NCube/papyrus huggingface dataset:
Transcription par les récepteurs des estrogènes : identification d’un gène cible et d’un nouveau corépresseur

Despite many advances in treatment of gynecological cancers, they remain the leading cause of cancer death in women. Chromosomal and genome instabilities at the 3p21.3 locus are frequent events related to epithelial cancers, including breast and ovarian cancers. It is in this region that the hyaluronidase HYAL-1, HYAL-2 and HYAL-3 genes are found. HYAL-1 is particularly overexpressed in several cancers, including prostate, bladder, neck, head and breast cancers where it promotes tumor progression and metastasis. We demonstrate here, that in the 3p21.3 locus, HYAL-1 is a target gene selectively repressed by ERα and estrogen. Integrative data mining using METABRIC dataset revealed a significant inverse correlation between ERα and HYAL-1 gene expression in human breast tumors. We identified binding sites for ERα at the 3p21.3 locus, among which a proximal ERE responsible for repression of HYAL-1 by ERα, in addition to an Sp-1 site required to achieve optimal repression. This repression of HYAL-1 is accompanied by an enrichment of the repressive mark H3K27me3 at the two sites ERE and Sp-1.  In addition to regulate the expression of many target genes, the transcriptional activity of estrogen receptors is also regulated by coregulators who are recruited on ERs. We identified a new unexpected interaction partner for ERs, the hematopoietic transcription factor TAL1. Despite its reputation as an oncogene in T-cell acute lymphoblastic leukemia, this transcription factor is an ERα-corepressor due to its direct repressive effect on the transcriptional activity of the receptor in response to estrogen and thus to expression of its target genes in breast cancer. Moreover, TAL1 also inhibits ERs activation in response to phosphorylation induced by the  MAPK/Erk pathway. This repression of ERα by TAL1 results in decreased growth and migration of mammary cancer cells.

Keyphrases: ER, Hyaluronidase-1, HYAL-1, TAL1, Régulation, Estrogen receptors, Estrogen, Hyaluronidase-1, HYAL-1, Target gene, 3p21.3 locus, Corepressor, Transcriptional regulation, Breast cancer
Survival of the fittest : understanding the role of eIF4E in cancer invasion and treatment evasion

Metastasis and chemoresistance are the leading cause of mortality among cancer patients. The discovery of molecular mechanisms governing these two processes is becoming an important area of research for the design of novel therapeutic strategies. In my thesis, I focus on understanding the role of the eukaryotic translation initiation factor 4E (eIF4E) in cancer invasion and describe a novel mechanism of resistance that we discovered while studying the development of resistance to a known eIF4E inhibitor, ribavirin.  eIF4E is a potent oncogene that is known to be elevated in a multitude of cancers including M4/M5 subtypes of acute myeloid leukemia (AML). It functions in mRNA translation and nucleocytoplasmic export by binding to the m7G cap of mRNAs possessing specific USER codes in their 5’ and/or 3’ UTRs. By recognizing these USER codes, eIF4E complex coordinately regulates the expression of genes essential for growth, proliferation and survival and as such has been placed as a central node of an RNA regulon governing proliferation. When analyzing which pathways have their export coordinately regulated by eIF4E and what physiological effects arise from it, I found an enrichment in the hyaluronic acid (HA) biosynthetic pathway as well as its major receptor CD44 which are known key mediators of cancer metastasis. I demonstrate that eIF4E elevation changes the surface of cancer cells sugar-coating them with HA-rich microvillus-like protrusions that are enriched with weapons of metastatic destruction.  Luckily, through degrading the HA-coat or using inhibitors of CD44 in combination with ribavirin we can strike back.  Given the proliferative advantage that eIF4E overexpression conveys, this rendered it as an attractive Achilles heel for the treatment of cancers where eIF4E levels are high. Indeed, in a phase II clinical trial in refractory and relapsed poor prognosis M4/M5 AML patients, ribavirin led to eIF4E targeting and resulted in significant clinical responses including complete and partial remissions. However, as it is expected for monotherapy treatment, all responding patients eventually developed resistance to the drug. My analysis revealed that resistance is due to a novel mechanism characterized by elevation of the Sonic Hedgehog transcription factor GLI1 which leads to drug glucuronidation and the subsequent loss of drug-to-target interaction. Fortunately, this mechanism can be reversed using Hedgehog pathway inhibitors. Taken together, these findings provide novel therapeutic venues for the treatment of aggressive and resistant cancer cells.

