NCube/papyrus huggingface dataset:
La reconnaissance juridique des contrats intelligents face à la réglementation globale des technologies

The Blockchain technology is essentially a decentralized and distributed network of digital transactions records. Its implementation on the cryptocurrency market was followed by other applications, such as the Decentralized Autonomous Organization (DAO) and Smart Contracts. This thesis will focus precisely on the legal recognition of smart contracts in the light of the established positive law and the regulations currently being drafted in various jurisdictions, including Quebec, as well as in the light of the soft law. The context of globalization, legal pluralism and state sovereignty changes are taken into consideration. The first part of this study focuses on the technological aspects in order to present the foundations of the Smart Contracts operation. The second part is dedicated to analyzing the current juridical panorama. The normative framework of the positive law already provides applicable regulations to Smart Contracts, some general, others more specific. It is further understood that the soft law could be a way of harmonizing the current context. A harmonization in this direction would be relevant in order to enhance the essential regulatory framework of new relations coming from the technological development. Given all these facts, the soft law along with hard law seem to be appropriate to chart the legal framework for the new technologies, in order to overcome the many legal uncertainties existing in this field.

Keyphrases: Corégulation, Régulation, Smart Contracts, Blockchain, Information Technology Law, Soft Law, Globalization, Co-regulation, Sovereignty, Regulation, Standardization
La mortalité précoce auprès des utilisateurs de clozapine

Objective: Early mortality is associated to psychiatric disorders, especially schizophrenia. Antipsychotics may explain, at least partly, this phenomenon. To our knowledge, there is no literature regarding early mortality among clozapine users. The purpose of this study is to explore the causes of early mortality among these individuals, including sudden, unexpected, and undetermined death, and their related characteristics.  Methodology: This study is a non-experimental, retrospective and descriptive case series. The population is aged from 18 to 64 years old and used clozapine at the time of their death. Sociodemographic, psychiatric, medical, pharmacological variables and others related to the cause, origin and circumstances of the death, including autopsy, were analyzed.  Results: The sample size is 100 participants. Of these, 67 were autopsied. The mean age at the time of death is 47,4 years (+/- 9,1 years). The leading cause of death is sudden, unexpected death of undetermined origin (n = 63, 63,0%). If a natural origin is determined, it is primarily related to a pulmonary disorder (n = 11; 37,9%), mainly pneumonia (n = 8, 72,7%). A significant association between sudden, unexpected, and undetermined death, and the diagnosis of schizophrenia (p-value = 0,022), dyslipidemia (p-value = 0,003), and time slot of occurrence of death (p-value = 0,020) is observed. Fifty-three percent of patients with sudden unexpected death of undetermined origin, meaning a medical cause could not be identified following an autopsy, died during their sleep or at night.  Conclusion: Sudden, unexpected and undetermined death is the leading cause of death among clozapine users. It is associated with schizophrenia and the time slot of the occurrence of death, whose preponderance is nocturnal, as Sudden unexpected death in epilepsy (SUDEP) is.  Declaration of interest: None.

Keyphrases: Clozapine, Convulsions, SUDEP, Mortality, Schizophrenia, Antipsychotics, Sudden and unexpected death, Unexplained or undetermined death, Pneumonia, Nocturnal death, Seizures
14-3-3zeta is required for PKA-dependent lipolysis in mature adipocytes

