NCube/papyrus huggingface dataset:
Importance of the HSP90 molecular chaperoning
pathway for antibody diversification by determining AID
stability

Activation induced deaminase (AID) plays a central role in adaptive immunity. AID deaminates deoxycytidine to deoxyuridine in defined regions of the immunoglobulin (Ig) genes and initiates somatic hypermutation (SHM), gene conversion (iGC) and class switch recombination (CSR). While being essential for an effective immune response by underpinning antibody affinity maturation and isotype switching, the mutagenic activity of AID can also be oncogenic and causes genomic instability leading to the development of cancer, or exacerbate autoimmune diseases. Therefore, AID regulation, including the control of its protein level, is central to balancing effective immunity with cancer/autoimmunity. Notably, AID shuttles between the cytoplasm and the nucleus but is predominantly cytoplasmic at steady-state, with cytoplasmic AID being much more stable than nuclear AID. These regulatory steps contribute to limit the exposure of the genome to AID but their mechanisms are unknown. This thesis aimed at identifying AID partners and intrinsic determinants regulating its stability and modulating its biological functions. Firstly, we identified AID as a novel HSP90 client protein. We demonstrated that HSP90 interacts with AID in the cytoplasm and prevents its polyubiquitination and subsequent proteasomal degradation. Consequently, HSP90 inhibition results in a significant reduction of endogenous AID levels and correlates with a proportional reduction in both AID-mediated antibody diversification and off-target mutations. Secondly, we showed that the first step in the HSP90 molecular chaperoning pathway and stabilization is the interaction of AID with the HSP40 and HSP70 system. In fact, a specific HSP40 protein, DnaJa1, is the limiting step in cytoplasmic AID stabilization. DnaJa1 farnesylation is required for DnaJa1-AID interaction and modulation of DnaJa1 levels or its farnesylation impacts endogenous AID levels and antibody diversification. In vivo, DnaJa1- deficient mice display compromized response to immunization, resulting from reduced AID protein levels and isotype switching. Thirdly, we found that AID is intrinsically less stable than its APOBEC paralogs. We identified the AID N-terminal aspartic acid residue at position two and an internal PEST-like motif as destabilizing modulators of AID protein turnover. Disruption of these motifs increases AID protein stability and antibody diversification.We conclude that AID’s intrinsic instability directly contributes to regulating antibody diversification. This intrinsic instability is at least partially compensated for in the cytoplasm by the protective action of the DnaJa1-HSP90 molecular chaperoning pathway. Pharmacologically targeting AID in an indirect way, by using HSP90 or farnesyltransferase inhibitors, could be relevant for treating some AID-associated lymphomas/leukemias and/or autoimmune diseases.

Keyphrases: Activation-Induced Deaminase (AID), B-lymphocyte, lymphocyte B, Somatic hypermutation, Class switch recombination, Antibody gene diversification, HSP90/HSP40, protein stability
Wittgenstein et le conventionnalisme : une critique du contextualisme sémantique de François Recanati

In Literal Meaning, François Recanati argues that what is said when a sentence is uttered corresponds to a content that is fundamentally pragmatic. To this end, he proposes two general arguments according to which what is said will be indeterminate if we stick to the rules of semantics. The first of these two arguments tries to establish that in many cases, the semantic content supposedly associated with a sentence does not correspond to what is said. The second one is rather an elaboration of Wittgenstein’s thesis to the effect that the meaning of linguistic types is indeterminate. As for me, I claim that if we indeed adopt a wittgensteinian conception of meaning, some of the examples that are supposed to illustrate the first of these two arguments can and should be criticized.