Keyphrases: eIF4E, Cancer, Résistance multi-drogue, Invasion, GLI1, CD44, Multidrug resistance, Hyaluronic acid
Identification des composantes du système ubiquitine-protéasome régulant la stabilité de la MAPK atypique ERK3

ERK3 kinase is an atypical member of the MAP Kinase family. Conventional MAP Kinases phosphorylate a wide array of substrates and have well characterized functions whereas ERK3 biological activity is still poorly described. ERK3 regulations are unique among MAP Kinase family. Indeed, ERK3 seems constitutively phosphorylated on its activation loop. Moreover, ERK3 is a highly unstable protein, constitutively degraded by the ubiquitin-proteasome system. These observations suggest that ERK3 stability is a key regulator of its biological activity. Nonetheless, components of the ubiquitin-proteasome machinery regulating ERK3 turnover remain to be identified.  The first part of my work identifies and characterizes USP20 deubiquitinase as a positive regulator of ERK3 protein expression and stability. By means of a direct enzymatic activity experiment, our results indicate that UPS20 is a bona fide deubiquitinase of ERK3. Finally, we identified a novel function of ERK3 in the control of cell migration and we determined the involvement of USP20 as an upregulator of this cellular function.  The second part of my research illustrates the product of a functional screen that identifies ubiquitin ligases and conjugases regulating ERK3 degradation. Our results discuss the development of a reporter system of protein turnover, suitable for high-throughput experiments. Among the identified regulators, we focused on E6AP ubiquitin ligase, for which we showed a function in the regulation of ERK3 protein abundance and turnover. Ultimately, we demonstrated the E6AP controls ERK3 ubiquitination.  In conclusion, our work permits the identification of regulators of ERK3 protein stability and characterization of new cellular functions. Moreover, this study provides innovative avenues to better understand the biological activity of ERK atypical MAP Kinase.

Keyphrases: MAP Kinase, ERK3, ubiquitination, Protein stability, Cell migration, Ubiquitin ligase, Deubiquitinase, Cell signaling
Génétique fonctionnelle et validation biologique d’un locus quantitatif d’expression lié en trans- à un réseau de gènes impliqués dans l’immunité innée

Unlike Mendelian genetic diseases, which depend on a single causal gene, complex quantitative traits are measurable characteristics of living organisms, which result from the interaction between several genes and environmental factors. Functional genomics has allowed us to identify many genetic loci linked to complex traits, which are called "quantitative trait loci" (QTL). However, such studies do not allow an accurate characterization of the genetic architecture of complex traits. More recently, it has become possible to identify genetic loci associated with gene expression levels, called "expression quantitative trait locus" (eQTLs). In such cases, the genetic variants can affect the expression of genes that are either located in their vicinity (cis-eQTLs) or that reside further away (trans-eQTLs). In particular cases, the same locus can affect the expression of several genes located on different chromosomes, forming so-called ‘trans-eQTLs hotspots’. These may have important biological interests, as they are generally enriched in functionally related genes, which may influence the same phenotypic trait. In this thesis, by analyzing the expression of genes in hearts from a panel of AxB / BxA mouse recombinant inbred strains, we detected a QTL linked in trans- to the expression of 190 transcripts, the majority of which are known to be sensitive to type I interferon. The same locus also corresponded to that of a cis-eQTL for the Ypel5 gene, suggesting that it could be a common regulator of the trans-eQTL genes. Therefore, the main purpose of this thesis was to biologically validate the role of the cis-eQTL gene in the regulation of the ‘trans-eQTL hotspot’. The work presented in this thesis showed that the silencing of Ypel5 expression in mouse macrophages stimulated the expression of several genes that belong to the ‘trans-eQTL hotspot’ in an IFNB1-dependent manner. YPEL5 knockdown also increased IFNB1 induction in human HEK293T cells. When the latter were subjected to stimuli that activate the TBK1/IKBKE kinases, we detected functional interactions of YPEL5 with the activity of these kinases and physical interactions with IKBKE. Our preliminary results (presented in Chapter 3) suggest also the involvement of YPEL5 in the regulation of cell cycle progression and / or senescence. In conclusion, we are among the first groups to provide biological evidence showing the role of a cis-eQTL gene as a common regulator of genes belonging to a ‘trans-eQTL hotspot’. The biological validation of genomic analysis thus revealed Ypel5 as a new negative regulator of the innate antiviral response that acts (at least in part) at the level of the TBK1 / IKBKE kinases.

