Dialogism and dialogicality in the study of the self

This article stems from the statement that dialogical approaches to a study of the self face a double challenge: that of developing a conception of the self that both avoids social reductionism and accounts for the stability of the self. In discussing this double challenge, we identify three much debated issues: (a) To what does the notion of "Alter" exactly refer? (b) How could we conceptualize the fact that Subject-Alter interactions are not only interpersonal but entail larger social entities, in particular institutions? (c)What importance should we attach to the materiality of objects? We discuss these three questions from two standpoints - that of linguistics and that of psychology - and illustrate our theoretical proposals with an analysis of an excerpt taken from a focus-group discussion. In conclusion, we argue that the dialogism of discourse provides us with some clues about the dialogicality of the mind, whereas the latter invites us to develop a theory showing the importance of interactions in the construction of the self, to pay more attention to the transpersonal dimension of the social, and to consider that the material world contributes to the construction of the self.

Use-dependent block of the voltage-gated Na+ channel by tetrodotoxin and saxitoxin: Effect of pore mutations that change ionic selectivity.

Voltage-gated Na(+) channels (NaV channels) are specifically blocked by guanidinium toxins such as tetrodotoxin (TTX) and saxitoxin (STX) with nanomolar to micromolar affinity depending on key amino acid substitutions in the outer vestibule of the channel that vary with NaV gene isoforms. All NaV channels that have been studied exhibit a use-dependent enhancement of TTX/STX affinity when the channel is stimulated with brief repetitive voltage depolarizations from a hyperpolarized starting voltage. Two models have been proposed to explain the mechanism of TTX/STX use dependence: a conformational mechanism and a trapped ion mechanism. In this study, we used selectivity filter mutations (K1237R, K1237A, and K1237H) of the rat muscle NaV1.4 channel that are known to alter ionic selectivity and Ca(2+) permeability to test the trapped ion mechanism, which attributes use-dependent enhancement of toxin affinity to electrostatic repulsion between the bound toxin and Ca(2+) or Na(+) ions trapped inside the channel vestibule in the closed state. Our results indicate that TTX/STX use dependence is not relieved by mutations that enhance Ca(2+) permeability, suggesting that ion-toxin repulsion is not the primary factor that determines use dependence. Evidence now favors the idea that TTX/STX use dependence arises from conformational coupling of the voltage sensor domain or domains with residues in the toxin-binding site that are also involved in slow inactivation.

