NCube/papyrus huggingface dataset:
Investigation des variants génétiques dans la dysfonction endothéliale et le risque de maladies cardiovasculaires

CVD is a global burden for the economy and health, whose prevalence continues to grow. In the last few years, there has been a considerable effort to understand the genetic aspect of those diseases with GWAS, associating nearly 500 SNPs. One of these, rs9349379, in the intron of PHACTR1 breaks the MEF2 factor binding motif and is an eQTL. As potential leads multiply, it is impossible to pinpoint causality by the lack of biological information. With regard to this problem, it is possible to combine transcriptomic and chromosomal conformation experiments to obtain a concordance of information in order to explain SNP’s involvement in the risk of CVD. RACE and PacBio experiments allowed to validate 6 different transcripts of the PHACTR1 gene: one long, four intermediate with two different initiation codons and with the alternative splice of internal exon 10.11 and one short. By qPCR, it was shown that eQTL was specific to intermediate transcripts with the additional exon 10.11. Variant prioritization is also performed by aggregating ATACsec, RNAsec and Hi-C data in a context of endothelial dysfunction, a phenotype underlying atherosclerosis and characterizing CVD. Thus, four loci of interest in the CVD are selected and edited by the CRISPR-Cas9 system and are under process of characterization in the laboratory. These experiments have made it possible to build an exhaustive mapping at the genome scale under a pathogenic phenotype and provides a wealth of information for understanding the mechanisms linking SNPs to CVD risk.

Keyphrases: Phosphatase and actin regulator 1 (PHACTR1), Transcriptome, Endothelial dysfunction, Genome-wide association studies (GWAS), Single nucleotide polymorphisms (SNPs), Splicing, Expression quantitative trait loci (eQTLs), Chromatin conformation, Adhesion molecules, Cardiovascular disease (CVD)
Perturbation des profils épigénétiques suite à une perte temporaire du maintien de la méthylation de l’ADN dans les cellules embryonnaires

In early embryos, a major reprogramming wave occurs and permits to reset DNA methylation profiles genome-wide. During the reprogramming wave, differentially methylated regions (DMRs) (imprinted genes) must be protected from demethylation by the continuous action of DNMT1 (DNA Methyltransferase 1) to ensure the proper development of the foetal epigenome. As the induction of a temporary loss of Dnmt1 expression in a mouse embryonic stem cell model leads to permanent losses of DNA methylation at DMR and DMR-like regions, my project aims to understand why those regions are unable to re-establish their initial DNA methylation patterns. Our hypothesis is that an epigenetic adaptation (erroneous rearrangement of certain histone modifications) occurs at regulatory regions controlling gene expression (promoters and enhancers) and impede directly or indirectly the affected regions to return to their initial epigenetic landscape. The goal of this project is thus to define how the temporary loss of Dnmt1 remodels the epigenetic landscape at promoter regions (H3K4me3, H3K27me3, H3K27ac, H3K4me1, H3K9me3, DNA methylation) and how the epigenetic adaptations are associated with changes in gene expression (ex: genes in DMR and DMR-like regions).

Keyphrases: Embryon, DNMT1, Enhancers, Epigenetics, Preimplantation, Embryo, Histone modifications, DNA methylation, Gene expression, Promoters
Exploring the role of fibronectin in spondylometaphyseal dysplasia

A widely expressed glycoprotein, fibronectin (FN), has been associated with many basic biological processes, but has never been implicated with skeletal disorders. Identification of mutations in the gene that encodes this protein in patients with a rare subtype of spondylometaphyseal dysplasia (SMD) reveals an unexplored aspect in the field. Recent studies have shown that these mutations impair FN secretion in HEK293 cells, but it is still not known how this defect mechanistically contributes to SMD pathogenesis. To investigate the effects of the mutations in vitro, a chondrocyte differentiation protocol was optimized and tested on ATDC5 cells. Furthermore, to determine if the patients’ phenotypes were caused by a global reduction of FN, single and double knockout (KO) mice that lack FN in the liver and/or the cartilage were generated. Results reveal that deletion of FN in these tissues does not impair growth or viability. No changes were detected in the body weight nor length in the KO compared to control mice, and no skeletal abnormalities were observed in radiographs. These results show that the deletion of FN in these two tissues does not lead to the phenotypes observed in SMD. Additionally, sequencing of the FN1 gene in individuals with suspected SMD identified a de novo mutation in one patient. This finding expands the clinical features of FN1-induced SMD.

