NCube/papyrus huggingface dataset:
Vers une meilleure compréhension de la pathogenèse de la maladie osseuse reliée à la fibrose kystique

With cystic fibrosis (CF) patients now being able to live past fifty years of age come a multitude of secondary complications; one of the most important being cystic fibrosis-related bone disease (CFBD). In Cftr-null mice, this disease is caracterized by a low bone mineral density caused by an uncoupled bone remodeling. However, the observation that various models of CF mice display a bone phenotype despite the absence of the usual human confounders (i.e. inflammation, steroid hormone use, pancreatic insufficiency, etc.) led us to propose that CFTR, itself, plays a non-negligible role in the regulation of bone metabolism. This project will study the impact of the absence of CFTR on the osteoblasts (Ob) and osteoclasts (Oc) in a CF mouse model, namely the BALB/c Cftr-/- mice. In addition, Ob are recognized as having a modulating effect on the leukocyte microenvironment of the bone marrow (BM). This project will also investigate the impact of the absence of CFTR on the leukocyte niche in the BM. Our bone densitometry and X-ray microtomography results showed that Cftr -/- mice have lower bone density and bone mineral content vs. Cftr +/+ mice as well as a decrease in trabecular bone volume and trabecular number, and a greater trabecular separation. To further understand this bone phenotype, we confirmed that BM- derived Ob expressed CFTR at the gene and protein level, but not BM-derived osteoclasts. Such observations support our findings showing that only Ob differenciation and function were affected by the absence of CFTR. The osteoblastic defect appears to adversely affect the BM leukopoiesis as decreased numbers of T cells, macrophages and dendritic cells were observed in Cftr -/- mice vs. Cftr +/+. In light of these findings, we believe that the absence of CFTR has an important impact on the Ob and the bone marrow.

Keyphrases: CFTR, Cystic fibrosis, Bone disease, Osteoblast, Bone marrow, Leukopoiesis
Altérations synaptiques à la jonction neuromusculaire dans un modèle murin de sclérose latérale amyotrophique

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. Denervation of the neuromuscular junction (NMJ) is an early pathological event in various ALS models. Motor units (MU) appear unequally susceptible to denervation, the fast fatigable (FF) MU being the most vulnerable and the slow (S) MU the most resistant. While previous studies in several ALS models have consistently reported alterations in synaptic transmission, their findings have been contradictory. Interestingly, the MU types were not taken into account in these studies, which could explain these discrepancies. We hypothesized that the MU selective vulnerabilities observed in ALS will be associated with MU-specific NMJ alterations throughout the disease course. Using electrophysiology, we studied synaptic transmission of different types of MU in the fast-twitch Extensor Digitorum Longus (EDL; fast fatigable (FF) MU) and the slow-twitch Soleus (SOL; slow (S) and fast fatigue resistant (FR) MU) of the SOD1 mice and their WT littermates. MU types were identified using immunohistochemical labelling of the respective myosine heavy chains. Immunohistochemistry was also performed to assess NMJ integrity by using antibodies against main NMJ components. At a presymptomatic stage (P160), while no morphological alterations of NMJs were seen in both muscles, evoked activity was altered in a MU-specific manner in SOD1 mice.  FF MU from SOD1 mice showed a decrease in EPP amplitude and quantal content whereas S MU showed the opposite. Mutant FR MU showed no difference in evoked activity compared to WT. At presymptomatic stage (P380), various morphological alterations were seen in the SOD1 EDL, including denervation, partial innervation and nerve sprouting. Evoked activity was still reduced in FF MU, as well as mEPP frequency. In contrast, at disease onset (P425), synaptic strength of the S MU was now similar to WT MU, whereas FR NMJs showed a decrease in EPP amplitude and quantal content. Surprisingly, paired-pulse facilitation was not altered in any MU type and at any age despite changes in synaptic strength. Taken together, these results reveal that NMJ function is differentially modified according to MU susceptibility in ALS. This study provides insights for a better understanding of NMJ physiology during the illness that is crucial to the development of a proper NMJ-targeted treatment in ALS.

