NCube/papyrus huggingface dataset:
Traumatisme craniocérébral, services de santé mentale et suicide de l'enfance à l'âge adulte : une étude épidémiologique et qualitative de la situation québécoise (1987 à 2013)

Introduction and Literature Review: Recent suicides of veterans and professional athletes have signalled a possible association between traumatic brain injury (TBI) and suicide. Guidelines for management of mental health and suicide prevention in this population remain fragmentary. The objectives of this thesis are to 1) determine whether there is an association between childhood TBI and future suicide, 2) explore whether persons who committed suicide consulted with a psychiatrist in the year prior to suicide and if persons with a TBI consulted more than those without a TBI 3) describe mental healthcare provided in rehabilitation in Quebec to children and adults TBI survivors. Methodology: The epidemiological component consists of a retrospective cohort study of 135,703 children receiving medical services in Quebec in 1987 and followed until 2008. The qualitative component includes a survey of managers of Quebec TBI rehabilitation programs, as well as focus groups with clinicians and interviews with TBI survivors and their caregivers. Results: Our epidemiological study confirms a significant association between TBI suffered in childhood (HR 1.49, 95% CI 1.04, 2.14) in adolescence (HR 1.57, 95% CI 1.09, 2.26) and in adulthood (HR 2.53, 95% CI 1.79, 3.59) and suicide. Despite a higher risk of suicide, people with a TBI who committed suicide did not consult a psychiatrist more often than people without TBI (OR 1.29, 95% CI 0.75- 2.24). According to our qualitative findings, current strengths include good quality of services, but there are weaknesses in access to specialized physicians, routine screening and access to long-term services. Our recommendations include the development of a coordinated approach to mental health, automatic involvement of a case manager and improvement of access to follow-up services after discharge. Conclusion: The risk of suicide is increased in young persons with TBI compared to those without.  Well-coordinated and long-term monitoring should be promoted.

Keyphrases: Suicide, Prestation de services, Psychiatrie, Adolescents, Traumatic brain injury, Mental health, Rehabilitation, Service delivery, Psychiatry, Children, Adults
Effets de la stimulation magnétique transcrânienne dans la maladie de Parkinson avec déficits cognitifs légers

Cognitive impairment affects many patients with Parkinson’s disease (PD) in the early phase of the disease and up to 80% of them will eventually develop dementia. Many studies suggests that these cognitive deficits are mediated by functional alterations in the dorsolateral prefrontal cortex (DLPFC), possibly in relation with the caudate nucleus. Previous results from our group showed an increase in activity and connectivity within the cognitive cortico-striatal loop when applying transcranial magnetic stimulation (TMS) using intermittent « theta burst »  (iTBS) parameters over left DLPFC. For this study, 24 idiopathic PD patients with cognitive impairment were recruited and divided into two groups : active iTBS group (N=15) and sham group (simulated stimulation, N=9). Detailed neuropsychological assessment of five cognitive domains (attention, executive functions, language, memory, visuospatial abilities) was performed on day 1, 8, 17 and 37. iTBS protocol over left DLPFC was performed on day 2, 4 and 7. Z scores were calculated for each domain and for the overall cognition performance.  Our results showed a significant increase in overall cognition up to 10 days after receiving active iTBS, improving mainly attention, executive functions and visuospatial abilities. This effect was not replicated in the sham group. Therefore, our results suggest that iTBS can modulate cognitive performance in PD patients with cognitive deficits.

Keyphrases: iTBS, Parkinson’s disease, Cognitive impairment, TMS
Corrélats neuronaux de la mémoire de travail en magnétoencéphalographie à l’état de repos

