Affect at Play: Politics via Videogames

This paper sets out to examine affect as a theoretical framework in the discussion of cognitive and pedagogical potentials of videogames. Using two social justice-focused videogames: 1000 Days of Syria, and This War of Mine, I illustrate the aesthetic and affective qualities which set videogames apart from any other mode of cultural communication. This medium challenges and breaks down the boundaries of the body/the player in order to visibilize forces, sensations and intensities that were otherwise impossible to perceive. I will particularly draw on the works of Gilles Deleuze and his analysis on the ability of art to turn the body into a zone of indiscernability wherein the potentials for becoming and formations of new relationalities are made possible. I explore the ways in which such aesthetic creations disrupt normative thinking and act as a point of rupture in our understanding of politics and question the multiplicity of truth

Affect & Play: Socio-political Videogames as a Site of Felt-knowledge Production

Videogames are affective networks, made up of organic and in-organic matters that come to create a space, where the player learns through doing and watching herself do. For decades, videogames researchers and players have discussed the myriad of ways in which videogames carry enormous pedagogical potentials through their procedures and the creation of a space of play that immerses the player in those procedures and the story of the game. This dissertation builds on this body of knowledge by bringing together the different understandings of affect and affective capacities to further examine the pedagogical potentials of socio-political games through the creation of a felt-knowledge-producing assemblage. I argue this felt knowledge is achieved through the processes of acting in the space of play, watching that action while it takes place, and then engaging with the consequences of the said action. The socio-political videogames curated for the purposes of this research are primarily from the perspectives of civilians living in a warzone, engaging in revolutionary efforts, or civilians who are forced to cross borders as refugees and immigrants as a result of chaos and violence of their homelands. I examine the affective capacities of the space of play through the works of D. W. Winnicott, and I assert that the unique space of videogame play is not only a space where we work through sensations that impact us through play, but we also experience affective intensities that would otherwise remain invisible. In order to access this space of play, I claim the player becomes an assemblage, a network of connectivity, with the power to observe itself forming and reforming through the connections that make the entity: the player+avatar. For this I turn to the work of Gilles Deleuze and assemblage theory. This dissertation, itself, is an assemblage of affect theories and socio-political videogames that capture the invisibilities of our socio-political reality and make them known through the process of play. These games put the player in the story of anothers suffering and oppression by capturing the affective sensations and intensities of a refugee camp or a war zone and ask the player to engage and experiment with what would have been otherwise remained unknown. These socio-political videogames are a new genre of art for an age of digital (mis)information that bring forth a space of play where we can experience and experiment with sensations, vibrations, and affective forces of oppression in order to feel something of it and to know it differently

Structural and functional characterization of matrix glycosaminoglycans of the human cartilage : For a specific use of GAGs and stem cells for cartilage repair in Osteoarthritis.

