NCube/papyrus huggingface dataset:
Increasing Axonal Arborization Size of Dopamine Neurons to Produce a Better Mouse Model of Parkinson's Disease

In Parkinson’s disease (PD), dopaminergic neurons of the substantia nigra pars compacta (SNC) are one of the key subsets of neurons particularly vulnerable to degeneration. Research has only started to elucidate some of the potential causes of this selective vulnerability, but the exceptionally large and complex axonal arborization of these neurons appears to play an important role due to its impact of cellular bioenergetics and oxidative stress. Unfortunately, genetic mouse models of PD have until now not been able to replicate the spontaneous loss over time of SNC dopaminergic (DA) neurons. This could be due in part to the fact that DA neurons in mice do not have an axonal arborization as developed as that of DA neurons in the human brain. We hypothesized that manipulations which increase axonal arborization size in SNC dopamine neurons in mice will increase their vulnerability to cellular stress, resulting in a greater risk of cell death. Our objective was to force SNC neurons to develop a larger than normal axonal arborization, thereby increasing their energy expenditures and vulnerability. An approximate 60% lesion of dopaminergic neurons was induced in the SNC through unilateral injection of 6-hydroxydopamine (6-OHDA) in male and female neonatal mice. Axonal arborization size was quantified at P90 using a conditional AAV-EYFP virus and confocal microscopy. In the second phase of the project, we examined the vulnerability of SNC DA at P135 neurons to subsequent viral overexpression of alpha-synuclein. Our results show that a partial lesion of SNc dopamine neurons in neonatal mice induced an approximate 2-fold increase in compensatory sprouting of surviving neurons and, by consequence, greatly increased the density of their axonal projections to the striatum. This compensatory process increased the vulnerability of the surviving SNC DA neurons to alpha-synuclein toxicity by nearly 3-fold. These findings are compatible with our initial hypothesis and suggest that producing mice that have DA neurons with larger axonal arborizations may facilitate the development of better mouse models of  PD.

Keyphrases: Dopamine, 6-hydroxydopamine, Parkinson’s disease, Dopamine, Animal Model, Neonatal, 6-hydroxydopamine, Axonal arborization, Compensatory Sprouting, Vulnerability, Substantia Nigra, Ventral tegmental area
Identification of the peripheral niche controlling CD4 homeostatic proliferation

Hematopoietic stem cell transplantation represents the best therapeutic option for patients with aggressive leukemia. Unfortunately, side effects are numerous and lymphocytes regeneration can take several months or years to occur. During this period of profound lymphopenia, patients are at higher risk of developing infectious complications or relapse from their disease. Lymphocyte regeneration can occur via thymopoiesis which recapitulates T cell production as it occurs early in life or via homeostatic proliferation (HP) of mature T cells in the graft. However, in most clinical settings of human lymphopenia, thymopoiesis is dysfunctional and T cell regeneration largely depends on HP. While HP is typically sufficient for CD8 regeneration, it is insufficient for restoring naïve CD4 counts. Access to IL-7 and major histocompatibility complex class II (MHCII) expressed by antigen presentation cells (APCs) are critical for HP of CD4+ T cells. This project aims to identify the APC subset(s) that control CD4 HP during lymphopenia. Adoptive transfer of T lymphocytes into lymphopenic mice with target APC subsets were utilized in this study. We were able to observe how CD11c+ dendritic cells (DCs) are critical components for HP of CD4+ T cells. Interestingly, the depletion of CD8a+DCs or plasmacytoid DCs (pDCs), or both subsets did not have a significant impact on CD4 proliferation. However, the depletion of CD8a+ DCs or pDCs influenced the CD4 numbers. The findings ultimately support a model where CD8a+ DCs and pDCs are not needed for HP but may affect CD4+ T cells survival during lymphopenia. Further research is needed in order to verify the potential role of CD11b+CD11c+ DCs in CD4 HP.

