NCube/papyrus huggingface dataset:
Immunorégulation de la réaction du greffon contre l'hôte (GvHD) dans un modèle murin xénogénique : le rôle des immunoglobulines intraveineuses (IVIG)

Graft-versus-Host Disease (GvHD) is a major complication following hematopoietic stem cell transplantation (HSCT). Prophylactic treatments for the prevention of GvHD rely mostly on the use of immunosuppressors, which contribute to inhibit the patient’s immune reconstitution and prolong their immunosuppressed state. Development of immunomodulator-based prophylactic treatments is therefore preferred. Using NOD/scid-IL2rγ-/- mice, we developed a xenogeneic mouse model to assess the immunomodulatory potential of intravenous immunoglobulins (IVIG) for the prevention of GvHD, along with assessing their effect on the kinetics and the quality of the immune reconstitution in mice. We determined that weekly IVIG treatments reduced the incidence of GvHD and its related mortality. The effectiveness of IVIG for the prevention of GvHD was similar to that of cyclosporine A, an immunosuppressive drug routinely used for the prophylactic treatment of GvHD. Furthermore, we demonstrated that IVIG has a mechanism of action that is different from that of immunosuppressors. IVIG induce the expansion and activation of NK cells from the graft, which is mandatory for the preventive effect of IVIG on GvHD development. Furthermore, this IVIG-induced expansion and activation of NK cells require the presence of activated T lymphocytes. Using our humanized mouse model, we have also demonstrated that weekly IVIG treatments cause a transient delay of the humoral reconstitution, but do not affect the overall quality of the immune reconstitution. We have demonstrated that activated T lymphocytes are mandatory for the effective expansion and activation of NK cells, which in turn are essential to the IVIG-induced prevention of GvHD, and immunosuppressors will always be part of the prophylactic regimen of GvHD, therefore shining a doubt on the usefulness of adding IVIG to the prophylactic treatments for the prevention of GvHD.

Keyphrases: GvHD, IVIG, Immunomodulation, NK cells, Xenogeneic mouse model, Humanized mouse model, Immune reconstitution
The influence of environmental contaminants on time to pregnancy

In this thesis, we aimed to evaluate the impact of selected environmental compounds on female fecundity as measured by time to pregnancy (TTP). This research was conducted in the framework of the Maternal-Infant Research on Environmental Chemicals (MIREC) study, a pregnancy cohort of 2001 women recruited during the first trimester of pregnancy in ten cities across Canada between 2008 and 2011. Questionnaire data and biological samples were analyzed to assess the effect of two groups of compounds: persistent [perfluorinated compounds - perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS)-] and nonpersistent chemicals (Bisphenol A, Triclosan, and phthalates). In addition, this thesis aimed to examine the potential of the second to fourth finger digit ratio (2D:4D) as a sensitive-endocrine endpoint. To this end, anthropometric measurements were obtained in about 800 children and their mothers during the Early Childhood Biomonitoring and Neurodevelopment Study (MIREC-CD Plus), a MIREC follow-up conducted to measure growth and development up to age five.  Overall, the results of this thesis have contributed to the evidence regarding the potential adverse effect of several environmental contaminants (ECs) on female fecundity as measured by TTP. In the first article, we found that PFOA and PFHxS were associated with diminished fecundity, supporting previous evidence that suggested a similar effect. In the second article, we assessed for the first time the effect of Triclosan on TTP, presenting evidence of delayed fecundity at the highest quartile of exposure. In addition, our findings agreed with those of the only study that has assessed the effect of Bisphenol A on female fecundity, and which showed no effect. Finally, we found some indication that female exposure to phthalates might be associated with a shorter TTP, although this finding did not reach statistical significance. With regard to the potential of the digit length ratio (2D:4D) as an endocrine-sensitive endpoint in women, our data do not support a strong association between 2D:4D and TTP. In children, we did not find an adverse impact of maternal smoking during pregnancy on children’s 2D:4D. Thus, our data do not support evidence to suggest that 2D:4D could be used as a potential reproductive endocrine-sensitive endpoint in women as measured by TTP, and in their offspring as measured by exposure to maternal smoking during the first trimester of pregnancy.

