NCube/papyrus huggingface dataset:
Altération du couplage neurovasculaire par l'angiotensine II : évaluation du rôle de la signalisation calcique astrocytaire

Neurovascular coupling (NVC) is an important homeostasis mechanism that regulates cerebral blood flow (CBF) according to neuronal activity. It however remains poorly understood how it is impaired by angiotensin II (Ang II), a hormone synthesized and released in the systemic circulation or produced in the brain partly by astrocytes. Astrocytes possess Ang II AT1 receptors and are involved in the orchestration of NVC by releasing vasoactive agents following their calcium response. We thus sought to investigate the involvement of astrocytic calcium in the impairment of NVC induced by Ang II. Using laser Doppler flowmetry, we found that Ang II attenuates C57BL/6 mice CBF response to activation of group I metabotropic glutamate receptors (mGluRI) by 32 % (p<0.05) in the somatosensory cortex. Similarly, Ang II decreased CBF elevations induced by whisker stimulation (-40 %, p<0.05). On acute brain slices, the polarity of the vascular response induced by a mGluRI agonist in parenchymal arteries was significantly shifted by Ang II toward vasoconstriction. In parallel, Ang II increased resting and maximal astrocytic calcium levels to respectively 192 % and 318 % of control levels (p<0.05). Both vascular and maximal calcium responses alterations induced by Ang II were prevented by the AT1 receptor antagonist candesartan. Our results suggest that Ang II via its AT1 receptor potentiates the astrocytic calcium responses to a level that favors vasoconstriction over vasodilation, thus altering CBF increases in response to neuronal activity.

Keyphrases: Astrocyte, Calcium, Angiotensin II, AT1 receptor, Metabotropic glutamate receptor, Neurovascular coupling
Les cytokines inflammatoires modulent la prolifération et la différenciation in vitro des cellules souches/progénitrices de la moelle épinière

The spinal cord is essential to link motor and sensory information between the brain and its periphery. However, it can be easily damaged following a traumatic injury or hit by pathology such as multiple sclerosis. In lower vertebrates, such as amphibians, the spinal cord has the ability to regenerate its endogenous stem cells, contrary to mammals that have a very limited capacity of post-traumatic regeneration. Recent works have shown that mammalian spinal cord contains quiescent neural stem corresponding to the ependymal cells localized in the central canal. Following spinal cord injury, ependymal stem cells proliferate, migrate towards the injury site and mainly differentiate into glial cells. Promoting spinal cord regeneration through modulation of its endogenous stem cells can be an interesting therapeutic solution. Isolating the spinal cord stem/progenitor cells through neurosphere culture in presence of inflammatory cytokines and conditioned macrophages media, our in vitro studies suggest that neuro-inflammatory response modulate proliferation and differentiation of spinal cord stem/progenitor cells. In order to define the genetic program related to ependymal stem cell activation, we have started the establishment of an experimental protocol for ependymal stem cell isolation with a transgenic mouse model.

Keyphrases: Neuro-inflammation, Cytokines, Spinal Cord, Spinal cord injury, Ependymal cells, Neural stem cell, Neurosphere, Neuroinflammation, Fluorescent activated cell sorting
Caractérisation et régulation du métabolisme des acides gras dans l’hypothalamus