Keyphrases: CD4., Dendritic cells, Interleukin-7, Antigen presenting cells, Lymphocytes
Étude de l'implication neurologique et immunologique de la voie costimulatrice CD27/CD70 dans la sclérose en plaques

Introduction: Multiple Sclerosis (MS) is a chronic inflammatory disease where pathogenic autoreactive lymphocytes, can disrupt the blood-brain barrier (BBB) integrity and transmigrate into the central nervous system. The CD27/CD70 pathway provides costimulatory signals that regulates lymphocyte effector function. Data obtained previously in our lab show that CD70 expression is higher on lymphocytes of MS patients compared to healthy controls. Our hypothesis is that the CD27/CD70 pathway is central to the proinflammatory pathogenic phenotype and migration of T lymphocytes seen in MS. Method: CD27/CD70 implication in lymphocytic transmigration across the BBB was analyzed using human brain endothelial cells (BBB-EC), an in vitro model of the BBB. Migration assays assessed the capacity of TH1 and TH17-polarized or TGF-β-stimulated T cells to cross the BBB- EC. CD70 and CD27 expression on BBB-EC was examined by flow cytometry, western blot and qPCR. Immunohistofluorescence was performed on human MS brain sections to detect immune cells in the inflamed CNS that express CD27 and CD70. Results: CD70 expression on BBB-EC is upregulated in proinflammatory culturing conditions. CD70+ TH1 and TH17-polarized lymphocytes maintain their proinflammatory profile after their transmigration across the BBB. CD70+ and CD27+ immune cells are present in lesions in the brain of MS patients. Conclusion: The CD27/CD70 costimulatory pathway is involved in the inflammatory response in the context of MS.

Keyphrases: CD27, CD70, transmigration leucocytaire, multiple sclerosis, central nervous system, blood-brain barrier, leukocyte transmigration, autoimmune disease
Profil transcriptionnel de lymphocytes T CD4+ infectés par le VIH-1 de manière latente chez des individus sous trithérapie antirétrovirale

Infection with HIV remains a serious public health issue as there is currently no preventive vaccine available, and the current treatment does not offer definitive curative results. Although significant progress has been made in efficacy and accessibility of treatment, its interruption in HIV-infected individuals who have undetectable viral load almost invariably leads to viral rebound. HIV establishes latency in CD4+ T cells and primarily in “central”, “transitional” and “effector” memory CD4+ T cell subsets (TCM, TTM et TEM, respectively). When the antiretroviral pressure is interrupted, these cells will produce new infectious virions that will be the cause of this viral rebound. It is generally accepted that one of the important factors regulating HIV latency resides in the inhibition of elongation, polyadenylation, and multiple-splicing of viral transcripts. We report in this work the successful generation of a robust and sensitive RT-PCR technique coupled with the use of RNA standards. This technique enables the absolute quantification of different transcripts of HIV-1 in total and in memory subsets of T CD4+ lymphocytes to establish their transcriptional profile in latent HIV-1 infection. We have identified potential blocks in transcription of long, polyadenylated and multiply spliced transcrits. In the curative context of the “Shock and Kill” approach, this work has also measured the impact of different latency reversing agents on the reactivation of HIV-1 transcription by analysing the changes in the transcriptional profile of CD4+ T lymphocytes. We have concluded that the utilization of different families of latency reversing agents are more efficient in the induction of transcription when combined rather than when used alone.

Keyphrases: Transcription, Elongation, Agents anti-lantence, HIV-1, Latency, Reactivation, Transcriptional profile, Completion, Multiple-splicing, Latency reversing agents
Caractérisation des systèmes à deux composantes chez Salmonella enterica sérovar Typhi

Bacteria are equipped with a variety of mechanisms allowing them to sense and adapt to their environment, which include the two-component systems (TCS) that trigger an adaptive response that typically translates into differential expression of specific genes. A classic TCS comprises a sensor in the inner membrane and a regulator located in the cytoplasm. When a signal is perceived, the sensor autophosphorylates, and activates the regulator. Once activated, the regulator acts as a transcriptional factor by targeting specific genes in response to the signal. The regulator can induce or repress the transcription of multiple genes simultaneously in response to the signal. Salmonella enterica serovar Typhi is a human specific pathogen and is the etiologic agent of typhoid fever, for which 28 TCS were identified. The role associated with TCS allows us to hypothesize that TCS are important for the adaptation of S. Typhi to its environment and therefore participate in the crucial stages of infection of this pathogen.  In order to study the TCS of S. Typhi, the objectives are 1) to remove the regulators individually by a non-polar deletion using a method of mutagenesis by allelic exchange, 2) to test each of the mutants obtained in infection assays with human cells and 3) establish their phenotype, using phenotypic assays for motility, the morphotype and the production of biofilms. This study presents for the first time the characterization of all S. Typhi TCS and identifies a potential role for each of them in its pathogenesis.