Altered hypertrophy and hyperplasia of adipocytes lie at the core of the development of obesity. We previously demonstrated that the molecular scaffold 14-3-3zeta (14-3-3ζ) had essential roles in adipogenesis. However, the contributions of 14-3-3ζ to mature adipocyte function are not known. 3T3-L1 cells and tamoxifen-inducible adipocyte-specific 14-3-3ζ knockout mice (adi14-3-3ζKO) models were used to examine the roles of 14-3-3ζ in lipolysis. siRNA-mediated knockdown of 14-3-3ζ impaired lipolysis in 3T3-L1 cells stimulated by the beta-adrenergic agonist isoproterenol (Iso), forskolin (an activator of adenylyl cyclase) and dibutyryl cAMP (dbcAMP). qPCR analyses revealed significant reductions in lipase transcript levels (Atgl and Hsl). Furthermore, reductions in the phosphorylated and total levels of PKA substrates such as HSL and CREB were detected in 14-3-3ζ-depleted 3T3-L1 lysates by immunoblotting. These findings were recapitulated in vivo, as reductions in phosphorylated and total HSL levels were detected in the gonadal adipose tissue of adi14-3-3ζKO mice. adi14-3-3ζKO mice and gonadal explants also displayed impaired lipolysis following i.p CL-316,243 (a beta-3 adrenergic agonist) injections and Iso treatment respectively. Interestingly, decreased 14-3-3ζ expression in 3T3-L1 cells and mice revealed reductions in characteristics of a mature adipocyte, such as Pparg, Lpl, and Fabp4 transcript levels, PPARγ levels, triglyceride content, and Oil Red O (ORO) incorporation. Collectively, these results demonstrate that 14-3-3ζ has essential roles in facilitating lipolysis and determining adipocyte maturity.

Keyphrases: Lipase, Adipocyte mature, Lipolysis, Mature adipocyte
Arterial stiffness and brain health : investigating the impact of sex-related differences

Introduction: It is well established that sex differences exist in the manifestation of vascular, cerebrovascular and cardiovascular disease. Arterial stiffness (AS), an independent predictor of cardiovascular disease (CVD), has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a steeper decline on executive function (EF) tasks. Decreased EF is also linked with reduction in CVR among older adults. Interestingly, the relationship between AS and CVR is more complex, where some works show decreased CVR with increased AS, and others demonstrate preserved CVR with higher AS. In addition, recent work suggests that measurements of AS may be affected by differences in the concentration of hematocrit (HCT). Here, we investigated the possible role of sex and HCT on these hemodynamic relationships. Methods: Acquisitions were completed in 48 healthy older adults (31 females, 63 ± 5 years) on a 3T MRI. Pseudo-continuous arterial spin labeling using dual-echo readouts were collected during a hypercapnia challenge (5mmHg CO2 change, during two, 2 min blocks). CVR was calculated as the %∆CBF signal per mmHg change in end-tidal CO2. Aortic PWV data was acquired using a cine phase contrast velocity encoded series during 60 cardiac phases with a velocity encoding of 180cm/s through plane. PWV in the aortic arch was computed between ascending and descending aorta. Statistical analyses were done using SPSS. Results: A moderation model test controlling for age and white matter hyperintensity volume revealed a significant direct effect of PWV on CVR (β=1.630, 95% CI [.654, 2.607), as well as PWV on EF (β=-.998, 95% CI [-1.697, -.299]). Sex moderated the relationship between PWV and CVR (β=-1.013, 95% CI [-1.610, -.4169]), and PWV and EF (β=.447, 95% CI [.020, .875]). In addition, there was a significant effect of HCT on the sex differences observed in the moderation effect (PWV*SEX) on EF (β=-0.7680, SE = 0.3639 ,95% CI [-1.5047, -0.0314], p=0.0414). Conclusion: Together, our results indicate that the relationships between PWV, CVR and EF is complex and in part mediated by sex and HCT. Future work should investigate the role of hormone variations (e.g., menopause) on these relationships to better personalize CVD prevention strategies.

Keyphrases: Arterial stiffness, Cerebrovascular reactivity, Magnetic resonance imaging, Arterial spin labeling, Cognition, Cardiovascular disease, Sex
Étude de l’établissement des réservoirs du VIH-1 et de l’impact de l’initiation précoce du traitement sur ces réservoirs chez l’enfant infecté par le VIH-1

