NCube/papyrus huggingface dataset:
Modulation of the 5-HT3 Receptor as a Novel Anti-Dyskinetic Target in Parkinson’s Disease

L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson’s disease However, with chronic administration of L-DOPA, patients develop motor complications such as dyskinesia. Previous studies have shown that 5-HT3 receptor blockade reduces dopamine levels within the basal ganglia, suggesting that it could mitigate the aberrant dopamine release that characterises the dyskinetic state. Here, we investigated the effects of the highly-selective 5-HT3 antagonist ondansetron at diminishing the expression of established, and preventing the development of L-DOPA-induced dyskinesia in the 6-hydroxydopamine-lesioned rat. In the first set of experiments, rats were primed with L-DOPA to induce abnormal involuntary movements (AIMs), after which L-DOPA was administered, in combination with ondansetron or vehicle. The effect of ondansetron on L-DOPA anti-parkinsonian action was subsequently determined by the cylinder test. In the second set of experiments, rats were administered effective doses of ondansetron, started concurrently with L-DOPA for 22 days, during which dyskinesia severity was monitored. After a 3-day washout period, an acute challenge of L-DOPA was administered and AIMs severity was assessed. We found that acute challenges of ondansetron 0.0001 mg/kg in combination with L-DOPA, significantly diminished the severity of AIMs compared to L-DOPA alone. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, attenuated the priming process leading to the development of dyskinesia. The anti-dyskinetic action of ondansetron did not compromise the therapeutic benefit conferred by L-DOPA. These results suggest that 5-HT3 receptor antagonism is a potentially new and effective therapeutic strategy to alleviate the severity, and prevent the development of dyskinesia.

Keyphrases: L-DOPA, 6-OHDA, rat, Parkinson’s disease, dyskinesia, serotonin, 5-HT3 receptor
Binder of SPerm protein interference in sperm-egg interaction

Binder of SPerm (BSP) proteins were first characterized in the laboratory of Dr. P. Manjunath, where the biochemistry of seminal plasma proteins and their interactions with sperm are being studied. These proteins were shown to bind to choline phospholipids on the ejaculated sperm membrane. In mice and humans, the Binder of SPerm homolog 1 (BSPH1) protein is exclusively expressed in the epididymis. BSPH1 proteins have been shown to be involved in the sperm membrane changes underlying capacitation. Findings from experiments with the recombinant mouse BSP homolog (rec-BSPH1) suggest that the protein initially resides on the surface of the sperm and then relocalizes over the head and mid-piece during capacitation and sperm-egg interaction, suggesting a potential role for BSPH1 in sperm-egg interaction. In the current study, we examined the role of the mouse recombinant BSP homolog 1 (rec-BSPH1) in sperm-egg interaction using an in vitro fertilization (IVF) assay. Oocytes were pre-treated with rec-BSPH1, control proteins or media alone, and inseminated with capacitated sperm. In addition to IVF assays, the potential binding of rec-BSPH1 to the oocyte surface was investigated using immunofluorescence. Finally, sperm-bound native BSPH1 was immuno-neutralized by anti-rec-BSPH1 antibodies in order to indirectly demonstrate the importance of BSPH1 in sperm-egg interaction and fertilization. Our results showed that eggs pre-incubated with rec-BSPH1 protein exhibited a dose-dependent decrease in fertilization rate compared to those exposed to control proteins or media alone. Since BSPH1 binding sites were not identified on the egg, the observed inhibition in fertilization rate when eggs were pre-incubated with rec-BSPH1 suggested that an alternate mechanism was at play. We hypothesize that bovine serum albumin contained in the media synergizes with rec-BSPH1 to provoke oocyte membrane lipid raft disorganization, which interferes with fertilization. In addition, anti-rec-BSPH1 antibodies could effectively immuno-neutralize native protein on sperm, which led to dramatic motility suppression and failed hyperactivation, followed by compromised fertilization. Taken together with previously published research, our findings suggest that BSPH1 would mostly be involved in the late events of sperm capacitation.

