created a method for modelling and evaluating both established and novel bone anchor technology in CT bone geometry, a procedure which could be expanded to other bone implants. It has been validated using the innovative approach of rapid prototyping.

eXfiltration Advanced Persistent Threats (XAPTs) increasingly account for incidents concerned with critical information exfiltration from High Valued Targets (HVT's) by terrorists, cyber criminals or enemy states. Existing Cyber Defence frameworks and data fusion models do not adequately address (i) the multi-stage nature of XAPTs and (ii) the uncertainty and conflicting information associated with XAPTs. A new data fusion theory, called the Markov Multi-phase Transferable Belief Model (MM-TBM) is developed, for tracking and predicting XAPTs. MM-TBM expands the attack kill-chain model to attack trees and introduces a novel approach for combining various sources of cyber evidence, which takes into account the multi-phased nature of XAPTs and the characteristics of the cyberspace. As a data fusion theory, MM-TBM constitutes a novel approach for performing hypothesis assessment and evidence combination across phases, by means of a new combination rule, called the Multi-phase Combination Rule with conflict Reset (MCR2). This is the first combination rule in the field of data fusion that formalises a new method for combining evidence from multiple, causally connected hypotheses spaces and eliminating the bias from preceding phases of the kill-chain. Moreover, this is the first time a data fusion theory utilises the conflict mass m(Ø) for identifying paradoxes. In addition, a diagnostic formula for managing missing pieces of evidence within attack trees is presented. MM-TBM is designed, developed and evaluated using a Design Science Research approach within two iterations. Evaluation is conducted in a relevant computer network environment using scenario-based testing. The experimental design has been reviewed and approved by Cyber Security Subject Matter Experts from MoD’s Defence Science Technology Laboratory and Airbus Group. The experimental results validate the novel capabilities introduced by the new MM-TBM theory to Cyber Defence in the presence of information clutter, conflict and congestion. Furthermore, the results underpin the importance of selecting an optimal sampling policy to effectively track and predict XAPTs. This PhD bridges the gaps in the body of knowledge concerned with multi-phase fusion under uncertainty and Cyber SA against XAPTs. MM-TBM is a novel mathematical fusion theory for managing applications that existing fusion models do not address. This research has demonstrated MM-TBM enables the successful Tracking and Prediction of XAPTs to deliver an enhanced Cyber SA capability.

Die Globalisierung der Wirtschaft und die Fortentwicklung des Europäischen Binnenmarktes führen zu einer Steigerung des grenzüberschreitenden Wettbewerbs und rufen bei vielen Gesellschaften das Bedürfnis hervor, sich durch grenzüberschreitende Restrukturierungen den neuen Gegebenheiten anzupassen. Da hierfür bisher gemeinschaftsrechtliche Regelungen fehlen und keine Rechtsangleichungen erfolgt sind, wurzeln entsprechende Maßnahmen in den nationalen Rechtsordnungen. Die zur Durchführung grenzüberschreitender Restrukturierungen notwendigen bilateralen Rechtsuntersuchungen werden in dieser Arbeit ausführlich für die Staaten Deutschland und Frankreich vorgenommen. Es wird geprüft ob und unter welchen Voraussetzungen bereits heute deutsch-französische Sitzverlegungen, Fusionen, Spaltungen und Eingliederungen zulässig sind. Hierzu werden die deutschen und französischen Vorschriften rechtsvergleichend analysiert, die Rechtslage nach beiden Rechtsordnungen dargestellt und deren Zusammenwirken untersucht. Dabei zeigt sich, dass einige deutsch-französische Restrukturierungen unter Berücksichtigung gewisser Bedingungen schon zum jetzigen Zeitpunkt zulässig sind. / Economic globalisation and further developments within the European market have led to an increase in commercial competition across national borders. Many companies feel the need to react to this situation through subsequent re-structuring across geopolitical borders. Since communal regulations have yet to be drawn-up to account for this situation, enterprises are constrained by national legal systems. This monograph investigates extensively the legal implications of cross-border restructuring initiatives between Germany and France, in an effort to clarify the current legal situation. It investigates whether German-French Head Quaters transfers, mergers, split-ups and incorporations are currently possible and, if so, under what conditions. To achieve this, German and French legal regulations have been presented, juxtaposed and analysed for their complements or restrictions. The study shows that bilateral restructuring initiatives between Germany and France are already possible, although they are subject to particular constraints.

