Études du ciblage intracellulaire des molécules non classiques du complexe majeur d'histocompatibilité de classe II

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

Les réseaux de chambres de culture de sphéroïdes : un outil pour la recherche de traitements combinatoires en oncologie

Le traitement du cancer requiert fréquemment la combinaison de plusieurs traitements tels la chimiothérapie et la radiothérapie afin d’accroitre les chances de survie des patients. L’efficacité de ces combinaisons repose sur les synergies entre les traitements et varie grandement en fonction de la nature du cancer ciblé et des traitements utilisés. Or, il n’existe peu ou pas d’outils spécialisés compatibles à la radiothérapie permettant de tester rapidement ces combinaisons en laboratoire. Nous avons donc développé un dispositif microfluidique composé d’un réseau de valves permettant la réalisation de 12 combinaisons et la culture de sphéroïdes, des agrégats cellulaires tridimensionnels formés d’un ou de plusieurs types de cellules. Le dispositif est composé d’un assemblage d’étages de PDMS, un matériau flexible, transparent et perméable à l’oxygène, et est réalisé à partir de moules fabriqués par impression 3D, permettant la réalisation de plusieurs itérations du dispositif rapidement et à moindre cout. Le dispositif devant être simple à utiliser, compatible aux techniques de culture cellulaire conventionnelles, nous avons conçu des valves magnétiques manuelles afin de pouvoir contrôler le flux des liquides dans le système. Chacune de ces valves peut être contrôlée manuellement et individuellement, conférant un haut degré de flexibilité au dispositif. Elles résistent aussi à des pressions élevées (> 10 kPa), même après une exposition à une dose de radiothérapie de 8 Gy et une incubation de 7 jours à 37°C. Le dispositif final, le réseau de chambres de culture de sphéroïdes (RCCS), est composé de 12 chambres de cultures contenant chacune 25 puits où peuvent se former les sphéroïdes. Chaque chambre de culture est entourée de quatre valves, ce qui permet de contrôler précisément le trajet emprunté par les solutions à l’intérieur du dispositif. En ajustant les valves, il est possible de remplir le RCCS en entier à partir d’une entrée et d’une sortie ou de faire circuler les solutions en empruntant seulement les canaux horizontaux ou verticaux. Les chambres de culture sont aussi séparées les unes des autres de plusieurs millimètres, ce qui permet d’exposer les différentes chambres d’un même dispositif à différentes doses de radiothérapie. Les RCCS ont permis la formation et l’imagerie des sphéroïdes provenant de trois lignées cellulaires différentes directement sur le dispositif. Il reste encore à évaluer leur potentiel dans un contexte réel de recherche de traitements combinatoires en oncologie, mais il ne fait aucun doute qu’une fois ces résultats obtenus, les RCCS pourraient devenir un outil clé pour la recherche en oncologie.----------ABSTRACT Cancer treatment frequently needs a combination of several treatments such as chemotherapy and radiotherapy in order to increase patients’ survival rates. Efficacy of these combinations relies on synergies between treatments and varies greatly in function of the nature of the targeted cancer and the treatments used. However, very few specialized tools exist that allow rapid testing of these combinations in laboratory, while being compatible to radiotherapy. Hence, we developed a microfluidic device composed of an array of valves allowing simultaneous testing of twelve combinations of treatments and culture of spheroids, tridimensional cell aggregates composed of one or more type of cells. The device is composed of an assembly of layers of PDMS, a flexible, transparent and oxygen permeable material. The layers were made from 3D printed molds, allowing cheap and adaptable fabrication of the device according to the different needs. In order for the device to be simple to use and compatible to day to day cell culture techniques, we designed manual magnetic valves to route liquids within the system. Each of these valves can be opened and closed manually, resulting in a high degree of flexibility. They also resist high pressures (> 10 kPa), even after being exposed to 8 Gy radiotherapy and incubated 7 days at 37°C. The final device, the spheroid culture chamber array (SCCA), is composed of 12 culture chambers each containing 25 wells where spheroids can form. Four valves, allowing precise control of solutions pathways within the device, surround each culture chamber. By adjusting the valves configuration, it’s possible to fill the entire device from a single inlet and outlet or to fill only the vertical or horizontal channels. The culture chambers are also separated by several millimeters, which allows exposure of the different chambers to different radiotherapy doses on a single device. SCCA allowed formation and imaging of spheroids from three different cell lines directly on-chip. The potential of the device in a real oncology combinatorial experiment still remains to evaluate, but there is no doubt that, once there experiments will be done, SCCAs could become a key tool in oncology research

An analysis of the impact of multi-threading on communication performance

International audienceAlthough processors become massively multicore and therefore new programming models mix message passing and multi-threading, the effects of threads on communication libraries remain neglected. Designing an efficient modern communication library requires precautions in order to limit the impact of thread-safety mechanisms on performance. In this paper, we present various approaches to building a thread-safe communication library and we study their benefit and impact on performance. We also describe and evaluate techniques used to exploit idle cores to balance the communication library load across multicore machines

Sistema de propulsió multidireccional per barques amb transformador mecànic hipocicloide.

