Translocation t(12;21) with the presence of the fusion gene ETV6-RUNX1 (TEL-AML1) is the most common chromosomal aberration found in acute lymphoblastic leukemia in childhood. The occurrence of the ETV6-RUNX1 is associated with excellent prognosis and high sensitivity to the treatment with the enzyme L-asparaginase (ASNase). Resistance to the drug aggravates the outlook of the patient and increases the risk of treatment failure, therefore, the CLIP working group has been for a long time involved in the identification of the mechanism of action of ASNase and the origin of the resistance to it. This thesis follows previous findings of the group and is devoted to the analysis of the importance of ETV6-RUNX1 and signalization and metabolic changes accompanying shifts in the L-asparaginase resistance. In the first part of the thesis, the knockout clones with stable increased resistance to ASNase have been established thanks to the CRISPR/Cas9 system, which created frameshift in the fusion gene. The accomplishment in this regard and removal of the fusion protein was confirmed on the level of DNA, mRNA a protein expression. The presence of other significant chromosomal aberrations affection the sensitivity to ASNase was ruled out by the means of SNP analysis. In the second part of the project, the signalization...

Understanding math is an important part of school, yet it is a common source of anxiety as many children find the subject difficult to grasp. One approach to encourage children to learn math is to implement game elements (gamification) in technology-enhanced learning (TEL) systems. However, designers must consider what motivates children to use such systems to better encourage them to learn. Therefore, the aim of this paper was to investigate how gamification can be implemented in the design of a mobile TEL application, in this case the Albert application, to motivate children to learn math. This was researched by designing a concept focusing on avatars for Albert and letting users between the ages of 10 and 12 evaluate it. The design process followed the Double Diamond model, and the game elements were designed according to three core drives from the Octalysis framework. The results showed that children who like math are more likely to become motivated by the presented gamification concept than the children who have a more negative attitude towards math. As a conclusion, one can motivate children to learn math using a TEL platform by including avatarism as a form of gamification. / Att förstå matte är en viktig del av skolgången, samtidigt kan det ofta vara ångestframkallande för barn som anser att ämnet är svårt att greppa. Ett sätt att uppmuntra barn att lära sig matte är att implementera spelelement i så kallade ”Technology-Enhanced Learning” (TEL)-system. Dock måste designers ha i åtanke vad som motiverar barn att använda sådana system för att bättre kunna uppmuntra dem att lära sig matte. Målet med denna uppsats var därför att undersöka huruvida spelelement kan implementeras i designen av en mobil TEL-applikation, i vårt fall Albertapplikationen, för att motivera barn att lära sig matte. Detta undersöktes genom att designa att koncept fokuserat på avatarer för Albert, och låta användare mellan åldrarna 10 och 12 utvärdera det. Designprocessen följde Double Diamond-modellen, och spelelementen designades utefter tre ”core drives” från Octalysis-ramverket. Resultaten visade att det är mer sannolikt att barn som gillar matte blir mer motiverade av det presenterade konceptet, än barn som har en mer negativ inställning gentemot ämnet. Vi kunde dra slutsatsen att en kan motivera barn att lära sig matte genom att inkludera avatarism i en TEL-applikation.

No description available.