The role of CTCFL/BORIS in Meiosis

The complexity of mammalian genome organization demands a complex interplay of DNA and proteins to orchestrate proper gene regulation. CTCF, a highly conserved, ubiquitously expressed protein has been postulated as a primary organizer of genome architecture because of its roles in transcriptional activation/repression, insulation and imprinting. Diverse regulatory functions are exerted through genome wide binding via a central eleven zinc finger DNA binding domain and an array of diverse protein-protein interactions through N- and C- terminal domains. CTCFL has been identified as a paralog of CTCF expressed only in spermatogenic cells of the testis. CTCF and CTCFL have a highly homologous DNA-binding domain, while the flanking amino acid sequences exhibit no significant similarity. Genome- wide mapping of CTCF binding sites has been carried out in many cell types, but no data exist for CTCFL apart from a few identified loci. The lack of high quality antibodies prompted us to generate an endogenously flag-tagged CTCFL mouse model using BAC recombination. IHC staining using anti-flag antibodies confirmed CTCFL localization to type Β spermatogonia and preleptotene spermatocytes and a mutually exclusive pattern of expression with CTCF. ChIP followed by high-throughput sequencing identified 10,382 binding sites showing 70% overlap but representing only 20% of CTCF sites. Consensus sequence analysis identified a significantly longer binding motif with prominently less ambiguity of base calling at every position. The significant difference between CTCF and CTCFL genomic binding patterns proposes that their binding to DNA is differentially regulated. Analysis of CTCFL binding to methylated regions on a genome wide scale identified approximately 1,000 loci. Methylation-independent binding of CTCFL might be at least one of the mechanisms that ensures distinct binding patterns of CTCF and CTCFL since CTCF binding is methylation- sensitive. Co-localization of CTCF with cohesin has been well established and analysis of CTCFL and SMC3 overlap identified around 3,300 binding sites from which two related but distinct consensus sequence motifs were derived. Because virtually all data for cohesin binding originate from mitotically proliferating cells, the anticipated overlap is expected to be considerably higher in meiotic cells. Meiosis-specific cohesin subunit Rec8 is specific for spermatocytes and 6 out of the 12 identified binding sites are also bound by CTCFL. In conclusion, this was the first genome-wide mapping of CTCFL binding sites in spermatocytes, the only cell type where CTCF is not expressed. CTCFL has a unique binding site repertoire distinct from CTCF, binds to methylated sequences and shows a significant overlap with cohesin binding sites. Future efforts will be oriented towards deciphering the role CTCFL plays in conversion of chromatin structure and function from mitotic to meiotic chromosomes. - La complexité de l'organisation du génome des mammifères exige une interaction particulière entre ADN et protéines pour orchestrer une régulation appropriée de l'expression des gènes. CTCFL, une protéine ubiquitaire très conservée, serait le principal organisateur de l'architecture du génome de par son rôle dans l'activation / la répression de la transcription, la protection et la localisation des gènes. Diverses régulations sont opérées, d'une part au travers d'interactions à différents endroits du génome par le biais d'un domaine protéique central de liaison à l'ADN à onze doigts de zinc, et d'autre part par des interactions protéine-protéine variées au niveau de leur domaine N- et C-terminal. CTCFL a été identifié comme un paralogue de CTCF exprimé uniquement dans les cellules spermatiques du testicule. CTCFL et CTCF ont un domaine de liaison à l'ADN très homologue, tandis que les séquences d'acides aminés situées de part et d'autre de ce domaine ne présentent aucune similitude. Une cartographie générale des sites de liaison au CTCF a été réalisée pour de nombreux types cellulaires, mais il n'existe aucune donnée pour CTCFL à l'exception de l'identification de quelques loci. L'absence d'anticorps de bonne qualité nous a conduit à générer un modèle murin portant un CTCFL endogène taggué grâce à un procédé de recombinaison BAC. Une coloration IHC à l'aide d'anticorps anti-FLAG a confirmé la présence de CTCFL au niveau des spermatogonies de type Β et des spermatocytes au stade préleptotène, et une distribution mutuellement exclusive avec CTCF. Une méthode de Chromatine Immunoprecipitation (ChIP) suivie d'un séquençage à haut débit a permis d'identifier 10.382 sites de liaison montrant 70% d'homologie mais ne représentant que 20% des sites CTCF. L'analyse de la séquence consensus révèle un motif de fixation à l'ADN nettement plus long et qui comporte bien moins de bases aléatoires à chaque position nucléotidique. La différence significative entre les séquences génomiques des sites de liaison au CTCF et CTCFL suggère que leur fixation à l'ADN est régulée différemment. Appliquée à l'échelle du génome, l'étude de l'interaction de CTCFL avec des régions méthylées de l'ADN a permis d'identifier environ 1.000 loci. Contrairement à CTCFL, la liaison de CTCF dépend de l'état de méthylation de l'ADN ; cette modification épigénétique constitue donc au moins un des mécanismes de régulation expliquant une localisation de CTCF et CTCFL à des sites distincts du génome. La co- localisation de CTCF avec la cohésine étant établie, l'analyse de la superposition des séquences de CTCFL avec la sous-unité SMC3 identifie environ 3.300 sites de liaison parmi lesquels deux mêmes motifs consensus distincts par leur séquence sont mis en évidence. La presque quasi-totalité des données sur la cohésine ayant été établie à partir de cellules en prolifération mitotique, il est probable que la similitude au sein des séquences consensus soit encore plus grande dans le cas des cellules en méiose. La sous-unité Rec8 de la cohésine propre à l'état de méiose est spécifiquement exprimée dans les spermatocytes. Or 6 des 12 sites de liaison identifiés sont également utilisés par CTCFL. Pour conclure, ce travail constitue la première cartographie à l'échelle du génome des sites de liaison de CTCFL dans les spermatocytes, seul type cellulaire où CTCFL n'est pas exprimé. CTCFL possède un répertoire unique de sites de fixation à l'ADN distinct de CTCF, se lie à des séquences méthylées et présente un nombre important de sites de liaison communs avec la cohésine. Les perspectives futures sont d'élucider le rôle de CTCFL dans le remodelage de la structure de la chromatine et de définir sa fonction dans le processus de méiose.