Keyphrases: Fecundity, Time to pregnancy, Perfluorinated compounds, Bisphenol A, Triclosan, Phthalates, Endocrine disruptors, Digit ratio, 2D:4D
Rôle des gènes HOX du paralogue 4 dans l'autorenouvellement des cellules souches et progéniteurs hématopoïétiques

Transplantation of hematopoietic stem cells (HSC) is a treatment commonly used to treat several types of hematological diseases such as leukemia. However, a major limitation of this type of treatment is the limited number of HSC available for transplantation. It is therefore important to develop ways to expand these cells ex vivo. The HOXB4 gene is a promising candidate for achieving this goal. It has indeed been shown that HOXB4 is able to expand HSC in vivo and in vitro without inducing leukemia. HOXC4, which belongs to the same paralog group, is also able to expand primitive hematopoietic cell suggesting a common role for paralog 4 HOX genes in the self-renewal of HSC. HOXA4 is ten times more expressed in fetal liver HSC during their primary expansion. Furthermore, Hoxa4 mutant HSC, unlike Hoxb4 mutant HSC, are unable to reconstitute an irradiated recipient when transplanted in competition. Therefore, HOXA4 could play a more important role than other paralog 4 genes for HSC expansion at the physiological level and we hypothesized that HOXA4 can expand HSC more efficiently than HOXB4.  The results obtained during this research project showed that the overexpression of HOXA4 expand HSC and primitive hematopoietic progenitors in the same order as HOXB4. Direct competitive culture and transplantation assays confirmed the equal capacity of HSC overexpressing HOXA4 and HOXB4 to proliferate and engraft at long-term. However, we observed a better short-term peripheral reconstitution by HOXA4+ HSC compared to HOXB4+ HSC, which was associated with a better lymphoid reconstitution. We also compared the expression levels of potential target genes in HSC overexpressing HOXA4 or HOXB4 and observed that many genes important for HSC function were upregulated following their overexpression, including several genes involved in the Notch and Wnt signaling pathway. These included both receptors as well as ligands, indicating that HOX4 genes might regulate the communication of primitive HSCs with their environment through these major signaling pathways and promote self-renewal. In addition, modulation of genes coding for transcription factors and molecules known for their function in pluripotency suggest that HOXA4 and HOXB4 have both intrinsic and extrinsic potential to control self renewal potential.   This knowledge can then be further explored and used to optimize ex vivo HSC expansion protocols for clinical purposes.

Keyphrases: HOXA4, HOXB4, Hematopoietic stem cell (HSC), HSC transplantation
Activité physique et insatisfaction de l'image corporelle chez un groupe d'adolescentes

Body image dissatisfaction (BID) is common among adolescent girls and is associated with the development of various psychological disorders. Physical activity (PA) is correlated with several psychological benefits and appears to be a promising variable that could change the BID. However, research findings show contradictory links between PA practice and BID during adolescence. The main objective of this study is to measure the relationship between PA and BID in teenage girls, aged between 12 and 19 (n=173), from Montreal. The secondary objective is to test the potential moderating effect of the reasons which underlie the practice of the PA on this relationship. Variables such as age, ethnicity and body mass index were controlled. The results suggest an absence of association between the duration of physical activity and the level of BID obtained by two instruments (Body Shape Questionnaire and body dissatisfaction scale of Eating Disorder Inventory-2; EDI-2). The relationship between duration of physical activity and the BID score on the EDI-2 is, however, moderated by one of the reasons underlying the practice of physical activity. For teenagers who engage in PA to lose weight, a higher level of PA is linked to a higher level of BID. We found no relationship between teenagers who do not engage in PA for this reason. This study highlights the importance of considering the reasons underlying the practice of PA when the link between the duration of physical activity and the BID is examined.