L'Osteoarthrose (OA) est la maladie articulaire la plus répandue avec un impact socio-économique croissant en raison du vieillissement de la population, de l’augmentation de l'obésité et surtout de l'absence d'un traitement efficace. En effet, l’OA est caractérisée par la dégradation inéluctable du cartilage articulaire, l'apoptose des chondrocytes, un remodelage osseux sous-chondral et une inflammation de la synovie. La matrice extracellulaire (MEC) du cartilage est constituée de collagènes et de protéoglycanes (PG) eux-mêmes composés de glycosaminoglycanes (GAG) liés à un corps proteique, présents dans l'ECM ou à la surface cellulaire. Les GAG sont des chaînes polysaccharidiques linéaires sulfatées comprenant les Héparine/Héparan Sulfate (Hep/HS), Chondroitin Sulfate (CS) et Keratan Sulfate (KS). L'acide hyaluronique (AH) est un GAG non sulfaté particulier, non associé à un corps proteique. Dans le cartilage, l'un des principaux composants de la MEC est l'aggrécan, un CS/KS PG qui forme des aggrégats par interaction avec de l’AH. Au cours du vieillissement, des changements dans la qualité des PG ouvrent la voie à l’OA et les études depuis 60 ans se concentrent sur les aggrécans et le catabolisme des CS. En effets, les niveaux d'expression des CS, la taille de leurs chaînes, leurs profils de sulfatation évoluent, affectant les propriétés mécaniques de la MEC. Cependant, les traitements actuels de visco-supplémentation à base d’injections locales de CS ont démontré leur limite puisque la réparation du cartilage n'est pas induite. Même si ils sont rares dans le cartilage adulte, les HSPG sont associés aux chondrocytes et leurs rôles a été démontrée lors du développement osseux. Or les HS sont des régulateurs de l’homéostasie très importants car ils peuvent lier et réguler l'activité de protéines liant l'héparine (HBP) (facteurs de croissance, cytokines, chimiokines, morphogènes), les protégeant contre la protéolyse et potentialisant leur liaison à leurs récepteurs. Tous ces effets sont contrôlés par les profils de sulfatation complexes des chaînes d’HS.Dans ce contexte les objectifs de cette thèse sont de caractériser l'évolution de la signature chimique et de la fonctionnalité des HS au cours de l’OA. En collaboration avec les Rhumatologistes et Orthopédistes de l’Hopital Henri Mondor, une évaluation quantitative des HS dans des échantillons de cartilage humain contrôle versus OA a été corrélée à la gravité des dommages. Grace à la plateforme glycomic du CRRET, des modifications dans les profils de sulfatation des disaccharides de HS ont été observées et confirmées par des analyses de l'expression des enzymes de la biosynthèse des GAG. Ces caractéristiques structurales ont été corrélées à des changements fonctionnels de l’affinité des GAG pour des HBP, telles que FGF-2, VEGF et PTN. Enfin, les GAG OA ont des capacités différentes à moduler les propriétés (prolifération, adhésion, phénotype) de cellules souches mésenchymateuses, chondrocytes, fibroblastes et cellules endothéliales. Ces résultats démontrent que des modifications des structures et fonctions des HS pourraient être impliquées dans l'évolution de l'homéostasie du cartilage vers des processus pathologiques au cours de l’OA. Ce projet se positionne clairement comme une recherche fondamentale et translationnelle qui permettra d'acquérir des connaissances sur les mécanismes régulant les interactions cellules/matrice au cours de l'OA. De plus, les outils développés au cours de ce projet ont permis de réaliser 2 projets collaboratifs sur l'hypertension artérielle pulmonaire et une pathologie éosophagique. Enfin, ces données confirment l'intérêt d’identifier de nouvelles cibles glycaniques basées sur la chimie des HS. Cela permettra de proposer une nouvelle stratégie thérapeutique basée sur des composes à même de contrôler les profils de sulfatation de la MEC, dans le but d'améliorer les propriétés de cellules souches thérapeutiques endogènes ou exogènes, associées.Osteoarthritis (OA) is the most prevalent joint disease with increasing socio-economic impact due to population aging, obesity , and absence of an efficient medical treatment that can repair cartilage. OA is characterized by degradation of articular cartilage, hypertrophy and apoptosis of chondrocytes, subchondral bone remodeling and joint synovial inflammation. Cartilage extracellular matrix (ECM) consists of collagens, glycoproteins and proteoglycans (PGs) that are composed of Glycosaminoglycans (GAGs) linked to core proteins, presents in the ECM or at the cell surface. GAGs are linear polysaccharidic sulfated chains including Heparine/Heparan Sulfate (Hep/HS), Chondroitin Sulfate (CS) and Keratan Sulfate (KS) families. Hyaluronic acid (HA) is a particular un-sulfated GAG no associated to core protein. In cartilage, one of the major ECM component is aggrecan, a CS/KS PG that form aggregate through HA interaction. During the aging process, changes in PGs quality pave the way for OA and studies are focus on aggrecans and CS catabolism since 60 years. CS expression levels, chain size, sulfation patterns evolved during OA, affecting the mechanical properties of ECM. However, treatments based on visco-supplementation with CS local injections have demonstrated their limit since cartilage repair is not induced. Even if rare in adult cartilage, HSPG are present associated to chondrocytes also and their relevance was demonstrated mainly during bone development. HS chains are very important homeostatic regulators because they are able to bind and regulate the activity of several heparin binding proteins (HBP) (growth factors, cytokines, chemokines, morphogens), protecting them against proteolysis and potentiating their binding to their receptors. These interactions provide a stock of regulatory factors that can be release by selective degradation of the HS chains too. All these regulatory effects are mediated through the complex sulfation/acetylation pattern of HS chains but no data are available on this aspect during OA.In this context, the goals of this Thesis were to characterize the evolution of HS chemical signature and functionality during OA. In collaboration with Rheumatology and Orthopedic clinical teams from Henri Mondor Hospital, a quantitative evaluation of HS and CS amount in control versus OA human cartilage samples was correlated to the structural damage severity. According to the tools of the CRRET’s lab glycomic platform, structural changes on HS and CS sulfated disaccharides compositions was observed using HPLC, confirmed by RQ-PCR analyzes of the expression of enzymes involved in GAG biosynthesis. These structural features were correlated to functional changes on HBP affinities, such as FGF-2, VEGF and PTN, through ELISA based competition assay. Finally, GAGs from OA have different abilities to modulate properties (adhesion proliferation, phenotype…) of Mesenchymal Stem Cells, chondrocytes, fibroblast and endothelial cells. These results clearly make the proof that modifications of HS structures and functions could be involved in the evolution of cartilage homeostasis and pave the way for altered pathological processes during OA. This project is clearly positioned as a fundamental and translational research that will permit to gain knowledge on the mechanisms regulating cartilage cells/matrix interactions during OA. All these results are summarized in 2 scientific and 1 review articles. Moreover, all the tools developed during this project have permit to realize 2 collaborative projects and associated articles on Pulmonary Hypertension and Eosophagic pathology also. Finally, all these data confirmed the interest of the team to identify new glycanic targets based on HS chemistry. This will permit to propose new therapeutic strategy based on HS compounds associated to endogenous or exogenous therapeutic stem cells, with the aim of improving cell properties according to HS ability to control sulfation panels of ECM