Genetic evidence that the higher plant Rab-D1 and Rab-D2 GTPases exhibit distinct but overlapping interactions in the early secretory pathway.

GTPases of the Rab1 subclass are essential for membrane traffic between the endoplasmic reticulum (ER) and Golgi complex in animals, fungi and plants. Rab1-related proteins in higher plants are unusual because sequence comparisons divide them into two putative subclasses, Rab-D1 and Rab-D2, that are conserved in monocots and dicots. We tested the hypothesis that the Rab-D1 and Rab-D2 proteins of Arabidopsis represent functionally distinct groups. RAB-D1 and RAB-D2a each targeted fluorescent proteins to the same punctate structures associated with the Golgi stacks and trans-Golgi-network. Dominant-inhibitory N121I mutants of each protein inhibited traffic of diverse cargo proteins at the ER but they appeared to act via distinct biochemical pathways as biosynthetic traffic in cells expressing either of the N121I mutants could be restored by coexpressing the wild-type form of the same subclass but not the other subclass. The same interaction was observed in transgenic seedlings expressing RAB-D1 [N121I]. Insertional mutants confirmed that the three Arabidopsis Rab-D2 genes were extensively redundant and collectively performed an essential function that could not be provided by RAB-D1, which was non-essential. However, plants lacking RAB-D1, RAB-D2b and RAB-D2c were short and bushy with low fertility, indicating that the Rab-D1 and Rab-D2 subclasses have overlapping functions.

Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.

The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12 mobility, as well as the involvement of individual residues with regard to peroxisome proliferator-activated receptor alpha (PPARalpha) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPARalpha helix 12 mutants were combined with free energy molecular dynamics simulations. The agreement between the results from these approaches allows us to make robust claims concerning the mechanisms that govern helix 12 functions. Our data support a model in which PPARalpha helix 12 transiently adopts a relatively stable active conformation even in the absence of a ligand. This conformation provides the interface for the recruitment of a coactivator and results in constitutive activity. The receptor agonists stabilize this conformation and increase PPARalpha transcription activation potential. Finally, we disclose important functions of residues in PPARalpha AF-2, which determine the positioning of helix 12 in the active conformation in the absence of a ligand. Substitution of these residues suppresses PPARalpha constitutive activity, without changing PPARalpha ligand-dependent activation potential.

Principaux résultats de l'étude suisse sur les DRG (étude Casemix). [Main results of the Swiss study on DRGs (Casemix Study)].

Sponsored by the Health Administrations of nine cantons, this study was conducted by the University Institute of Social and Preventive Medicine in Lausanne in order to assess how DRGs could be used within the Swiss context. A data base mainly provided by the Swiss VESKA statistics was used. The first step provided the transformation of Swiss diagnostic and intervention codes into US codes, allowing direct use of the Yale Grouper for DRG. The second step showed that the overall performance of DRG in terms of variability reduction of the length of stay was similar to the one observed in US; there are, however, problems when the homogeneity of medicotechnical procedures for DRG is considered. The third steps showed how DRG could be used as an account unit in hospital, and how costs per DRG could be estimated. Other examples of applications of DRG were examined, for example comparison of Casemix or length of stay between hospitals.