Challenges in the South African education system arise from inter alia inadequate training, social and environmental problems, parental inefficiency, insufficient professionalism among teachers, as well as negative attitudes of learners. An urgent need exists to establish “a moral underground, an army of volunteers” (Jansen, 2012) who would be willing to provide another chance to “abandoned children” in poorer schools to develop their full potential for a brighter future. To assist learners to achieve a better future, this study focused on teacher-students and to enhance their learning experiences and consequently their teaching performance. By motivating the teacher-students to develop their potential in order to achieve better, they could, in turn, break the barriers of mediocrity in the learners they taught. The aim of this study was to uncover how a social network service (SNS) like Facebook could be used as an academic tool to support and enhance the affective learning experience of open distance teacher-students in the rural Eastern Cape. The main research question which guided this study was: How can the affective learning of open distance learning teacher-students in the rural Eastern Cape be supported through academic Facebook? The research intervention which elicited data, comprised coaching and scaffolding of the learning content relating to research methodology, as well as guiding the participants to engage with an SNS as a learning technology in an academic environment. The researcher created a support group on Facebook where participants could, at any time, interact with peers and the facilitator. Non-probability purposive sampling selected the participants according to the following criteria: isiXhosa home language speaking teacher-students from the rural areas around Queenstown in the Eastern Cape, enrolled with NWU for a BEd Honours degree, and who owned cellular phones which could connect to the Internet. While 74 teacher-students were invited to participate in the research, only 34 attended some of the coaching and scaffolding sessions, and 22 joined the FaceFunda group page. This qualitative bounded case study was conducted from a postmodern pragmatic view. Data were collected through individual interviews, a focus group interview, text from the FaceFunda group page and the researcher’s reflective diary. The data were analysed with Atlas. ti™. Three patterns emerged which described participants’ affective experiences: (i) emotions while learning with technology, (ii) experiences with technology, and (iii) need for support. In each case, the patterns related to emotions of competence (codes that captured positive and enabling experiences), and emotions of incompetence (codes that captured negative and incapacitating experiences). A secondary analysis of the findings uncovered the guidelines for the academic use of Facebook for rural distance teacher-students. Four themes emerged as guidelines: i) coaching and scaffolding support, (ii) technological support, (iii) peer support, and (iv) communication with the higher education institution. The guidelines highlighted that the affective learning of open distance learning of rural teacher-students in the Eastern Cape can be supported through the academic use of Facebook. ODL teacher-students require support coaching and scaffolding in order to adopt the use of SNSs for academic purposes. Adult learners should be supported to overcome technophobia to enable engagement with learning content. With adequate supportive measures, SNSs can contribute towards positive learning experiences of rural students. / MEd (Learner support), North-West University, Potchefstroom Campus, 2014

Challenges in the South African education system arise from inter alia inadequate training, social and environmental problems, parental inefficiency, insufficient professionalism among teachers, as well as negative attitudes of learners. An urgent need exists to establish “a moral underground, an army of volunteers” (Jansen, 2012) who would be willing to provide another chance to “abandoned children” in poorer schools to develop their full potential for a brighter future. To assist learners to achieve a better future, this study focused on teacher-students and to enhance their learning experiences and consequently their teaching performance. By motivating the teacher-students to develop their potential in order to achieve better, they could, in turn, break the barriers of mediocrity in the learners they taught. The aim of this study was to uncover how a social network service (SNS) like Facebook could be used as an academic tool to support and enhance the affective learning experience of open distance teacher-students in the rural Eastern Cape. The main research question which guided this study was: How can the affective learning of open distance learning teacher-students in the rural Eastern Cape be supported through academic Facebook? The research intervention which elicited data, comprised coaching and scaffolding of the learning content relating to research methodology, as well as guiding the participants to engage with an SNS as a learning technology in an academic environment. The researcher created a support group on Facebook where participants could, at any time, interact with peers and the facilitator. Non-probability purposive sampling selected the participants according to the following criteria: isiXhosa home language speaking teacher-students from the rural areas around Queenstown in the Eastern Cape, enrolled with NWU for a BEd Honours degree, and who owned cellular phones which could connect to the Internet. While 74 teacher-students were invited to participate in the research, only 34 attended some of the coaching and scaffolding sessions, and 22 joined the FaceFunda group page. This qualitative bounded case study was conducted from a postmodern pragmatic view. Data were collected through individual interviews, a focus group interview, text from the FaceFunda group page and the researcher’s reflective diary. The data were analysed with Atlas. ti™. Three patterns emerged which described participants’ affective experiences: (i) emotions while learning with technology, (ii) experiences with technology, and (iii) need for support. In each case, the patterns related to emotions of competence (codes that captured positive and enabling experiences), and emotions of incompetence (codes that captured negative and incapacitating experiences). A secondary analysis of the findings uncovered the guidelines for the academic use of Facebook for rural distance teacher-students. Four themes emerged as guidelines: i) coaching and scaffolding support, (ii) technological support, (iii) peer support, and (iv) communication with the higher education institution. The guidelines highlighted that the affective learning of open distance learning of rural teacher-students in the Eastern Cape can be supported through the academic use of Facebook. ODL teacher-students require support coaching and scaffolding in order to adopt the use of SNSs for academic purposes. Adult learners should be supported to overcome technophobia to enable engagement with learning content. With adequate supportive measures, SNSs can contribute towards positive learning experiences of rural students. / MEd (Learner support), North-West University, Potchefstroom Campus, 2014

