NCube/papyrus huggingface dataset:
Le rôle du récepteur B1 des kinines dans l'insulite et dans les complications du diabète de type 1 dans un modèle de choc spectique

Kinins are vasoactive peptides and central neuromediators involved in cardiovascular control, pain and inflammation. Their effects are mediated by two G protein-coupled receptors: the constitutive B2 receptor (B2R) and the inducible B1 receptor (B1R) that is upregulated during tissue injury, in the presence of proinflammatory cytokines, bacterial endotoxins and diabetes. Diabetes has reached epidemic level and its etiology is complex. Diabetes mellitus worsens severe infections and increases mortality caused by hyperbacteremia resistant to therapeutic control and management in intensive care units. Mortality is largely secondary to the occurrence of disseminated intravascular coagulation (DIC). This project examines the role of B1R in DIC in a model of type 1 diabetes induced by streptozotocin (STZ) (Article 1) and insulitis (Article 2). DIC was induced by injection of lipopolysaccharide (LPS, 2 mg/kg i.p.) four days after treatment with STZ (65 mg/kg, i.p.). In the first article, we have shown a significant increase in edema and vascular permeability (Evans blue) in kidney, lung, heart and liver in rats treated with LPS and/or STZ, increasing the haemoconcentration and the development of hypercoagulability state. Also, we showed the presence of thrombus formation and tissue damage by histological studies, and increased expression of B1R in the heart, kidney and platelets. Treatment with the B1R antagonist, SSR240612, alleviated all those abnormalities, in addition to reducing hyperglycemia in STZ rats, LPS-induced hyperthermia and improving survival. The beneficial effects of SSR240612 were reproduced by the inhibition of iNOS with 1400W and of COX-2 with niflumic acid, suggesting that the mediators of these proinflammatory enzymes act downstream to B1R. In the second article, STZ rats were treated with SSR240612 (10 mg/kg/d, per os) from day 4 to day 7. This B1R antagonist blocked the infiltration of the pancreas by macrophages andTCD4+ lymphocytes which express B1R. The antagonist also prevented the increased expression of iNOS, TNF-α, B1R and TRPV1 in the pancreas of STZ-diabetic rats. The treatment with the B1R antagonist limited the loss of Langerhans β cells, which improved plasma insulin and normalized hyperglycemia. These studies highlight a primary role for B1R in lethality associated with septic shock, thrombosis and insulitis. Therefore, kinin B1R is a promising therapeutic target in the treatment of diabetes and its complications.

Keyphrases: Lipopolysaccharide, TRPV1, lymphocyte TCD4+, TRPV1, Diabetes, Immune assault, Kinin B1 receptor, Streptozotocin, hyperglycemia, Macrophage
Analysis of intrinsic cardiac neuron activity in relation to neurogenic atrial fibrillation and vagal stimulation

Atrial fibrillation is the most frequent sustained rhythm disorder in humans and often leads to severe complications such as heart failure and stroke. A neurogenic mechanism of atrial fibrillation has been hypothesized. Tachyarrhythmia induction by mediastinal nerve stimulation has been proposed as a model to study neurogenic atrial fibrillation. In this thesis, we studied the activity of intrinsic cardiac neurons and their interactions inside the right atrium ganglionated plexus in a canine model of neurogenic atrial fibrillation. These activities were recorded by a multichannel microelectrode array that was paled into the right atrium ganglionated plexus. The recording was done for up to 4 hours and it covered the neuronal activity during different interventions such as vascular (aorta occlusion, inferior vena cava occlusion, left anterior descending coronary artery occlusion), mechanical (touching atrium and ventricle) and electrical (stimulating of vagus nerve or stellate ganglion) stimuli as well as atrial fibrillation induction. Neuronal identification and classification were done using the principal component analysis and cluster on measurements analysis in Spike2 software. New method based on principal component analysis was proposed to cancel superimposed atrial activity on neuronal signal to increase the accuracy of the neuronal response identification and classification. Based on the neuronal response, we defined subtypes of neurons (afferent, efferent and local circuit neurons) and their related activity to different stressors which provided a more detailed description of the intrinsic cardiac nervous system. The majority of recorded neurons reacted to episodes of atrial fibrillation by becoming more active. This hyperactivity of intrinsic cardiac neurons during atrial fibrillation suggested that controlling that activity might help preventing neurogenic atrial fibrillation. Since low-level vagus nerve stimulation obtunds the intrinsic cardiac neuronal activity (especially for afferent and convergent local circuit neurons), we investigated whether this intervention could be applied as a therapy for atrial fibrillation. Our results showed that right vagus nerve stimulation was able to mitigate atrial fibrillation in 12 of 16 cases and showed an adverse pro-arrhythmic effect in 1 of 16 cases. The protective action however decreased over time and became ineffective after ~40 minutes for 3 minutes vagus nerve stimulation.