Revision of the genus acrochordiceras hyatt, 1877 (Ammonoidea, Middle Triassic): Morphology, biometry, biostratigraphy and intra-specific variability

The family Acrochordiceratidae Arthaber, 1911 ranges in age from latest Spathian to the middle/late Anisian boundary, and it represents a major component of ammonoid faunas during that time. The middle Anisian genus Acrochordiceras Hyatt, 1877 is the most widespread taxon of the family and occurs abundantly worldwide within the low paleolatitude belt. However, there is a profusion of species names available for Acrochordiceras. This excessive diversity at the species level essentially results from the fact that sufficiently large samples were not available, thus leading to a typological approach to its taxonomy. Based on new extensive collections obtained from the Anisian (Middle Triassic) Fossil Hill Member (Star Peak Group, north-west Nevada) for which a high resolution biostratigraphic frame is available, the taxonomy and biostratigraphy of the genus Acrochordiceras Hyatt, 1877 is herein revised with respect to its intra-specific variation. Morphological and biometric studies (c. 550 bedrock-controlled specimens were measured) show that only one species occurs in each stratigraphic level. Continuous ranges of intra-specific variation of studied specimens enable us to synonymize Haydenites Diener, 1907, Silesiacrochordiceras Diener, 1916 and Epacrochordiceras Spath, 1934 with Acrochordiceras Hyatt, 1877. Three stratigraphically successive species are herein recognized in the low paleolatitude middle Anisian faunas from Nevada: A. hatschekii (Diener, 1907), A. hyatti Meek, 1877 and A. carolinae Mojsisovics, 1882. Moreover, an assessment of intra-specific variation of the adult size range does not support recognition of a dimorphic pair (Acrochordiceras and Epacrochordiceras) as previously suggested by other workers (Epacrochordiceras is the compressed and weakly ornamented end-member variant of Acrochordiceras). The successive middle Anisian species of Acrochordiceras form an anagenetic lineage characterized by increasing involution, adult size and intra-specific variation. This taxonomic revision based on new bedrock-controlled collections is thus an important prerequisite before studying the evolution of the group.

A search for the origin of cadmium in the soil of the Swiss Jura

The top soil of a 14.5 km(2) region at la Chaux-de-Fonds in the Swiss Jura is exceptionally rich in cadmium. It contains an average of 1.3 mg per kg of soil. The spatial distribution of the metal has no simple pattern that could be explained by atmospheric deposition or agricultural practices. Thin soil contained most of its Cd at the surface; in thicker soil Cd is mainly concentrated between 60 and 80 cm depth. No specific minerals or soil fractions could account for these accumulation, and the vertical distribution of Cd is best explained by leaching from the topsoil and further adsorption within layers of nearly neutral pH. The local Jurassic sedimentary rocks contained too little Cd to account for the Cd concentrations in the soil. Alpine gravels from glacial till were too sparse in soils to explain such a spreading of Cd. Moreover this origin is contradictory with the fact that Cd is concentrated in the sand fraction of soils. The respective distributions of Fe and Cd in soils, and soil fractions, suggested that the spreading of iron nodules accumulated during the siderolithic period (Eocene) was not the main source of Cd. Atmospheric deposition, and spreading of fertiliser or waste from septic tanks seem the only plausible explanation for the Cd concentrations, but at present few factors allow us to differentiate between them.

Capitalism in the classroom : the impact of self-enhancement values and normative assessment on student motivation, goals and attitudes towards cheating

Abstract The neo-liberal capitalist ideology has come under heavy fire with anecdotal evidence indicating a link between these same values and unethical behavior. Academic institutions reflect social values and act as socializing agents for the young. Can this explain the high and increasing rates of cheating that currently prevail in education? Our first chapter examines the question of whether self-enhancement values of power and açhievement, the individual level equivalent of neo-liberal capitalist values, predict positive attitudes towards cheating. Furthermore, we explore the mediating role of motivational factors. Results of four studies reveal that self-enhancement value endorsement predicts the adoption of performance-approach goals, a relationship mediated by introjected regulation, namely desire for social approval and that self-enhancement value endorsement also predicts the condoning of cheating, a relationship mediated by performance-approach goal adoption. However, self-transcendence values prescribed by a normatively salient source have the potential to reduce the link between self-enhancement value endorsément and attitudes towards cheating. Normative assessment constitutes a key tool used by academic institutions to socialize young people to accept the competitive, meritocratic nature of a sociéty driven by a neo-liberal capitalist ideology. As such, the manifest function of grades is to motivate students to work hard and to buy into the competing ethos. Does normative assessment fulfill these functions? Our second chapter explores the reward-intrinsic motivation question in the context of grading, arguably a high-stakes reward. In two experiments, the relative capacity of graded high performance as compared to the task autonomy experienced in an ungraded task to predict post-task intrinsic motivation is assessed. Results show that whilst the graded task performance predicts post-task appreciation, it fails to predict ongoing motivation. However, perceived autonomy experienced in non-graded condition, predicts both post-task appreciation and ongoing motivation. Our third chapter asks whether normative assessment inspires the spirit of competition in students. Results of three experimental studies reveal that expectation of a grade for a task, compared to no grade, induces greater adoption of performance-avoidance, but not performance-approach, goals. Experiment 3 provides an explanatory mechanism for this, showing that reduced autonomous motivation experienced in previous graded tasks mediates the relationship between grading and adoption of performance avoidance goals in a subsequent task. The above results, when combined, provide evidence as to the deleterious effects of self enhancement values and the associated practice of normative assessment in school on student motivation, goals and ethics. We conclude by using value and motivation theory to explore solutions to this problem.