Tumor cells often hijack endoplasmic reticulum (ER) mediated signaling to facilitate tumor progression by adapting to the cellular stress evoked by oncogene overexpression and adverse microenvironment. Despite the prevalence of MYC-driven cancers, how the MYC oncoprotein regulates ER stress response pathways during tumorigenesis remains incompletely understood. Here we show that MYC drives continuous upregulation of ubiquitin fusion degradation 1 (UFD1) during T-cell acute lymphoblastic leukemia (T-ALL) development. As the E2 component of an ER-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER. We found that genetic and pharmacological disruption of UFD1 function exacerbates ER stress and activates the unfolded protein response (UPR). Specifically, UFD1 knockdown in human T-ALL cells impairs ERAD and promotes the proapoptotic UPR through the PERK-CHOP-BCL2 axis. This effect is demonstrated by an upregulation of PERK, phospho-PERK and its downstream effector CHOP, as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor-cell apoptosis induced by UFD1 knockdown. Allelic loss of ufd1 in zebrafish similarly induces tumor-cell apoptosis and impairs MYC-driven T-ALL progression without affecting general animal health. These studies establish the UFD1-mediated ER stress response as an important mediator of MYC-driven tumor progression and suggest strategies for targeted therapy in T-ALL, and perhaps other MYC-driven cancers. Although UFD1-specific inhibitors have yet to be developed, inhibitors that target the p97 co-factor in UFD1-mediated ERAD are readily available. Importantly, we show that treatment with CB-5083, a selective and oral bioactive inhibitor of p97, can effectively kill human MYC-overexpressing T-ALL patient cells ex vivo and inhibits tumor progression in zebrafish models of MYC-driven T-ALL. Thus, CB-5083 treatment may represent an effective targeted therapy for T-ALL, especially relapsed/refractory ones with gain-of-function NOTCH1 mutations and thus MYC-overexpression.

La détection de changements dans une scène est l’un des problèmes les plus complexes en télédétection. Il s’agit de détecter des modifications survenues dans une zone géographique donnée par comparaison d’images de cette zone acquises à différents instants. La comparaison est facilitée lorsque les images sont issues du même type de capteur c’est-à-dire correspondent à la même modalité (le plus souvent optique multi-bandes) et possèdent des résolutions spatiales et spectrales identiques. Les techniques de détection de changements non supervisées sont, pour la plupart, conçues spécifiquement pour ce scénario. Il est, dans ce cas, possible de comparer directement les images en calculant la différence de pixels homologues, c’est-à-dire correspondant au même emplacement au sol. Cependant, dans certains cas spécifiques tels que les situations d’urgence, les missions ponctuelles, la défense et la sécurité, il peut s’avérer nécessaire d’exploiter des images de modalités et de résolutions différentes. Cette hétérogénéité dans les images traitées introduit des problèmes supplémentaires pour la mise en œuvre de la détection de changements. Ces problèmes ne sont pas traités par la plupart des méthodes de l’état de l’art. Lorsque la modalité est identique mais les résolutions différentes, il est possible de se ramener au scénario favorable en appliquant des prétraitements tels que des opérations de rééchantillonnage destinées à atteindre les mêmes résolutions spatiales et spectrales. Néanmoins, ces prétraitements peuvent conduire à une perte d’informations pertinentes pour la détection de changements. En particulier, ils sont appliqués indépendamment sur les deux images et donc ne tiennent pas compte des relations fortes existant entre les deux images. L’objectif de cette thèse est de développer des méthodes de détection de changements qui exploitent au mieux l’information contenue dans une paire d’images observées, sans condition sur leur modalité et leurs résolutions spatiale et spectrale. Les restrictions classiquement imposées dans l’état de l’art sont levées grâce à une approche utilisant la fusion des deux images observées. La première stratégie proposée s’applique au cas d’images de modalités identiques mais de résolutions différentes. Elle se décompose en trois étapes. La première étape consiste à fusionner les deux images observées ce qui conduit à une image de la scène à haute résolution portant l’information des changements éventuels. La deuxième étape réalise la prédiction de deux images non observées possédant des résolutions identiques à celles des images observées par dégradation spatiale et spectrale de l’image fusionnée. Enfin, la troisième étape consiste en une détection de changements classique entre images observées et prédites de mêmes résolutions. Une deuxième stratégie modélise les images observées comme des versions dégradées de deux images non observées caractérisées par des résolutions spectrales et spatiales identiques et élevées. Elle met en œuvre une étape de fusion robuste qui exploite un a priori de parcimonie des changements observés. Enfin, le principe de la fusion est étendu à des images de modalités différentes. Dans ce cas où les pixels ne sont pas directement comparables, car correspondant à des grandeurs physiques différentes, la comparaison est réalisée dans un domaine transformé. Les deux images sont représentées par des combinaisons linéaires parcimonieuses des éléments de deux dictionnaires couplés, appris à partir des données. La détection de changements est réalisée à partir de l’estimation d’un code couplé sous condition de parcimonie spatiale de la différence des codes estimés pour chaque image. L’expérimentation de ces différentes méthodes, conduite sur des changements simulés de manière réaliste ou sur des changements réels, démontre les avantages des méthodes développées et plus généralement de l’apport de la fusion pour la détection de changements

Usando um modelo de um canal efetivo, o qual contem efeitos de acoplamento de canais através da presença de um potencial de polarização dependente da energia, nós estudamos, em energias abaixo da barreira, as reações de fusão dos sistemas A1 ANTPOT. Ni+ A2 ANTPOT. Ni e 16ANTPOT. O + A ANTPOT. Sm. Com o auxilio de uma relação de dispersão inversa, obtivemos a parte imaginária desse potencial em termos da parte principal da integral envolvendo a parte real do mesmo. A consistência deste método foi verificada através da comparação entre este potencial empírico e o potencial de polarização efetivo determinado a partir de um acoplamento específico de canais. Foram também calculados o primeiro e segundo momentos da distribuição de momentos angulares da seção de choque parcial de fusão. / Using an effective one channel model which contains channel coupling effects through the presence of an inclusive energy dependent polarization potential, we studied sub - barrier fusion of the systems A1Ni + A2Ni and 16O+ASm . With the aid of an inverse dispersion relation, we obtained the imaginary part of this potential. The consistency of this method is c hecked by comparing this empirical polarization potential with the one determined from the explicit consideration of a specific channel coupling. The first and the second moments of the angular momentum distribuition of the partial fusion cross-section were calculated also.