Keyphrases: Atrial arrhythmias, Intrinsic cardiac nervous system, Local circuit neurons, Vagus nerve stimulation, Stochastic neuronal interactivity
Rôle des acides gras polyinsaturés essentiels dans l'infarctus du myocarde

Cardiovascular diseases are the second most common cause of death in North America. This may be explained by the increase in the consumption of fat, especially in omega-6 polyunsaturated fatty acid, in the last decade. Contrariwise, Inuits and Japanese have a diet rich in omega-3 polyunsaturated fatty acid associated with a low risk of cardiovacular diseases. Omega-3 are beneficial in myocardial infarction, they prevent incidence of secondary infarction and are cardioprotective when consumed before myocardial infarction. The aim of the first study is to use a metabolite of omega-3, resolvine D1, which is implicated in the resolution of inflammation, at the time of myocardial infarction thus in a more clinical context. Indeed, resolvin D1 showed cardioprotection when given just before ischemia by decreasing inflammation and by activating a cardioprotective pathway.  Afterwards, the aim of the second study was to determine if omega-6 could prevent the beneficial effect of resolvin D1, given the high intake of omega-6 in North America. Hence, linoleic acid was given at the same time as resolvin D1 just before ischemia. Resolvin D1 lost its cardioprotective effects when given with linoleic acid. Linoleic acid seems to worsen ischemic lesions by generating pro-inflammatory and vasoconstrictors metabolites, which enhance the effect of ischemia. Thus, it is essential to consider omega-6 intake in patients before using resolvin D1 as a therapeutic option, and to encourage patients to decrease omega-6 consumption while increasing omega-3.  Finally, the aim of the third study was to demonstrate the mechanism of cardioprotection conferred by omega-3, and more specifically by its metabolites. The use of the 15-lipoxygenase and the cyclooxygenase-2 inhibitors inhibited cardioprotection conferred by a diet rich in omega-3. Inhibitors decreased resolvin D1 plasmatic concentration. When resolvin D1 is given with the inhibitors, the cardioprotection is restored. Metabolites issued from omega-3, such as resolvin D1, are essential to show a cardioprotection and a decrease in infarct size.      To conclude, resolvin D1 could be an interesting option to benefit from the effect of omega-3 given to the time of myocardial infarction. Although metabolites of omega-3 are essential for cardioprotection, it seems that they are source of cardioprotection produced by omega-3. However, omega-6 are highly present in diets, consequently they need to be diminished in order to be able to benefit from omega-3 cardioprotection effect.

Keyphrases: Omega-3, Omega-6, Resolvin D1, Myocardial Infarction
Les immunoglobulines intraveineuses et la réponse spécifique des cellules T dans la prévention de la maladie lymphoproliférative post-greffe associée au virus Epstein-Barr chez les enfants greffés de cellules souches hématopoïétiques