Stochastic stability and the evolution of coordination in spatially structured populations.

Animals can often coordinate their actions to achieve mutually beneficial outcomes. However, this can result in a social dilemma when uncertainty about the behavior of partners creates multiple fitness peaks. Strategies that minimize risk ("risk dominant") instead of maximizing reward ("payoff dominant") are favored in economic models when individuals learn behaviors that increase their payoffs. Specifically, such strategies are shown to be "stochastically stable" (a refinement of evolutionary stability). Here, we extend the notion of stochastic stability to biological models of continuous phenotypes at a mutation-selection-drift balance. This allows us to make a unique prediction for long-term evolution in games with multiple equilibria. We show how genetic relatedness due to limited dispersal and scaled to account for local competition can crucially affect the stochastically-stable outcome of coordination games. We find that positive relatedness (weak local competition) increases the chance the payoff dominant strategy is stochastically stable, even when it is not risk dominant. Conversely, negative relatedness (strong local competition) increases the chance that strategies evolve that are neither payoff nor risk dominant. Extending our results to large multiplayer coordination games we find that negative relatedness can create competition so extreme that the game effectively changes to a hawk-dove game and a stochastically stable polymorphism between the alternative strategies evolves. These results demonstrate the usefulness of stochastic stability in characterizing long-term evolution of continuous phenotypes: the outcomes of multiplayer games can be reduced to the generic equilibria of two-player games and the effect of spatial structure can be analyzed readily.

Cross-cultural adaptations of the Oxford-12 HIP score to the French speaking population.

BACKGROUND: An objective measurement of surgical procedures outcomes is inherent to professional practices quality control; this especially applies in orthopaedics to joint replacement outcomes. A self-administered questionnaire offers an attractive alternative to surgeon's judgement but is infrequently used in France for these purposes. The British questionnaire, the 12-item Oxford Hip Score (OHS) was selected for this study because of its ease of use. HYPOTHESIS: The objective of this study was to validate the French translation of the self-assessment 12-item Oxford Hip Score and compare its results with those of the reference functional scores: the Harris Hip Score (HHS) and the Postel-Merle d'Aubigné (PMA) score. MATERIALS AND METHODS: Based on a clinical series of 242 patients who were candidates for total hip arthroplasty, the French translation of this questionnaire was validated. Its coherence was also validated by comparing the preoperative data with the data obtained from the two other reference clinical scores. RESULTS: The translation was validated using the forward-backward translation procedure from French to English, with correction of all differences or mistranslations after systematized comparison with the original questionnaire in English. The mean overall OHS score was 43.8 points (range, 22-60 points) with similarly good distribution of the overall value of the three scores compared. The correlation was excellent between the OHS and the HHS, but an identical correlation between the OHS and the PMA was only obtained for the association of the pain and function parameters, after excluding the mobility criterion, relatively over-represented in the PMA score. DISCUSSION AND CONCLUSION: Subjective questionnaires that contribute a personal appreciation of the results of arthroplasty by the patient can easily be applied on a large scale. This study made a translated and validated version of an internationally recognized, reliable self-assessment score available to French orthopaedic surgeons. The results obtained encourage us to use this questionnaire as a complement to the classical evaluation scores and methods.