A re-examination of our Monte-Carlo modeling of the high-temperature radiolysis of liquid water by low-linear energy transfer (LET~0.3 keV/[micro]m) radiation has been undertaken in an attempt to reconcile our computed g-values (primary yields) of the various radiolytic products (e[superscript -][subscript aq], ¨OH, H¨, H[subscript 2], and H[subscript 2]O[subscript 2]) with recently reevaluated experimental data over the range from 25 up to 350 [degrees]C. The temperature dependence of the rate constant for the self-reaction of the hydrated electron (e[superscript -][subscript aq]) measured under alkaline conditions, and in particular the abrupt drop observed above 150 [degrees]C, was assumed, in contrast to previous study, to be valid also in near-neutral pH water. To best reproduce the currently available temperature-dependent g-values, we found it necessary to introduce a discontinuity in the temperature dependence at 150 [degrees]C of certain parameters that intervene in the physicochemical stage of the radiolysis, including the thermalization distance (r[subscript]th) and the dissociative attachment (DEA) of subexcitation electrons, and the dissociative decay of electronically and vibrationally excited water molecules. With the exception of g(H[subscript 2]) above 200 [degrees]C, all calculated g-values were consistent with the general observation that when the temperature is increased, the yields of free radicals g(e[superscript]-[subscript]aq), g(¨OH), and g(H¨) increase while the molecular yield g(H[subscript 2]O[subscript 2]) decreases.Although H[subscript 2] is a molecular product, g(H[subscript 2]) was observed to continue to increase with temperature for a reason that has been a matter of controversy recently. Our simulations show that the reaction of H¨ atoms with water previously proposed by Swiatla-Wojcik and Buxton can indeed account for the anomalous increase in g(H[subscript 2]) at high temperature if we use for the rate constant of this reaction the value of 10[superscript 4] M[superscript 1] s[superscript -1] at 300 [degrees]C. Finally, as a direct application of the Fricke (ferrous sulfate) dosimeter, we have calculated the spur lifetime ([tau]s) and its temperature dependence. The results show that our calculated [tau]s value is decreasing from 4.2×10[superscript -7] to 5.7×10[superscript -8] s over the temperature range 25-350 [degrees]C.

Le travail que nous présentons dans cette thèse s’inscrit dans une problématique générale des EIAH. Il s’intéresse plus particulièrement aux Massives Open Online Courses (MOOC) et concerne plus précisément l’activité de conception de scénarios pédagogiques par des enseignants dans les environnements MOOC connectivistes (cMOOC). Le but principal est de proposer une approche, des modèles et des outils pour assister les enseignants dans le processus de scénarisation et d’opérationnalisation des scénarios pédagogiques dans le contexte des cMOOC. Afin de répondre à ces besoins, la première partie de cette thèse est consacrée à la spécification du processus de création et de déroulement d’un cMOOC. La deuxième partie du manuscrit est consacrée au modèle cORPS de description de scénarios pédagogiques orientés cMOOC.Pour réifier nos propositions, nous avons développé un outil de scénarisation pédagogique adapté au contexte des cMOOC, appelé MOOCAT. Cet outil est doté d’un service de déploiement automatique des scénarios pédagogiques et exploite la notion de workflow à travers la réutilisation et l’adaptation de la notation BPMN. Finalement, l’environnement MOOCAT a été expérimenté auprès de différents publics d’un point de vue utilité et utilisabilité. Les résultats obtenus permettent de confirmer que MOOCAT permet de concevoir des scénarios pédagogiques connectivistes. Les feedbacks des participants ont souligné particulièrement sa simplicité d’utilisation et le bénéfice d’avoir un outil de scénarisation visuelle. / The work presented in this thesis is part of a broader issue of Technology Enhanced Learning (TEL) field. It is particularly interested in Massive Open online Courses (MOOC) environments and concerns more specifically the activity of designing and conceiving pedagogical scenarios by teachers in connectivist MOOC (cMOOC).The main goal is to provide an approach, models and tools to assist teachers in the scenario conception process and the operationalization of pedagogical scenarios in a cMOOC context.In order to meet these needs, the first part of this thesis is devoted to specification of the cMOOC creation and execution process describing the involved stakeholders and the characteristics of each process step. The second part of the manuscript is consecrated to the cORPS model, which describes and defines a cMOOC-oriented pedagogical scenario.To reify our proposals, we have developed an authoring environment for cMOOC context, called MOOCAT. One of the specific characteristics of our tool lies in the exploitation and reuse of the BPMN notation. This tool and the associated operationalization service are covered in the third part of this manuscript.Finally, different publics of practitioners tested MOOCAT notably from a utility and usability point of view. The obtained findings confirm that MOOCAT can be used to design connectivist pedagogical scenarios and provide all the necessary elements for the design of such courses. Feedback from participants particularly highlighted its ease of use and the benefit of a visual authoring tool.