Keyphrases: FN1, SMD, Chondrocyte, Cartilage, Fibronectin, Skeletal dysplasia, Corner fractures, Extracellular matrix
Identification of the molecular pathways mediating the anti-AML activity of statins

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. The overall 5-year survival is as low as ~27%; however treatment for AML has only recently evolved with marginal impact on this low survival. In a large viability screen performed to identify better anti-AML molecules, we identified statins (3-Hydroxy-3-Methyl-glutary-CoA reductase (HMGCR) inhibitors) for their ability to differentially target AML specimens. Interestingly, AML specimens belonging to good outcome AML patients were 10 times more sensitive to statins compared to specimens belonging to adverse outcome patients. This discriminatory effect is lost with statin analog A405, synthesized by our team, which lacks anti-HMGCR activity, suggesting that HMGCR inhibition is essential for statin’s discriminatory effect. Statins are cholesterol- lowering drugs and are widely known for their inhibitory action on HMGCR, a rate-limiting enzyme in the mevalonate pathway. In addition to being excellent inhibitors of cholesterol production, statins are also known for their independent pleiotropic effects attributed by other products of the mevalonate pathway. These branches play important roles in various cellular functions such as signal transduction, protein synthesis and cytoskeletal regulation. In this study, we hypothesized that statin’s anti-AML differential effect is modulated by sub-branch(es) of the mevalonate pathway. As proof of principle, we confirmed that shRNA-mediated reduction of HMGCR activity in OCI-AML-5 cell line led to a significant increase of sensitivity to statins but not to its analog A405. We further demonstrated that complete loss of HMGCR using CRISPR technology was lethal and that mevalonate supplementation rescued both cell viability and sensitivity to statins. To further dissect the anti-AML activity of statins, we used RNAi technology to target each of the downstream sub-branches of the mevalonate pathway and investigated the consequences on cell viability and statin sensitivity. Our study showed that knocking down enzymes of single sub-branches did not affect significantly OCI-AML-5 cells sensitivity to statins. Interestingly, we observed that reduction of branch point enzyme, farnesyl diphosphate synthase (FDPS) was lethal in OCI-AML-5 cells. Unexpectedly, we also observed that FDPS knockdown caused a biphasic response to statin. While high concentrations of atorvastatin aggravates the phenotype caused by FDPS reduction, low concentrations led to a near complete rescue of this phenotype. These results uncovered a novel unsuspected statin resistance mechanism in AML. Overall, this study highlights the importance of understanding the metabolic background of AML prior to drug treatment, in order to prevent drug resistance.

Keyphrases: Acute myeloid leukemia, statins, chemo-genomics, cancer metabolism, target identification, therapy resistance, Acute myeloid leukemia, Statins, Chemo-genomics, Cancer metabolism, Target identification, Therapy resistance
RPA exhaustion as a major cause of genomic instability in polymerase eta-deficient cells