Dose reconstruction in the context of tomotherapy

In vivo dosimetry is a way to verify the radiation dose delivered to the patient in measuring the dose generally during the first fraction of the treatment. It is the only dose delivery control based on a measurement performed during the treatment. In today's radiotherapy practice, the dose delivered to the patient is planned using 3D dose calculation algorithms and volumetric images representing the patient. Due to the high accuracy and precision necessary in radiation treatments, national and international organisations like ICRU and AAPM recommend the use of in vivo dosimetry. It is also mandatory in some countries like France. Various in vivo dosimetry methods have been developed during the past years. These methods are point-, line-, plane- or 3D dose controls. A 3D in vivo dosimetry provides the most information about the dose delivered to the patient, with respect to ID and 2D methods. However, to our knowledge, it is generally not routinely applied to patient treatments yet. The aim of this PhD thesis was to determine whether it is possible to reconstruct the 3D delivered dose using transmitted beam measurements in the context of narrow beams. An iterative dose reconstruction method has been described and implemented. The iterative algorithm includes a simple 3D dose calculation algorithm based on the convolution/superposition principle. The methodology was applied to narrow beams produced by a conventional 6 MV linac. The transmitted dose was measured using an array of ion chambers, as to simulate the linear nature of a tomotherapy detector. We showed that the iterative algorithm converges quickly and reconstructs the dose within a good agreement (at least 3% / 3 mm locally), which is inside the 5% recommended by the ICRU. Moreover it was demonstrated on phantom measurements that the proposed method allows us detecting some set-up errors and interfraction geometry modifications. We also have discussed the limitations of the 3D dose reconstruction for dose delivery error detection. Afterwards, stability tests of the tomotherapy MVCT built-in onboard detector was performed in order to evaluate if such a detector is suitable for 3D in-vivo dosimetry. The detector showed stability on short and long terms comparable to other imaging devices as the EPIDs, also used for in vivo dosimetry. Subsequently, a methodology for the dose reconstruction using the tomotherapy MVCT detector is proposed in the context of static irradiations. This manuscript is composed of two articles and a script providing further information related to this work. In the latter, the first chapter introduces the state-of-the-art of in vivo dosimetry and adaptive radiotherapy, and explains why we are interested in performing 3D dose reconstructions. In chapter 2 a dose calculation algorithm implemented for this work is reviewed with a detailed description of the physical parameters needed for calculating 3D absorbed dose distributions. The tomotherapy MVCT detector used for transit measurements and its characteristics are described in chapter 3. Chapter 4 contains a first article entitled '3D dose reconstruction for narrow beams using ion chamber array measurements', which describes the dose reconstruction method and presents tests of the methodology on phantoms irradiated with 6 MV narrow photon beams. Chapter 5 contains a second article 'Stability of the Helical TomoTherapy HiArt II detector for treatment beam irradiations. A dose reconstruction process specific to the use of the tomotherapy MVCT detector is presented in chapter 6. A discussion and perspectives of the PhD thesis are presented in chapter 7, followed by a conclusion in chapter 8. The tomotherapy treatment device is described in appendix 1 and an overview of 3D conformai- and intensity modulated radiotherapy is presented in appendix 2. - La dosimétrie in vivo est une technique utilisée pour vérifier la dose délivrée au patient en faisant une mesure, généralement pendant la première séance du traitement. Il s'agit de la seule technique de contrôle de la dose délivrée basée sur une mesure réalisée durant l'irradiation du patient. La dose au patient est calculée au moyen d'algorithmes 3D utilisant des images volumétriques du patient. En raison de la haute précision nécessaire lors des traitements de radiothérapie, des organismes nationaux et internationaux tels que l'ICRU et l'AAPM recommandent l'utilisation de la dosimétrie