Submitted by Sara Ribeiro (sara.ribeiro@ucb.br) on 2017-04-10T13:40:31Z No. of bitstreams: 1 VeruscaNajaradeCarvalhoCunhaTese2015.pdf: 1703847 bytes, checksum: a9661f4b3c0b28fe801235efd03b727c (MD5) / Approved for entry into archive by Sara Ribeiro (sara.ribeiro@ucb.br) on 2017-04-10T13:40:39Z (GMT) No. of bitstreams: 1 VeruscaNajaradeCarvalhoCunhaTese2015.pdf: 1703847 bytes, checksum: a9661f4b3c0b28fe801235efd03b727c (MD5) / Made available in DSpace on 2017-04-10T13:40:39Z (GMT). No. of bitstreams: 1 VeruscaNajaradeCarvalhoCunhaTese2015.pdf: 1703847 bytes, checksum: a9661f4b3c0b28fe801235efd03b727c (MD5) Previous issue date: 2015-07-14 / Telomeres are composed of complex deoxyribonucleic acid and proteins located at the ends of chromosomes, formed by a short sequence of nitrogenous bases (5'-TTAGGGn -3 ') repeated several times. Are connected to a multiprotein complex called "shelterin" consists of six proteins (TRF1, TRF2, POT1, TIN2, RAP1 and TPP1) which maintains telomere homeostasis, preventing degradation. Telomeres are affected by the DNA polymerase inability fully replicate the tape 5' end of the chromosome. The results of such failure are successors shortenings with each cell division, which leads to extremely short telomeres at the end of cell division, resulting in cell senescence. Therefore telomeres are considered a potential biomarker of aging at the cellular level. The shortening of telomeres has been associated with an increased risk of developing age-related diseases such as diabetes, cardiovascular disease and obesity. In contrast, it is believed that physical exercise can attenuate the shortening rate of telomeres, even in the elderly. However, it is possible that there is a 'dose' ideal of physical exercise that can enhance this beneficial effect. The objective of this study was to analyze and compare the effects of aerobic training intensity swimming conducted in two intensity domains (high and low) on the expression of genes encoding the protective telomeric proteins (trf1 and trf2), associated proteins cellular senescence (p53 and Chek2), in addition to measuring telomere length in gastrocnemius and myocardium old mice. Sixteen animals were divided into four groups: two groups submitted to twelve weeks of physical training of swimming at low intensity (BI) and high intensity (AI) and two who remained sedentary for the same period, with a group of young animals (CONTj) and elderly animals (CONTi). Training consisted of swimming exercise three times a week, 20 minutes per session for the group AI and 40 minutes for BI with load corresponding to 3% body weight (%PC) (BI) and 6%PC (AI). An incremental test for functional evaluation was performed every four weeks to measure the maximum load (Gm??x). After the training period, animals were sacrificed for removal of tissue samples for analysis of genes expression related to telomeres. The results suggest that high intensity exercise is "teloprotetor" in the gastrocnemius tissue, since telomere length of the elderly animals did not differ from each other, however, the animals in this group (AI) had a lower expression of genes of proteins protective (trf1 and trf2) and cellular senescence (p53). These results suggest that the intensity at which the exercise is performed interfere with telomere length and that this response is tissue dependent, since the same results were not observed in cardiac tissue of animals. / Tel??meros s??o complexos compostos por ??cido desoxirribonucleico e prote??nas, localizados nas extremidades dos cromossomos, formados por uma pequena sequ??ncia de bases nitrogenadas (5???