Keyphrases: Neuromuscular Junction, Motor Unit, Amyotrophic lateral sclerosis, Electrophysiology, Synaptic Transmission
A Mediated Presence : Uncovering Nietzsche in Art History from its Foundations to Contemporary Anglo-American Curricula

Nietzsche’s philosophy has played an active role in many recurring art historical debates that have permeated the discipline since its inception, yet there exists no systematic analysis of his impact. His influence has been mediated through various interlocutors, art historical and other, that have framed these discussions, while using his writings as an intellectual backdrop to their own ideas. This thesis attempts to show that Nietzsche’s engagement with art history has been submerged or overshadowed by an emphasis on the mediators of his thought with little direct engagement with his work, particularly so in the Anglo-American context. The consequence of this is that his genealogical importance for many of the founders of the discipline is left unacknowledged; hence, his actually potent presence is translated as an absence or oversight. In order to demonstrate this, we explore the Nietzschean heritage that informed the works of art historians like Jacob Burckhardt and Aby Warburg, and that of philosophers and writers who have marked the art historical discipline (particularly so with the surge of “French Theory” in Anglo-American art history as of the late 1970s): Martin Heidegger, Michel Foucault, Jacques Derrida, Gilles Deleuze and Georges Bataille. Once we have identified some of the trajectories on which his ideas have gained relevancy for art history, we look at the potential reasons for their subsequent occlusion. In order to do this, we begin by examining the evolving methodologies in historiography so as to situate his contribution to this domain of study and see where these reflections have intersected with those of art historians who either broadened or reshaped the methods and analytical structures of their own discipline. We finally compare Nietzsche’s 'art' to the “art of art history” (Preziosi 2009) and determine whether these two expressions can be bridged or whether there is a fundamental incompatibility that may explain the discrepancy between his treatment of art and that which concerned art history at the moment of its contemporaneous institutionalisation.

Keyphrases: Nietzsche, Aby Warburg, Jacob Burckhardt, transmission culturel, French Theory, Art history, Historiography, cultural transmission, anachronism, French Theory, philosophy of art
Les trajectoires de femmes victimes de violence conjugale : les facteurs qui expliquent la dynamique de la violence physique à travers le temps

Intimate partner violence can take many forms and violence experienced by victims tends to vary over time. One cannot rule out the possibility that the expression of violence in individual trajectories will depend on the context in which the victim is.  Life course perspective is thus an appropriate theoretical framework for understanding these temporal changes. However, empirical support on factors behind these changes in intimate partner violence chronicity and intensity over time is thin; especially because of scarcity of longitudinal or retrospective data required for this type of research. This study proposes to fill these gaps in analyzing individual trajectories of women who have been victims of intimate partner violence. Specifically, it analyses the variation of occurrence and intensity of physical violence over the time. The data issued in this study include a sample of 53 victims of intimate partner violence referred by different organisms such as shelters, therapy centres, halfway house, crime victim’s assistance center and Health and Social Services Centres. This research is based on retrospective data that recap circumstances surrounding the life of these women over the past 36 months. These short-term individual trajectories were reconstructed using the method of life history calendars; method that has proven itself in the understanding of criminal careers. Multilevel models deployed allow to examine the impact of individual characteristics as well as life circumstances on changes in frequency and intensity of violence. Findings allow a better understanding of static and dynamic elements behind trajectories of women victims of intimate partner violence. This research is intended to be exploratory and opens the door to a multiplicity of possibilities with future researches.

Keyphrases: Intimate partner violence, Trajectories of victimization, Life history calendars, Life-course perspective
Traitement de la douleur chronique non cancéreuse à l’aide d’opioïdes : efficacité à long terme

