Après la découverte des mutations de la calréticuline dans les néoplasmes classiques myéloproliferatifs négatifs pour le Ph1, les travaux se sont focalisés sur les deux mutations les plus fréquentes, c'est-à-dire la calréticuline del52 et l’ins5, mais il existe environ 20% de mutants rares de la calréticuline (une cinquantaine), qui ont été classés en type-1 « like » et type-2 « like », classification basée sur leur structure. Cependant il reste à déterminer si cette classification est pertinente du point de vue fonctionnel, ce qui pourrait avoir des conséquences pour la prise en charge des patients et leur traitement. Ici, nous démontrons que deux mutants rares de type-1 (del34 et del46) et un de type-2 (del19) se comportent de manière similaire aux deux mutations fondatrices de cette classification, del52 et ins5, respectivement. Ces résultats ont été validés par des expériences in vivo chez la souris. Tous les mutants de la calréticuline (del19, del34 et del46) nécessitent absolument le récepteur de la thrombopoïétine, appelé MPL, pour induire une transformation cellulaire en provoquant une activation indépendante de la thrombopoïétine de la voie MPL / JAK2-STAT, comme les mutants del52 et ins5. Dans les expériences de transplantation de moelle osseuse de souris, les mutants rares de type-1 sont associés à une progression fréquente de la maladie d’un tableau proche d’une thrombocytémie essentielle à une myélofibrose, tandis que le mutant rare de type 2 est associé à une légère thrombocytose. Du point de vue hématopoïétique, les mutants rares de type-1 provoquent une amplification au niveau des cellules souches hématopoïétiques donc à un stade précoce tandis que les mutants rares de type-2 provoquent une amplification tardive de la mégacaryopoïèse. Grâce à une modélisation protéique basée sur l'homologie des mutants de calréticuline, nous avons identifié des domaines oncogènes qui seraient potentiellement responsables de l'interaction pathologique de la calréticuline et de MPL pour conduire à une activation indépendante de la thrombopoïétine. Maintenant, ces résultats in silico doivent être absolument validés par des études structure fonction. Enfin, nous avons modélisé un nouveau mécanisme de signalisation dans la leucémie myéloïde chronique comprenant IRE-1alpha, un bras de la voie de réponse des protéines mal repliées (UPR), qui pourrait être responsable de la perte de la fonction de la p53 pendant la progression de la leucémie myéloïde chronique vers une leucémie aiguë. Un tel mécanisme pourrait être impliqué dans les autres MPN. / After the discovery of calreticulin mutations in classical Ph1- Myeloproliferative Neoplasms, extensive investigation is underway on the two most frequent mutations, i.e., del52 and ins5, but it remains that the rare calreticulin mutants, which include both type-1 like and type-2 like require a similar investigation for ascertaining whether the classification of type-1 and type-2 has a functional relevance as well as for therapeutic intervention and patient management. Here we demonstrate that type-1 like (del34 and del46) and type-2 like (del19) mutants behave similarly as del52 and ins5 mutants, respectively. Moreover, we validate our findings with in vivo experiments. All the calreticulin mutants (del19, del34 and del46) absolutely require the thrombopoietin receptor, MPL, to induce cell transformation by causing ligand independent activation of the MPL/JAK2-STAT pathway. In mouse bone marrow transplantation experiments, type-1 like mutants are associated with frequent progression from an essential thrombocythemia-like phenotype to myelofibrosis whereas type-2 like mutant is associated with mild thrombocytosis. Type-1 like mutants cause clonal amplification of early hematopoetic stem cells whereas the type-2 like mutant causes late platelet amplification. Further, by homology based protein modeling of calreticulin mutants, we have identified possible oncogenic domains responsible for pathologic interaction of CALR and MPL leading to ligand independent activation of MPL. Now they must be validated by structural-functional studies Finally, we have modelled a novel signaling mechanism in chronic myeloid leukemia comprising of IRE-1alpha, an unfolded protein response (UPR) pathway arm, which may be responsible for loss of the WT p53 function during leukemic development and progression. Such a mechanism may be involved in the other MPNs