Purpose: There are few studies demonstrating the link between neural oscillations in magnetoencephalography (MEG) at rest and cognitive performance. Working memory is one of the most studied cognitive processes and is the ability to manipulate information on items kept in short-term memory. Heister & al. (2013) showed correlation patterns between brain oscillations at rest in MEG and performance in a working memory task (n-back). These authors showed that delta/theta activity in fronto-parietal areas is related to working memory performance. In this study, we use resting state MEG oscillations to validate these correlations with both of verbal (VWM) and spatial (SWM) working memory, and test their specificity in comparison with other cognitive abilities.  Methods: We recorded resting state MEG and used clinical neuropsychological tests to assess working memory performance in 18 volunteers (6 males and 12 females). The other neuropsychological tests of the WAIS-IV were used as control tests to assess the specificity of the correlation patterns with working memory. We calculated means of Power Spectrum Density for different frequency bands (delta, 1-4Hz; theta, 4-8Hz; alpha, 8-13Hz; beta, 13-30Hz; gamma1, 30-59Hz; gamma2, 61-90Hz; gamma3, 90-120Hz; large gamma, 30-120Hz) and correlated MEG power normalised for the maximum in each frequency band at the sensor level with working memory performance. We then grouped the sensors showing a significant correlation by using a cluster algorithm. Results: We found positive correlations between both types of working memory performance and clusters in the bilateral posterior and right fronto-temporal regions for the delta band (r2 =0.73), in the fronto-middle line and right temporal regions for the theta band (r2 =0.63) as well as in the parietal regions for the alpha band (r2 =0.78). Verbal working memory and spatial working memory share a common fronto-parietal cluster of sensors but also show specific clusters. These clusters are specific to working memory, as compared to those obtained for other cognitive abilities and right posterior parietal areas, specially in slow frequencies, appear to be specific to working memory process. Conclusions: Slow frequencies (1-13Hz) but more precisely in delta/theta bands (1-8Hz), recorded at rest with magnetoencephalography, predict working memory performance and support the role of a fronto-parietal network in working memory.

Keyphrases: MEG, Working memory, Resting state, MEG
Modifications post-traductionnelles des canaux calciques cardiaques de type L : identification des résidus asparagine qui participent à la glycosylation de la sous-unité auxiliaire CaVα2δ1

L-type CaV1.2 channels play a key role in the excitation-contraction coupling in the heart. They are formed of a pore-forming CaVα1 subunit in complex with the intracellular CaVβ and the disulfur-linked CaVα2δ accessory subunits. CaVα2δ significantly increases peak current densities of CaV1.2. The mechanism underlying this effect is still under study but requires that CaVα2δ be trafficked at the cell surface. CaVα2δ contains 16 putative N-glycosylation sites. A study was carried out to identify the role of N-glycosylation in the trafficking and protein stability of the subunit CaVα2δ. Herein we show that enzymatic removal of N-glycans produced a 50 kDa shift in the mobility of cardiac and recombinant CaVα2δ1 proteins. Simultaneous mutation of the 16 Asn sites was required to fully account for this change in protein mobility. Nonetheless, the mutation of only 6/16 sites was sufficient to 1) significantly reduce the steady-state cell surface fluorescence of CaVα2δ1 as characterized by two-color flow cytometry assays and confocal imaging; 2) accelerate the degradation kinetics estimated from cycloheximide chase assays; and 3) prevent the CaVα2δ1-mediated increase in peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational 6 Asn mutant functionally rescued CaVα2δ1. Single mutation N663Q and double mutations N348Q/ N468Q, N348Q/ N812Q, N468Q/N812Q decreased protein stability/synthesis and abolished steady-state cell surface density as well as upregulation of L-type currents. These results demonstrate that Asn663, and to a lesser extent Asn348, Asn468, and Asn812 contribute to the stability of CaVα2δ1 function and furthermore that N- glycosylation of CaVα2δ1 is essential to produce functional L-type Ca2+ channels.

Keyphrases: Expression recombinante, «Gating», Calcium channels, Cell surface density, Gating, Recombinant expression, Electrophysiology, Flow cytometry, Confocal imaging
Biopacemaker acceleration without increased synchronization by chronic exposure to phorbol myristate acetate