The major barrier to eradicating HIV is the existence of cellular reservoirs of HIV, which escape the treatment and immune response of the host. This reservoir is established very early in the infection, typically leading to the destruction of a large number of CD4+ T cells. However, a small proportion of these cells return to quiescent state after integrating the viral genome. The size and evolution of the reservoir in adults have been well understood. However, we know less about the size and distribution of the HIV reservoir, and the impact of early initiation of combination antiretroviral therapy (cART) on it in the infant population. Our study is a part of the Early Pediatric Initiation Canada, Child Cure Cohort (EPIC4); a prospective, multicenter study, which enrolled 221 vertically HIV-1 infected children in nine Canadian pediatric centers. We hypothesize that very early initiation of cART in HIV-infected children would reduce the reservoir to its lowest levels, leading to better control of viral replication following a possible interruption of treatment. A strong positive correlation was observed between reservoir size in peripheral blood and both the age at initiation of cART and the age at which sustained viral suppression (SVS) was achieved. We found a strong negative correlation between the size of the viral reservoir and the proportion of life spent on effective cART or the proportion of life with SVS and CD4+ T lymphocytes count. This study shows that starting cART within 6 months from birth is a predictor of faster and more sustained virological suppression in infants. Our findings suggest that early cART initiation in infants and long-term viral suppression are key factors leading to limited viral reservoir size. Furthermore, we established for the first time that the size of the inducible HIV-1 reservoir in peripheral blood CD4+ T lymphocytes of children, quantified by the prostratin analogue stimulation test, correlates with the size obtained using proviral DNA measurement. Thus, we have validated a new inducible reservoir measurement technique that is fast, less expensive, and, importantly requires a lower blood volume. This assay could be very promissing for evaluating inducible HIV-1 reservoirs in pediatric HIV-1 studies.

Keyphrases: HIV reservoir, Infants, Early treatment, Virological suppression, HIV-1 DNA, Inducible RNA, Prostratin
Développement de nouvelles immunothérapies pour le traitement de la lymphohistiocytose hémophagocytaire (HLH) à l’aide d’un modèle murin

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyper-inflammatory disease affecting mainly young children. There are two types of HLH : primary and secondary. Primary HLH is caused by defects in genes of the perforin-granzyme cytotoxic pathway, whereas secondary HLH develops following a pre-existing underlying condition, such as a cancer, a chronic infection or a transplantation. HLH is characterized by extreme inflammation, a very high secretion of inflammatory cytokines and a massive tissue infiltration by activated T cells and macrophages. Currently, treatment for HLH consists of reducing the inflammation with a course of highly toxic chemotherapy agents and corticosteroids, followed by hematopoietic stem cell transplantation (HSCT) for patients with primary HLH, which is the only available curative treatment for these patients. However, current therapies often fail to properly manage the extreme inflammation of HLH in many patients, so that the pre-HSCT fatality still stands around 20% to 25%. Thus, the development of new, more potent anti-inflammatory treatments would be a major advance in the treatment of HLH. It had already been shown in relevant mouse models that blocking antibodies targeting IFNg (anti-IFNg) or ruxolitinib, a Janus activated kinase 1/2 (JAK1/2) inhibitor, could efficiently, but partially, improve the pathological manifestations of HLH. Thus, we hypothesized that combined therapies targeting both JAK-dependent and independent cytokines would be more effective than either one alone to reduce the symptoms of this pathology. Using a perforin knock-out (PKO) mouse model, we compared the effects of targeting IL-6 and IL-18, which are highly expressed cytokines during HLH, in combination with either anti-IFNg or ruxolitinib. We also tested the efficacy of a therapy combining anti-IFNg with ruxolitinib on the manifestations of HLH. We found that anti-IL-6R and anti-IL-18, when used in combination with either anti-IFNg or ruxolitinib, showed small, but not significant improvements on the pathological manifestations of HLH. However, combination therapy using ruxolitinib and anti-IFNg showed a major synergistic effect on the resolution of the symptoms of HLH. Our findings support that anti-IFNg and ruxolitinib, although effective independently, should be used in combination to suppress HLH progression. This is particularly relevant since the former was recently approved for treating HLH while the latter is in clinical trials.