Keyphrases: ‘trans-eQTL hotspot’, YPEL5, IFNB1, ISGs, TBK1, IKBKE, Trans-eQTL hotspot, YPEL5, IFNB1, ISGs, TBK1, IKBKE
Architecture et cartographie à la lumière du numérique : naissance du Système d’information géographique du Canada

The main topic of this thesis is the development of the Canada Geographic Information System (CGIS) initiated in 1962, an integrated computer system capable of combining national statistical information and cartographic documents, specifically intended for decision-making in regional planning. The text revisits the political and economic context leading to the development of the first system of this type, arising from the Canada Land Inventory (CLI), a government program stemming from the Agricultural Rehabilitation and Development Act (ARDA), which was expanded to include all rural development. It establishes relations between the CLI and private companies (Spartan Air Services, Canada and IBM Canada) and scholars. This research presents material from the Library and Archives Canada.  It is the cartographic nature of this system developed in Canada, and the transfer of hand-drawn cartographic documents into a digital format through the binary system, which provides renewed insights into important changes concerning conventional representation theory. Through close examination of these automatic and non-automatic transcription devices developed in the 1950s and 1960s, and more precisely, through the development of a device specifically designed for this system, the Special Cartographic Scanner, this text deals with the transition from hand-drawn maps to manipulable digital databases. This thesis examines the nature of cartographic information in terms of point, line, surface, scale and frame, disrupting certain conventions of representation and drawing, through digitising procedures, as well as a new technique of sequencing files, the introduction of the world’s coordinate system, regions of processable data, and their overlay. This thesis demonstrates that notions of position, line and frame in conventional representation have changed for the benefit of a digital point and selection.  In an effort to link digital cartography to architectural design, this thesis exemplifies the transition from representations based on the human eye, developed since the Renaissance, to the use of remote sensing devices and computer-generated imageries, pattern recognition, influencing decision-making and design, with the system’s capacity to generate new knowledge with the overlay and combination processes of point elements. This thesis situates the Canada Geographic Information System within the context of Cybernetics and Information theories, and in turn positions it within philosopher Gilbert Simondon’s theory of concretization of technical objects and of his key points theory, linking technical objects to the territory, considered as subjective and aesthetic productions.

Keyphrases: GIS, Scanner, Cartography, Database
Le rôle du discours dans la construction de l'ASEAN comme communauté de sécurité

The formal establishment of an ASEAN Community on December 31st, 2015 marks an important milestone for an organization whose resilience through time has continuously mystified International Relations Theory. Dominant IR approaches still struggle with explaining the awkward position, somewhere between inertia and change, the Association of Southeast Asian Nations finds itself in since the turn of the 21st century. While the longstanding debate on the status of ASEAN as a “security community” still continues unabated today, this has not prevented the organization from claiming this objective for itself, while considerably adapting its meaning in practice. ASEAN’s approach to regional security can be seen as combining three broad objectives: providing the conditions for peace among regional states; responding effectively to non-military and transnational threats to security; and contributing to the enhancement of the security, well-being, and dignity of the peoples of Southeast Asia through a people-oriented, people-centered approach. Therefore, the way ASEAN defines its role and, more importantly, its identity as a regional security organization departs in significant ways from the conventional definition of “security community”. This study offers a new explanation of the organization’s resilience in the 21st century by treating ASEAN as a “community of discourse”. The following pages highlight the coexistence of divergent interpretations of regional security in the context of ASEAN, and focuses on the effects of this polysemy on the articulation of the organization’s identity, and its performance as a security community in the making.