Keyphrases: Binder of SPerm Homolog, BSPH1, In vitro fertilization, Sperm-egg interaction, Capacitation, Protéine «Binder of SPerm Homolog» (BSPH1)
L’étude du rôle de l’interleukine 6 dans le métabolisme lipidique de la cardiomyopathie diabétique

Diabetic cardiomyopathy is associated with an accumulation of lipids in the heart muscle and to understand the effect of lipotoxicity, we wanted to know what are the signaling pathways of lipid metabolism that are disrupted in heart disease. We have previously shown that palmitate, a toxic saturated fatty acid, induces IL-6 in primary cardiomyocytes. In contrast, co-treatment of these cells with oleate, a non-toxic monounsaturated fatty acid, promotes a decrease in IL-6 expression and palmitate toxicity. This suggests that the lipotoxicity of palmitate may be caused by the IL-6. To confirm this, we tested the effect of IL-6 knockdown (KD), using two different siRNAs targeting the sequences of the IL-6 gene. Interestingly, the decrease of IL-6 with siRNAs did not attenuate the palmitate-induced cell death, but on the contrary accentuated it. In addition, the KD of IL-6 in cells treated with oleate, which is normally nontoxic, caused cell death. This last finding had led to the work of this master. Our objective was to evaluate the effect of IL-6 on lipid metabolism. Firstly, we measured the level of exogenous IL-6 secreted by primary cardiomyocytes treated with oleate or palmitate. Then, we tested the effect of IL6-Recombinant in cardiomyocytes, using the cardiomioblasts H9C2, on viability and on lipotoxicity using thin layer chromatography. Our preliminary results support that IL-6 could be necessary for lipid metabolism, with a cardioprotective effect at a certain dose by protecting cardiomyocytes against lipotoxicity by promoting β-oxydation (degradation of fatty acids) in the mitochondria. This results should be validated using an animal model. All of our results is a rough sketch to understand the role that IL-6 could play in the lipid metabolism of diabetic cardiomyopathy.

Keyphrases: IL-6, Cytokine, Inflammation, Diabetic cardiomyopathy, Lipotoxicity
Impact des biais introduits lors de différents types de mesures de pression artérielle

High blood pressure is a major cardiovascular risk factor that affects up to one fourth of the Canadian adult population. Its diagnosis, treatment and follow-up depend largely on accurate blood pressure (BP) measurements. There are different types of measurements and they are complementary in some aspects. BP assessments methods include the office manual measurement, the automated office blood pressure measurement (AOBP) and home blood pressure monitoring (HBPM). To address hypertension adequately, clinicians must have reliable tools to estimate BP. This master thesis focuses on three potential biases and tries to quantify their impact on BP measurement. The biases that are addressed are first, the difference between manual measurement and AOBP in clinical and research contexts, second, the bias existing in incomplete HBPM schedules and finally, the difference between the two most used AOBP devices in different clinical environments. The first study demonstrated that the AOBP is equivalent to manual measurement when standardized and performed by well-trained nurses, in both clinical and research contexts. The second study shows that incomplete HBPM schedules can have a significant impact on the precision and diagnostic validity of HBPM when compared to complete schedules. Our data shows that incomplete schedules composed of 21 measures give precision and diagnostic validity similar to the complete schedule. Our third study showed that the two most used AOBP devices, the Omron HEM 907 and the BpTRU BPM-100, were equivalent around diagnostic threshold. However, these two devices showed statistically and clinically significant differences when estimating low BP.

Keyphrases: Blood pressure, Blood pressure measurement, Automated office blood pressure measurement, Home blood pressure monitoring
La régulation transcriptionnelle de Neuroligine-1 par les facteurs de transcription de l’horloge

The post-synaptic adhesion molecule Neuroligin-1 (NLGN1) plays an important role in glutamatergic transmission and synaptic plasticity. Localized mainly at excitatory synapses, it regulates the number of functional N-methyl-D-aspartate (NMDA) glutamatergic receptors, in addition to being involved in synaptogenesis and in the regulation of wakefulness and sleep. It has been shown that the transcriptional factors CLOCK and BMAL1 bind to the promoter of Nlgn1 gene in the mouse cerebral cortex, suggesting a possible implication in its transcriptional regulation. For my master project, our objectives are to test if CLOCK and BMAL1, as well as their homologs NPAS2 and BMAL2, regulate the transcription of Nlgn1 via in vitro luciferase assays; and to verify in vivo the levels of Nlgn1 mRNA and NLGN1 protein in Clock mutant mice. Our in vitro results revealed a transcriptional activation of Nlgn1 by the CLOCK/BMAL1 heterodimer, as well as combinations with their homologs NPAS2 and BMAL2. This observed activation is however repressed when adding the GSK3β kinase. In vivo, levels of Nlgn1 mRNA transcript variants with or without insert A were significantly decreased in Clock mutant mice, whereas for variants with or without insert B, mRNA expression rhythm was inverted. No change in NLGN1 protein levels was observed. These results increase our understanding about NLGN1 regulation in vitro and at the organism level.