Keyphrases: Salmonella Typhi, infection, TCS, sensor (SK), regulator (RR)
Contribution différentielle des variations du nombre de copies aux troubles du spectre autistique et aux traits cognitifs

Copy Number Variations (CNVs) represent highly studied genetic mutations in Autism Spectrum Disorders (ASD). We use in our study, 1 ASD cohort composed from 2591 individuals with ASD (N=2591) and their first degree related (N=7282) and 2 general population cohorts (imagen, sagueney) with a total N = 4072 individuals.  The level of intolerance to mutations of genes contained in CNVs allows us to model the effect of those CNVs on the risk of autism along with NVIQ impairment. We find, using this model, that CNVs are associated with a decrease of NVIQ which is 2 times more important for deletions than for duplications.  Even though large CNVs seems associated with a higher risk of autism, our study shows that deletions are associated more specifically with intellectual disability than specifically to ASD. Duplications in the other hand increase risk for ASD independently from NVIQ. Our observations are strengthened by the fact that we observe an excess of duplications and not deletions, in first degree related to ASD individuals compared to controls which suggest an aggregation of those CNVs in ASD families.

Keyphrases: NVIQ, Cognition, CNV, Autism, Genetic, Copy number variation
Corrélation entre la sévérité de la maladie et le profil granulocytaire en maladie de Crohn

Neutrophils infiltrate the inflamed colon in Crohn’s disease (CD). However, correlation between endoscopic severity, and frequency and/or activation of neutrophils and other granulocytes like basophils and eosinophils remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Patients with active disease were stratified according to Montreal classification or subdivided into typical CD and UC-like endoscopic features. Harvey Bradshaw Index (HBI) and Simple Endoscopic score (SES-CD) were performed at the time of ileocolonoscopy. Frequency and expression of CD66b and CD64 on granulocytes were assessed in paired blood and colonic biopsies using flow cytometry. SES-CD correlated with neutrophil CD66b expression in mucosa but not blood and conversely, with neutrophil CD64 expression in blood but not mucosa in CD patients with inflammatory (B1) active disease. Frequencies of neutrophils and basophils but not eosinophils, increased in inflamed colon, but only in a subgroup of CD patients presenting “UC-like” endoscopic features were the frequencies of colonic neutrophils correlated with SES-CD. Furthermore, a neutrophil activation score (CD66b X CD64 on neutrophils) and a blood granulocyte score (CD66b on eosinophils X CD64 on neutrophils) discriminated between mild and severe disease in the entire cohort of patients with active disease. Activation of granulocytes in blood and/or mucosa correlated with SES-CD in subgroups of patients with B1 inflammatory disease while granulocyte activation scoring systems may be clinically relevant to evaluate disease severity and predict prognosis in the entire cohort of active disease patients.

Keyphrases: granulocyte, SES-CD, CD64, CD66b, Crohn's disease, neutrophil
Caractérisation des fonctions de transport du cholestérol des sous-types de macrophages M1 et M2 issus de cellules THP-1

Atherosclerosis is now known as an inflammatory disease characterized by macrophage infiltration of the vascular wall. Different stimuli present in the plaque can polarize macrophages to pro- and anti-inflammatory subtypes. Even though it has been established that macrophages are implicated in plaque formation by becoming foam cells following cholesterol accumulation, information on cholesterol uptake and efflux of macrophage subtypes remains scarce. Our main objective was to determine if the mechanisms involved in cholesterol transport functions in macrophages differ between the pro- and anti-inflammatory subtypes. Accordingly, we polarized THP-1 cells to pro-inflammatory M1 subtypes by exposing them to 20 ng/ml interferon gamma (IFNγ), along with a low dose of lipopolysaccharides (LPS) (10 pg/ml, M1C) or a higher dose of LPS (1 μg/ml), to generate M1 subtypes with distinct inflammation levels. M2 subtype was polarized with 20 ng/ml of interleukin-4 (IL-4). We then compared mRNA and protein expression of cholesterol transport proteins, cholesterol efflux capacity, association of cholesteryl esters (CE) from lipoproteins and cholesterol accumulation susceptibility in each macrophages subtypes. M1C and M1A had higher mRNA and protein expression of ABCA1, but had reduced LDLr, CD36 and SR-BI mRNA and protein expression than M2 macrophages. M1C and M1A also show reduced cholesterol efflux to apo A-I compared to M2. M1C subtype had reduced cholesterol efflux to HDL compared with M1A and M2 subtypes. Moreover, M1C and M1A macrophages had lower CE-association from HDL, LDL and AcLDL compared to M2, matching reduced expression of SR-BI, LDLr and CD36 in M1C and M1A. All subtypes show similar cholesterol concentration following AcLDL incubation, which indicates that all subtypes accumulated cholesterol in a similar manner. These results suggest that M2 macrophages have higher cholesterol uptake and efflux capacity than M1 subtypes, which indicates that the M2 subtype has increased cholesterol transport capacity and may decrease cholesterol accumulation in the plaque.