An imbalance of energy balance is the main cause of the development of metabolic diseases such as obesity and type 2 diabetes. Within the brain, the hypothalamus plays an important role in the control of food intake and peripheral metabolism, via the autonomic nervous system. This control relies on the existence of different neuronal populations in the medio-basal hypothalamus (MBH), including neuropeptide Y (NPY), agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons, the activity of which, is directly modulated by changes in the circulating levels of nutrients such as glucose and fatty acids (FA). While mechanisms governing the detection and the intracellular metabolism of glucose have been extensively studied, the involvement of FA intracellular metabolism, in their central effects is poorly understood. It is currently unknown if glucose regulates long chain fatty acids (LCFA) metabolism in the MBH.  The aim of our first study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), a sensor of cellular energy status, and to establish if changes in LCFA metabolism, and its regulation by glucose, vary as a function of LCFA type, cell type and brain region.  We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures and MBH slices, ex vivo, but not in cortical astrocytes and slice preparations. In addition, our results show that glucose increases palmitate but not oleate esterification into neutral lipids, in neurons and MBH slices, but not in hypothalamic astrocytes.  These findings reveal the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons and established for the first time the metabolic coupling of glucose and LCFA as a specific feature of the MBH, whose role is critical for the control of energy balance. During the second part of this thesis, we were interested to determine the intracellular mechanisms involved in the role of Acyl-CoA binding protein (ACBP), in the central metabolism of FA. We have shown that the metabolism of oleate but not palmitate is ACBP -dependent in hypothalamic astrocytes and MBH slices. Thus, our results demonstrate That ACBP, a protein originally identified as an allosteric modulator of GABA receptor peptide, acts as a regulator of intracellular metabolism of FA. These results open a new avenues of research related to the central regulation of fatty acid metabolism and the new function of ACBP protein in the regulation of FA metabolism in the central nervous system, which could help to identify molecular targets that may contribute to the development of new therapeutic approaches of diseases such as obesity and type 2 diabetes.

Keyphrases: Hypothalamus, Astrocytes, Glucose, Palmitate, AMPK, ACBP, Neural metabolism, Oleate
Impact du sexe et du profil génétique sur la sécrétion d’insuline dans une cohorte de patients atteints de fibrose kystique

Introduction: Cystic Fibrosis (CF) is the most common autosomal recessive disease among Caucasians and is caused by a mutation in the gene encoding for a chloride channel, the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. The main change is the deletion of the phenylalanine amino acid at position 508. Due to increasing life expectancy, new complications such as CF related diabetes (CFRD) have emerged. CFRD seems mainly due to a defect in insulin secretion. Studies have shown that women and people with homozygous ΔF508 have a higher risk of developing CFRD. Objectives: To compare insulin secretion between men and women according to their CFTR genotype. Our hypothesis was that, in CF, women had a lower insulin secretion than men. Methods: Two hundred adult subjects without known diabetes were recruited from the CF clinic at the CHUM and included in this study. One hundred and sixteen were reviewed after a follow-up of 24 ± 10 months. Their CFTR genotype was extracted from medical records. All subjects underwent a 2-h oral glucose tolerance test (OGTT) to determine their glucose tolerance: normal (NGT), intolerance (IGT) or CFRD. Blood samples were collected at 0, 30, 60, 90, and 120 min of the OGTT. Insulin secretion and insulin sensitivity were evaluated using the Stumvoll indices and the area under the curve (AUC) of insulin during the OGTT. Results: For a similar glycemic excursion, there were significant gender differences in insulin concentrations and according to the CFTR genotype. Thus, women and heterozygous subjects had insulin concentrations higher than men and homozygous. This remained significant regardless of their glucose tolerance. The calculation of the disposition index, representing insulin secretion adjusted for the degree of insulin sensitivity, suggested a higher insulin secretion in women than in men. Prospective follow-up showed that higher insulin secretion was associated with more favorable evolution of glucose tolerance. Interestingly, this finding was only applicable for women. Conclusion: In a large prospective observational cohort of CF patients without known diabetes, we demonstrated that, despite similar age and pulmonary function, women had a higher insulin secretion than men and that this could have a protective effect for the development of CFRD.

Keyphrases: Cystic Fibrosis, Diabetes, Insulin, Secretion
Evaluation des liens entre l’indice de la qualité alimentaire globale C-HEI, des paramètres nutritionnels et anthropométriques et des indicateurs de santé dans la cohorte «NuAge»