Caracterisations structurales et fonctionnelles des glycosaminoglycannes matriciels dans le cartilage humain : pour une utilisation spécifique de GAG et de cellules souches pour la réparation du cartilage dans l'Osteoarthrose.

Osteoarthritis (OA) is the most prevalent joint disease with increasing socio-economic impact due to population aging, obesity , and absence of an efficient medical treatment that can repair cartilage. OA is characterized by degradation of articular cartilage, hypertrophy and apoptosis of chondrocytes, subchondral bone remodeling and joint synovial inflammation. Cartilage extracellular matrix (ECM) consists of collagens, glycoproteins and proteoglycans (PGs) that are composed of Glycosaminoglycans (GAGs) linked to core proteins, presents in the ECM or at the cell surface. GAGs are linear polysaccharidic sulfated chains including Heparine/Heparan Sulfate (Hep/HS), Chondroitin Sulfate (CS) and Keratan Sulfate (KS) families. Hyaluronic acid (HA) is a particular un-sulfated GAG no associated to core protein. In cartilage, one of the major ECM component is aggrecan, a CS/KS PG that form aggregate through HA interaction. During the aging process, changes in PGs quality pave the way for OA and studies are focus on aggrecans and CS catabolism since 60 years. CS expression levels, chain size, sulfation patterns evolved during OA, affecting the mechanical properties of ECM. However, treatments based on visco-supplementation with CS local injections have demonstrated their limit since cartilage repair is not induced. Even if rare in adult cartilage, HSPG are present associated to chondrocytes also and their relevance was demonstrated mainly during bone development. HS chains are very important homeostatic regulators because they are able to bind and regulate the activity of several heparin binding proteins (HBP) (growth factors, cytokines, chemokines, morphogens), protecting them against proteolysis and potentiating their binding to their receptors. These interactions provide a stock of regulatory factors that can be release by selective degradation of the HS chains too. All these regulatory effects are mediated through the complex sulfation/acetylation pattern of HS chains but no data are available on this aspect during OA.In this context, the goals of this Thesis were to characterize the evolution of HS chemical signature and functionality during OA. In collaboration with Rheumatology and Orthopedic clinical teams from Henri Mondor Hospital, a quantitative evaluation of HS and CS amount in control versus OA human cartilage samples was correlated to the structural damage severity. According to the tools of the CRRET’s lab glycomic platform, structural changes on HS and CS sulfated disaccharides compositions was observed using HPLC, confirmed by RQ-PCR analyzes of the expression of enzymes involved in GAG biosynthesis. These structural features were correlated to functional changes on HBP affinities, such as FGF-2, VEGF and PTN, through ELISA based competition assay. Finally, GAGs from OA have different abilities to modulate properties (adhesion proliferation, phenotype…) of Mesenchymal Stem Cells, chondrocytes, fibroblast and endothelial cells. These results clearly make the proof that modifications of HS structures and functions could be involved in the evolution of cartilage homeostasis and pave the way for altered pathological processes during OA. This project is clearly positioned as a fundamental and translational research that will permit to gain knowledge on the mechanisms regulating cartilage cells/matrix interactions during OA. All these results are summarized in 2 scientific and 1 review articles. Moreover, all the tools developed during this project have permit to realize 2 collaborative projects and associated articles on Pulmonary Hypertension and Eosophagic pathology also. Finally, all these data confirmed the interest of the team to identify new glycanic targets based on HS chemistry. This will permit to propose new therapeutic strategy based on HS compounds associated to endogenous or exogenous therapeutic