Keyphrases: Atherosclerosis, THP-1, Monocytes, Macrophages, Phorbol 12-myristate 13-acétate, Foam cells, M1, M2, ABCA1, SR-AI/AII, SR-BI, CD36, LDLr, Efflux, Uptake, Lipoproteins, HDL, Apo A-I, Apo E
Design d’un système d’une tomographie par cohérence optique sensible à la polarisation

The aim of this work is to develop a polarization-sensitive full-field optical coherence tomography, able to answer to a problem in neuroanatomy research. Recent findings suggest an association between disturbances in white matter (WM) and cognitive impairment. White matter is composed mainly of myelinated nerve fibers that connect the various regions of the brain and are oriented from different angles. The problem is that the conventional OCT (Optical Coherence Tomograpghy) technique is insensitive to the orientation of fibers, especially displaced in a perpendicular direction to the optical axis. Furthermore, the spatial resolution is still too low to characterize very small fibers (~ 1μm). By exploring the intrinsic birefringence optical properties of nerve fibers, it will be possible to visualize the orientation of nerve fibers of the white matter. The system is based on a Linnik interferometric microscope, with a quartz halogen source centered at λ0=750 nm. The experimental setup produces en face (XY) a 2D image of the sample without the scanning of the incident beam transverse direction as in conventional OCT, owing to the use of a full-field illumination coupled to CMOS cameras. The final image is calculated with a differential linear combination of four interferometric images, recorded simultaneously by two CMOS cameras at a frame rate of 120 Hz. A micrometric resolution axial resolution is achieved at 1.7 μm at low cost, due to the use of a short coherence length of the source and the use of the same objective in the two arms. The setup is tested on a birefringent material such as a crystal and a biological tissue.

Keyphrases: Oct, Polarization, Birefringence, Optical coherence, Sinusoidal phase modulation, Full field
La responsabilité civile du psychiatre lors du suicide d’un patient : une perspective canadienne

The psychiatrist, as an expert, is frequently asked to assess the suicide risk presented by a patient. Therefore, he may have his liability engaged and so, could be sued in the event of the death of the patient. Thus, although a large number of suicide risk assessment and management tools have been developed, the practice is still not standardized. Hence, this research aims to propose a reflection on the prevention of suicide and more specifically, on the responsibility of the psychiatrist. As a first step, we wish to present the phenomenon of suicide regarding epidemiological data and etiology, among other things. Next, we focus on the assessment of the suicide risk and what are the challenges related. In the third section, we expose the tools that can support practitioners in this evaluation process and discuss their relevance. Finally, referring to Canadian court decisions, we explore the issue of the civil responsibility of the practitioner. Our research shows that most of the decisions are in favor of the psychiatrist, considering that the absence of scientific agreement on a single and optimal practice makes it difficult to qualify the psychiatrist’s practice as reprehensible. Thus, if a "standardization" of practice would undoubtedly be well greeted, it seems unlikely in the near future as suicide is a particularly complex social phenomenon.