Post-transplant lymphoproliferative disease (PTLD) is a serious complication in immunosuppressed transplant patients following infection by the Epstein-Barr virus (EBV). In the absence of an efficient cytotoxic T-lymphocyte response, EBV-infected B cells can expand in number and give rise to PTLD. In the immunosuppressed setting, EBV infected B cells are postulated to be lytically activated, such that the virions released can infect bystander B cells, resulting in polyclonal B cell expansion. Because gp350, a lytic-cycle protein located in the viral envelope, plays an important role in EBV infection, anti-gp350 neutralizing antibodies are thought to be a key player in blocking infection, hence preventing the development of PTLD. The use of intravenous immune globulin (IVIG) as a prophylactic against opportunistic infections (including EBV) for patients receiving hematopoietic stem cell transplantation calls into question the effectiveness of IVIG to inhibit or temper EBV infection in this patient group. Therefore the first objective of this thesis proposed to evaluate the efficacy of IVIG against EBV infection and PTLD in hematopoietic stem cell recipients. The second objective proposed to determine, using the ELISpot technique, whether the presence of a strong T cell response against the EBV lytic-cycle antigen BMLF1 could constitute a marker for protection against PTLD in hematopoietic stem cell transplant recipients. The results revealed firstly that, while IVIG can efficiently neutralize EBV infection in vitro, it does not effectively protect transplant patients against EBV infection in vivo. Secondly, the study of the T-cell response against EBV antigens demonstrated that T cells from certain patients are able to recognize the BMLF1 lytic-cycle antigen. This specific T-cell response may prove to be a good marker of protection against PTLD.  In summary, the results of this thesis demonstrate that EBV lytic infection plays a fundamental role in PTLD development. The data also indicate that the presence of a specific T-cell response against an EBV lytic-cycle antigen may constitute a good marker of protection against PTLD. However, IVIG treatment of patients receiving hematopoietic stem cell grafts does not appear effective in preventing PTLD.

Keyphrases: Immunosuppression, Epstein-Barr virus, Post-transplant lymphoproliferative disease, Bone marrow, Intravenous immune globulin, T cells
Caractérisation et objectivation de l’acouphène subjectif chronique idiopathique

Objective: The main objective of this thesis was the implementation and validation of applying the gap prepulse inhibition of the acoustic startle reflex (GPIAS) paradigm in humans, in order to objectively measure tinnitus. To do this, three experiments were carried out. Experiment 1 was designed to validate the inhibition of the acoustic startle reflex by using a short gap within high and low frequency narrowband noise in normal hearing humans (without tinnitus) to determine the optimal paradigm parameters. Experiment 2 was designed to validate the accuracy and the test-retest fidelity of a tinnitus psychoacoustic characterization method (intensity and frequency matching). Finally, Experiment 3 applied the GPIAS paradigm to participants with chronic tinnitus using the techniques developed in experiments 1 and 2. Methods: Experiment 1 included 157 participants tested with only one gap duration (5, 25, 50, 100, 200 ms) and with one of the two paradigms (gap imbedded in the background noise or following it) including high and low frequencies background noise. Experiment 2 included two groups of participants with tinnitus, one group consisting of musicians (n=16) and one group without musical experience (n=16). A third group consisted of adults who were instructed to simulate having tinnitus (n = 18). Tinnitus pitch and intensity matching abilities were assessed for all participants. A subgroup of participants was retested several weeks later. Experiment 3 included 15 participants with tinnitus and 17 controls assessed with the GPIAS. The psychoacoustic parameters of tinnitus were also measured. A subgroup of participants was retested several weeks later. Results: Experiment 1: the GPIAS is applicable in humans with normal hearing. Experiment 2: psychoacoustic measurements of tinnitus frequency and intensity using a computerized matching procedure produced precise and accurate measurements of the tinnitus percept. Experiment 3: an inhibition deficit was found using the GPIAS paradigm in the tinnitus group for background noise of high and low frequency compared to the control group, at test and retest. The frequency matching measurements revealed a 16,000 Hz tinnitus predominant frequency for most tinnitus participants. Discussion: It is possible to apply the gap prepulse inhibition of the startle reflex paradigm on human participants with tinnitus, as used in animal research to "objectify" the presence of tinnitus. However, the inhibition deficit found in the tinnitus group was not specific to their tinnitus frequency. This was validated by psychoacoustic tinnitus pitch matching. Our results question the original interpretation of the GPIAS paradigm for objectifying the presence of tinnitus.