Keyphrases: IFN gamma, Ruxolitinib, Hemophagocytic lymphohistiocytosis, Immunotherapy, Hematology, Combination therapy
Étude de la relation entre la consommation de cannabis et la violence chez les individus atteints de troubles mentaux graves

Worldwide, violence is responsible for 2.5% of deaths, besides having an important impact on victims’ physical and mental health. Therefore, it is a priority public health problem. Recent studies of individuals with severe mental illnesses (SMI) have shown that an association exists between cannabis use and violent behaviours. Considering that these individuals are at higher risk of drug consumption and crime than the general population, this discovery is particularly important in the current context of the legalization. My research project therefore aimed to validate and to specify the relationship between cannabis use and violence in SMI individuals. To do so, three studies were conducted. The first one was to report current literature through a meta-analysis. By grouping the studies that calculated such an association among SMI, a moderate association was found between cannabis use and violence. As for the second study, we identified the main dynamic and static risk factors for violence and criminality in SMI; in both cases, cannabis use was one of these factors. The last study confirmed the unidirectional relationship between persistent cannabis use and violence in a population with schizophrenia. Finally, these results will be particularly important in order to formulate relevant clinical recommendations. However, future studies will need to be conducted to elucidate the underlying mechanisms of this association.

Keyphrases: Violence, Cannabis, Criminality, Severe mental illnesses, Schizophrenia, Substance use disorders, Risk Factors, Meta-analysis, Longitudinal profiling, Cross-lag models
The adoption of sustainable menu practices in healthcare institutions in Quebec : a study of feasibility

Background: In many societies, as in Quebec, there is an increased interest towards sustainable food systems. Food sustainability aims to maintain human and planetary health through nutritious food, all the while promoting economic and social development. In this perspective, foodservice managers in healthcare institutions can prioritize sustainable menu practices (SMPs). As there is little research on SMPs in this context, it is of uttermost importance to understand their feasibility in healthcare institutions. Objective: This study aimed to analyze the feasibility of adopting SMPs in Quebec healthcare institutions. Methods: Following an integrated knowledge translation and exchange approach and in partnership with Nourish (McConnell Foundation), a qualitative study was carried out using semi-structured interviews with seventeen foodservice managers, recruited through purposeful sampling in ten of thirty healthcare institutions in Quebec. The revised Diffusion of innovations theory, describing the nine principal determinants of the processes of the diffusion of an innovation (SMPs) in a complex social system (healthcare organization), structured the interview guide for data collection and the codebook for data analysis.  Results: Managers report being motivated by food sustainability, however this does not always translate to concrete actions due to its lack of prioritization in foodservices. Challenges to adopt and implement SMPs are considerably more recurrent than facilitators. Key barriers include perceived SMP complexity, the context of the healthcare system, a substantial lack of resources and shortfalls in clear political directives from Ministry of Health. Amongst enhanced support and ministry guidance, foodservice managers need increased collaboration between all food system actors for better SMP adoption.  Discussion: This research contributes to in-depth understanding of the managerial experience in SMP adoption in various regional and institutional settings. Findings suggest the need for food system partnerships, as well as support and strategies that would remove important barriers in SMP adoption.

Keyphrases: Alimentation durable, Nutrition, Food sustainability, Foodservice, Diffusion of Innovations
Analysis of the dietary taboos affecting dietary diversity of women of reproductive age in the South and Grand’Anse departments of Haiti

Context. Undernutrition, including micronutrient deficiencies, is a global public health issue, particularly for women and children in developing countries. Dietary taboos in this population have been found to exist in many regions of the world, including in Haiti. This thesis describes research looking at dietary taboos and other factors impacting dietary diversity of Women of Reproductive Age (WRA). It is part of an intervention project aiming to decrease maternal and child mortality in the South and Grand’Anse of Haiti, a country where approximately half of WRA are anemic and one third of preschool-age children are deficient in vitamin A (WHO 2009, ICF 2018). Objectives. The objective of this research is to identify and understand food taboos for pregnant and breastfeeding women in the area, to determine what factors influence dietary diversity of WRA and if pregnant or breastfeeding women consume a diet that is less diverse than that of a woman who is not. Methodology. The research design included both qualitative and quantitative components. Qualitative data regarding food taboos was collected through focus groups. Quantitative data was collected through surveys and 24-hour recalls done with WRA who have a child under the age of five. Dietary diversity of survey participants was assessed using the FAO’s MDD-W and it’s determinants were analyzed through adjusted logistic regression calculations. Results. The focus groups revealed over 100 dietary taboos. Determinants of dietary diversity were related to the region, as well as characteristics of the household and mother. Breastfeeding women were less likely to attain the MDD-W and to consume “other fruits” and “other vegetables” though these findings were only significant in the non-adjusted model. Conclusion. Dietary taboos exist in the Grand’Anse and South areas of Haiti for pregnant and breastfeeding women. These taboos vary largely between communes and even within the same community. The restriction of these foods could negatively impact the dietary intake of many micronutrients, including vitamin A and iron. Key messages to include at educative activities through the intervention project will be formed based on results of this work.