Introduction: Several diet quality indicators have been developed based on nutrient intakes, foods or food groupings, or a combination of nutrient and foods. Measures of overall diet quality consider numerous aspects of dietary intake. It is within this framework that the Canadian Healthy Eating Index (C-HEI) was adapted to Canadian dietary and nutritional guidance using Canada’s Food Guide and Nutrition recommendations for Canadians. Objectives: To determine the links between the C-HEI using the mean of three 24-hour diet recalls, and certain health outcomes at entry into the study (T1). The analyses were carried out using data collected from participants in the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). Methodology: Bivariate analyses (Spearman correlation, cross-tabulation and chi-square) were carried out to assess relationships between nutritional and anthropometric variables, the number of chronic disease and the C-HEI. Results and Discussion: Participants met or exceeded most Dietary Reference Intakes (DRI). The C-HEI did not show consistent relationships with individual nutrients (rs= 0.14-0.52, p<0.01). However, selected sub-scores of the C-HEI reflect attainment of Canada’s Food Guide recommendations, showing a strong association with dietary fiber intakes (rs= 0.51) and nutrition recommendations addressing percent energy as fat (rs=-0.60) and as saturated fat (rs= -0.59), p<0.01. Energy and protein adequacy increased from Q1 to Q 4 of C-HEI (p<0.05). In addition, proportions of subjects with anthropometric measures associated with a health risk decreased from quartiles Q1 to Q4 (p<0.05), attesting to links between good diet quality and lower health risks associated with overweight and obesity. Conclusion: The C-HEI discriminates overall diet quality based on dietary data collected from 24HR, providing further evidence on the links between the C-HEI and selected nutritional and anthropometric parameters as applied to quantitative dietary data obtained from community-dwelling older adults.

Keyphrases: C-HEI, Diet quality index, 24 hour recall, elderly
Impact de l’indice glycémique sur la performance physique de cyclistes de haut niveau

Many studies have shown that the consumption of a low glycemic index (LGI) meal before exercise promotes lipid oxidation, thus lowering the amount of hypoglycemic occurrence and improving physical performance. However, other studies have not observed such benefits. The objective of this study is to demonstrate the impact of ingesting various glycemic index (GI) breakfasts on the endurance performance of high-level cyclists. Ten men completed three randomly allocated protocols, and each was separated by a time interval of a minimum of seven days. Each protocol was composed of a time trial, where a measure was taken three hours either after consuming a breakfast of low or high glycemic index containing three grams of glucose per kg of body weight, or after completing exercise while fasting. The race time results demonstrated that there were no significant differences between the protocols. However, the number of revolutions per minutes (RPM) was significantly higher with the high glycemic index level protocol (94,3 ± 9,9) in comparison to the fasting protocol (87,7 ± 8,9) (p<0,005). Furthermore, the capillary glycemic profile showed that, during exercise at 30 minutes, blood glucose level was significantly higher in the fasting protocol (5,47 ± 0,76 mmol/L) in comparison to the high glycemic index (HGI) protocol (4,99 ± 0,91 mmol/L) (p<0,002).  Our study did not confirm that the consumption of a LGI meal before physical exercise significantly improves physical performance. Yet it demonstrated that the diversity of protocols used to evaluate the impact of glycemic index on physical performance could generate positive impact during the race time. Therefore, there is a need to conduct further research that can reproduce athletic competition situations, such as time trials.

Keyphrases: endurance, glycemic index, endurance, carbohydrate
Immunopathogenèse de la cryptococcose chez la souris transgénique exprimant le génome du VIH-1

The most common cause of cryptococcosis in HIV-1-infected patients is Cryptococcus neoformans var. grubii, while Cryptococcus gattii usually infects immunocompetent people.  We used a novel inhalation model of cryptococcosis in CD4C/HIVMutA transgenic mice expressing nef, env, and rev of HIV-1 to examine the mechanisms that cause differential susceptibility to these species of Cryptococcus in the context of HIV-1 infection.  HIV-1 transgene expression increased alveolar macrophage but decreased pulmonary CD4+ and CD8+ T lymphocyte recruitment.  Pulmonary production of the CC chemokines MCP-1 (CCL2) and RANTES (CCL5) was reduced in transgenic mice infected with C. neoformans or C. gattii, and concentrations were lower after infection with C. gattii compared to C. neoformans.  Production of MIP-1α, MIP-1β, TNF-α, TGF-β, IL-2, IL-4 and IL-13 was increased in mice infected with C. neoformans compared to C. gattii. Production of MIP-1β by alveolar macrophages harvested from Tg mice was enhanced after agonist exposure in vitro, but production of the chemokines MCP-1 and RANTES was undetectable.

