NCube/papyrus huggingface dataset:
Rôles fonctionnels de la ligase de l’ubiquitine ITCH dans l’endocytose dépendante de la clathrine du récepteur du facteur de croissance épidermique

ITCH is a ubiquitin ligase involved in various cellular processes including endocytosis. It contains a proline rich region (PRR) which allows it to bind the SH3 domain of endophilin and other SH3 domain-containing proteins involved in Clathrin-mediated endocytosis (CME). CME is an important regulatory mechanism for growth factor receptor activity. The epidermal growth factor receptor (EGFR) is actively internalized in Clathrin-coated vesicles after activation. This endocytosis is facilitated by a protein complex formed by CBL, CIN85 and Endophilin. ITCH is known to ubiquitinate both CBL and endophilin, providing a potential functional link between the ligase and receptor internalization. In order to determine the role of ITCH in this process, several experiments were performed. First, the mapping of molecular binding sites between the ligase ITCH and SH3 domain proteins has been studied in detail. A series of mutations in the PRR region of ITCH helped us identify three arginine residues (R252, R255, R258) as necessary for its interaction with endophilin and all the tested SH3-domain containing proteins. Secondly, HeLa and Cos7 cell lines were genetically modified by CRISPR to prevent ITCH expression. These knockout cell lines were characterized for use in an EGFR endocytosis assay and for mass spectrometry analysis. EGFR internalization was monitored by confocal microscopy using fluorescent EGF ligand in both ITCH-/- cell types. In the absence of ITCH, a significant decrease in the level of internalized EGF compared to parental cells is visible. Overexpression of WT ITCH in the knockout cells restores normal internalization of EGF, confirming the involvement of ITCH in the process. Overexpression of Endophilin-binding defective or catalytically inactive ITCH does not restore the internalization of EGF in ITCH-/- cells. These results show that the ITCH- Endophilin interaction as well as the catalytic function of ITCH are necessary for the endocytosis of EGFR. In addition, ITCH-/- cells show a delay in the degradation of phosphorylated EGFR accompanied with an extended period of mitogen-activated protein kinase (MAPK) activation. In a last set of experiments, we explored the influence of the absence of ITCH on its substrates and molecular partners. We performed a proteomic comparison of ITCH-binding partners and potential substrates using the ITCH-/- and WT cell lysates. The results showed that the lack of ITCH expression alters the peptide count of proteins mainly related to EGFR signaling, theubiquitin-dependent proteolytic pathway and cell adhesion. This study shows for the first time that the protein ITCH is required for the clathrin-dependent endocytosis of EGFR.

Keyphrases: EGFR, EGF, CBL, ITCH, Ubiquitylation, Transferrine, Endocytosis, Endophilin, Ubiquitination, Ubiquitin, Signaling, Endocytic trafficking, Transferrin
Quand et comment exercer son autorité comme parent : le rôle socialisateur du lien problème-contrainte et du domaine social

Experimental studies focusing on the socialization role of parental authority exertion in persistent rule-breaking contexts involving non-personal issues have recently shown the advantages of using logical consequences over alternative strategies (mild punishments, reasoning and no-authority). Using an experimental vignette approach and a sample of 214 adolescents (Mage = 15.28 years), the present study extended these findings by comparing the same parental interventions in a hypothetical rule-breaking setting involving a multifaceted issue. Specifically, and based on research anchored in social domain theory, we evaluated how adolescents’ perceptions of the issue underlying the multifaceted transgression (personal vs. non-personal) moderated their beliefs regarding authority exertion strategies. When adolescents perceived the transgression as a non-personal issue, past results were replicated and enhanced. Adolescents perceived the logical consequence as at least as effective as the mild punishment to prevent future transgressions (i.e., more so than reasoning and no-authority) and as the most acceptable strategy. Furthermore, contrary to the mild punishment, they did not perceive the logical consequence as more autonomy-thwarting than reasoning. In contrast, adolescents who categorized the transgression as a personal matter rated the logical consequence less favorably, leaving reasoning as a preferred form of intervention. Implications for optimal parenting are discussed.