Keyphrases: Tinnitus, Startle reflex, Psychoacoustic, Pitch matching, Intensity matching, Near-Gap, Gap-Following, Startle-inhibition, Diagnostic, Near-Gap, Gap-following, Startle-inhibition, Diagnostic
Régulation de la division asymétrique chez C. elegans

Asymmetric cell division is essential to generate cell diversity during development and for maintaining a proper balance between self-renewal and differentiation in adult stem cells. In the first case it is mostly dependent on intrinsic polarity and in the second case on extrinsic polarity cues. C. elegans is an excellent model to study the cellular and molecular mechanisms of asymmetric division in vivo. In the embryo, the establishment and maintenance of an antero-posterior axis of polarity depends on conserved PAR proteins that are themselves localized asymmetrically in two mutually exclusive groups; the anterior complex with PAR-3, PAR-6, PKC-3 and the posterior group with PAR-2 and PAR-1.The absence of any PAR protein causes a loss of polarity and subsequent embryonic lethality. A genome wide RNAi screen performed by Jean-Claude Labbé identified cyb-2.1 and cyb-2.2, encoding for two B-type cyclins, as suppressors of par-2 lethality. I found that CYB-2.1 and CYB-2.2 intervene in polarity with their associated kinase CDK-1 but without affecting cell cycle progression, by regulating PAR-6 levels. This work further helped deciphering the complex links that exist between the regulation of cell cycle and cell polarity.  The C. elegans germline is an excellent model for studying stem cell divisions in vivo. However, contrary to what is observed in other model systems, C. elegans germline stem cells do not show an obvious preferential orientation for their self-renewal divisions, perhaps because the complex niche architecture could offer multiple possible axis. Indeed, the C. elegans germline niche is a single somatic cell, called the distal tip cell (DTC) that extends multiple processes in contact with germ stem and progenitor cells (GSPCs) at adulthood. While addressing the regulation of the niche morphology, I found that GSPCs could support the formation of the DTC processes. I also identify conditions that greatly simplify the niche morphology allowing future investigations of mitotic germ cell division toward a unique DTC process.    My work helped decipher the links between different bio-cellular processes implicated in asymmetric cell division both by the determination of the role played by key cell cycle regulators in embryonic polarity and by the characterization of a bi-directional communication between the niche and the GSPC at adulthood.

Keyphrases: cycline B, CDK-1, PAR, niche, DTC, Notch, C. elegans, asymmetric division, polarity, cyclin B, germline stem cell
La petite GTPase Rab11 et ses interacteurs orchestrent la migration cellulaire collective et la cytocinèse chez la Drosophile

Vesicle trafficking allows coordinated exchange of molecules between the cell organelles and depends largely on small GTPases of the Rab family which contains 27 members in Drosophila and 70 in Human. One challenge is to identify the cellular mechanisms which coordinate Rab activity to ensure ordered vesicle transport within the cell. Rab proteins act like molecular switch by cycling between an active and an inactive state. Rab activity is regulated by helper proteins, whereas downstream effector proteins coordinate the Rab functions. The small GTPase Rab11 is crucial for Drosophila, C. elegans and mouse development since Rab11 is at the heart of different transport routes. Thus, Rab11-dependent trafficking of molecules is perturbed in different pathologies. Despite its central role during vesicle trafficking, the regulation of Rab11 in vivo is poorly characterized. This thesis focus on the molecular mechanisms controlling the function of Rab11 and its effectors during collective cell migration and cytokinesis.   We identify Evi5 as a novel key regulator of collective cell migration and we show that Evi5 has Rab11-GAP activity essential for maintaining active guidance receptors at the leading edge. We then show that Rab11 regulates cell communication during collective cell movement through its interaction with Moesin. A question still remained unanswered: knowing that Rab11 has more than 13 effectors, which mechanisms assure the specificity of interaction between this small GTPase and a particular effector? Part of the answer might come from our observation that class I Rab11-FIPs, known Rab11 effectors, are able to bind to the 14-3-3 scaffolding proteins. In Drosophila, Rip11 is the sole member of the class I Rab11-FIPs and we show that Rip11 has unexpected functions during cytokinesis which are coordinated by 14-3-3. Our research allows us to better understand the molecular mechanisms regulating Rab11 and its effectors in vivo.