-TTAGGGn -3???) repetida diversas vezes. Encontram-se ligados a um complexo multiprot??ico denominado ???shelterin??? composto por seis prote??nas (TRF1, TRF2, POT1, TIN2, RAP1 e TPP1) que mant??m a homeostase telom??rica, prevenindo sua degrada????o. Os tel??meros s??o afetados pela incapacidade da DNA polimerase replicar completamente o final da fita 5??? do cromossomo. Os resultados de tal falha s??o sucess??veis encurtamentos a cada divis??o celular, o que leva ?? tel??meros extremamente curtos ao t??rmino das divis??es celulares, resultando na senesc??ncia celular. Sendo assim, considerados um potencial biomarcador do envelhecimento a n??vel celular. O encurtamento dos tel??meros tem sido associado a um maior risco de desenvolvimento de doen??as associadas ao envelhecimento, tais como, diabetes mellitus, doen??as cardiovasculares e obesidade. Em contrapartida, acredita-se que o exerc??cio f??sico possa atenuar a taxa de encurtamento dos tel??meros, mesmo em indiv??duos idosos. Contudo, ?? poss??vel que exista uma ???dose??? ideal de exerc??cio f??sico que possa potencializar este efeito ben??fico. Assim, o objetivo do presente estudo foi analisar e comparar os efeitos do treinamento aer??bio de nata????o realizado em dois dom??nios de intensidade (alta e baixa) sobre a express??o dos genes que codificam as prote??nas de prote????o telom??rica (trf1 e trf2), prote??nas associadas ?? senesc??ncia celular (p53 e Chek2), al??m de mensurar o comprimento do tel??mero no gastrocn??mio e no mioc??rdio de camundongos idosos. Dezesseis animais foram divididos em quatro grupos: dois grupos submetidos a doze semanas de treinamento f??sico de nata????o em baixa intensidade (BI) ou alta intensidade (AI) e dois que permaneceram sedent??rios pelo mesmo per??odo, sendo um grupo de animais jovens (CONTj) e um de animais idosos (CONTi). O treinamento consistiu do exerc??cio de nata????o, tr??s vezes por semana, 20 minutos por sess??o para o grupo AI e 40 minutos para o BI, com carga correspondente a 3% do peso corporal (%PC) (BI) e 6%PC (AI). Um teste incremental para avalia????o funcional fora realizado a cada quatro semanas para mensura????o da carga m??xima (Gm??x). Ap??s o t??rmino do per??odo de treinamento, os animais foram sacrificados para retirada de amostras de tecido para an??lise da express??o dos genes relacionados aos tel??meros. Os resultados obtidos sugerem que o exerc??cio de alta intensidade seja ???teloprotetor??? no tecido gastrocn??mio, uma vez que o comprimento do tel??mero dos animais idosos n??o diferiu entre si, embora, os animais desse grupo (AI) apresentaram uma menor express??o dos genes das prote??nas protetoras (trf1 e trf2) e da senesc??ncia celular (p53). Esses resultados sugerem que a intensidade na qual o exerc??cio ?? realizado interfere no comprimento dos tel??meros e que tal resposta ?? tecido dependente, uma vez que os mesmos resultados n??o foram observados no tecido card??aco dos animais.