stem cells, with the aim of improving cell properties according to HS ability to control sulfation panels of ECM.L'Osteoarthrose (OA) est la maladie articulaire la plus répandue avec un impact socio-économique croissant en raison du vieillissement de la population, de l’augmentation de l'obésité et surtout de l'absence d'un traitement efficace. En effet, l’OA est caractérisée par la dégradation inéluctable du cartilage articulaire, l'apoptose des chondrocytes, un remodelage osseux sous-chondral et une inflammation de la synovie. La matrice extracellulaire (MEC) du cartilage est constituée de collagènes et de protéoglycanes (PG) eux-mêmes composés de glycosaminoglycanes (GAG) liés à un corps proteique, présents dans l'ECM ou à la surface cellulaire. Les GAG sont des chaînes polysaccharidiques linéaires sulfatées comprenant les Héparine/Héparan Sulfate (Hep/HS), Chondroitin Sulfate (CS) et Keratan Sulfate (KS). L'acide hyaluronique (AH) est un GAG non sulfaté particulier, non associé à un corps proteique. Dans le cartilage, l'un des principaux composants de la MEC est l'aggrécan, un CS/KS PG qui forme des aggrégats par interaction avec de l’AH. Au cours du vieillissement, des changements dans la qualité des PG ouvrent la voie à l’OA et les études depuis 60 ans se concentrent sur les aggrécans et le catabolisme des CS. En effets, les niveaux d'expression des CS, la taille de leurs chaînes, leurs profils de sulfatation évoluent, affectant les propriétés mécaniques de la MEC. Cependant, les traitements actuels de visco-supplémentation à base d’injections locales de CS ont démontré leur limite puisque la réparation du cartilage n'est pas induite. Même si ils sont rares dans le cartilage adulte, les HSPG sont associés aux chondrocytes et leurs rôles a été démontrée lors du développement osseux. Or les HS sont des régulateurs de l’homéostasie très importants car ils peuvent lier et réguler l'activité de protéines liant l'héparine (HBP) (facteurs de croissance, cytokines, chimiokines, morphogènes), les protégeant contre la protéolyse et potentialisant leur liaison à leurs récepteurs. Tous ces effets sont contrôlés par les profils de sulfatation complexes des chaînes d’HS.Dans ce contexte les objectifs de cette thèse sont de caractériser l'évolution de la signature chimique et de la fonctionnalité des HS au cours de l’OA. En collaboration avec les Rhumatologistes et Orthopédistes de l’Hopital Henri Mondor, une évaluation quantitative des HS dans des échantillons de cartilage humain contrôle versus OA a été corrélée à la gravité des dommages. Grace à la plateforme glycomic du CRRET, des modifications dans les profils de sulfatation des disaccharides de HS ont été observées et confirmées par des analyses de l'expression des enzymes de la biosynthèse des GAG. Ces caractéristiques structurales ont été corrélées à des changements fonctionnels de l’affinité des GAG pour des HBP, telles que FGF-2, VEGF et PTN. Enfin, les GAG OA ont des capacités différentes à moduler les propriétés (prolifération, adhésion, phénotype) de cellules souches mésenchymateuses, chondrocytes, fibroblastes et cellules endothéliales. Ces résultats démontrent que des modifications des structures et fonctions des HS pourraient être impliquées dans l'évolution de l'homéostasie du cartilage vers des processus pathologiques au cours de l’OA. Ce projet se positionne clairement comme une recherche fondamentale et translationnelle qui permettra d'acquérir des connaissances sur les mécanismes régulant les interactions cellules/matrice au cours de l'OA. De plus, les outils développés au cours de ce projet ont permis de réaliser 2 projets collaboratifs sur l'hypertension artérielle pulmonaire et une pathologie éosophagique. Enfin, ces données confirment l'intérêt d’identifier de nouvelles cibles glycaniques basées sur la chimie des HS. Cela permettra de proposer une nouvelle stratégie thérapeutique basée sur des composes à même de contrôler les profils de sulfatation de la MEC, dans le but d'améliorer les propriétés de cellules souches thérapeutiques endogènes ou exogènes, associées

Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies

International audienceGraft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50% of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNFα-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells

Weighted correlation network analysis revealed novel long non-coding RNAs for colorectal cancer

International audienceAbstract Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, which after breast, lung and, prostate cancers, is the fourth prevalent cancer in the United States. Long non-coding RNAs (lncRNAs) have an essential role in the pathogenesis of CRC. Therefore, bioinformatics studies on lncRNAs and their target genes have potential importance as novel biomarkers. In the current study, publicly available microarray gene expression data of colorectal cancer (GSE106582) was analyzed with the Limma, Geoquery, Biobase package. Afterward, identified differentially expressed lncRNAs and their target genes were inserted into Weighted correlation network analysis (WGCNA) to obtain modules and hub genes. A total of nine differentially expressed lncRNAs (LINC01018, ITCH-IT, ITPK1-AS1, FOXP1-IT1, FAM238B, PAXIP1-AS1, ATP2B1-AS1, MIR29B2CHG, and SNHG32) were identified using microarray data analysis. The WGCNA has identified several hub genes for black (LMOD3, CDKN2AIPNL, EXO5, ZNF69, BMS1P5, METTL21A, IL17RD, MIGA1, CEP19, FKBP14), blue (CLCA1, GUCA2A, UGT2B17, DSC2, CA1, AQP8, ITLN1, BEST4, KLF4, IQCF6) and turquoise (PAFAH1B1, LMNB1, CACYBP, GLO1, PUM3, POC1A, ASF1B, SDCCAG3, ASNS, PDCD2L) modules. The findings of the current study will help to improve our understanding of CRC. Moreover, the hub genes that we have identified could be considered as possible prognostic/diagnostic biomarkers. This study led to the determination of nine lncRNAs with no previous association with CRC development