Chronic non-cancer pain (CNCP) is a complex phenomenon and multimodal interventions that address both its biological and psychosocial dimensions are considered as the optimal approach for treating this type of disorder. Prescription of opioids for CNCP has dramatically increased over the past two decades but little is known about the long-term effectiveness of this type of medication for reducing pain severity and improving quality of life of CNCP patients. The objective of the present study was to investigate in a real life context the long-term effectiveness of opioids for reducing pain intensity and interference, and improving health-related quality of life in patients with CNCP over a one-year period. Methods: Participants were 1,490 patients (mean age = 52.37 (SD = 13.9); female = 60.9%) enrolled in the Quebec Pain Registry between October 2008 and April 2011  who completed a series of questionnaires before initiating treatment at a tertiary multidisciplinary pain management facility as well as 6 and 12 months thereafter. Based on their opioid use profile (OUP), patients were categorized into 1) non users, 2) non-persistent users, and 3) persistent users. Data were analyzed using generalized estimating equation models. Results: Among the users of opioids, 52% stopped taking them during the follow-up period. After adjusting for age and sex, patients’ OUP significantly predicted pain intensity felt during 7-day periods (p < 0.001) and physical quality of life (pQOL) over time p < 0.001). Compared to non-users, persistent users had significantly higher levels of pain intensity and poorer pQOL. A significant interaction was found between patients’ OUP and time in the prediction of worst pain intensity (p = 0.001) but the persistent users reported the highest pain scores across time. A significant interaction was also observed between patients’ OUP and type of pain in the prediction of pain interference (p = 0.048) and mental quality of life (mQOL) (p = 0.042). Irrespective of the type of pain they suffered, persistent users reported higher pain interference scores and lower mQOL compared to non users. However, all effect sizes were small (Cohen’s d < 0.5), thus questioning the power and clinical significance of these group differences. Conclusion: These results contribute to the debate by adding evidences on the effectiveness of long term opioid therapy and question the role this type of medication should play in the therapeutic arsenal for managing CNCP.

Keyphrases: opioids, chronic pain, Quebec Pain Registry, multidisciplinary pain management, treatment effectiveness, opioid use profile
Femmes autochtones et intersectionnalité : féminisme autochtone et le discours libéral des droits de la personne

Indigenous women live an intersectional discrimination, in that it comes from at least two sources: gender and race (or culture), and is more complex than the sum of its sources. Therefore, the claims of indigenous women are on at least two fronts: as Aboriginals, they claim their right to self-determination, but they also claim their rights as women inside their own communities.  Starting from the premise that the Canadian state must recognize the right of self-governement to indigenous peoples and thereby indigneous law, we question the ways in which indigenous women are to exercise influence to gain recognition and accept their political and legal claims in decision-making process of their communities.  Are feminist and indigenous claims necessarily contradictory? For some indigenous authors, a liberal approach based on human rights is incompatible with indigenous values. How to overcome these apparently unshakable objections? Is the native women's problem simply a question of unrecognized rights? Is it not rather a problem of power relations outside, but also inside communities?  In what follows, we try to show that beyond a theoretical framework based on human rights, the democratic principle-based approach would allow indigenous women to assert their claims as women and as an indigenous in a more efficient manner. Indeed, the democratic participation of all community members would bypass the theoretical problems related to a dichotomy between individual and collective rights, with an emphasis on decision-making rather than on the value of the resulting decisions. In this perspective, feminism and native claims can ally advantageously.

Keyphrases: Feminism, Indigenous women, Indigenous law, Intersectionality, Federalism
Sélection in vivo par phage display dans un modèle de sténose valvulaire aortique chez la souris pour la découverte de nouveaux peptides ciblant la valve aortique

Aortic valve stenosis (AVS) is the most prevalent valvular heart disease that affects the elderly in developed country. The active disease process is characterized by lipid deposition, inflammation, fibrosis and active leaflet calcification that progress into the thickening and stiffening of the aortic valve, decreasing the aortic valve orifice. We hypothesized that the pathogenesis of AVS modifies progressively the valvular endothelium leading to the expression of tissue and disease-specific biomarkers. Here, we report the use of in vivo phage display screenings of random peptide libraries to discover new peptide candidates that target impaired aortic valves in mice. Old Ldlr-/-;hApoB+/+ mice with AVS were used for the in vivo screening of a constrained or a linear random 7 amino acids phage library. After 4 rounds of screening, we characterized 14 different phages that were separated in 5 repeated consensus motifs for the linear library and 11 different phages representing 5 different consensus motifs for the constrained library. The specificity of 4 candidate phages from the linear library and of 5 phages from the constrained library was studied by immunostaining of phages displaying the consensus peptide sequence of interest in tissue slices of aortic valve compared to control tissues from liver, kidney, ventricle, spleen and lungs. Among those, 4 phages represent interesting candidate peptides that will need to be further tested to assess their in vivo specificity to the valve.  Although further validation remains to be performed, the candidate homing peptides found could represent useful molecular imaging agents or therapeutic delivery carriers to target diseased aortic valves.