Cette thèse de doctorat vise à identifier la politique de la littérature dans la trilogie autobiographique de Pierre Guyotat formée par Coma (2006), Formation (2007) et Arrière-fond (2010). L'œuvre de Pierre Guyotat s'articule autour d'une scène originaire d'affrontement entre exploiteurs et exploités qui se présente à la fois comme une poétique et une pensée politique. Selon les moments de l'œuvre, elle prend la forme d'une opposition entre putains et proxénètes, entre généraux et soldats, entre violeurs et violés, entre maîtres et esclaves. Les amis et les ennemis y sont toujours divisés et le vivre-ensemble n'y est pas fondé sur des rapports idylliques entre les sujets, mais plutôt sur un partage, entendu ici au sens de division. Cette inégalité fonde une communauté littéraire peuplée d'un ensemble hétérogène de figures à la fois héroïques et réversibles. À partir de ce noyau, Guyotat met en place un univers où s'expriment les injustices du monde et les rapports de domination qui le traversent. La première partie de la thèse propose une présentation de l'œuvre de Guyotat. Entre la fin des années soixante, où Éden, Éden, Éden est considéré « libre de tout sujet, de tout objet, de tout symbole » par Michel Foucault et comme un texte sans héros qui se résumerait à « l'aventure même du signifiant » par Roland Barthes, et la trilogie autobiographique, il y a un immense fossé. C'est cet écart qui justifie l'analyse de la trilogie selon une méthode à rebours : partir des textes récents pour mettre en place un cadre qui permet de repenser les œuvres anciennes et, inversement, considérer l'ensemble de l'œuvre pour mieux saisir la spécificité de ses manifestations contemporaines. La première partie expose également les fondements théoriques qui gouvernent notre réflexion sur les rapports entre littérature et politique. Notre travail s'appuie principalement sur les théories de Jacques Rancière qui envisagent l'art dans sa portée émancipatrice hors des paramètres de l'engagement littéraire ou d'une téléologie avant-gardiste. La deuxième partie expose d'abord la constitution du sujet en établissant une typologie des différentes modalités énonciatives et représentatives qui en balisent l'action. Nous observons la construction d'un sujet autobiographique, notamment par le dévoilement d'un intertexte critique avec certains textes canoniques, mais aussi en envisageant la trilogie comme une scène d'aveu. Coma et Arrière-fond sont orientés vers une utopie du Verbe et, pourtant, ils sont écrits dans une « langue normative ». La trilogie témoigne de l'échec du projet absolu du Verbe, avouant l'impuissance de la littérature. Ce clivage entre le contenu de la représentation et la forme de l'énonciation met en lumière les limites et la puissance du Verbe. Nous exposerons finalement la manière dont le sujet est captif de son propre corps, tout comme il est sous le joug des mots. Si les mots sont aussi des outils d'émancipation, il en est de même pour le corps, qui devient un lieu potentiel de résistance. Lorsque Guyotat représente un corps individuel assujetti à des dispositifs collectifs, il place en effet le sujet sur une scène historique. La biopolitique, terme issu de la théorie de Foucault, désigne bien le geste de Guyotat qui fait de la massification des corps à la fois une pratique disciplinaire et une découpe de l'histoire. Chacun des nouages exposés met en jeu des formes spécifiques de subjectivation, tendues entre identification et désidentification. Trois modes de subjectivation sont mis au jour : le retour réflexif du sujet à soi, l'assujettissement du sujet au langage et le rapport problématique du sujet à son corps et au monde. La troisième partie concerne d'abord la mise en œuvre d'une temporalité spécifique à la trilogie. L'énonciation au présent qui caractérise ces trois récits impose un regard singulier sur l'histoire. L'idée de messianisme du présent, que Walter Benjamin élabore dans ses ultimes fragments, nous aide à penser les réminiscences du passé dans le présent qui structurent la trilogie. L'interprétation figurative analysée par Erich Auerbach dans Figura nous éclaire quant à elle sur le temps déployé dans la trilogie. Comme les Pères de l'Église qui voient dans la figura une trace de l'événement historique dont l'énonciation dans la Bible a un caractère à la fois préfiguratif et commémoratif, liant le passé à l'avenir, Guyotat décrit des « figures » de l'histoire, dont l'énonciation au présent revêt un caractère à la fois prophétique et mémoriel. Nous analysons par la suite les figures de Jeanne d'Arc, de Charles de Gaulle ainsi que des membres de la famille qui incarnent un certain patriotisme, mais également une politique de la résistance qui complexifie souvent le sentiment d'appartenance à la France. Ces figures sont gouvernées par les lois d'alternance et de réversibilité qui infléchissent leur récupération mémorielle. La transmission de l'histoire par ses personnages révèle également son caractère sensible. Le « paysage » et la « géographie » manifestent une spatialisation de l'histoire, qui inscrit le passé dans différents lieux. Guyotat circonscrit les traces que l'histoire laisse dans le présent, déployant un rapport aux lieux de mémoire qui n'est pas strictement patrimonial. Il assimile l'histoire par les détails qui la composent et rend ses matériaux appropriables, perceptibles, disponibles. Le partage entre l'histoire légitime et l'histoire illégitime est sans cesse remis en question, l'écriture de Guyotat oscillant entre l'histoire et la mémoire, entre son expérience subjective et la présence fantomatique de la « masse historique des corps exploités ». ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Pierre Guyotat, politique de la littérature, littérature française contemporaine, société, langage, corps, histoire, mémoire, sujet, subjectivation, Jacques Rancière, Tel Quel, textualisme.