The normal heartbeat is initiated by the spontaneous generation of action potentials in pacemaker cells of the sinoatrial node (SAN) region. Dysfunction of this region leads to electrical instability of the heart. The majority of the patients with sinus node dysfunction require surgical implantation of electronic pacemaker devices; however, limitations of this therapeutic approach lead to a need to search for alternatives. To date, the molecular basis of the ionic currents which play pivotal role in SAN action potential has been discovered. It is thought that an important component of the pacemaker cells are HCN channels, responsible for the funny current (If) in the SAN. Meanwhile, T-box factor 3 known as an evolutionary conserved transcription factors is necessary for development of the conduction system. In previous studies, it has been shown that Phorbol 12-myristate 13-acetate (PMA) activates Tbx3 gene expression in a PKC-dependent manner in several cell lines. The main objective of this study is to test if PMA can increase the frequency and synchronization of spontaneous activity of cultured biopacemakers. More precisely, we studied the effects of chronic exposure to PMA on the expression of the Tbx3 transcription factor and HCN4 in neonatal rat ventricular myocytes monolayers and how spontaneous activity was altered. Our results show that PMA significantly increases the Tbx3 transcription factor and HCN4 mRNA expression favoring an increased in the rate and spatial-temporal stability of the spontaneous activity. In addition, a significant decrease in conduction velocity was found that is attributed to decrease electrical intercellular coupling of the cells. The decrease in the conduction velocity could explain the negative effect PMA has on synchronization of spontaneous activity of the biopacemaker. These findings are confirmed by a multicellular mathematical model implying that faster frequency and higher intercellular resistance of the pacemaker cells may lead to a more stable and less synchronous activity. This study provides important new knowledge to produce efficient and robust biological pacemakers.

Keyphrases: Biopacemaker, Spontaneous activity, Synchronization, Spatial-temporal stability
Développement et utilisation de modèles in vitro et de données précliniques pour augmenter la prédictibilité de la perméabilité et du métabolisme intestinal chez l'humain

To reach the systemic circulation, orally administered drugs have to be absorbed and not metabolized by the intestine and the liver. Even though it has a major impact on the first pass effect of many xenobiotics, the intestinal metabolism is often neglect compare to the hepatic metabolism. The objective of this work is to use, characterize and develop multiple in vitro and in vivo tools to better understand and predict the impact of intestinal metabolism on the first pass effect of xenobiotics compared to the liver. To do so, multiple substrates of metabolic enzymes were incubated in intestinal and hepatic microsomes and differences between the rate of metabolism and the production of metabolites were demonstrated. To better understand the impact of these differences in vivo, mechanistic studies were undergone in rats cannulated or treated with enzymatic inhibitors with the substrate metoprolol. These studies demonstrated the impact of intestinal metabolism on the first pass of metoprolol. Moreover, they exposed the effect on gastric emptying of 1-aminobenzotriazole, a cytochrome p450 inhibitor, avoiding its wrong utilisation in future studies. This work helped increase the knowledge about the different in vitro and in vivo tools to study intestinal metabolism and to better understand the differences between the role of the intestine and the liver on the first pass effect.

Keyphrases: cytochrome p450, 1-aminobenzotriazole, Intestinal metabolism, pharmacokinetics, metoprolol, first pass effect
Investigating the thymopoiesis stimulating property of interleukin-21 in aging mice

Vaccines have been largely sought for the generation of protective tumor-specific T cells. Unfortunately however, this strategy is not suitable for the elderly as their thymus regresses with age leading to a decline in T-cell production and accumulation of aged lymphocytes endowed with stimulation-related defects. Interleukin (IL)-21 has been shown to display thymostimulatory properties. Therefore, we hypothesized that IL-21 administration to ageing host may boost T-cell production and restore a competent peripheral T-cell compartment. Our study shows that IL-21 injection to aged mice lead to an increase in the thymocytes absolute number and an increase in thymocytes egress to the periphery where they enhance the T-cell receptor (TCR) diversity. Furthermore T-cell in the periphery express higher level of miR-181a and thus less TCR-inhibiting phosphatases SHP-2 and DUSP5/6 enable them to be more responsive upon stimulation. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly.