Keyphrases: adolescence, clinical psychology, body image dissatisfaction, physical activity
Étude de la fonction de la protéine RPAP4 et de son association avec l’ARN polymérase II

RNA polymerase II, the enzyme responsible for transcription of messenger RNA, decodes the genome of living organisms. This function requires the concerted action of several proteins, including transcription factors, which form a protein-protein interaction network. Many of them are implicated in the regulation of RNAPII transcription. Although regulation of transcription has been largely studied during the last four decades, little is known about mechanisms that regulate RNAPII prior and after the transcription reaction.  In the first part of this thesis, we continue the characterization of the RNAPII interaction network of RNAPII in the soluble fraction of the human cell. This network, developed using tandem affinity purification method coupled with mass spectrometry (AP-MS) and bioinformatic analysis, provides a wealth of information about RNAPII regulation prior and after its interaction with chromatin for transcription. We identified proteins that can be involved in RNAPII assembly, including chaperones and the cochaperone complex R2TP prefoldin-like, and proteins involved in nucleocytoplasmic shuttling. RPAP4 is a GTPase that occupies a central position in this network being at the interface between these regulatory proteins and RNAPII. We therefore started to study the function of RPAP4, which lead us to conclude that RPAP4 is essential for RNAPII nuclear import. We also report that G domains and the GPN motif are essential for RPAP4 function. Treatment of the cells with benomyl suggests that microtubules are required for RPAP4 function and RNAPII nuclear import.   The second part concerns another protein found in the network that is also centrally positioned in the network, called RPAP2. RPAP2 shares many interactions with RPAP4. This protein is also essential for the nuclear import of RNAPII as it interacts directly with it. RPAP4 and RPAP2 being cytoplasmic proteins that shuttle between the cytoplasm and the nucleus, we show evidences that RPAP4 is implicated in RPAP2 nuclear export to make it available for RNAPII nuclear import.   In the third part, we study RPAP4 post-translational modifications, which help us to understand its own regulation and its function with RNAPII. RPAP4 is phosphorylated in mitosis by the MAP kinase ERK5. This phosphorylation promotes the interaction between RPAP4 and RPAP2. It prevents RPAP2 and RNAPII interaction and RNAPII chromatin localization in mitosis where transcription is mostly nonexistent.

Keyphrases: RPAP4/GPN1, RPAP2, Phosphorylation, ERK5, RNA polymerase II, Nucleocytoplasmic transport, RNAPII biogenesis, Protein-protein interaction, Tandem affinity purification
Le rôle d’Akt dans la réponse cellulaire aux dommages à l’ADN induits par les ultraviolets dans les cellules de mélanomes humains

Malignant melanoma is one of the deadliest cancers whose incidence continues to rise each year with a few effective long-term treatments. It is caused and initiated mainly by excessive exposure to ultraviolet radiation generating highly genotoxic DNA photoproducts. It is well known that the PI3K/Akt signaling cascade plays a crucial role in the regulation of processes commonly deregulated in tumor development such as proliferation, cell cycle control and apoptosis. Nevertheless, the nuclear involvement of this molecular pathway in the genotoxic response is poorly characterized. In mammals, three Akt kinase isoforms have been identified: Akt1, Akt2 and Akt3. Although these exhibit a high degree of homology, several studies have shown that they have distinct biological functions; therefore, we suggest that these isoforms may contribute differently to the regulation of genotoxic response. The objectives of this project were to: (i) evaluate Akt activation in UV-irradiated melanoma cells, (ii) determine the effect of the Akt phosphorylation inhibition on the regulation of the cellular response to UV, (iii) evaluate whether the loss of the expression of one or more of Akt isoforms can regulate the cellular response to UV. We demonstrated that Akt undergoes transient hyperactivation after UV treatment in melanoma cell lines. To determine the importance of this activation, our approach was to reduce (i) the phosphorylation of Akt by the use of pharmacological inhibitors or (ii) the expression of each individual Akt isoform using RNA interference. We have shown that inhibition of Akt phosphorylation leads to increased rates of UV-induced apoptosis in an isoform specific manner, while exerting no effect on regulation of nucleotide excision repair (NER), the only human pathway for eliminating UV-induced DNA damage. In summary, our study provides a better understanding of the molecular mechanisms of malignant melanoma development in response to UV.