Genotoxic agents from the surrounding environment represent an omnipresent danger to the integrity of DNA. For example, humans are constantly exposed to solar ultraviolet (UV) radiation, which induces the formation of highly-genotoxic replication-blocking DNA lesions in skin cells that are the major cause of cutaneous tumor development. Fortunately, cells are equipped with mechanisms that mitigate the deleterious effects of UV, particularly i) nucleotide excision repair (NER) for error-free removal of UV-induced dipyrimidine adducts (i.e. 6-4 pyrimidine pyrimidone photoproducts; 6-4PP and cyclobutane pyrimidine dimers; CPD), and ii) translesion DNA synthesis (TLS) via DNA polymerase eta (polη) for accurate bypass specifically of CPD. Germline mutations in NER pathway genes lead to the autosomal recessive syndrome Xeroderma pigmentosum (XP), characterized by increased sun sensitivity and extremely high risk of developing skin cancer. On the other hand, inactivating germline mutations in polη cause Xeroderma pigmentosum variant (XPV) also characterized by sun sensitivity and high incidence of skin cancer. Upon UV exposure, compared to normal counterparts, XPV cells exhibit i) exquisite hypermutability ii) increased cell death iii) elevated DNA replication stress, and iv) defective NER exclusively during S phase. The major goal of this thesis is to better understand the molecular basis for these deleterious phenotypes. Recent studies have highlighted the role of uncontrolled replication stress in exhaustion of the trimeric replication protein A (RPA) and subsequent increase in DNA damage/repair defects. Since the deficiency of polη leads to increased levels of replication stress in UV-exposed cells, we hypothesized that such replication stress can lead to reduced availability of RPA and subsequent genomic instability. Our aim was to evaluate the dynamics of RPA on chromatin post-UV and to test if a surplus of RPA can rescue UV genotoxicity. Interestingly, cell lacking polη experience persistent RPA loading on chromatin  iv which was associated with elevated H2AX phosphorylation and cell death. In addition, RPA overexpression mitigates the UV-induced genotoxicity including cell cycle progression defect, increased UV sensitivity, and double strand break formation; however, RPA overexpression did not rescue the increased mutagenesis. Our data indicate for the first time that RPA availability is a major determinant of the cellular response to UV in polη-deficient cells.

Keyphrases: Ultraviolet, NER, XPV, RPA, Polη, Skin cancer
The risk of telling : a dyadic perspective on romantic partners' responses to child sexual abuse disclosure and their associations with sexual and relationship satisfaction

Survivors of childhood sexual abuse (CSA) often experience adverse trauma-related long term consequences, which vary widely among survivors. Some authors argued that this variability might be explained in part by the response of others to survivors’ disclosure of the CSA. However, disclosure during adulthood has received little empirical attention, in particular, disclosure to a romantic partner. Among 70 community couples who reported CSA and disclosure to their partner, this study examined associations between survivors’ perception of partner responses to their disclosure, and both partners’ sexual and relationship satisfaction. Participants completed self-report questionnaires online. Results of path analyses within an actor-partner interdependence model indicated that survivors’ perceived partner responses of emotional support to disclosure were associated with their own and their partners' higher sexual satisfaction. Survivors’ perceived responses of being stigmatized/treated differently by the partner were associated with their own and their partners’ poorer relationship satisfaction. Findings suggest that survivor-perceived partner responses to the disclosure of CSA can have both a positive and a negative impact on the sexual and relationship satisfaction of both partners.

Keyphrases: Childhood sexual abuse, Disclosure, Responses to disclosure, Sexual satisfaction, Relationship satisfaction, Adult survivors, Clinical psychology
Approche génomique pour l’étude de la polydactylie dépendante de Hoxa11

Limb development requires HoxA and HoxD complexes genes, the expression domain of Hoxa11 and Hoxa13 are mutually exclusive, with Hoxa11 being restricted to the proximal part of the limb bud, and Hoxa13 being restricted to the distal part. It has been shown that ectopic expression of Hoxa11 in the autopod domain induces a limb with polydactyly, but we have found that the combined Gli3 loss-of-function (Xt/Xt) with Hoxa11 gain-of-function (Prx1Cre; Rosa26Hoxa11/Hoxa11) induces the development of an oligodactyl limb, with less than 5 digits formed. The aim of this project was to characterize the effect of the ectopic expression of HOXA11 transcription factor in the modulation of the digit number. We show by in situ hybridization that Grem1 expression in the limb bud with ectopic Hoxa11 and inactivated Gli3 is reduced or lost, which leads to an alteration of the SHH – GREM1 – FGFs positive feedback loop. In addition, we have used genomic approaches (ChIP-Seq) for the HOXA11 transcription factor and the epigenetic mark H3K27Ac to characterize the effects of distal expression of Hoxa11 genome-wide. We provide evidence that HOXA11 contributes to the regulation of Grem1 expression, but also to the regulation of other anterior genes like Alx4, Irx3/5 and Hand1.