Keyphrases: Recanati, Wittgenstein, Semantic, Pragmatic, Contextualism, Minimalism, Psychologism, Conventionalism, Indeterminacy
Les transformations microbiennes de l’azote dans les grandes rivières

Rivers receive nitrogen (N) from their watershed and are the final sites of nutrient processing before delivery to coastal waters. Transformations of dissolved inorganic N (DIN) to gaseous N are highly variable and can impact both coastal eutrophication and greenhouse gas emissions. With anthropogenic N loading to aquatic ecosystems on the rise, nitrous oxide (N2O) emission from rivers should increase. Direct measurements of N2O from lake St. Pierre (LSP), an enlargement of the St. Lawrence River (SLR) indicate that although LSP is a net atmospheric source of N2O to the atmosphere fluxes are low compared to others rivers. Emissions are seasonally and inter-annually highly variable due to changes in hydrological conditions. N2O: N2 is also influenced by hydrology and lower ratios are observed in conditions of higher water discharge and elevated N charge into the ecosystem.   In a cross system analysis, hydraulic load mitigates the relation between annual N2O flux and nitrate concentrations in rivers.  In SLR, cyanobacterial mats colonizing low nitrate areas are a net source of N with high negative di-nitrogen (N2) fluxes. Given that fixation occurred during daylight and that oxygen concentrations in the water column were supersaturated, we hypothesize that N2 fixation is performed by the dominant cyanobacteria in anoxic micro-zone of the mat and/ or possibly by heterotrophic diazotrophs. Our estimates indicate that N fixation in the mats account for the replacement of up to 33% of the N loss via denitrification in the entire ecosystem during the study period.  In the tidal Hudson River N2 production is highly variable between vegetated shallows and was associated with species-driven differences in dissolved oxygen (DO) dynamics during the ebb tide. N2 production was extremely high in invasive floating-leaved plants (Trapa natans) but was insignificant in submersed native vegetation. An estimate of summertime N2 production in Trapa beds suggests that these beds are a major seasonal hotspot for N removal.  Large Trapa beds represent only 2.7% of the total area of the tidal Hudson but they remove between 70 and 100% of the total N retained in this section of the river during summer months and contribute to as much as 25% of the annual N removal.

Keyphrases: Nitrification, Denitrification, Nitrification, Invasive species, Ecosystem services, Nitrogen limitation, Cyanobacteria, Nitrogen fixation, nitrous oxide yield
Le Réel dans le texte : lecture et interprétation de la figure de Bartleby le scribe

The short story “Bartleby The Scrivener. A Story of Wall Street” raises questions about reading and literary interpretation. Using approaches where language is the object or means of knowledge (rhetoric, etymology, psychoanalysis, pragmatics) along with writings from Herman Melville, we aim to consider what is represented by Bartleby, who is often described as unaccountable. This very word structures the study. The first part of the thesis examines this word, taken as a whole or broken down into morphemes, as conveying universes of meaning in which Bartleby appears as marginal, short-circuiting diverse systems: the universe of language (unaccountable), the universe of the law (count) and the universe of the numbers (account, count). The second part links the implicit threads of meaning thus revealed to the theme of the strange and unexplainable (unaccountable), explicit in the text, allowing for interpretations bearing on the world of literary texts, their conveyance and circulation through reading and interpretation.

Keyphrases: Bartleby, "Unaccountable", Bartleby, Reading, Interpretation, Text addressee, Negation, Text as object, Circulation of the signifiers, Unaccountable
Lewis’ Theory of Counterfactuals and Essentialism

Modern logic since the end of the Second World War has undergone many developments.  Two of the most interesting of these are the Kripkian Possible World Semantics and Lewis’ system of Counterfactuals.  The first was developed by Saul Kripke in the 1960s and the second was developed by David Lewis in the 1970s.  In some senses we can say that Lewis’ system of counterfactuals or Counter Factual Semantics (CFS) is built on top of the architecture which Kripke created with his Possible Worlds Semantics (PWS).  But, what is the Kripkian Possible World Semantics itself built on?  The answer it seems is very finely tuned ontology founded on the notion of possible worlds.  This paper will attempt to do the following. First, attempt to draw a distinction between on the one hand conditionals and the other counterfactuals and at the same time attempt to look at some of the historical literature surrounding counterfactuals and their application in various fields like the philosophy of science.  Second, recapitulate Lewis’ system of counterfactual semantics as developed primarily in Lewis’ book Counterfactuals.  Finally this paper will attempt to explore the metaphysical foundations of the possible worlds account argued for by David Lewis in his conception of Modal Realism.