Keyphrases: Rab, 14-3-3, Rip11, Rab11, Evi5, Vesicular trafficking, Small GTPases, Cell migration, Cytokinesis
Identification et étude de mécanismes régulant l’expression de MAPK

The classical model of eukaryotic cellular signalling generally involves hierarchically organized linear pathways involving a restricted set of elements. These generally function together as an insulated circuit, transmitting information from the outside to the intracellular compartment involved in eliciting a response. These models, often the fruit of reductionist experimental approaches, do not allow for the integration of multiple inputs nor for a gradation of responses. The recent emergence of more holistic investigation techniques has brought about the re-evaluation of these classical models in favor of multiparametric signalling networks. This thesis focuses on the RAS/MAPK pathway, one of the cell’s main proliferation and differentiation signalling conduits, beginning with a historical perspective covering the contributions of model organism genetics to the current pathway model. This provides context for the description of a whole-genome RNAi screen experiment that we carried out to obtain a global view of regulators in Drosophila. Three groups of factors emerging from this screen were then examined in more detail. A first article shows that the exon junction complex (EJC) plays a role in mapk alternative splicing, an observation that is unexpected given that this complex was not previously known to act on splicing. A second paper details the genome wide screening campaign and focuses on a large set of splicing factors that also regulate mapk, albeit in a distinct manner than the EJC’s. Finally, a manuscript in a third segment examines Usp47 function and finds it to control MAPK levels post-translationally. An RNAi-based genetic interaction screen is then used to identify factors functionally related to Usp47 capable of counteracting its impact on MAPK levels. Three such factors identified through this technique are linked to the N-end rule protein degradation pathway. Regulation of core pathway component expression is a poorly described process, which makes the identification of a large set of factors regulating MAPK expression all the more unusual. Moreover, the absence of such regulation linked to other pathway components suggests that MAPK may act as a node incorporating inputs of this type into RAS/MAPK signaling dynamics.

Keyphrases: RAS/MAPK signalling, Drosophila melanogaster, RNAi screen, exon junction complex, EJC, alternative splicing, spliceosome, exon definition, intron definition, ubiquitin-proteasome system, N-end rule
L’évolution des finalités de l’université québécoise dans un contexte de mondialisation : analyse critique des politiques publiques de 1998 à 2009

This research focuses on the evolution of the aims of the Québec University in the context of globalization by completing a content analysis of public policies concerning universities (1998-2009). The method used is rooted in a socio-historical approach. It resulted in the comprehension of the concept of globalization in its three dimensions (economic, political and cultural), and the purpose of university by its missions (training, research and “third mission”). The conceptual framework subsequently developed allowed the examination of the evolution of the university's goals in its complexity. The analysis revealed that the themes rarely follow a linear evolution through time, but rather can undergo reification, stagnation, or change of meaning. The transversal analysis of the two objects draws dialectical tensions that are aligned with the movement of the economic, political and cultural dimensions of globalization. The influence of the first object causes a semantic shift which redefines the role of the University and the nature of knowledge in light of the knowledge economy. In terms of political dimension, the application of the new public management also raises semantic shifts, namely the reification of the definition of the quality of the missions. The cultural dimension, for its part, suggests a form of individualization of relationships to University, particularly in light of the social contract university must commit to, along with society moving towards a management contract. If the documents analysed show a dichotomy between disinterested and useful knowledge, it is proposed in the context of this research to look past these arguments, as they emerge from ideological positions.

Keyphrases: Québec, Public policies, Globalization, University, Founding principles