Central driving forces in the pathogenesis of liver disease are hepatocyte death and immune cell-driven inflammation. The interplay between outcomes, stemming from these two major cell types, is present from the earliest ethanol exposure, and are both determinants in advanced stages of liver disease particularly in alcoholic liver disease (ALD). The complexities associated with advanced ALD are many and therapies are limited. Due to the liver’s role in ethanol metabolism and filtering gut-derived products, it is becoming increasingly clear that innate immunity plays a central role in triggering activation of cell death and inflammatory pathways in ALD. We identified interferon regulatory factor 3 (IRF3) activation as a mediator of hepatocyte death as the first event after ethanol exposure, and the inflammasome as a protein complex responsible for the subsequent inflammatory cascade, driven by the NLRP3 inflammasome. Our novel findings in murine samples and human patients with alcoholic hepatitis demonstrate that ethanol-induced inflammasome activity results in Caspase-1-mediated pyroptosis and extracellular ASC aggregates in the liver and circulation. Pyroptosis can be abrogated by therapeutic inhibition of inflammasome components, NLRP3 or Caspase-1. Taken together, the event leading to mtDNA release into the cytoplasm is the inception of the pathogenesis of ALD, triggering hepatocyte death, culminating in a pro-inflammatory cascade driven by the NLRP3 inflammasome and pyroptotic release of ASC.

The purpose of this study is to analyze the events that occurred throughout the Egyptian Revolution from January 2010 to February 2010 through pragmatic humanism. Tweets will be looked at from the book Tweets from Tahrir to show how the process unfolded. Building on the previous research, the tweets will be looked at through the lens of pragmatic humanism. The study will show how individuals can better the world they live in by experimenting with different methods and adapting to any failures they may encounter. The study will also show how the reach of the individual has become faster and further than previously possible. The elements of pragmatic humanism will be broken down into five main tenets. The study will take a thematic approach in analyzing the tweets through the perspective of the particular tenet. The study will also show the power of individual desires when they are able to combine with the social context of the time. The advent of Twitter has allowed individuals to test and experiment with hypotheses much quicker than before and allows them to make monumental changes to their reality in a much shorter period of time. / Graduation date: 2013

Classical planning is the problem of nding a sequence of actions that take an agent from an initial state to a desired goal situation, assuming deter- ministic outcomes for actions and perfect information. Satis cing planning seeks to quickly nd low-cost solutions with no guarantees of optimality. The most e ective approach for satis cing planning has proved to be heuristic search using non-admissible heuristics. In this thesis, we introduce several such heuristics that are able to take into account costs on actions, and there- fore try to minimize the more general metric of cost, rather than length, of plans, and investigate their properties and performance. In addition, we show how the problem of planning with soft goals can be compiled into a classical planning problem with costs, a setting in which cost-sensitive heuristics such as those presented here are essential. / La plani caci on cl asica es el problema que consiste en hallar una secuencia de acciones que lleven a un agente desde un estado inicial a un objetivo, asum- iendo resultados determin sticos e informaci on completa. La plani caci on \satis cing" busca encontrar una soluci on de bajo coste, sin garant as de op- timalidad. La b usqueda heur stica guiada por heur sticas no admisibles es el enfoque que ha tenido mas exito. Esta tesis presenta varias heur sticas de ese g enero que consideran costes en las acciones, y por lo tanto encuentran soluciones que minimizan el coste, en lugar de la longitud del plan. Adem as, demostramos que el problema de plani caci on con \soft goals", u objetivos opcionales, se puede reducir a un problema de plani caci on clasica con costes en las acciones, escenario en el que heur sticas sensibles a costes, tal como las aqu presentadas, son esenciales.