Keyphrases: Transcription, Neuroligin-1, Transcription, Clock proteins, Luciferase assay, Gene expression, Mice
The yeast Rts1, a subunit of PP2A phosphatase, is involved in stress response

The reactive oxygen species (ROS), generated endogenously and exogenously, following treatment with oxidizing agents is well-known to induce double strand deoxyribonucleic acid (DNA) breaks (DDSB). Saccharomyces cerevisiae has been used widely as a tool to study the mechanisms that confer sensitivity or resistance to oxidative DDSB repair. Thesis herein describes two separate studies designed to better understand the DDSB repair mechanisms.   The aim of the first study was to assess the role of rts1, and its associated genes, in the regulation of oxidative DNA-damage repair mechanisms. The study involved treatment of wild-type (WT) and mutant BY4741 yeast strains with Zeocin, hydrogen peroxide and hygromycin. The nuclear proteins from WT and rts1Δ strains were fractionated using fast protein liquid chromatography (FPLC), and the fractions were run on polyacrylamide gel followed by analyses of bands generated or lost using mass spectrometry. Our findings here show an Apn1-dependent functional role of rts1 in DDSB-repair mechanisms. Furthermore, analysis of the FPLC fractions using mass spectrometry revealed up-regulation of eno1 and down-regulation of cdc19 following deletion of rts1. However, confirmatory experiments only showed significant association of rts1 with that cdc19. Hence, further studies are required to better understand the association of rts1 with that of cdc19 and eno1, and how their interaction affects the DNA-repair processes and/or cell cycle.  In the second study, we investigated the role of histone H2A in the nuclear localization of Apn1. Furthermore, the study also characterized the role of H2A-E130A residue in methyl methanesulfonate (MMS)-induced DNA-repair response. Out findings herein demonstrated a role for Glu130 residue of Histone H2A in the nuclear localization of Apn1. Importantly, our data also show the role of the Glu130 in determining the sensitivity as well as the growth rate of the H2A strain to MMS. Future investigation of the APN1-related genes will facilitate better understanding of the role of Apn1 and its associated genes in regulating the repair mechanisms following double strand DNA breaks induced by alkylating agents.

Keyphrases: Zeocin, Rts1, Cdc19, Histone H2A, Apn1, NLS, Sites AP, Protein phosphatase 2A, Chromosomal DNA, AP sites
Role of the multidrug-based approach to control chronic pain and cognitive impairment in people with chronic refractory pain : literature review

Chronic pain is a multifactorial clinical condition that has negative impacts on physical, social, and emotional states of the patients.  Globally, it affects approximately 20% of the population, especially in developed countries, and continues to exist as a significant problem in the elderly. However, in last two decades, there have been advances in pain treatment regarding analgesic medications and technical procedures. This review will provide a mechanism- and evidence-based approach to enhance the outcome for the pharmacologic management of chronic refractory pain while minimizing the negative impact on cognitive function. Therefore, this approach will discuss different types of medications that affect chronic pain, as well as the cognitive function (morphine, ketamine, bupivacaine, naloxone, clonidine, and neostigmine).

Keyphrases: Morphine, Bupivacaine, Ketamine, Clonidine, Dexmedetomidine, Neostigmine, Naloxone, Chronic pain, Cognitive functions, Depression, Cognition
La réadaptation sociale : l’identité professionnelle de travailleuses sociales œuvrant en réadaptation en déficience physique

Working in a rehabilitation establishment with people who have physical disabilities comes with different identity challenges, just like belonging to the group of social workers, whose professional identity – its disciplinary project – is often described as fragmented or under pressure (Favreau, 2000; Fortin, 2003; Lecomte, 2000). This explains why the present thesis concentrates on grasping a better understanding of the perception social workers have of their own professional identity, in the structured space of physical disabilities rehabilitation establishments in Quebec.  From a constructivist grounded theory standpoint, we proceeded to an empirical data collection in two phases. Twenty in-depth interviews were first undergone with social workers who had been employed by physical disabilities rehabilitation establishments for at least a year. These interviews were analysed in two waves (Wave 1 = 14 interviews; Wave 2 = 6 interviews), to allow for a coding matrix to emerge. With the use of theoretical sampling, this preliminary coding matrix led us to identify themes and participants to study more in depth in the second phase of data collecting. Then, 5 semi-directed individual interviews were undergone. Data analysis of these interviews allowed us to identify an emerging core category, which we theorised with the help of sensitising concepts and our theoretical sensibility.  This core category is what we refer to as social rehabilitation, representing the perception participants have of their professional identity. This category rests on two identity pillars, social work on one hand, and rehabilitation on the other, and is characterised by five core tensions. These tensions are located at each pillar, at the meeting points of these pillars, and in the individual position to choose between these pillars. This identity is not only characterised by these tensions, but also by identity challenges, which are dealt with by participants using different identity strategies.  From these elements, the concept of social rehabilitation is further theorised through the theories of two symbolic interactionist authors. First, from the negotiated social orders theory of Straus (1992), we conclude that having a professional identity characterised by social rehabilitation demands a diachronic identity negotiation, which cannot be completely strategic in a constantly changing context such as is the participants’. Then, from the theory of Dubar (2000b), we maintain that this negotiation is not only necessary between a person and those surrounding them, but also between the multiple aspects of that person’s professional identity.