Keyphrases: Ultraviolet, PI3K, Akt, PTEN, Malignant melanoma, DNA damage response, Ultraviolet, Nucleotide excision repair, Apoptosis
TDP-43 régule la dynamique et la fonction des Granules de Stress via G3BP1

Stress Granule (SGs) are cytoplasmic inclusions sequestering proteins and mRNAs following a stress exposure. Their assembly is part of the cell stress response and is considered an important step for stress resistance and cell survival. SG are currently linked to different pathogenesis from viral infection to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).ALS is an aggressive disease, characterized by neuronal death leading to paralysis and death within five years. Pathogenesis mechanisms are still not fully understood. TDP-43 (TAR DNA binding protein 43) and FUS (Fused in liposarcoma) are two proteins linked to the disease that share many structural features and functions suggesting a common toxicity mechanism. TDP-43 and FUS are both recruited to SGs in stress conditions. We demonstrate for the first time that SGs function to protect mRNA from degradation induced after stress exposure, a function that was only suspected until now. We also prove that G3BP1 (Ras GTPase-activating protein-binding protein 1) is the effector of this function via it’s implication in the dynamics of SG formation. As TDP-43 is a regulator of G3BP1, we prove that loss of TDP-43/G3BP1 function leads to a stress response defect yielding increased cellular vulnerability. Furthermore, we have discovered that the mechanism of toxicity for FUS is different from TDP-43, and does not implicate a loss of function mechanism during the cell stress response.

Keyphrases: TDP-43, G3BP1, FUS, P-Body, Stress Granule, mRNA, Amyotrophic Lateral Sclerosis, Stress response
The Independence of CXCR4’s Pathways, Gαi and β-Arrestin2, and Their Modulation by AMD3100 and TC14012

CXCR4, a chemokine receptor involved in metastasis and homing of hematopoietic stem cells, signals through two major pathways: Gαi and β-arrestin2. β-arrestin2 terminates G-protein signaling and targets the receptor to endocytosis. This project proposed to study the effect of a previously described set of CXCR4 mutants on both these signaling pathways, as well as their localization. These mutants were assayed by different Bioluminescence Resonance Energy Transfer (BRET) systems. Using these systems, we confirmed that N119S is a constitutively active mutant (CAM), spontaneously activating Gαi. As well, we found that R134A is a constitutively inactive mutant (CIM), devoided of G-protein signaling, but spontaneously recruiting β-arrestin2. In addition, we studied the dependency of β-arrestin2 recruitment on the Gαi activity. By targeting R134A and N119S with pertussis toxin, an inhibitor of the Gαi activation, we showed efficient blocking of the Gαi pathway, while maintaining the constitutive recruitment of β-arrestin2. This demonstrated that for CXCR4, β-arrestin2 recruitment is independent of the Gαi pathway. Finally, two synthetic ligands of CXCR4, AMD3100 and TC14012 were tested for their ability to recruit β-arrestin2. AMD3100 is a clinically approved drug used for stem cell transplantation, with considerable side effects. We found it to be an antagonist on both Gαi and β-arrestin2 recruitment. On the other hand, TC14012 was found to be an inverse agonist on Gαi and an antagonist on β-arrestin2 recruitment. Based on this finding, it would be preferable to use of TC14012 as it will further reduce any basal Gαi activity, without affecting β-arrestin2 recruitment. These results support the development of TC14012 for stem cell mobilization trials.