Keyphrases: Conditional, Counterfactual, Possible Worlds, Semantics, Logic
Les perceptions d’étudiants au baccalauréat en sciences infirmières de l’utilisation du journal d’apprentissage

The competency-based approach is increasingly chosen to guide university curriculum. In according an essential interest to the competency development, the responsible for programs developed using this approach must determine the most effective learning strategy. In the last 30 years (Cameron et Mitchell, 1993; Wellard et Bethune, 1996), the learning journal promote the building of clinical knowledge and the development of reflexive thinking, a competency that is necessary to the practice nurses inspired by a specific vision of the discipline, like the McGill model (Kravitz et Frey, 1989; Thorpe, 2003). Despite this, the studies on the student’s perceptions on the learning journal are rare, especially in Canada (Epp, 2008). It is important to look at student’s perceptions to attain the optimal efficacy of the tool. The purpose of this study was to explore the perceptions of undergraduate students in nursing of the utilization of learning journal. It was realized with 2nd and 3rd year undergraduate students in nursing, using a qualitative exploratory research design. The participants (N=52) completed a form presenting a simulated situation that contained 5 open ended questions. The three main themes that emerged during data analysis on the utilization of the learning journal were: a personal tool, a communication tool and a learning practice tool. Recommendations for education and future research are offered.

Keyphrases: approche McGill, Learning journal, competency-based approach, Nursing education, McGill nursing model
Déstabilisation d'un réseau criminel pratiquant le trafic de stupéfiants

This research focuses on the disruption of a drug distribution network and is based on a case study of a law-enforcement investigation conducted in a major Canadian city. The aim of the investigation was to dismantle a criminal network that was perceived to be hierarchically structured. Different strategies were applied by the investigating team to disrupt the network. Five of these strategies are studied in the present research. Network analyses and an assessment of the evolution of the drug distribution operation demonstrate that, amongst the set of disrupting strategies, those aimed at the selective removal (arrests) and addition (infiltration) of actors to the network were most effective. The details surrounding such findings highlight the importance of preparing well-planned and systematic investigations following such guidelines, while also pointing to the limits of massive crackdowns that lead to the arrests of all participants in a criminal network. Conceiving such a focus will not only meet the short-term objectives of a police investigation, but also allow for an understanding that is crucial to develop long-term disruptive practices of not simply the operation under investigation but the wider criminal network environment surrounding it.

Keyphrases: Criminal network, Drug trafficking, Network analysis, Impact analysis, Police investigation
La conciliation travail-famille pour les professionnels de la réadaptation : un défi d'une participation sociale optimale au quotidien?

Introduction: Optimal social participation, which is the ultimate goal targeted by rehabilitation professionals for their clients, can be defined as perfect congruence between an individual's expectations and reality. Work-family dynamic requires balance between the different spheres of a worker's life. This raises questions about the perception that rehabilitation professionals have regarding their own optimal social participation, reconciling various life spheres, and the factors influence this participation. Purpose: To explore the perception of rehabilitation professionals regarding their optimal social participation, and the factors they identify as influencing this participation. Method: Qualitative study with a phenomenological orientation among 13 rehabilitation professionals using an interview guide consisting of open questions. The data was audio-recorded and transcribed in full (verbatim) followed by content analysis. Results: Participation were mostly women (12/13) aged 31 to 44 years having one to three children aged from 7 months to 12 years old. Optimality of participation is perceived as the ability (or not) to carry out important activities while fulfilling one's various responsibilities. Of the five environmental factors perceived to have an influence (financial aspects, spousal support, time, flexible work schedule, and family organization), family organization appears to be a determinant of possibility and thus greatly influences individual expectations. Conclusion: Work-life balance is a complex phenomenon that should be studied holistically rather in a siloed mode.