Keyphrases: Professional identity, Identity tensions, Identity crises, Social work, Rehabilitation, Physical disabilities, Recognition, Professional autonomy, Interprofessional collaboration, Grounded theory
The politics of Burden-Sharing : three essays on NATO, Canada, and fair-share

This dissertation analyses the original burden-sharing debates in the North Atlantic Treaty Organization (NATO) during its formative years. In calling for a qualitative approach to studying NATO burden-sharing, this dissertation demonstrates that the NATO burden-sharing problem was normatively rooted in politics. In contrast to the dominant systemic, rationalist, and hypothetical-deductive studies, this dissertation explores the political, ethical, and practical dimension of burden-sharing at the level of national leaders. This conceptual, method-driven, and policy-oriented dissertation uses interpretation as its research strategy and develops a qualitative approach with a political, normative, and historical focus of inquiry. The in-depth and context-sensitive analysis of archival materials reconstructs how the practitioners themselves made sense of, and discursively framed, the NATO burden-sharing problem in both their public and private discourse. Furthermore, this doctoral research employs the traditions of normative ethics as analytical tools to better grasp national contribution strategies and to interpret the burden-sharing problem through the lenses of distributive justice. The Politics of Burden-Sharing consists of three separate articles connected through the common theme of NATO burden-sharing. While focusing primarily on the Canadian political, bureaucratic, and senior military leaders under the St. Laurent Premiership (1948-1957), the dissertation links these traditional burden-sharing debates with the contemporary post-2014 NATO discussions to draw some lessons learned for a fairer burden-sharing within the Alliance.

Keyphrases: North Atlantic Treaty Organization, Burden-sharing, Interpretive-qualitative methodology, Normative ethics, Distributive justice, Cold War
Individual differences in the prediction of metabolic dysfunction from physiological responses to stress : a target for intervention?

Nearly one in four Canadians reports feeling significantly stressed on a daily basis.  Stress has been associated with the onset and progression of cardiovascular disease, which is the leading cause of death in men and women worldwide.  One pathway by which stress may contribute to CVD is through its impact on intermediary risk factors of CVD, such as the metabolic syndrome.  Metabolic syndrome represents a constellation of CVD risk factors that have been grouped into a clinically meaningful construct; its presence doubles risk of CVD, independent of its individual components.   Prior to the preparation of this thesis, little was known regarding the relation between our responses to psychological stress and metabolic syndrome risk.  This thesis specifically examined the contribution of physiological stress responses to metabolic dysfunction, both concurrently and prospectively (Articles 1 & 2).   It also investigated the potential moderating effect of sex and age.    Results suggested that non-normative autonomic stress responses are associated with metabolic abnormalities, though these associations are moderated by sex. Specifically, in men (Study 1) and women (Study 2), exaggerated autonomic reactivity to interpersonal stressors was associated with metabolic dysfunction.  Non-normative autonomic responses such as a blunted response (lack of or minimal vagal withdrawal during stress) and stress-related increase in vagal activity were linked to greater metabolic abnormalities in women.  Additionally, a stress response pattern including high basal HR, greater HR reactivity, and delayed HR recovery, was also associated with increased odds of meeting metabolic syndrome criteria in Study 2.    This thesis also included a pilot proof-of concept study examining the feasibility and acceptability of mindfulness-based stress reduction as an adjunct to usual treatment for older adults with current or past metabolic syndrome.   Results (summarized in Chapter 3) were favorable in this regard; the study was moderately feasible and largely acceptable to participants.  We also investigated whether elevations in metabolic parameters could be reversed through MBSR and tested whether MBSR influenced the magnitude of stress responses in both heightened and blunted responders.  Although results need to be replicated in large-scale research before conclusions can be drawn, initial evidence suggests the reversibility of stress-induced changes in metabolic profile, further highlighting the role of stress responses in the pathogenesis of metabolic syndrome.  MBSR also showed promise in normalizing autonomic stress responses.  The theoretical and clinical implications of these findings are discussed in detail in the final section of this thesis.  Future directions as well as strategies for transfer of knowledge are also provided.

Keyphrases: stress, metabolic syndrome, cardiovascular disease, heart rate variability, mindfulness-based stress reduction, sex differences