Keyphrases: CXCR4, GPCR, AMD3100, Plerixafor, TC14012, CAM, CIM, N3.35, RCPG
Le syndrome métabolique et ses associations avec les troubles de la mobilité : différence de genre dans l'étude internationale sur la mobilité des personnes âgées (IMIAS)

Background: Few international studies have examined differences in metabolic syndrome (MetS) between men and women. Objectives: To compare the prevalence of MetS in women and men and to assess the role of gender in the association between MetS and mobility disability. Methods: We used baseline data from the International Mobility in Aging Study of community samples aged 65-74 years (n = 1995) of the cities of Kingston (Ontario), Saint- Hyacinthe (Quebec), Tirana (Albania), Manizales (Colombia), Natal (Brazil). Of these, 1,728 people donated a blood sample. Prevalence ratios of MetS and mobility disability were estimated by Poisson regression. Results: In non-Canadian cities the prevalence of MetS was significantly higher in women while in Canadian cities there was no significant sex difference. Among women, comparing with Kingston, MetS prevalence was significantly higher for women in Tirana (PR= 2.66; 95%CI = 1.98 to 3.58) and Natal (PR=2.21; 95%CI =1.52 - 3.22), but no significant differences were observed for women in Manizales and Saint-Hyacinthe. Among men, few significant differences were observed across cities. In non-Canadian sites, MetS was not associated with mobility disability. Conclusion Our results suggest that gender is a risk factor for MetS. Research on the relationship of MetS, mobility and gender need to be initiated. Keywords: Metabolic syndrome, mobility disability, gender, international health.

Keyphrases: Metabolic syndrome, Mobility disability, Gender, International health
Mouvement vers l’inclusion et évolution de la politique d’intégration scolaire au Québec : entre permanence et changement, une difficile légitimation de la mise en œuvre

These prolegomena inquire on the political and conceptual evolution of school integration as a mere introduction to the analysis of the making of a legitimized policy regarding special education. It first explore the different schooling trends, and their evolutive core, designed for students with handicaps, social maladjustments or learning disabilities; then situate it within three frame of reference unique to Quebec : the study of the evolution between 1978 and 1999 of the policies on special education and their positioning, the management of such services as well as the grouping and labeling of any student concerned by those policies. These variations are later questioned by the application of such policies by the different players, as their application is considered to be the mold for any problem diagnosis as well as a legitimising podium. Ultimately, the highlights of this particular evolution of policies on special education is positioned between changes and durability of the schooling approach for special students, and is underlained by a difficult implementation and legitimization.

Keyphrases: inclusion, segregation, integration, inclusion, policy on special education, Quebec, students with handicaps or social maladjustments or learning disabilities, organization of services, categories, implementation
Vieillissement actif : le maintien à domicile des baby-boomers

This study is about the stakes of how the baby boomer generation, in particular those born between 1945 and 1954 who are currently retiring, will deal with their living spaces. I shall take into account the multiple visions of Benoit Goetz (2011), Heidegger (1958), Bachelard (1957), Benjamin (1955), Büber (1962) and Deleuze (1980) who analyze what it means to live in a given living space. Indeed not only must porosity factors and increasing relations between beings be analyzed but also the characteristics of these baby boomers themselves with regards to who they are as Jean Francois Sirinelli (2003) and Josée Garceau (2012) have done. This new generation of baby boomers hopes to remain active and in order to do so seeks to adapt and influence their living spaces as well as their conceptualizations of what it means to “live”.  This current study has asked baby boomers what their visions are for their future residential choices in order to grasp on what values and for what goals their project is based on,. This was done by having five baby boomer between the age of 60-65 to watch the movie Et si on vivait tous ensemble. Afterwards, semi-directed interviews, based on their memory of the movie, what adaptions they foresee in addition to how they see their future, were conducted in two different phases with approved verbatim. The findings were then compared and confirmed with different theoretical frameworks such as porosity and opening of a physical and virtual window. At the same time, retirement homes and the financial considerations behind an aging population were taken into account.  This generation, immersed in technology wants to have access to such modern technology without losing the feeling of controlling their lives and story. Born in an innovation and changing time, they have already proven capable of changing and reinventing each stage of their life. This, therefore, leaves us to believe that they will do the same with their vision of retirement and living spaces.  Hence, tomorrow’s design models will have to renew itself for its new users.

Keyphrases: autonomy, baby boomer, living space, economy, porosity