Keyphrases: Grem1, Limb development, Enhancer, Oligodactyly, Polydactyly, Transcriptional regulation
Le processus de création de liens sociaux entre les joueurs de jeux vidéo multijoueurs en ligne

This master’s thesis aims to engage a sociological reasoning on the relationships that emerge from online multiplayer video games leading to a better understanding of the dimensions that revolve around the creation of social links and the digital world. Are multiplayer video games social spaces? Are there norms of communication in games? What types of relationships can you create in games? All these questions are at the origin of this thesis. This research is based on the pooling of different gaming experiences of players with different habits. In order to understand the different interactions in depth existing between the players, this study is based on the combining of multiple playing habits, insertion or the attempts of integration inside different communities and norms of communication . Using a research method based on a series of 12 interviews of players and professionals as well as an observation work in the games, the analysis highlights a process of social link creation consisting of three phases: the approach , integration and detachment. Without claiming to be able to generalize these results on a larger scale, the process remains useful to a better understanding of the experiences of social contacts encountered by online multiplayer gamers.

Keyphrases: Videogames, Online multiplayer, Social link, Socialization, Social norms, Communication tool, Virtual community
La reconnaissance et la visibilité de l’homoparentalité féminine en milieu rural

This thesis examines the social recognition that same-sex mothers living in rural areas receive by focusing on their feelings of visibility or invisibility and on their relation to heteronormativity. Moreover, this research aims to question the existence of a rural specificity in the female experience of same-sex parenting, in response to common representations of rurality as a homogenous environment that is intolerant to diversity. The methodology is qualitative, based on semi-directive interviews with seven mothers of same-sex parent families residing in an area that is qualified as rural. Following the analysis, it appears that the participants currently receive a social recognition that, despite not necessarily being complete, satisfies them. In fact, although their status of same-sex parent family is, at times, the object of disapproving looks or comments, these negative experiences are not the ones that the mothers retain. In retrospect, the participants note the preponderance, in their social and familial environment, of support and care towards their family model. In several instances, this recognition is attributed to the “normality” of their family life, and therefore to their ability to make visible the image of a family life that is “like others”. Thereby, the feeling of recognition is rooted in a tension between, on one part, the desire to affirm the specificity of their family model and, on the other part, a rationalization of the normative looks from certain members of their social circles.

Keyphrases: Same-sex parenting, Same-sex parent families, Social recognition, Visibility, Heteronormativity, Rurality
L'usage des produits de santé naturels par les individus de 18 à 34 ans au Québec : pratiques, motivations et représentations

More and more Canadians are consuming natural health products (NHPs) in Canada. In Quebec, doctors and pharmacists are worried about this consumption, which continues to climb, because of the risk of interactions with drugs and regularly warn Quebecers against NHPs. Despite these warnings, NPH consumption is not declining and is even expanding in the population, especially among young people aged 18 to 34, who are generally healthy. This Master's thesis seeks to know and understand the reasons why Quebecers aged 18 to 34 consume NHPs, their practices, their motivations and their portrayals of NHPs. To understand the craze of NHPs among the 18-34 year olds, a sociological survey was conducted among 14 individuals (8 women and 6 men) who use NHP in Quebec. The survey was conducted in the form of semi-structured interviews, where participants explain the context of their uses of NHPs, the reasons that led them to use these forms of therapy, and what NHPs represent for them. The results were then coded and analyzed in the Dedoose software. The analysis reveals that if the limits of the health system are the first reasons for the use of the NHPs, it is the impacts of the social relations with the environment of the user which determine whether it continues or not to consume NHPs. These impacts are strongly influenced by the different symbolic representations of health, illness and therapy that users adopt during their experimentation of NHPs, and where scientific evidence weighs little on the impact of the weight of social relationships and symbolic representations of NHPs.