Keyphrases: Suicide, Psychiatrie, Risk factors, Protective factors, Civil liability, Malpractice, Standard of care, Psychiatry
Acute and long-term healthcare professionals’ perspectives on the role of the emergency department in pediatric palliative care

Little is known regarding the role of the pediatric Emergency Department (ED) in Pediatric Palliative Care (PPC). This research aims to explore acute and long-term care professionals’ perspectives about PPC for children with medical complexity presenting with acute deterioration.   Semi-structured focus groups were held with professionals from pediatric emergency medicine, palliative care, complex care and intensive care. Data was analysed using NVivo© software and performing thematic analysis and theoretical sampling.   58 participants were interviewed. PPC is well recognized by healthcare professionals from different specialties. Each group demonstrated different culture that influence their role in palliative care and their perceptions on other groups’ roles. Suggested roles for the ED in PPC include evaluating the clinical situation, contacting known teams, developing a caring environment and alleviating distressing symptoms. Disagreements regarding when and how to discuss goals of care were expressed. Personalized care, communication with families and continuity of care were key elements to improve quality of care and professionals’ satisfaction.  Perspectives in caring for PPC patients in the ED are heterogeneous despite homogenous theoretical vision of PPC. Solutions to improve quality of PPC in the ED aim at creating an interprofessional collaboration to care using the mutual learning approach.

Keyphrases: Pediatric Palliative Care, Pediatric Emergency Medicine, Clinical ethics, continuity of care, Critical care, Complex care
L’association entre la fonction diaphragmatique préopératoire et le développement de complications respiratoires de la chirurgie cardiaque

Postoperative pulmonary complications increase mortality, length and cost of hospitalization. A multifactorial reduction of respiratory system compliance occurs after cardiac surgery. The strength of the diaphragm may help patients face this increased work of breathing postoperatively. We therefore sought to determine if a low preoperative diaphragm thickening fraction (TFdi) determined by ultrasonography was associated with an increased incidence of pulmonary complications after cardiac surgery. We conducted a single center prospective cohort study from November 2015 to April 2016, including adults undergoing elective cardiac surgery. Before the operation, we measured the TFdi as well as indicators of frailty, sarcopenia and pulmonary function. We repeated TFdi measurements following extubation to characterize its evolution. The primary composite outcome of this study was the occurrence of postoperative pulmonary complications, defined as pneumonia or clinically significant atelectasis or prolonged mechanical ventilation (PMV) (>24 h). Of the 115 patients included, 34 (29.6%) developed PPCs, including 2 pneumonias, 4 PMVs and 32 clinically significant atelectasis. In multiple logistic regression, a TFdi < 40% was associated with significant and independent increase in the risk of postoperative pulmonary complications (OR 2.84 [1.14-7.07]; p=0.02). A relative preoperative diaphragm weakness is thus associated with an increased incidence of pulmonary complications after cardiac surgery. TFdi is an easily accessible marker of diaphragm weakness could therefore help identify vulnerable patients who would benefit the most from preventive strategies such as preoperative inspiratory muscle training.

Keyphrases: Diaphragm, Ultrasonography, Cardiac surgery, Post-operative pulmonary complications
La prévention de l'hypoglycémie associée à l’activité physique chez les adultes vivant avec le diabète de type 1

Rational : For its benefits, physical activity should be encouraged in individuals living with type 1 diabetes (T1D) but is limited by the fear of hypoglycemia. People treated with continuous subcutaneuous insulin infusion (insulin pump) have the option to temporarily reduce basal insulin infusion rate. For an exercise practiced in the late post-prandial phase, this is the preferred method for preventing exercise-induced hypoglycemia, but no study has validated the optimal timing to reduce basal insulin infusion. Objective: To compare the efficacy of three timings to decrease basal insulin infusion rate by 80%, either at the start (T0), 20 minutes (T-20), or 40 minutes (T-40) before a 45-min exercise on a stationary bicycle at moderate intensity (60% VO2peak) performed 3 hours after a standardized meal. Results: No significant difference between the three strategies in terms of percentage of time spent under 4.0 mmol/L and time spent between 4.0 and 10.0 mmol/L was observed. With a reduction at T-40, although not significant, the glucose level at exercise onset was higher, fewer participants needed additional carbohydrates before and during exercise, and the time to first hypoglycemia was longer in comparison with T0 and T-20. Conclusion: In people living with T1D and treated with an insulin pump, an 80% reduction in basal insulin infusion 40 minutes before a 45-min moderate intensity exercise practiced in a late post-prandial state is not enough to reduce hypoglycemia. Further studies are needed to determine whether this reduction should be greater, earlier and/or combined with carbohydrates.

Keyphrases: Type 1 diabetes, exercise, continuous subcutaneous insulin infusion, insulin pump, hypoglycemia