NCube/papyrus huggingface dataset:
Comparaison d'estimateurs de la variance du TMLE

In the context of causal inference where we seek to estimate the average causal effect of a binary exposure on an outcome variable, the TMLE of M. Van der Laan and D. Rubin is a technique which applies to an initial estimate of the conditional expectation of the outcome a modification whose purpose is to reduce bias in the corresponding estimation of the average causal effect. The gold standard for estimation of the variance of the TMLE is a sandwich-type estimator. Various alternative estimators are identified and compared to the gold standard when the sample size is small, when the propensity scores are high or low and when the initial estimate of the propensity score or of the conditional expectation of the outcome is bad. for each of the variance estimator, a confidence interval for the TMLE is constructed. We find that the Jackknife estimator yields coverage rates equivalent or better than all the other estimators in all these situations.

Keyphrases: Causal inference, TMLE, variance estimation, sandwich estimator, Jackknife
Rôle de la tomodensitométrie à double énergie/double source pour la personnalisation des traitements de radiothérapie

The future of radiotherapy lies in the development of strategies to adapt treatments to each individual. Dual energy / dual source computed tomography (DECT/DSCT) is an imaging technology that allows for accurate tissue characterisation (organs at risk or tumors) and that can capture precisely the anatomy of the heart in motion. DECT/DSCT technology has the potential to be important player in personalized radiotherapy. We explored the role of DECT/DSCT in radiotherapy planning in the context of 3 prospective clinical studies.  First, we evaluated the role of DECT imaging for the assessment of lung function in lung cancer radiotherapy planning (both conventionally fractionated and stereotaxic radiotherapy). We hypothesized that accurate quantification of DECT iodine concentration could be used in treatment planning to assesses and preserve functional parenchyma. We demonstrated the feasibility and validity of a novel lung function quantification method using DECT iodine mapping. In addition, we showed that incorporating this information into radiotherapy planning could help improve lung dosimetry, and thus potentially reduce toxicities.  In a second approach, we evaluated the role of DSCT for individualized assessment of cardiac motion in radiotherapy planning. We showed that the DSCT allows visualization and quantification of motion of cardiac sub-structures, including the pulmonary veins and coronary arteries, and therefore can be used to determine personalized target volume for each patient. In addition, we quantified the dosimetric impact of cardiac-gated radiotherapy in left breast cancer radiotherapy and demonstrated significant sparing of cardiac sub-structures with this method, in particular sparing of left anterior descending artery, a critical structure involved in radiation-induced cardiovascular toxicities.   Finally, we assessed the role of DECT in determining tumor perfusion in larynx/hypopharynx cancers using the iodine concentration quantification method. In an exploratory prospective cohort of 25 patients with cancer of the larynx or hypopharynx, we demonstrated that histogram statistics derived from tumor iodine maps could predict locoregional control in these patients. This finding supports the role of iodine concentration maps as functional biomarkers to predict tumor aggressiveness.   The results of our work focused on these various strategies demonstrate that DECT/DSCT has the potential to play an important role in the following 3 avenues of personalized radiotherapy: 1) for the evaluation of functional healthy tissues; 2) for individualized determination of optimal margins or cardiac-gating window in radiotherapy involving the heart and, 3) for prediction of cancer control outcomes.

Keyphrases: Cancer, Dual-energy computed tomography (DECT), Dual source computed tomography (DSCT), Radiotherapy, Toxicities, Personalized medicine, Functional imaging, Cardiac imaging
Étude des traductions en chinois de la poésie d’Emily Dickinson