Keyphrases: Dietary diversity, Taboos, Women, Maternal, Pregnant, Breastfeeding, Haiti, Micronutrients, Undernutrition
Régulation de la SUMOylation, de la phosphorylation et de l'ubiquitination en réponse au trioxyde d'arsenic

Acute promyelocytic leukemia (APL) is a cancer of white blood cells characterized by the accumulation of immature granulocytes called promyelocytes. In most cases, the disease is caused by the reciprocal translocation of the RARα and PML genes, leading to the expression of the PML/RARα fusion protein that compromises both the functions normally provided by RARα and by PML. Thus, repression of the transcription of RARα target genes and disruption of the formation of PML nuclear bodies may cause the non-differentiation of promyelocytes and the promotion of their survival by inhibition of apoptosis. One of the therapeutic agents used to treat the disease is arsenic trioxide (ATO) and despite the fact that its effectiveness is proven, the molecular mechanisms through which it exerts its action are not fully characterized. Since PML is SUMOylated in response to ATO, it is likely that other proteins may also exhibit changes in their post-translational modifications (PTMs) and play a role in the response. By using large-scale proteomic workflows on HEK293 cells following ATO treatment, we identified 92 proteins that shown significant changes in SUMOylation, including some known capase-3 substrates. Following this observation, we surmised that SUMOylation may protect these substrates from caspase-3 cleavage. Using in vitro assays and immunoblots, we confirmed that SUMOylation of PARP1 prevents its cleavage by caspase-3, an event that could mediate cell fate.

Keyphrases: SUMOylation, Phosphorylation, Ubiquitination, PML, PARP1, Capase-3, Ubiquitylation, Arsenic trioxide, Acute promyelocytic leukemia, Proteomics, Mass spectrometry, Apoptosis
Localisation de l'ARNm STAT3 aux protrusions des cellules du carcinome hépatocellulaire associées à un phénotype métastatique

Subcellular mRNA localization regulates cell polarization. Asymmetric distribution of transcripts is important in cell division, cell migration, neuronal function and embryonic development. In all cell types, the mechanisms of mRNA localization are well defined, but their involvement in cancer development is still unknown. A recent study has identified protrusion-localized STAT3 mRNA in metastatic hepatocarcinoma cells (HCCLM3). In comparison, the STAT3 mRNA was not found to be enriched in the non-metastatic cells (SMMC7721) protrusions. The enrichment of the STAT3 mRNA at the protrusions of HCC cells associated with a metastatic phenotype was studied by smiFISH. Our results showed that the serum starvation assay induced lamellipodia-based migration in SMMC7721, HCCLM3 and MHCC97H cells. Also, expression of GFP-α-actinin allowed to mark the protrusive regions of migrating HCC cells. The smiFISH results and RT-qPCR quantification revealed that the metastatic cells (HCCLM3 and MHCC97H) express lower levels of STAT3 mRNA compared to the non-metastatic cells (SMMC7721). Absolute quantification of localization and enrichment revealed that STAT3 mRNA mainly localizes in the cell bodies of all HCC cell lines. The ratio of the number of single molecules of STAT3 mRNA localized in the protrusions on the number of single molecules localized in the cell bodies is smaller for the metastatic cells than the non-metastatic cells. In the metastatic cells protrusions, the density of STAT3 mRNA / unit of surface was found the be lower than the non-metastatic cells. Altogether, these results confirm that there is no enrichment of STAT3 mRNA at the protrusions of metastatic HCC cells.

Keyphrases: smiFISH, cancer, Microscopy, Cell migration, Metastasis, HCC