Post-decellularization techniques ameliorate cartilage decellularization process for tissue engineering applications

International audienceDue to the current lack of innovative and effective therapeutic approaches, tissue engineering (TE) has attracted much attention during the last decades providing new hopes for the treatment of several degenerative disorders. Tissue engineering is a complex procedure, which includes processes of decellularization and recellularization of biological tissues or functionalization of artificial scaffolds by active cells. In this review, we have first discussed those conventional steps, which have led to great advancements during the last several years. Moreover, we have paid special attention to the new methods of post-decellularization that can significantly ameliorate the efficiency of decellularized cartilage extracellular matrix (ECM) for the treatment of osteoarthritis (OA). We propose a series of post-decellularization procedures to overcome the current shortcomings such as low mechanical strength and poor bioactivity to improve decellularized ECM scaffold towards much more efficient and higher integration

Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells

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Research and Therapeutic Approaches in Stem Cell Genome Editing by CRISPR Toolkit

The most widely used genome editing toolkit is CRISPR (clustered regularly interspaced short palindromic repeats). It provides the possibility of replacing and modifying DNA and RNA nucleotides. Furthermore, with advancements in biological technology, inhibition and activation of the transcription of specific gene(s) has become possible. Bioinformatics tools that target the evolution of CRISPR-associated protein 9 (Cas9) turn this protein into a vehicle that is specific for a DNA or RNA region with single guide RNA (sgRNA). This toolkit could be used by researchers to investigate the function of stem cell gene(s). Here, in this review article, we cover recent developments and applications of this technique in stem cells for research and clinical purposes and discuss different CRISPR/Cas technologies for knock-out, knock-in, activation, or inhibition of gene expression. Additionally, a comparison of several deliveries and off-target detecting strategies is discussed

TNFα priming through its interaction with TNFR2 enhances endothelial progenitor cell immunosuppressive effect: new hope for their widespread clinical application

International audienceAbstract Background Bone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the chance of immune rejection, especially by T cells, before exerting the desired regenerative functions. TNFα is one of the main mediators of EPC activation that recognizes two distinct receptors, TNFR1 and TNFR2. We have recently reported that human EPCs are immunosuppressive and this effect was TNFα-TNFR2 dependent. Here, we aimed to investigate if an adequate TNFα pre-conditioning could increase TNFR2 expression and prime EPCs towards more immunoregulatory functions. Methods EPCs were pre-treated with several doses of TNFα to find the proper dose to up-regulate TNFR2 while keeping the TNFR1 expression stable. Then, co-cultures of human EPCs and human T cells were performed to assess whether TNFα priming would increase EPC immunosuppressive and immunomodulatory effect. Results Treating EPCs with 1 ng/ml TNFα significantly up-regulated TNFR2 expression without unrestrained increase of TNFR1 and other endothelial injury markers. Moreover, TNFα priming through its interaction with TNFR2 remarkably enhanced EPC immunosuppressive and anti-inflammatory effects. Conversely, blocking TNFR2 using anti-TNFR2 mAb followed by 1 ng/ml of TNFα treatment led to the TNFα-TNFR1 interaction and polarized EPCs towards pro-inflammatory and immunogenic functions. Conclusions We report for the first time the crucial impact of inflammation notably the TNFα-TNFR signaling pathway on EPC immunological function. Our work unveils the pro-inflammatory role of the TNFα-TNFR1 axis and, inversely the anti-inflammatory implication of the TNFα-TNFR2 axis in EPC immunoregulatory functions. Priming EPCs with 1 ng/ml of TNFα prior to their administration could boost them toward a more immunosuppressive phenotype. This could potentially lead to EPCs’ longer presence in vivo after their allogenic administration resulting in their better contribution to angiogenesis and vascular regeneration