Keyphrases: Work-family conflict, Job stress, Social-environment, Work-life balance, health professionals, Actvities of daily living
La sélectivité fonctionnelle des ligands du récepteur delta opiacé

G protein coupled receptors (GPCRs) are one of the largest families of membrane receptor coded by the human genome and certainly the biggest family of receptors. Localized at the plasma membrane, they are responsible for a wide variety of cellular responses. Activation of GPCRs by ligands has been traditionally associated with change in protein conformation, switching from an inactive to an active state. However, some observations were inconsistent with this theory suggesting the presence of several active conformations of the receptor. These different conformations could be active in some signalling or regulatory pathways and inactive in others. This phenomenon, originally called biased agonism, is now described as the functional selectivity of GPCRs ligands. In theory, this type of selectivity could lead to the development of drugs that therapeutic action without activating signalling pathways responsible for side effect. The delta opioid receptor (DOR) is a GPCR involved in chronic pain management. However, analgesic action of its ligands is subject to tolerance that develops over the course of long-term treatment, limiting their clinical use. This thesis focuses on functional selectivity of DOR ligands to assess the possibility of reducing the effects of tolerance produced by these molecules. First, we determined that DORs adopt ligand-specific active conformations with distinct ability to activate different signalling pathways and regulatory responses. Second, we established that DORs constitutively associate with Gαi heterotrimeric subunits, and that different receptor ligands induce distinct conformational changes within these signalling complexes. These observations are inconsistent with a two-state model of receptor activation, pointing instead the presence of multiple active conformations. Finally, we demonstrated that conformations stabilized by different agonists distinctively interact with βarrestin2, such that the agonist who promoted a transient receptor interaction with this regulatory protein produced more recycling, less desensitization and less acute analgesic tolerance than the ligand who promoted a stable DOR-βarrestin2 interaction. Taken together, the results presented in this thesis show DORs adopt ligand-specific conformations that support ligand-specific profiles of analgesic tolerance. This type of functional selectivity of opioid ligands could be eventually exploited in the development of novel therapeutic agents with longer analgesic actions.

Keyphrases: Recyclage, G protein coupled receptor, Opioid, Tolerance, βarrestin, Regulation, Delta opioid receptor, Pain, analgesic, Functional selectivity, Desensitization
La formation linguistique des professionnels en administration à l'université : ce que nous apprennent les évaluations de programme

This study was designed to analyse undergraduate programme reviews of languages for specific purposes (LSP) in order to discover the stakes and the pertinence of this training offered at Canadian institutions of higher learning.  The three research questions are: • Which Canadian institutions of higher learning offer curricula integrating competences in LSP and professional know-how? • Taking into account the nature and function of LSP programs and courses within higher education, what are the major stakes? • What are the most frequent recommendations found in the external reviewers’ program assessments, taking into account the nature and function of LSP programs and courses?  The analysis revealed that the most important stakes in providing quality, pertinent training in LSP are contribution of course content to professional training; correspondence to the needs of the learners; systematic programme evaluation including proof for decision-making; systematic programme revision, updating and evaluation; interdisciplinary and interuniversity collaboration; teaching language competences related to the underlying professional discipline; teaching intercultural perspectives; constitutive or instrumental objective of language acquisition; professionalization of the discipline rather than the “service” function; promoting programmes, collaborations and international exchanges; integrating information and communication technologies; and providing learners with opportunities for formal language certification in LSP.  The external evaluators recommended modernising and reorganising courses, setting up collaborations, improving international exchanges and methods for promoting them, elaborating strategies for studying and implementing initiatives, promoting the benefits of language study to other disciplines and faculties, creating strategies for programme revision, and formulating plans of action to take advantage of new technological resources.  These findings therefore shed light on the value of the formative function of curriculum evaluation mechanisms for the field of language teaching and on the stakes involved for teaching practitioners in providing quality, pertinent LSP training.  They also shed light on the importance and the impact of evaluation practices on decision-making.