Keyphrases: authority exertion, logical consequences, mild punishments, parenting, social domain theory
Conduite automobile risquée et cannabis : rôle de la fréquence de consommation et effet du soutien parental de l'autonomie

Although driving a vehicle is one common activity, road accidents are one of the top ten causes of death in the world. In recent years, a decrease of on road deaths in Canada and Quebec have shown that road safety prevention campaigns can be effective. However, these advances are insufficient, and there is a need for better intervention and prevention strategies. A better knowledge of individuals likely to be involved in road accidents would allow the development of more targeted and relevant prevention campaigns. Thus, it is already known that men, individuals aged between 15 and 29, and users of alcohol or psychoactive substances before driving have an increased risk of being involved in a road accident. Therefore, one of the objectives of this thesis is to have a better understanding of the role of frequency of cannabis use in young males’ risky driving. Also, studies have already examined the role of parents in the road behaviors of their children. However, no study seems to have focused on the role of parental autonomy support in young drivers’ risky driving. The second objective of this thesis is to investigate the impact of parental autonomy support on risky driving among young cannabis users.  In this line of thinking, Article 1 investigates the association between frequency of cannabis use and self-reported risky driving among a sample of male drivers aged between 18 and 25 years old. In addition, it evaluates the role of parental autonomy support in self-reported risky driving. Results indicate that frequency of cannabis use is positively associated with risky driving (measured with self-reported measure of driving under the influence of cannabis), and is a predictor of this measure. However, results did not show that parental autonomy support is a predictor of self-reported risky driving.  Article 2 studies risky driving through behavioral measures. These behavioral measures are observed in a driving simulator. Results of this article reveal a contribution of frequency of cannabis use in predicting observed risky driving in a driving simulator. In addition, results indicate a significant effect of the frequency of use levels on risky driving behaviors observed in the simulated driving task. Finally, results show a contribution of parental autonomy support in observed risky driving in the simulator.  The theoretical contributions of this thesis to the scientific literature on road safety, as well as its practical implications for prevention and intervention are discussed.

Keyphrases: Risky driving, Cannabis use, Frequency of consumption, Young drivers, Autonomy support, Road safety, Driving simulator
Langue(s) en portage : résurgences et épistémologies du langage dans les littératures autochtones contemporaines

Considering the context of multiple dispossessions, the extraction and invisibilization of Indigenous languages, and the subsequent imposition of colonial languages, which residential school literature recounts in great detail, this dissertation reflects on how contemporary Indigenous women writers, who write in English or in French (Virginia Pésémapéo Bordeleau, Kateri Akiwenzie-Damm, Marie-Andrée Gill, Leanne Betasamosake Simpson, Natasha Kanapé Fontaine and Cherie Dimaline), are attempting to (re)negotiate both Indigenous and colonial languages in their works. More specifically, through a close reading of selected texts, this thesis explores how Indigenous literatures are deeply embodied, situated, and relational places of knowledge and, as such, they convey the possibilities of language through their literary interventions. Thus, I argue that contemporary Indigenous literatures enable the creation of critical theories of language, in which body, language, and land (both physical and metaphysical) are intimately connected; language, and its conceptualization by women writers, enables a web of relations through writing that presents this interconnectedness between the sensible and spiritual worlds, and between human and other-than-human beings. Building on Indigenous epistemologies (Kovach, Wilson, Ermine, Bazile, Sioui, Simpson, Bacon, Vizenor), this thesis argues that through poetic and narrative imagination, which differs from a return to the linguistic structures of Indigenous languages, the creative writers explored in this dissertation are reclaiming epistemologies and creating theories of language by putting them at the forefront of their literary practices.

Keyphrases: Indigenous literatures, language epistemologies, critical theory, resurgence, survivance, Indigenous literary studies, corporality, Land, Indigenous languages, Residential school literature
Conflit et complicité : la communauté des femmes chez Clarice Lispector

If there are two words that still call us, summon us, make us dream and at the same time resist in many ways to deliver their "truth", they are community and woman. This thesis strives to bring them closer, to keep them in proximity in referring to the writings of Clarice Lispector. Since the work of the Brazilian writer, composed largely of female characters and narrators, often features women's face-to-face, we examine how these encounters reflect a possible community of women. However, as announced in the title of this study, the community of women in question in Lispector's work is one that exists sporadically oscillating between conflict and complicity. In an attempt to give form and vocabulary to such a community of women, we go through the main theories of the community, especially those developed by Jean-Luc Nancy, Maurice Blanchot, Jacques Derrida and Roland Barthes as well as some theories of feminism. Then we explore concepts that "provoke" the emergence of the community of women as repetition, rhythm, inspiration and gift. Ultimately, this summary could have had only one sentence, one sentence that sums up the whole thesis: the community of women without community or not a community like the others.