Keyphrases: Cryptococcus neoformans, Cryptococcus gattii, Cytokines, Cryptococcosis, HIV-1, Transgenic mice
Analyse des altérations de l'immunité T-dépendante à l'égard de Candida albicans chez la souris transgénique exprimant le génome du VIH-1

Oropharyngeal candidiasis (OPC) is the most common opportunistic fungal infection in HIV-infected individuals. OPC resolution involves Il-17 and Il-22 production by Th17 cells through oral antifungal peptide production and polymorphonuclear neutrophil recruitment. Conversely, Th17 cells are preferentially depleted in HIV-infected individuals. The OPC model in transgenic (Tg) mice expressing nef, env and rev from the HIV-1 genome enables the study of the quantitative and functional defects of the CD4+ T-cell subpopulations. The Th1, Th2, Th1Th17, Th17 and Treg subpopulations, as well as naïve CD4+ T-cell precursors, are severely depleted in the cervical lymph nodes (CLNs) of Tg mice. However, the differentiation capacity of naïve CD4+ T-cells in response to polarizing cytokines was maintained in vitro in Tg mice, as well as their ability to produce the signature cytokines of the various subpopulations. Moreover, the polarizing cytokines were not reduced in the CLNs of Tg mice, 7 days after infection. The S100a8, Ccl20, Il17 and Il22 genes were up-regulated in response to OPC in non-Tg mice, but not in Tg mice. Treatment of infected Tg mice with a combination of Il-17 and Il-22 cytokines significantly reduced the oral fungal burdens of C. albicans as well as the number of hyphae in the tongue epithelium. Treatment also restored S100a8, Ccl20 and Il22 up-regulation in Tg mice. These results show that defective induction of innate immunity, normally mediated by Il-17 and Il-22, increases the susceptibility to OPC in these Tg mice.

Keyphrases: Cytokine, Il-17, Il-22, Th17, Animal model, HIV-1, Oropharyngeal candidiasis, Regulatory T-cell
La protéine accessoire Vpu du VIH-1 inhibe l'activité antivirale des pDCs à travers un processus ILT7-dépendant

Viral protein U (Vpu) is an accessory protein of HIV‐1 that efficiently targets BST2/Tetherin, a cellular restriction factor that acts as molecular anchor impeding the release of various enveloped viruses from the cell surface. The recently discovered natural receptor of BST2 is ILT7, a molecule exclusively expressed at the surface of the professional type 1 interferon (IFN‐1) producing cells, plasmacytoid dendritic cells (pDCs). The interaction between BST2 and ILT7 has been reported to efficiently induce a repression of IFN­‐1 secretion by pDCs. Here, we investigated the impact of Vpu mediated antagonism of BST2, in regards to this newly described immune function of BST2. Using a system of CD4+ T cell lines infected with wild type or Vpu‐deficient HIV-­1 cultured with peripheral blood mononuclear cells or purified pDCs, we report that the presence of Vpu efficiently reduces IFN-­1 production from sensing pDCs. Furthermore, we observed that this Vpu effect is dependent on the availability of BST2 molecules at the surface of the infected cells, since the Vpu's immunoregulation is abrogated when blocking any potential BST2 trans interaction with anti­‐BST2 antibodies. Similarly, depleting ILT7 from pDCs by means of small interfering RNA treatment equally negates the downregulation of pDC IFN-­1 secretion by Vpu. Finally, the use of recombinant soluble ILT7 competes with pDC‐bound ILT7 for the free BST2 and similarly results in high IFN-­1 production, causing an identical phenotype. Overall, our results demonstrate that Vpu heightens ILT7 activation and subsequent repression of IFN‐1 production by pDCs in response to HIV­‐1 infected CD4+ T cells by promoting it's trans interaction with infected T cell bound BST2, through a yet uncharacterized mechanism. By allowing efficient particle release and restraining pDCs antiviral functions, Vpu exerts a double role on BST2 that seems crucial for the replication and dissemination of HIV‐1.