Keyphrases: Formation, Specialised languages, Languages for specific purposes (LSP), Training, Undergraduate programme review, Major stakes, Recommendations, Canadian universities
Les partenaires d'interactions de Cirhin, la protéine portant la mutation responsable de la Cirrhose Amérindienne Infantile (NAIC)

North American Indian childhood cirrhosis (NAIC) is a nonsyndromic form of hereditary autosomal recessive cholestasis, described only in children of Algonquin origin from the Abitibi region of north-western Québec and issued from a founder effect. NAIC typically presents with transient neonatal jaundice in a child who is otherwise healthy, but progresses to biliary fibrosis in childhood or young adulthood. The survival rate at adulthood is lower than 50% and liver transplantation is currently the only effective therapy for patients with advanced disease.   Previous research by the group allowed the identification of the locus and the gene responsible for NAIC, which encodes the nucleolar protein Cirhin. Cirhin is expressed only in the liver and all patients are homozygous for the R565W mutation. Cirhin’s function is unknown, but it is a WD40-repeat containing protein, which indicates that it would participate in protein-protein interactions and would be involved in a basic molecular mechanism. Cirhin interacts with the nuclear protein Cirip, which has a significant positive effect on the transcription of the HIV-1 LTR enhancer element and has a role in cellular proliferation. The interaction between Cirhin and Cirip is affected by the R565W mutation.  Using the yeast two-hybrid technique, the nucleolar protein Nol11 was identified as an interacting partner of Cirhin. By its interaction with MARK3 and c-Myc, Nol11 may be involved in cellular processes such as cell cycle control, polarity, cell growth and possibly ribosome biogenesis. The C-terminal portion of Nol11 interacts with Cirhin and the R565W mutation abolishes the interaction. The residue R565 may thus be important for Cirhin’s functionality.

Keyphrases: Nol11, MARK3, North American Indian Childhood Cirrhosis, NAIC, Interaction network, Two-hybrid, Cirhin, Cholestasis, Liver
La contribution du récepteur B1 des kinines dans les complications diabétiques chez le rat traité au glucose, un modèle de résistance à l'insuline

Kinins act on two G-protein-coupled receptors, denoted as B1 and B2, and play an important role in cardiovascular regulation, nociception and inflammation. We have considered the hypothesis that kinin B1 receptor is upregulated and involved in diabetic complications, notably hypertension, pain sensory neuropathy, the oxidative stress in the vasculature, vascular inflammation, insulin resistance and obesity in rats treated for 8 or 12 weeks with D-glucose (10% of glucose in their drinking water). In this model of insulin resistance, we assessed the effects of one-week treatment with SSR240612 (10 mg/kg/day), a selective kinin B1 receptor antagonist. Data show that SSR240612 reverses high blood pressure, tactile and cold allodynia, the production of oxidative stress (superoxyde anion) in the aorta, the overexpression of iNOS, IL-1β, macrophage (CD68, CD11), ICAM-1, E-selectine, MIF and B1R in the aorta and iNOS, IL-1β, TNF-α and macrophage (CD68) in adipocytes. Moreover, SSR240612 reverses insulin resistance, plasma fatty acids composition changes and body and tissue fat gain.  These data support a key role for kinins in diabetic complications in a rat model of insulin resistance and suggest that kinin B1 receptor is a promising therapeutic target in diabetes and obesity.

Keyphrases: allodynia, type 2 diabetes, arterial hypertension, inflammation, inflammation, kinin receptors, obesity, insulin resistance