Keyphrases: Clarice Lispector, Inspiration, Clarice Lispector, Community, Woman, Gift, Repetition, Rhythm, Inspiration, Literary creation
Application de la stratégie de séparation de phase à la synthèse de macrocycles complexes et développement d’une réaction de thioalcynylation pour la synthèse de macrocycles sulfurés

Macrocyclization reactions can be problematic due to poor selectivity of cyclization versus oligomerization. As such, difficult purification of complex mixtures and/or the use of complex and cumbersome experimental setups are often necessary. The drawbacks can complicate synthetic pathways and deter chemists from exploring the unique chemical space of macrocycles. Our group has developed a new macrocyclization strategy called phase separation strategy, a protocol enabling one-pot macrocyclization reactions at much higher concentration. In the present thesis, the challenges associated with macrocyclization reactions are tackled by the development and the application of new strategies. First, the phase separation strategy protocol was used to synthesize the backbone of complex macrocycles like the natural product ivorenolide A (Chapter 4) and the antiviral vaniprevir (Chapter 6). With the use of the phase separation strategy protocol, macrocyclization reactions were performed at concentrations 120 times higher than traditional protocols while maintaining a high level of macrocyclization selectivity. Second, the development of a new copper-catalyzed synthesis of alkynyl sulfides for the synthesis of a macrocyclic peptide library is described (Chapter 8). The macrocyclic peptides were also tagged with several biomarkers by diversification of the resulting alkynyl sulfide motif. Finally, the scope of the intermolecular copper-catalyzed reaction was explored (Chapter 9). Using the method, bis-heteroatom substituted alkynes were synthesized and modification of unprotected cysteine sidechains was possible. Furthermore, the mechanistic reaction pathway of the new alkynyl sulfide synthesis was studied experimentally and computationally.

Keyphrases: Macrocycle, Ivorenolide A, Macrocyclization, Macrocycle, Phase separation, Alkynyl sulfide, Copper
Méthodes de synthèse de quinoléines et d’indoles polysubstitués : «la chimie traditionnelle modernisée»

The heterocycle chemistry is one of the most important fields in organic chemistry. Indeed, 65% of the literature in organic chemistry is about heterocycles. They are widely present in nature, essential to life and their applications are endless. Among them, the so-called privileged structures, attract particular attention. Privileged structures, of which quinolines and indoles are a part, play a crucial role in medicinal chemistry, for the production of libraries of therapeutic targets. Therefore, the development of new synthetic methods, simple, efficient and sensitive to environmental impact remains a challenge for chemists. Many synthetic methods require the use of o-acylated anilines, but these substrates are not easily available. The copper catalyzed addition reaction of a Grignard reagent on methyl anthranilate allows to form an o-acylated aniline, never reported before, with a quantitative yield. The latter will then serve as starting material for the synthesis of several privileged heterocycles including quinolines and indoles. The Friedlander reaction has been used for several centuries but suffers from the use of extreme reaction conditions which are harmful to the environment. It has therefore been modernized to give access to a series of eight trisubstituted quinolines, without solvent, strong acid or high temperatures. Furthermore, Heumann's process consists of the synthesis of indoles substituted in position by o-acylated anilines alkylation, followed by saponification and intramolecular cyclization steps. Patented by B.A.S.F. in 1895, this process quickly became obsolete due to low yields and difficult reaction conditions. Continuous flow chemistry has resurrected this process through the development of a more efficient and safer protocol. All in all, the work presented in this thesis contributes to the development of simple, effective methodologies, sensitive to environmental issues and leading to increasingly complex structures.

Keyphrases: Indoles, Friedlander, Heumann, Quinolines, Heterocycles, Preferred structures, Methyl anthranilate, Cascade addition
Entre respect de l’intégrité des sources et volonté de création : le cinéma de Péter Forgács

This article intends to address the creative uses of visual archives in connection with the representation of the Holocaust. It’s based on a comparison between the use of one 1944 shot in two cinematic essay Meanwhile somewhere. 1940-1943 (Péter Forgács, 1994) and Respite (Harun Farocki, 2007). The author demonstrates the relevance to think about reuse in terms of "dispositif" created during the editing process. This is a way to deal with archives without addressing only the questions of archives misuses, archives refusal or archives fetishism. In this perspective, the creative gestures dealing with the materiality of the document are understood as mediating resources to deal with past, present and future of the visual archives.

Keyphrases: Archives, Médiation, History, Mediation, Intermediality, Reuse
Développement de méthodes bio-informatiques pour la découverte de variants codants et non codants dans le cadre des traits sanguins