Occupying an important position in the American and world literary landscape, Emily Dickinson’s poetry fascinates her translators and raises delicate and exciting issues on the translation of poetry. In order to deepen our reflections on these issues, our thesis analyzes the work of three Chinese translators: Yu Guangzhong, Jiang Feng and Pu Long. We first present the history of Dickinson’s translation and the state of related studies in China. Then we observe how these translators created three following characteristics of the original: its hermeticism, its cultural dimension including intertextuality and its prosody. Inspired by theoretical works of Antoine Berman, Barbara Folkart and Chinese translators such as Yu Guangzhong and Jiang Feng, our research questions the expectations with regard to poetic translation, the principles that the translators have followed and the factors that devote to the virtues and weaknesses of the versions in question.  Yu Guangzhong presents an elegant, harmonious version with a particular taste of traditional Chinese literature. It is a poetic recreation of Dickinson characterized by Yu Guangzhong’s style. Jiang Feng’s translation resembles the original in the point of view of form and spirit. As concise and sober as the latter, it nevertheless contains dry and ambiguous expressions. Generally fluid and clear, Pu Long’s version is studded with clumsy, verbose expressions or those of familiar register. In spite of his respect for the principle of fidelity, each translator leaves a unique imprint on his text, which reflects his translating position and translation project, as well as the gaps between his practice and his discourses on translation.  We apply the methodology developed by Berman (1995) and try to make a productive criticism that could inspire new retranslations of Dickinson’s work. Our analysis corrobo-rates two ideas: an approach similar to the writing of the poet should be followed; instead of restoring the meaning and the formal characteristics in isolation, the translator should recreate the inseparable unity of spirit and form, ideas and their expression, render at the same time the “robbe-corps-âme” of the original.

Keyphrases: Emily Dickinson, Yu Guangzhong, Jiang Feng, Pu Long, poetry, hermetism, americanism, prosody, translation
Emploi des anglicismes par les adolescents et les jeunes adultes dans les SMS : comparaison entre le Québec et la Suisse

This research project is based on a sociolinguistic approach and presents a comparison between Quebec French and Swiss French of anglicisms in SMS messages made by teenagers and young adults. Using two sub-corpora, one Quebecer sub-corpora and one Swiss sub-corpora, both provided by the sms4science project, we selected the 12 to 25 year old group. In order to identify the anglicisms, we chose the Office québécois de la langue française (OQLF) categorization: lexical borrowing (anglicisme intégral), hybrid borrowing (anglicisme hybride), semantic borrowing (anglicisme sémantique), syntactic borrowing (anglicisme syntaxique), morphological borrowing (anglicisme morphologique) and phraseological borrowing (anglicisme phraséologique). The results reveal that, of all six categories of anglicisms, the lexical borrowing is the most used by both Quebecers and Swiss and that the 18 year olds and the 21 year olds are most prone to use anglicisms.

Keyphrases: SMS, Anglicism, Quebec French, Swiss French, Teenager, Young adult
Framework for Real-time collaboration on extensive Data Types using Strong Eventual Consistency

Real-time collaboration is a special case of collaboration where users work on the same artefact simultaneously and are aware of each other’s changes in real-time. Shared data should remain available and consistent while dealing with its physically distributed aspect. Strong Consistency is one approach that enforces a total order of operations using mechanisms, such as locking. This however introduces a bottleneck. In the last decade, algorithms for concurrency control have been studied to keep convergence of all replicas without locking or synchronization. Operational Transformation and Conflict free Replicated Data Types (CRDT) are widely used to achieve this purpose. However, the complexity of these strategies makes it hard to integrate in large software, such as modeling editors, especially for complex data types like graphs. Current implementations only integrate linear data, such as text. In this thesis, we present CollabServer, a framework to build collaborative environments. It features a CRDTs implementation for complex data types such as graphs and gives possibility to build other data structures.

Keyphrases: Concurrency Control, Concurrent Algorithms, Distributed Systems, Optimistic concurrency control, Software Engineering, Shared Data, Strong Eventual Consistency, Gestion de concurrence, Strong Eventual Consistency
Improved training of energy-based models

Maximum likelihood estimation of energy-based models is a challenging problem due to the intractability of the log-likelihood gradient. In this work, we propose learning both the energy function and an amortized approximate sampling mechanism using a neural generator network, which provides an efficient approximation of the log-likelihood gradient. The resulting objective requires maximizing entropy of the generated samples, which we perform using recently proposed nonparametric mutual information estimators. Finally, to stabilize the resulting adversarial game, we use a zero-centered gradient penalty derived as a necessary condition from the score matching literature. The proposed technique can generate sharp images with Inception and FID scores competitive with recent GAN techniques, does not suffer from mode collapse, and is competitive with state-of-the-art anomaly detection techniques.