Keyphrases: Virus, Vpu, BST2, ILT7, IFN-1, pDCs, HIV-1, Accessory proteins, TLR, Restriction factors
Étude du goulot d’étranglement dans la transmission mère-enfant du virus de l’hépatite C

Mother-to-child transmission (MTCT) of hepatitis C virus (HCV) represents the first cause of infection in children of developed countries. MTCT of HCV may take place in <10% when the mother is solely infected with HCV. However, maternal coinfection with type 1 human immunodeficiency virus (HIV-1) leads to a drastic increase of this rate. Besides, there is no mean of prevention of MTCT of HCV. HCV replication leads to a prominent variability due to the absence of correction mechanism of its RNA-dependent RNA polymerase. Consequently, it is retrieved in its host as a swarm of genetically closely related but different variants named quasispecies. When HCV transmission occurs between adults, only a very limited number of variants are responsible for the infection. This phenomenon is called a genetic bottleneck and whether it exists during MTCT of HCV is to confirm. Based on the detection by RT-PCR of HCV’s RNA at birth, MTCT is believed to take place both in utero and peripartum. Nevertheless, such dynamics of MTCT of HCV have never been demonstrated directly. Here we report, using next generation sequencing, a longitudinal analysis of MTCT of HCV in 5 mother-child pairs, in 3 cases the mother was also infected with HIV-1. Identity analysis based on nucleotide sequence of the glycoprotein E2 hypervariable regions 1-2 (positions 1491-1787 of the isolate H77) reveals that a tight genetic bottleneck exists during MTCT of HCV (n= 1-4 variants transmitted) when the mother is only infected with HCV. However, in the case of maternal coinfection with HIV-1, this number is radically increased (n = 111-118). Also, the detection of variants shared between mother and child that are only present at the 2nd trimester of pregnancy in the mother but not found after suggest that MTCT of HCV can take place as early as the 2nd trimester of gestation. Lastly, we show that the dynamics of the establishment of the infection in the young child involve a transitional increase of the viremia concomitant with reduced diversity of HCV quasispecies. Together, these results show the first direct evidence of a genetic bottleneck occurring during MTCT of HCV. This bottleneck appears to be much less constricted when the mother is coinfected with HIV-1 and HCV. It appears possible that the MTCT can take place as early as the second trimester of pregnancy and that a limited number of variants may be responsible for the essential of the viral production during early childhood.

Keyphrases: Hepatitis C virus, Transmission bottleneck, Pyrosequencing, Vertical transmission, Mother to child transmission
Suivi des vaisseaux sanguins en temps réel à partir d’images ultrasonores mode-B et reconstruction 3D : application à la caractérisation des sténoses artérielles

Locating and quantifying stenosis length and severity are essential for planning adequate treatment of peripheral arterial disease (PAD). To do this, clinicians use imaging methods such as ultrasound (US), Magnetic Resonance Angiography (MRA) and Computed Tomography Angiography (CTA). However, US examination cannot provide maps of entire lower limb arteries in 3D, MRA is expensive and invasive, CTA is ionizing and also invasive. We propose a new 3D-US robotic system with B-mode images, which is non-ionizing, non-invasive, and is able to track and reconstruct in 3D the superficial femoral artery from the iliac down to the popliteal artery, in real time.  In vitro, 3D-US reconstruction was evaluated for simple and complex geometries phantoms in comparison with their computer-aided-design (CAD) file in terms of lengths, cross sectional areas and stenosis severity. In addition, for the phantom with a complex geometry, an evaluation was realized using Hausdorff distance, cross-sectional area and stenosis severity in comparison with 3D reconstruction with CTA. A mean Hausdorff distance of 0.97± 0.46 mm was found for 3D-US compared to 3D-CTA vessel representations. In vitro investigation to evaluate stenosis severity when compared with the original phantom CAD file showed that 3D-US reconstruction, with 3%-6% error, is better than 3D-CTA reconstruction, with 4-13% error. The in vivo system’s feasibility to reconstruct a normal femoral artery segment of a volunteer was also investigated.  All of these promising results show that our ultrasound robotic system is able to track automatically the vessel and reconstruct it in 3D as well as CTA. Clinically, our system will allow firstly to the radiologist to have 3D images readily interpretable and secondly, to avoid radiation and contrast agent for patients.

Keyphrases: Medical robotics, Peripheral arterial disease, Phantoms, Vascular imaging, Freehand scanning, Stenosis