Keyphrases: Interleukine-21, miR-181a, Vaccin, Thymic Involution, Interleukin-21, T cells, Signaling, miR-181a, Tumor Vaccine
Étude sur le rôle de SIGIRR chez les cas pédiatriques dans la maladie de Crohn

It is recognized that the Crohn's disease (CD) is the result of immunological, genetic and environmental factors. SIGIRR, an anti-inflammatory receptor, has never been studied in the context of the CD, and many discoveries about it led many to focus on its usefulness in mitigating inflammatory disease. Moreover, IL-37 has been recently identified as a ligand of SIGIRR-IL-18Rα complex. Thus, we supposed that SIGIRR and IL-37 might be inflammatory actors deregulated in CD. We have studied them in the context of pediatric CD, in order to characterize their effects. We have identified a decrease in the expression of SIGIRR on certain types of immune cells. In addition, our results showed that CD patients possess an altered protein expression of soluble SIGIRR, IL-37, IL-18BP and IL-18 which tends to return to normal when the inflammation is controlled by medication. In addition, the concentration of free IL-18 follows the same pattern. By linear regression analysis of soluble SIGIRR and IL-37, IL-18BP and IL-18 and IL-37 and IL-18, diverging trends were found between patients non-treated and controls or patients treated. Our results suggest that IL-37-SIGIRR system is compromised in patients with CD. Since this system is a crucial factor in the negative regulation of inflammation, it will be interesting to determine whether SIGIRR and IL-37 may be important therapeutic targets in the attenuation and resolution of inflammation in patients with CD.

Keyphrases: Sigirr, Interleukine-37, Interleukine-18, Interleukine-18BP, IL-18Rα, Sigirr, Soluble sigirr, Pediatric Crohn's disease, Interleukin-37, Interleukin-18, Interleukin-18BP, IL-18Rα
Développement d’un nouveau modèle murin expérimental de sclérodermie

Systemic sclerosis (SSc) is a rare disease of unknown etiology that affects people that have a genetic predisposition to autoimmunity. Despite the latest advancement and development in the field, the mechanisms underlying disease development remain poorly understood. The lack of animal model that encompasses the cardinal features of human systemic sclerosis is a major cause of the slowdown in the understanding of this disease. In fact, some mouse models such as the bleomycin induced-SSc and TSK-1 mouse are widely used in preclinical studies of scleroderma. However, these models have several shortcomings since these mice do not display all the cardinal features of the disease found in humans. To contribute to the research of SSc, postdoctoral fellow  Dre Heena Mehta has developed in Dre Sarfati’s laboratory in collaboration with Dr Senécal, an experimental murine model of SSc induced by dendritic cells loaded with topoisomerase I peptide. In order to characterise the model and establish an immune profile of our experimental mice, my analysis focused mainly on the cardinal features of scleroderma such as fibrosis, inflammation and polyclonal hyper-γ-globulinemia, vasculopathy and cytokines gene expression. Hence, immunization with dendritic cells loaded topoisomerase I peptides (TOPOIA and TOPOIB) induced pulmonary and dermal inflammation together with diffuse form of fibrosis. The mice also showed symptoms of vasculopathy and high levels of polyclonal antibodies. These results showed that TOPOIA peptides are effective in inducing fibrosis and inflammatory response while TOPOIB peptides are involved in skin fibrosis. Together with the results, the preliminary data on cytokine profile in tissue suggested that our mouse model could possibly replace/complement other current animal models of scleroderma.

Keyphrases: Fribrose, Maladie auto-immune, Inflammation, Systemic sclerosis, Scleroderma, Dendritic cells, Topoisomerase I, Experimental murine model, Fibrosis, Autoimmune disease, Vasculopathy
Étude de la migration des populations de lymphocytes B du sang de patients infectés
par le virus d’immunodéficience humaine (VIH)