Keyphrases: ASEAN, discours, discourse, security, security community, regionalism, Asia-Pacific
Comment favoriser l’adaptation des rapatriés? Une exploration du rôle des attentes, de la perception du soutien organisationnel et de la proactivité

Nowadays, internationalisation of markets is a pressing economic reality, bringing many organizations to increasingly choose to extend their activities abroad. This still relevant today as a very large proportion of organizations expect their international assignments to either increase or at least remain stable (Brookfield, 2015).  While many studies have examined the adaptation of expatriates (Bhaskar-Shrinivas, Harrison, Shaffer, & Luk, 2004), a much smaller number of researchers have focused on the adaptation of these individuals once they have returned home. However, several difficulties are associated with repatriation and they are often more important than those encountered abroad (Forster, 2000). This thesis attempts to bridge this gap by examining, firstly, the role of two antecedents of adaptation: perceived organizational support (POS) and repatriates’ proactivity and secondly, the mediating role of expectations. To this end, a total of 125 police officers returning from a mission abroad participated in this study. Due to a considerable number of missing data for some variables, the multiple imputation method was used (m = 5). Two mediations were carried out in order to test the hypotheses, controlling for the elapsed time since the return of the repatriate. Our findings indicate that satisfied expectations mediate both the relationship between POS and repatriates’ adaptation (b = 0,25, BCa IC [0,11 - 0,40]) and proactivity and adaptation (b = 0.16, BCa IC [0.01 - 0.32]). The results therefore seem to support both hypotheses. In other words, POS and proactivity lead to increased adaptation by allowing repatriates to develop more realistic expectations of repatriation. This suggests that both the organization and the individual have a role to play in the adaptation of repatriates, although the impact of the latter appears to be less than that of the organization. In light of these findings, the final chapter explores some possible explanations in order to understand the smaller effect of proactivity, and also discusses more extensively the theoretical and practical implications of the results. Finally, limits and avenues for future research are presented.

Keyphrases: Adaptation, International mobility, Repatriates, Perceived organizational support, Proactivity, Expectations, Police officers, Mediation analysis
Profils d'inadaptation psychosociale au primaire : perceptions de soi, engagement et rendement scolaire

Student engagement and academic achievement are now well documented for their positives long-term outcomes. Yet, several factors can alter students’ investment and success in school. Past studies have indeed shown that psychosocial maladjustment is an important risk factor for later disengagement. However, less is known about the risk of disengagement when externalizing, internalizing, and social difficulties tend to co-occur and accumulate in some students. Also, there is actually no theoretical framework explaining the association between maladjustment characteristics and motivational process crucial to ensure school success. A few models suggest that self-perceptions are important mechanisms leading to student engagement. These self-perceptions, as student engagement, are indeed associated with maladjustment characteristics. The goal of this thesis is thus to deepen our understanding of psychosocial maladjustment factors leading to student disengagement when approaching adolescence, which is a developmental period where the risk for disengagement increases. Therefore, a first article (Chapter II) allowed identifying psychosocial maladjustment profiles among 5th and 6th grade boys and girls. These profiles were then linked with students’ later behavioral engagement and academic achievement. Results first showed that the identified maladjustment profiles were distinct between boys and girls. Findings also highlight that students belonging to maladjusted profile tend to have lower behavioral engagement and academic achievement, but distinctly between profiles and between sexes. Next, a second article (Chapter III) relied on Self-System Model of Motivational Development (Connell & Wellborn, 1991) in order to position self-perceptions of competence, autonomy, and relatedness as mediating mechanisms linking psychosocial profiles to behavioral, emotional, and cognitive engagement. Results show the crucial role of sense of relatedness associated with the lower emotional engagement of students in maladjusted profiles. Furthermore, the risk of having a lower engagement was especially salient for girls as a result of negative self-perceptions. In sum, findings from this thesis suggest that students’ psychosocial maladjustment is well captured by establishing profiles distinctly between sexes for students approaching adolescence. On the one hand, this thesis reemphasizes that studying sexual differences is especially relevant to understand maladjusted student’s disengagement. On the other hand, as belonging to a maladjusted profile impacted students’ self-perception and, in turn, classroom engagement, results support the inclusion of psychosocial maladjustment in theoretical frameworks explaining motivation, engagement, and academic success.