Aquest projecte consisteix en l’estudi d’una patent sobre un sistema de propulsió multidireccional (SPM) amb transformador hipocicloide, per barques. Aquest sistema vol imitar la forma de nedar dels peixos, basant-se amb la Biomímesis. L’objectiu principal d’aquest projecte consisteix en estudiar el funcionament del SPM per poder dissenyar en 3D les seves parts i realitzar la simulació mitjançant el Catia V5. A partir de la realització del seu disseny, s’estudia i s’analitzen les proves de rendiment realitzades i s’arriba a una conclusió segons la comparació d’aquest rendiment amb diferents tipus d’hèlixs convencionals. Finalment, hi ha un petit anàlisi dels materials utilitzats, els processos de fabricació, el medi ambient i el pressupost necessari per realitzar tot el sistema

A multicore-enabled multirail communication engine

International audienceThe current trend in clusters architecture leads toward a massive use of multicore chips. This hardware evolution raises bottleneck issues at the network interface level. The use of multiple parallel networks allows to overcome this problem as it provides an higher aggregate bandwidth. But this bandwidth remains theoretical as only a few communication libraries are able to exploit multiple networks. In this paper, we present an optimization strategy for the NewMadeleine communication library. This strategy is able to efficiently exploit parallel interconnect links. By sampling each network's capabilities, it is possible to estimate a transfer duration a priori. Splitting messages and sending chunks of messages over parallel links can thus be performed efficiently to reach the theoretical aggregate bandwidth. NewMadeleine is multithreaded and exploits multicore chips to send small packets, that involve CPU-consuming copies, in parallel

Effect of carbonation on the hydro-mechanical properties of Portland cements

International audienceWe evaluate experimentally the effect of carbonation on the hydro-mechanical properties of Portland cement. Samples were carbonated at 90 °C and 28 MPa under wet supercritical CO2. Two types of carbonation features were achieved, either the samples were homogeneously carbonated or they displayed sharp carbonation fronts. Using a tri-axial apparatus, the static elastic moduli and the mechanical strength were measured at in-situ pressure conditions (28 MPa) and showed a degradation of the mechanical properties of the samples where a carbonation front prevailed. Water and gas permeabilities were measured and showed that the samples with a carbonation front exhibit a stress sensitive permeability. P and S elastic wave velocities were measured to evaluate dynamic (ultrasonic range, 1 MHz) elastic moduli. The use of an effective medium theory approach enabled us to characterize the density and distribution of cracks within the samples. This approach outlines that the samples which developed a carbonation front were damaged

A sampling-based approach for communication libraries auto-tuning

International audienceCommunication performance is a critical issue in HPC applications, and many solutions have been proposed on the literature (algorithmic, protocols, etc.) In the meantime, computing nodes become massively multicore, leading to a real imbalance between the number of communication sources and the number of physical communication resources. Thus it is now mandatory to share network boards between computation flows, and to take this sharing into account while performing communication optimizations. In previous papers, we have proposed a model and a framework for on-the-fly optimizations of multiplexed concurrent communication flows, and implemented this model in the \nm communication library. This library features optimization strategies able for example to aggregate several messages to reduce the number of packets emitted on the network, or to split messages to use several NICs at the same time. In this paper, we study the tuning of these dynamic optimization strategies. We show that some parameters and thresholds (\rdv threshold, aggregation packet size) depend on the actual hardware, both host and NICs. We propose and implement a method based on sampling of the actual hardware to auto-tune our strategies. Moreover, we show that multi-rail can greatly benefit from performance predictions. We propose an approach for multi-rail that dynamically balance the data between NICs using predictions based on sampling

A multithreaded communication engine for multicore architectures

International audienceThe current trend in clusters leads towards an increase of the number of cores per node. As a result, an increasing number of parallel applications is mixing message passing and multithreading as an attempt to better match the underlying architecture's structure. This naturally raises the problem of designing efficient, multithreaded implementations of MPI. In this paper, we present the design of a multithreaded communication engine able to exploit idle cores to speed up communications in two ways: it can move CPU-intensive operations out of the critical path (e.g. PIO transfers offload), and is able to let rendezvous transfers progress asynchronously. We have implemented these methods in the PM2 software suite, evaluated their behavior in typical cases, and we have observed good performance results in overlapping communication and computation

Reconfigurable microfluidic magnetic valve arrays: Towards a radiotherapy-compatible spheroid culture platform for the combinatorial screening of cancer therapies

We introduce here a microfluidic cell culture platform or spheroid culture chamber array (SCCA) that can synthesize, culture, and enable fluorescence imaging of 3D cell aggregates (typically spheroids) directly on-chip while specifying the flow of reagents in each chamber via the use of an array of passive magnetic valves. The SCCA valves demonstrated sufficient resistance to burst (above 100 mBar), including after receiving radiotherapy (RT) doses of up to 8 Gy combined with standard 37 degrees C incubation for up to 7 days, enabling the simultaneous synthesis of multiple spheroids from different cell lines on the same array. Our results suggest that SCCA would be an asset in drug discovery processes, seeking to identify combinatorial treatments