Cardiovascular health, immune function, hemostasis and the response to other illnesses depend on the abundance and specific features of blood cells. Over the years, a considerable effort has been made to find which genetic variants, genes and regulatory mechanisms are involved in the creation of these cells.  The inactivation of an allele, called a loss-of-function (LoF), is a type of coding variant we would like to associate with blood phenotypes. For obvious ethical reasons, these mutations cannot be artificially induced in human, so we fall back on natural occurrences and hope that large cohorts will provide enough samples to find statistically significant associations.  The inactivation of both alleles, called a knockout (KO), may have stronger consequences than a simple loss-of-function. We also hope to find naturally occurring knockouts thanks to the size of a large cohort. The combination of two different LoF variants is called a compound heterozygote knockout.  We are also interested in non-coding variants that affect the expression of genes that are involved in hematopoiesis. Some of these variants create or disrupt the binding sites of transcription factors (TF), the proteins that bind to specific DNA sequences and regulate gene expression. Transcription factors binding sites (TFBS) are found in gene promoters and cell type specific enhancers.  While some of these mutations can be benign or even beneficial, the presence of a LoF or KO may be too detrimental for the individual to survive. The results of this study are limited by survival bias.  Compared to a genome-wide association study, this study focuses on a smaller number of genetic variants to increase statistical power and give an interpretation to the statistically significant findings.  The Trans-Omics for Precision Medicine (TOPMed) program collects and ensures the quality of the 45,000 whole-genome sequences we used in this study, as well as the corresponding complete blood counts. Thanks to this raw data, we were able to find several known and novel associations between rare variants and blood phenotypes.

Keyphrases: GWAS, SNP, meta-analysis, Gene expression, Hematopoiesis, Transcription factor, Promoter
Analyzing KDM4A protein interaction network using proximity-dependent biotin identification assay

This study was designed to identify potential interacting proteins of Lysine-specific demethylase 4A (KDM4A) in the context of cancer using proximity-dependent biotin identification 2 (BioID2) assay. KDM4A is a lysine demethylase and an epigenetic regulator that plays a role in carcinogenesis by promoting proliferation. Herein, we sought out to identify the protein interactome of KDM4A in cervical cancer cell line HeLa. These protein interactions were characterized by their dependency on KDM4A’s catalytic activity and/or Tandem Tudor domain. It succeeded at detecting novel interactors of KDM4A as well as previously studied interactions, such as FBXO22. KDM4A seems to be interacting with some members of the pBAF chromatin remodeling complex, specifically, ARID2, BRD7, and SMARCA2. The pBAF complex facilitates or prevents accessibility to DNA by restructuring the nucleosome. Further analysis is required to validate whether the KDM4A-pBAF complex interaction is direct or indirect. This study also implied the importance of the Tandem Tudor domain in KDM4A’s role in the double stranded break repair. Finally, we also propose the potential involvement of KDM4A in mRNA splicing and organic anion transport. This study provides new insights into KDM4A’s role in cancer development.

Keyphrases: KDM4A, JMJD2A, BioID2, Cancer, pBAF, FBXO22, ARID2, ELAVL2, SLC16A3/1, SLC2A1
Volumetric velopharyngeal space modifications in patients with and without cleft palate undergoing Le Fort 1 maxillary advancement

Background & Purpose: The effects of maxillary advancement (MA) on velopharyngeal anatomy have primarily been studied using lateral cephalometric radiographs. However, with recent advances in orthognathic surgery, there is an increased need for more detailed and precise imaging such as computerized tomographic (CT) scan reconstructions, to help in surgical planning and to measure outcomes. The purpose of this study is to compare the pre-and post-operative velopharyngeal space configuration modifications as measured on CT scans. The aim is also to assess differences in these airway measures between patients with and without history of prior repaired cleft palate (CP).   Methods: This is a retrospective cohort study of 44 patients with and without CP who were treated with MA for midface hypoplasia and secondary malocclusion at skeletal maturity. The pre-and post-operative CT scans were compared with respect to pre-established landmarks. Linear distances, cross-sectional areas, and volumes were measured using 3-dimensional (3D) CT scan reconstructions.   Results: For the linear distances measured, a statistically significant difference was found when comparing the pre-and post-operative measures of the narrowest part of the nasopharynx and the narrowest part of the retropalatal airway space (25.1 vs 28.5 mm p=0.001 and 6.5 vs 7.6 mm p=0.026, respectively). Retropalatal cross-sectional areas, nasopharyngeal cross-sectional areas and the volumetric assessment of the nasopharyngeal space showed no statistically significant differences when comparing pre-and post-operative scans (p>0.05). The main effect of palatal repair (CP vs. Non-CP) showed that there was only a statistically significant difference for the measures of the narrowest part of the nasopharynx and the nasopharyngeal cross-sectional area (p=0.045 and p=0.04, respectively). Mean changes in the measures did not differ over time (pre-and post-op) depending on whether there was prior history of CP repair.  Conclusion: Our results support the hypothesis that although structural modifications of the pharyngeal space are inherent to MA in patients with CP, its surface area and volume do not change significantly. These changes are also independent of history of previous CP repair.

Keyphrases: Cleft lip, Cleft palate, Velopharyngeal insufficiency, Orthognathic surgery, Maxillary advancement, Computed tomography, Cephalometric, Anatomy