Keyphrases: Phage display, In vivo, Aortic valvular stenosis, Animal model, Imaging
Régulation du facteur de transcription FOXK1 par O-GlcNAcylation : implications dans la différenciation adipocytaire

Post-translational modifications such as phosphorylation, O-GlcNAcylation and ubiquitination play critical roles in coordinating protein function and are therefore involved in diverse cellular processes. Of relevance here, ubiquitination may be removed by deubiquitinases such as the tumour suppressor BAP1, which represents the most mutated deubiquitinase gene in the human genome. Recent studies have revealed that important and dynamic post-translational modifications regulate several functions of the BAP1 complex. Indeed, BAP1 has been shown to form a multi-protein complex with several transcriptional regulators including the polycomb group protein OGT and the transcription factors FOXK1 and FOXK2. OGT is a unique enzyme that catalyzes the addition of an O-GlcNAc moiety to target proteins, which impacts protein function including enzymatic activity, protein-protein interactions and subcellular localization. This modification is also highly linked to cellular metabolism, as the donor substrate for the reaction, UDP-GlcNAc, is derived from the hexosamine biosynthesis pathway. Similarly, FOXK1 and FOXK2 have been shown to be implicated in metabolic processes such as myogenesis and autophagy. During our studies, we identified FOXK1 but not FOXK2 as a novel substrate of OGT. Further, we found that this OGlcNAcylation is modulated during the entry/exit of cell cycle. We also found that FOXK1 is critical for adipogenesis and that the interaction between FOXK1/BAP1 is compromised during nutrient starvation. Thus, our studies have revealed that OGT selectively modulates and regulates components of the BAP1 complex which may impact different cellular processes, notably chromatin remodelling and could help understanding how BAP1 acts as a tumor suppressor.

Keyphrases: FOXK1, FOXK2, BAP1, OGT, Ubiquitination, O-GlcNAcylation, Polycomb, Adipogenesis, Metabolism
La victimisation par les pairs et le développement de l’anxiété sociale au début de l’adolescence : l’effet modérateur des caractéristiques des amis

The aim of this study was to explore to what extent the number of friends and friends’ characteristics interact with peers’ victimization to predict the development of social anxiety over time. More specifically, friends’ characteristics considered by this study were peers’ victimization, peers’ rejection and social anxiety average levels as potential aggravating factors. Data was collected two consecutive years, from 576 adolescents of 13,5 years old average. The data was collected first during the fall semester of 8th grade, and a second time during the spring semester of 9th grade. Participants answered self-reported questionnaires concerning peers’ victimization and social anxiety. They also participated in a sociometric nomination procedure within their school and classroom concerning social status and friends’ identification. Results indicated that peers’ victimization and friends’ characteristics (i.e. social anxiety and rejection levels) have an additive contribution when predicting concurrent social anxiety. Results also showed that peers’ victimization predicted subsequent increase in social anxiety 1.5 year later. However, the number of friends and friends’ characteristics did not show any additive effect in predicting development of ulterior social anxiety. Moreover, friends’ characteristics do not interact with victimization to predict ulterior social anxiety. Nonetheless, exploratory analysis showed that friends’ victimization acts as an aggravating factor for participants with a negative social status: peers’ rejection being positively associated to an increase in social anxiety in students with victimized friends.