Keyphrases: alicament, nutricament, complementary and alternative medicine (CAM), natural health products (NHP), nutraceutical, self-medication, drug representations, health believes, medicine of compassion, symbolic representation of health, symbolic representation of illness, symbolic representation of therapy
L’homoparentalité au masculin : entre différence et distinction

Under the impulse of the rationalization of pleasure and the rise of a renewed form a sexual nationalism (Béjin et Pollack, 1977; Jaunait, Le Renard et Marteu, 2013), same-sex parenting has made its apparition and gained attention in the public domain over the past 15 years. Moved by their desire for social recognition, which oscillates between being like everybody else and being acknowledged for their distinct identities, gay fathers use multiples discursive strategies, combining differentiation and in differentiation, to distinguish themselves in the institution of family.  Tracing the history of their parenthood which crosses, without ever being confused with, that of the parents themselves, it is possible to highlight common aspects connecting parenthood and people going through it: symbolic representation systems, norms, but also the principle of distinction of the sexes. In their speeches, it is in the name of being men that gay fathers strive to show on a daily basis that they are not mothers, while giving, each in their own way and according to their position, a distinct meaning to this relational identity. Thus they demonstrate, similarly to all parents, specialized educational places according to relational poles, while drawing their references from the symbolic father-mother figures. Through their educational practices, between social integration and self-determination, they do a job of transmitting gender norms and stereotypes, and thus participate to pass on the difference between sexes.  This thesis, based on a socio-anthropological background and greatly inspired by the work of Irène Théry, allows us to rehabilitate the concept of “person”, highlights what connects distinct identities together, and this beyond the temptation to essentialize and substantialize. Ultimately, it invites to revisit the evidence that the identical is only replica.

Keyphrases: same-sex parenting, parenting roles, sexual diversity, gendered socialization
Sociologie de la bohème contemporaine : coqueter avec un style de vie à Leipzig et à Montréal

The current study focuses on contemporary bohemia through an empirical inquiry conducted in Leipzig and Montreal, exploring the social life of young adults connected to emerging artistic scenes. Drawing on classical German authors, I conceive bohemia as a form, visible through tensions between the center of society and its margins. The fictitious case of Tonio Kröger (1903), a novel by Thomas Mann (1875-1955), is my starting point: it describes tensions, which  are also of central importance to German sociology. Both Georg Simmel (1858-1918) and Siegfried Kracauer (1889-1966) paid attention to problems that relate to the bohemian lifestyle; both have developed conceptual tools and a form of writing to deal with the tensions at the very heart of this phenomenon. These tools can–I suggest–be used to seize these tensions today. By immersing myself in these worlds of art, adventure and sociability, I see through ethnographic observations of the daily lives of my respondents in Leipzig and Montreal how these tensions gradually materialize. I present these observations through a collection of short texts inspired by a particular writing form, the “feuilleton”: the texts act as miniatures, fragments of reality, which–taken together–form a “mosaic” on the theme of bohemia. This mosaic will reveal, in the final analysis, the problem of the respondents, one related to the form of contemporary bohemia. Rather than choosing between one camp or the other–the middle of society or its fringes–, they are drawn to a coquettish attitude with a set of ideas. This attitude relates to the bohemian lifestyle.

Keyphrases: Leipzig, feuilleton, Siegfried Kracauer, Georg Simmel, artistic scenes, lifestyle, coquetry, sociability