Keyphrases: deep learning, unsupervised learning, generative models, energy-based models
Étude de l’implication des voies non-canoniques de TGF-beta durant la régénération de la patte chez l’axolotl

The strength of basic research lies in the ability to translate discoveries to real human problems, whether they are medical, social or practical. Generally, research begins with a problem that needs to be solved. Humans have a healing capacity that can be defined as rapid, but resides more in repairing promptly than in quality healing. If the injury in question is not life threatening, usually the human body is able to heal in order to keep the organism alive, but the function is not always restored. For example, in the case of an amputation the healing will be done by scar formation, and will form a stump rendering the amputated part non-functional. Our lab studies regeneration and scar-free healing in a model that does it phenomenally well, the axolotl (Ambystoma mexicanum). Understanding the signaling that allows this animal to regenerate perfectly may allow us to transfer these discoveries to treatments for humans.  Our signaling regulatory model of the regeneration process puts the cytokine TGF-β at the heart of our research. This protein is responsible for blastema formation, by allowing migration and proliferation following the amputation. Our research has shown that during the first phase of regeneration, TGF-β activates SMAD2 and SMAD3, and that the healing process mainly goes through SMAD2, since the level of SMAD3 is very low. Also, by only blocking SMAD3, regeneration proceeds normally. The importance of TGF-β for the formation of the blastema is now very well demonstrated, however, its role in wound closure has not yet been determined.  The function of TGF-β is associated with a multitude of processes including epithelial to mesenchymal transitions (EMT). This process is characterized by phenotypic changes of epithelial cells allowing them to migrate. EMTs occur during development, cancer progression and during wound healing. We therefore tried to understand how EMTs could play a role in the regeneration of the limb and how TGF-β could influence it.  During my Ph.D., we determined that EMTs were associated with wound closure, an essential step to regeneration. In addition, their regulation is dependent in part on TGF-β. Wound closure is dependent of the TGF-β/SMAD pathway (known as the canonical pathway) and the TGF-β/p38/JNK pathway (one of the non-canonical pathways). Additionally, we showed that p38 and JNK are essential for blastema progression, and in this case, independently of TGF-.  The results obtained during this thesis provide a better understanding of what signaling pathway allows perfect regeneration in axolotl.

Keyphrases: Axolotl, Signaling, MAPK
Sensibilisation à la protection de la vie privée dans un contexte d’utilisation de dispositifs portables intelligents

Smart wearable devices are becoming increasingly popular in sports, leisure, time management and calendar activities. Their potential is recognized in several scenarios. Specifically, their ability to collect a wealth of information about their owner and his entourage through the various sensors, can potentially undermine his privacy.  With the arrival of smartwatches and fitness trackers on the market, we are faced with real small computers. When combined with the use of a proprietary application residing on a smartphone / computer and the use of a direct (or indirect) connection to the Internet, these open the door to a large aggregation of data.  The purpose of this research is therefore to explore the security risks related to portable devices, with the aim of inferring the impacts on privacy.  We then present an adaptive training approach (CLEOPATRA), based on a ITS (Intelligent Tutoring System) that considers the learning style of individuals according to their generational cohort. It is a web application using a knowledge overlay model obtained using an assessment test, as well as an expert model, subset of a training curriculum developed by our research group. The training modules are extracted from documents freely available on the Internet, and of an appropriate genre for the generation that it applies to. The training uses a PLE (Personal Learning Environment) along with a microlearning approach. At the end of the training, participants are invited to pass the assessment test again, in order to validate the retention of their recently acquired knowledge.