Dentre as características desejáveis em leveduras fermentadoras alcóolicas estão a capacidade de floculação, a não produção de H2S e o caráter "killer". Neste trabalho foram selecionadas sete linhagens de Saccharomyces cerevisiae com algumas destas características, que passaram por testes confirmativos e pela cariotipagem eletroforética resultando na escolha de duas linhagens: ATCC 26602 (altamente floculante) e K1 (H2S - e possuidoras do caráter "killer"). Estas linhagens foram utilizadas em um cruzamento via fusão de protoplasto para se obter um produto de fusão estável com as características de interesse tecnológico. Na seleção das linhagens híbridas com base em caracteres naturais foram isolados 1291 híbridos em meio seletivo e entre essas colônias somente 1,5% foram inicialmente consideradas híbriadas. Após três subcultivos em YEPD líquido, estes produtos de fusão não se mostraram estáveis. / Flocculative and "killer" skills and lack in production of H2S are desirable characteristics of the ethanolic fermentative yeasts. Seven selected strains of Saccharomyces cerevisiae with some of these characteristics were evaluated for confirmation of these habilities and their genetic characterization was undertaken by eletrophoretic kariotyping. The strain ATCC 26602 had flocculant hability and the strain K1 was H2S - and "killer". The strains were selected for protoplast fusion aiming to obtain a stable fusion strain with these desirable technologyc characteristics. The selection of the hybrid strains were based on natural characters and have shown 1291 hybrids (frequency of 1,5%) in the medium for the isolation of the fusionants (protoplasts). The protoplast stability were monitored by three continuous growth in the YEPD liquid midium and the stable fusion products were not obtained.

Com o objetivo de estudar o processo de fusão entre íons pesados, realizamos medidas da seção de choque do processo de fusão nuclear para o sistema 16O + 60Ni no intervalo de energia de bombardeio ao redor da barreira coulombiana (ELAB -> 40 - 72 mEv). A técnica utilizada para a detecção dos resíduos de evaporação do núcleo composto, foi a da medida do tempo de voo, associada a um sistema de deflexão eletrostática para separar esses resíduos, das partículas com massa perto da do feixe incidente. As distribuições angulares dos resíduos de evaporação foram medidas no intervalo angular de 2° <= ? <= 18°. A função de excitação de fusão foi analisada inicialmente via modelo de penetração de barreira unidimensional que mostrou subestimar a seção de choque de fusão em energias em torno e abaixo da barreira coulombiana; desta forma procuramos ajustar os dados desta região, através do modelo de canais acoplados, que não se mostrou totalmente satisfatório. Em energias acima da barreira (na região de anomalia) também foram detectados desvios dos dados experimentais com relação às previsões teóricas do modelo unidimensional, que são explicados através de considerações de potenciais ópticos. Com o objetivo de se obter uma melhor compreensão de efeitos de estrutura nuclear nos processos de reação envolvidos, comparamos o sistema até aqui citado com o sistema 18O + 58Ni (que leva ao mesmo núcleo composto do sistema 16O + 60Ni). A comparação revelou que o primeiro sistema possui um aumento significativo na seção de choque de fusão na região subcoulombiana, em relação ao 16O + 60Ni. Isto pode estar relacionado com o fato de que as estruturas internas dos núcleos são diferentes, mas não nos foi possível confirmar esta afirmação. / With the objective to study the process of fusion between heavy ions, we measured the nuclear fusion cross section for the system 16O + 60Ni, at an energy range around the Coulomb barrier (ELAB -> 40 - 72 mEv). In order to detect the evaporation residues following the fusion process, the time of flight method was adopted in conjunction with an electrostatic deflector capable of separating the evaporations residues from the beam particles. The angular distributions of the evaporation residues were measured in the angular range of 2° <= ? <= 18°. The excitation function was analyzed using the unidimensional barrier penetration model. Theoretical fusion cross sections obtained from this analysis were smaller than our measured values, in the energy region near and below the Coulomb barrier. In order to discover which channels enhance the fusion cross section in this region, a coupled channel calculation was performed, but did not lead to satisfactory results. Theoretical predictions for the unidimensional model were compared to the experimental fusion cross section (anomaly region). We compared the systems 18O + 58Ni and 16O + 60Ni (which lead to the same compound nucleus) to understand the nuclear structure effects in the reaction process. This comparison showed that the cross section of the first system is larger than for 16O + 60Ni, at energies below the Coulomb barrier. This could be possibly to the different internal structures of the nuclei, but it was not possible to confirm this affirmation.