Deregulation of the B-cell compartment is an important consequence of human immunodeficiency virus (HIV-1) infection. We observe a decrease in blood B lymphocyte numbers accompanied by variations in the relative frequency of B cell populations in infected individuals when compared to healthy controls. Our lab has previously exposed the implication of dendritic cells in B-cell deregulation via excessive production of B lymphocyte stimulator (BLyS/BAFF). Additionally, the study of BLYS/BAFF-transgenic mice as well as mice exhibiting an AIDS-like disease revealed an expansion of the marginal zone (MZ) of the spleen. Interestingly, we found reduced relative frequencies of mature MZ-like B cells in the blood of elite controllers while rapid and classic HIV progressors had increased ‘precursor’ MZ-like cells. This variation in elite controllers is the only one observed for all population analyzed and could be the reflection of active recruitment of these cells to the periphery to help control infection. To try and understand these variations in B-cell frequencies we have analyzed the Btropic chemotaxis axes CXCL13-CXCR5, CXCL12-CXCR4/CXCR7, CCL20-CCR6 and CCL24-CCR9. The longitudinal study of patients with varying degrees of disease progression and control shows a modulation of the levels of most chemokines in the blood of rapid and classic progessors. Meanwhile, elite controllers maintain normal levels of these chemokines, demonstrating their ability to preserve homeostasis. Our results suggest that the type of disease progression impacts B-cell migration, resulting in modified B-cell population frequencies. The decrease in mature MZ-like B-cells and the increased frequency of cells expressing CXCR7, a receptor associated to the MZ in mice, in elite controllers suggest an important role for the MZ in controlling HIV-1 infection. Overall, our results provide more information about the B-cell compartment in the context of HIV-1 infection and can contribute to the elaboration of preventive and therapeutic strategies for HIV-1.

Keyphrases: migration, progression clinique, B lymphocytes, Human Immunodeficiency Virus, HIV, chemotaxis, chemokine, migration, clinical progression, marginal zone, longitudinal analysis
Étude du rôle des régions variables 4 et 5 dans les changements de conformation de la gp120 du VIH-1

HIV infects cells by fusing its membrane with the membrane of the target cell. This fusion is performed by the envelope glycoproteins (Env) which are synthesized as a precursor, gp160, which is later cleaved into gp120 and gp41. The transmembrane protein gp41 anchors the envelope complex to the viral particle whereas the gp120 ensures the binding to the cell receptor CD4 and coreceptor CCR5 or CXCR4. These sequential interactions trigger conformational changes on Env that fuel the viral entry process ultimately leading to the insertion of the gp41-derived-fusion peptide into the target cell membrane. The exterior subunit gp120 contains five variable regions (V1 to V5), of which three (V1, V2 and V3) have been shown to restrain the spontaneous sampling of the CD4-bound conformation by gp120. However, the role of variable regions V4 and V5 in these conformational changes remains unknown. To investigate their effect, mutants of the clade B YU2 primary isolate, comprising a deletion of the V5 or mutating all V4 potential N-linked glycosylation sites (PNGS), have been generated. The effect of mutations on the conformation of the envelope glycoproteins was analyzed by immunoprecipitation with conformation-dependent antibodies and surface plasmon resonance. Neither the removal of the V4 PNGS nor the removal of V5 affected Env conformational changes as measured by these techniques. Thus, suggesting that variable regions V1, V2 and V3 are the major players in preventing Env from spontaneously snapping into the CD4-bound conformation.

Keyphrases: Gp120, V4, V5, Hiv, Variable regions, Conformational changes
Optimisation du promoteur CR5 inductible au cumate

Biologics are a very promising therapeutic avenue for the treatment of incurable diseases such as cancer. The market’s demand for these products is very high, so reliable and efficient industrial bioprocesses must be set up in order to answer it. The cumate gene switch (CR5) developed by Bernard Massie’s group allows high and fine-tuned expression of proteins of interest in CHO cells. Optimisation of this system is however a necessary work to maximise the expression and improve the leakiness of the system. For this purpose, promoters with different spacing configurations, transactivators with different activation domains, and a synthetic operator sequence have been assayed to evaluate their ability to drive high protein expression while improving the leakiness of the CR5 system. Thus, a promoter containing three operator sequences with a six base pairs spacing between them has been found to be the most efficient configuration in terms of yield and leakiness in comparison to the current CR5 configuration. Also, a new configuration of the CR5 where the transactivator is regulated by the coumermycin gene regulation system has been studied, showing very tight regulation ability. This optimisation work can only be applied to our specific experimental conditions and its application to other cell lines and promoters needs to be demonstrated.

Keyphrases: cumate, CR5, optimisation, coumermycin, inducible systems, CHO cells