Keyphrases: Social anxiety, Victimization, Social rejection, Friendships, Friends’ characteristics, Number of friends, Adolescents, Longitudinal study
Le CpG et le poly(I:C) agissent en synergie avec le trastuzumab contre le cancer du sein HER2+

In murine models, anti-HER2 therapy has been shown to be dependent on IFN-γ-producing CD8+ T cells and type I IFN responses. These IFN are induced by TLRs following the recognition of danger signals, called PAMPs or DAMPs. Both TLR-3 and TLR-9 are well known inducers of type I IFN and were also shown to act synergistically to enhance the levels of IFN-γ, TNF-α, and IL-12. Our hypothesis thus was that the stimulation of those two TLRs would lead to an enhancement of the activity of trastuzumab against tumor cells by the recruitment and activation of immune cells. Our goals were to assess the potential therapeutic effects of a combination of anti-HER2 mAbs, TLR-3 agonist poly(I:C) and TLR-9 agonist CpG ODN. In vivo and in vitro studies enabled us to discover a synergy between all agents resulting in a more efficient targeted cytotoxicity. Moreover, this therapy was fully effective in a CD8-dependant cell line as well as a CD8-independent one. Mice were able to completely reject their tumor and remain tumor-free weeks after the injections. Those mice were also protected against a rechallenge, thus underlining the presence of an immune memory. We also discovered that the combined administration of trastuzumab and the TLR agonists leads to systemic responses. Depleting studies confirmed that T CD8+ cells are crucial for the animal to remain tumor-free on the long term, but that pDC are far less involved than what we could have thought. Their absence only modestly affected the outcome of our therapy. On the counterpart, NK cells were important mediators of the therapeutic effect. ADCC assays revealed that both CpG ODN and poly(I:C) are able to enhance the functions of NK cells, but that simultaneous stimulation of the TLR-3 and TLR-9 allows to maximize the beneficial effects of trastuzumab. The same way, the addition of both CpG ODN and poly(I:C) to the anti-HER2 mAbs further enhanced pro-inflammatory responses, more specifically IFN-γ, TNF-α, IP-10 and IL-12.

Keyphrases: HER2/ErbB2, Trastuzumab, in vivo, in vitro, CpG ODN, poly(I:C), ADCC, CTL
Caractérisation et surexpression des fimbriae de type chaperon-placier de Salmonella enterica sérovar Typhi

Salmonella enterica serovar Typhi (S. Typhi) is the etiological agent of typhoid fever which causes more than 200 000 deaths and 27 million cases worldwide, mostly in south Asia. This pathogen can only cause significant symptoms in humans, which are the only recognized animal reservoir. This host restriction is not clearly understood and could depend on the expression of adhesion systems during critical pathogenesis steps. Bioinformatic studies on S. Typhi predict 12 chaperone-usher fimbriae, one curli and one type IV secretion system. The aim of the project was to study those poorly described adhesion systems using two different methodologies. First, transcription levels were evaluated in different in vitro growth conditions using both gfp and β-galactosidase reporter genes. The expression of the 14 adhesion systems was detected, even if some of them were poorly expressed. The expression of bcf and csg was higher during iron-deficiency. Also, the availability of nutrients had an impact on bcf, csg, pil, sef, sta, stc, stg and sth expression, independently of the presence of iron. Most of the adhesion systems showed higher expression levels in liquid LB media with aeration compared to the same media without aeration or supplemented with agar. Secondly, several S. Typhi adhesion systems were cloned into an inducible expression plasmid introduced in both an afimbriated E. coli K-12 strain (ORN172) and an afimbriated S. Typhi strain (ISP1820). This approach enabled us to directly observe the presence of tcf by electron microscopy. Furthermore, the expression of tcf was correlated with a reduction of the capacity of bacteria to adhere to INT-407 human intestinal epithelial cells in an in vitro assay. In summary, this work demonstrates that the putative adhesion systems found in S. Typhi can indeed be expressed and this expression can be regulated by environmental signals. Furthermore, tcf encodes for a functional fimbria which has never before been observed. Taken together, our results suggest a significant contribution of the putative adhesion systems during normal pathogenesis.

Keyphrases: Salmonella enterica serovar Typhi, Fimbriae, Surexpression, Gene expression, Overexpression, Microscopy, Adhesion