Ces dernières années, le paradigme de la radiobiologie selon lequel les effets biologiques des rayonnements ionisants ne concernent strictement que les dommages à l'ADN et les conséquences liées à leur non réparation ou à leur réparation défectueuse, a été remis en question. Ainsi, plusieurs études suggèrent que des mécanismes «non centrés » sur l'ADN ont une importance significative dans les réponses radio-induites. Ces effets doivent donc être identifiés et caractérisés afin d’évaluer leurs contributions respectives dans des phénomènes tels que la radiorésistance, les risques associés au développement de cancers radio-induits, les conséquences des expositions aux faibles doses. Pour ce faire, il est nécessaire : (i) d'analyser la contribution de ces différentes voies de signalisation et réparation induites en fonction de la dose et de la zone d’irradiation; (ii) d’’étudier les réponses radio-induites suite à l’irradiation exclusive de compartiments subcellulaires spécifiques (exclure les dommages spécifiques à l'ADN nucléaire); (iii) d’améliorer la connaissance des mécanismes moléculaires impliqués dans les phénomènes de radiosensibilité/radiorésistance dans la perspective d’optimiser les protocoles de radiothérapie et d’évaluer in vitro de nouvelles thérapies associant par exemple les effets des rayonnements ionisants et de nanoparticules d’oxydes métalliques. Les microfaisceaux de particules chargées offrent des caractéristiques uniques pour répondre à ces questions en permettant (i) des irradiations sélectives et en dose contrôlée de populations cellulaires et donc l’étude in vitro des effets « ciblés » et « non ciblés » à l'échelle cellulaire et subcellulaire, (ii) de caractériser l’homéostasie de cultures cellulaires en réponses à des expositions aux rayonnements ionisants et/ou aux nanoparticules d’oxydes métalliques (micro-analyse chimique multi-élémentaire). Ainsi, au cours de ma thèse, j'ai validé et exploité des méthodes d’évaluation qualitatives et quantitatives (i) in cellulo et en temps réel de la réponse radio-induite de compartiments biologiques spécifiques (ADN, mitochondrie, …) ; (ii) in vitro de la radiosensibilité de lignées sarcomateuses issues de patients; et (iii) in vitro des effets induits par des expositions à des nanoparticules d'oxydes métalliques afin d’évaluer leur potentiel thérapeutique et anti-cancéreux. / Few years ago, the paradigm of radiation biology was that the biological effects of ionizing radiations occurred only if cell nuclei were hit, and that cell death/dysfunction was strictly due to unrepaired/misrepaired DNA. Now, next this “DNA-centric” view several results have shown the importance of “non-DNA centered” effects. Both non-targeted effects and DNA-targeted effects induced by ionizing radiations need to be clarified for the evaluation of the associated radiation resistance phenomena and cancer risks. A complete overview on radiation induced effects requires the study of several points: (i) analyzing the contribution of different signaling and repair pathways activated in response to radiation-induced injuries; (ii) elucidating non-targeted effects to explain cellular mechanisms induced in cellular compartments different from DNA; and (iii) improving the knowledge of sensitivity/resistance molecular mechanisms to adapt, improve and optimize the radiation treatment protocols combining ionizing radiations and nanoparticles. Charged particle microbeams provide unique features to answer these challenge questions by (i) studying in vitro both targeted and non-targeted radiation responses at the cellular scale, (ii) performing dose-controlled irradiations on a cellular populations and (iii) quantifying the chemical element distribution in single cells after exposure to ionizing radiations or nanoparticles. By using this tool, I had the opportunity to (i) use an original micro-irradiation setup based on charged particles microbeam (AIFIRA) with which the delivered particles are controlled in time, amount and space to validate in vitro methodological approaches for assessing the radiation sensitivity of different biological compartments (DNA and cytoplasm); (ii) assess the radiation sensitivity of a collection of cancerous cell lines derived from patients in the context of radiation therapy; (iii) study metal oxide nanoparticles effects in cells in order to understand the potential of nanoparticles in emerging cancer therapeutic approaches.