Keyphrases: Student engagement, Academic achievement, Psychosocial maladjustment, Selfperceptions
Search for heavy gluons from composite Higgs model through vector-like top quark decay topologies with the atlas experiment

A search for production of the lightest Kaluza-Klein excitation of gluon (gKK), in theories with a warped extra dimension, that decays into Standard Model (SM) top quark pairs (t¯t) or into one vector-like top quark (VLQ top) in association with a SM top quark (Tt) is presented in this thesis. The search is based on proton proton collisions at 8 TeV recorded in 2012 with the ATLAS detector at the CERN Large Hadron Collider and corresponding to an integrated luminosity of 20.3 fb^−1. For the analysis of gKK -> tT , we performed targeting three cases: VLQ top (T) with significant branching ratio to a W boson and a b-quark (T -> W b), VLQ top with significant branching ratio to a composite Higgs boson and a standard model top quark (T -> H t) and VLQ top with significant branching ratio to a Z boson and a standard model top quark (T -> Z t). Data are analyzed in the lepton-plus-jets final state, characterized by an isolated electron or muon with high transverse momentum, large missing transverse momentum and multiple jets. The invariant mass spectrum of t¯t and t¯t + jets is examined for local excesses or deficits that are inconsistent with the Standard Model predictions. No evidence for a top quark pairs resonance is found, and 95% confidence-level limits on the production rate are determined for massive states in benchmark models. On the one hand, a Kaluza–Klein excitation of the gluon of width 15.3% with a branching ratio of 100% into a SM top quark pairs in a Randall–Sundrum model, is excluded for masses below 2.0 TeV. On the other hand, in a composite model where the heavy gluon decays to tT , using benchmark parameters for mixing angles, a 1.0 TeV Kaluza–Klein excitation of the gluon of width 10% that decay to one SM and a 0.6 TeV VLQ top, considering any VLQ top branching ratio scenario, is excluded at 95% Confidence Level (CL). Finally, a 2.0 TeV Kaluza–Klein excitation of the gluon, of width 10%, that decays into one SM in association with a 1.4 TeV VLQ top, with any scenario with BR (T -> Wb) < 0.80, is excluded at 95% CL. The samples used in these analyses were validated by ATLAS collaboration, however the results shown in this thesis were not reviewed by the ATLAS collaboration for publication.

Keyphrases: Atlas, Quarks vectoriels, Analyse, Collider, Vector-like quarks, Resonance, analysis, Kaluza-Klein gluon, Composite Higgs
Automates cellulaires quantiques et relativité déformée

We show that a quantum field model based on a quantum cellular automaton requires a deformed special relativity. By associating the laws of physics with the automaton evolution rule, we obtain a version of the relativity principle where states evolving on the automaton must transform according to modified Lorentz transforma- tions. We then show that a non-linear momentum and energy space gives rise to the phenomenon of relative locality and that, under appropriate conditions, the relativistic length contraction effect must be reversed. We also consider simulations of physics on a philosphical level, asking if we might live inside such a simulation and seeing how observers from outside might interact if they attempt to observe us in such a context.

Keyphrases: Quantum information, Cellular automaton, Deformed special relativity, Simulated universe