Keyphrases: Curriculum, Microlearning, Andragogie, Heutagogie, Smart wearable, Security, Privacy, Intelligent tutoring system, Personal learning environment, Microlearning, Andragogy, Heutagogy
Déterminants structuraux et moléculaires de la sélectivité fonctionnelle du récepteur β2-adrénergique

G proteins-coupled receptors (GPCRs) form the largest family of membrane receptor. Due to their variety of ligands and their capacity to activate several signaling pathways, they are involved in various biological processes and are a target of choice for the development of drugs in many clinical indications. It has been shown that a given GPCR can activate several pathways and that different ligands of the same GPCR can differentially activate these pathways, a concept known as ligand biased signaling. These discoveries open the possibility to generate drugs that selectively activate the therapeutically relevant pathways while avoiding the one leading to side effects. However, the mechanisms leading to bias signaling remains unclear. The first objective of my thesis was to develop a conformational sensor of the β2-adrenergic receptor (β2AR), a prototypical GPCR and to characterize the conformational changes induced by different ligands and effectors. The results have shown the stabilization of different conformation ensembles for unbiased ligands and ligands biased against β-arrestin. The second objective of my thesis was to identify the interactions between the receptor and the ligand leading to functional selectivity. To achieve that objective, we did a structural comparison between the epinephrine and salmeterol bound crystal structures. The analysis has revealed a network of polar interactions that might help stabilize the binding pocket contraction. The role of these residues has been confirmed by a mutagenesis study. The last objective of my thesis was to study the role of residues connecting structural motifs important for GPCR activation, known as “microswitches”, for ligand biased signaling. More specifically, the study was on the residue L1243.43 of the β2AR that forms interactions with the v PIF and NPxxY motifs. The results have shown that a loss of interaction between the position 124 and the two motifs lead to a gain of constitutive activation of Gs and a loss of β-arrestin recruitment and observed conformational changes upon ligand stimulation. In contrast the gain of interaction between the two motifs and the position 124 lead to increased β-arrestin recruitment and observed conformational changes induced by bias ligands. These data suggest that the link between the PIF and NPxxY motifs is important for the selection of which pathways are activated by the receptor. The results of the three projects have allowed the identification of different conformational changes between unbiased and biased ligands and the identification of two regions playing an important role for specific activation of β-arrestin leading to a better understanding of mechanisms governing ligand bias signaling.

Keyphrases: Structure, G proteins-coupled receptors (GPCRs), β2-adrenergic receptor (β2AR), Ligand biased signaling, Biosensors, Cell signaling
Coordination entre les microtubules et le complexe Smc5-Smc6 dans le maintien de l'intégrité génomique

There is a tight coordination between the mechanisms of DNA repair and DNA segregation to maintain genomic integrity. On one side, members of the SMC (Structural Maintenance of Chromosome) family are involved in the reparation and reorganization of DNA. On the other side, microtubules are part of a macromolecular machine, called the mitotic spindle, and are responsible for chromosome segregation in mitosis. Recently, a study performed in our laboratory revealed a tight functional link between the Smc5-Smc6 complex, the DNA damage response and microtubules. The objective of this thesis is to deepen our knowledge on this functional link.   First, we were interested to identify novel cellular functions for the Smc5-Smc6 complex with regard to its association with microtubules. To achieve this, we performed a genome-wide genetic screen in the yeast S. cerevisiae using a unique mutant of SMC5. Results from the screen suggest that the Smc5-Smc6 complex perform multiple functions in the cells, especially in the processes of DNA repair and replication. Moreover, we also identify a role for the Smc5-Smc6 complex in promoting kinetochore functions and centromeric DNA integrity.   The second part of this thesis focuses on the role of microtubules in the cellular response to DNA damage. We identified microtubules mutants exhibiting a strong sensitivity to different genotoxic agents, especially to DNA replication stress. The apparent cause of this sensitivity is linked to defects in cell cycle progression during mitosis after exposure to DNA replication stress in S phase. These results suggest that microtubule are active participants in the cellular response to DNA replication stress.   Taken together, these results highlight the complex connection between microtubules and components of the DNA damage response. This thesis provides a deeper understanding on the functions of both the Smc5-Smc6 complex and microtubules.

Keyphrases: Structural Maintenance of Chromosomes, Microtubules, Genome integrity, Structural maintenance of chromosomes, Smc5-Smc6 complex, Microtubules, Mitotic spindle, Mitosis, DNA replication stress
Étude combinatoire et algorithmique de la médiane de permutations sous la distance de Kendall-Tau

A permutation can be seen as a ranking which orders elements or candidates by a criteria or a preference. This ranking can be an elector’s vote to rank candidates in order of preference, athletes in a sports competition or a list of the best movies of 2018. However, in these examples, the electors may not all have the same preferences and the athletes might be judged on more than one challenge in which rankings differ. This is why "consensus" rules of permutation exist as the best compromise for the different rankings. One of these consensus is the median permutation, or the Kemeny consensus. This method respects some properties which justify its use, but is NP-hard to compute. Consequently, numerous researchers have devoted time to study this problem. This master’s thesis aims to study the calculation of the Kemeny consensus in special cases of the problem, which are set of permutations with specific characteristics.

Keyphrases: Distance de Kendall-τ, Permutations, Kemeny method, Median of permutations, Kendall-τ distance, Kemeny consensus
Rôle de la CTNNB1 et de ses nouveaux partenaires dans la régulation de l'immunité antivirale innée et de la voie WNT

The host innate response to viral infection relies on the presence of pattern recognition receptors (PRR) that specifically recognize pathogen associated molecular patterns (PAMPs) and then initiate signaling pathways and activate key transcription factors such as IRF3 and NF-қB, which lead to the synthesis of type I interferon (IFN-α/β). In a research program aimed at the discovery of regulators of innate immunity, we performed the first genome-wide silencing screen in response to Sendai virus (SeV) infection. The RNAi screen identified WNT2B and WNT9B as negative regulators of RLR-mediated antiviral response. We next showed that WNT2B and WNT9B are secreted upon viral infection and negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF. We further investigated a canonical-like WNT pathway that culminates in CTNNB1 accumulation. Coherently, we found that viral infection induces the accumulation of a stabilized form of CTNNB1 and that CTNNB1 gene silencing increases SeV-induced IFNB1, IFIT1 and TNF expression. Conversely, CTNNB1 stabilization using GSK3 inhibitors resulted in a drastic reduction of virus-induced IFNB1 transcription and IFIT1 expression, but this decrease is restored in CTNNB1 knockdown cells. To uncover mechanistically how CTNNB1 regulated the antiviral immunity, we used quantitative mass-spectrometry to identify CTNNB1 interactome upon SeV infection or GSK3 inhibition. We identified DNA damage-binding protein 1 (DDB1) as an interactor of CTNNB1 that is reduced of CTNNB1 upon SeV or WNT3A stimulations. We showed that DDB1 negatively regulates CTNNB1 transcriptional activity by promoting its ubiquitination and reducing protein half-life following WNT3A stimulation. Strikingly, CTNNB1 ubiquitination is inhibited in SeV-infected cells and restored upon DDB1 depletion, consistent with a distinct role of DDB1 in preventing CTNNB1 degradation and inhibiting the antiviral innate response. We also identified the transcriptional repressor NKRF (NF-қB repressing factor) as a CTNNB1 interactor upon viral infection that negatively regulates IFNB1 production of SeV-infected cells without modulating the canonical pathway with WNT3A. We showed that NKRF KD, CTNNB1 KD and combination increase IFNB1, IFIT1 and TNF transcription to similar fold induction of mRNA levels. The data highly support the recruitment of CTNNB1-NKRF containing protein complexes to turn off IFNB1, TNF and IFIT1 transcription by epigenetic and/or transcriptional repression mechanisms, and control innate immune gene expression after virus recognition signals have resolved. Overall, our findings identify a novel regulation of antiviral innate immunity by CTNNB1 and its regulators, paving the way for novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection.

Keyphrases: DDB1, NKRF, ARNi screen, Innate antiviral immunity, WNT/CTNNB1 signaling, Mass spectrometry