in vivo, qui est devenue obligatoire dans certains pays dont la France. Diverses méthodes de dosimétrie in vivo existent. Elles peuvent être classées en dosimétrie ponctuelle, planaire ou tridimensionnelle. La dosimétrie 3D est celle qui fournit le plus d'information sur la dose délivrée. Cependant, à notre connaissance, elle n'est généralement pas appliquée dans la routine clinique. Le but de cette recherche était de déterminer s'il est possible de reconstruire la dose 3D délivrée en se basant sur des mesures de la dose transmise, dans le contexte des faisceaux étroits. Une méthode itérative de reconstruction de la dose a été décrite et implémentée. L'algorithme itératif contient un algorithme simple basé sur le principe de convolution/superposition pour le calcul de la dose. La dose transmise a été mesurée à l'aide d'une série de chambres à ionisations alignées afin de simuler la nature linéaire du détecteur de la tomothérapie. Nous avons montré que l'algorithme itératif converge rapidement et qu'il permet de reconstruire la dose délivrée avec une bonne précision (au moins 3 % localement / 3 mm). De plus, nous avons démontré que cette méthode permet de détecter certaines erreurs de positionnement du patient, ainsi que des modifications géométriques qui peuvent subvenir entre les séances de traitement. Nous avons discuté les limites de cette méthode pour la détection de certaines erreurs d'irradiation. Par la suite, des tests de stabilité du détecteur MVCT intégré à la tomothérapie ont été effectués, dans le but de déterminer si ce dernier peut être utilisé pour la dosimétrie in vivo. Ce détecteur a démontré une stabilité à court et à long terme comparable à d'autres détecteurs tels que les EPIDs également utilisés pour l'imagerie et la dosimétrie in vivo. Pour finir, une adaptation de la méthode de reconstruction de la dose a été proposée afin de pouvoir l'implémenter sur une installation de tomothérapie. Ce manuscrit est composé de deux articles et d'un script contenant des informations supplémentaires sur ce travail. Dans ce dernier, le premier chapitre introduit l'état de l'art de la dosimétrie in vivo et de la radiothérapie adaptative, et explique pourquoi nous nous intéressons à la reconstruction 3D de la dose délivrée. Dans le chapitre 2, l'algorithme 3D de calcul de dose implémenté pour ce travail est décrit, ainsi que les paramètres physiques principaux nécessaires pour le calcul de dose. Les caractéristiques du détecteur MVCT de la tomothérapie utilisé pour les mesures de transit sont décrites dans le chapitre 3. Le chapitre 4 contient un premier article intitulé '3D dose reconstruction for narrow beams using ion chamber array measurements', qui décrit la méthode de reconstruction et présente des tests de la méthodologie sur des fantômes irradiés avec des faisceaux étroits. Le chapitre 5 contient un second article intitulé 'Stability of the Helical TomoTherapy HiArt II detector for treatment beam irradiations'. Un procédé de reconstruction de la dose spécifique pour l'utilisation du détecteur MVCT de la tomothérapie est présenté au chapitre 6. Une discussion et les perspectives de la thèse de doctorat sont présentées au chapitre 7, suivies par une conclusion au chapitre 8. Le concept de la tomothérapie est exposé dans l'annexe 1. Pour finir, la radiothérapie «informationnelle 3D et la radiothérapie par modulation d'intensité sont présentées dans l'annexe 2.

Revisiting the heteromultimeric structure of ENaC in Xenopus leavis oocytes

The epithelial sodium channel (ENaC) regulates the sodium reabsorption in the principal cells of collecting duct of the nephron, and is essential for the maintenance of Na+ balance and blood pressure. ENaC is regulated by hormones such as aldosterone and vasopressin, by serine proteases. The functional ENaC channel expressed at the cell surface is a hetemultimeric complex composed by the homologous a, ß and y subunits. Several functional and biochemical studies have provided evidence that the ENaC is a heterotetramer formed by 2a lß and ly subunits. Recently, a channel homologue of ENaC, the acid-sensing ion channel ASIC1 has been crystallized as a homotrimer. This discrepancy in the subunit composition of these two channels of the same family, motivated us to revisit the subunit oligomerization of the purified functional abg EnaC channel complex. His(6)ENaC a ß y subunits were expressed in Xenopus leavis oocytes. The three ENaC subunits copurify on Ni+2-NTA agarose beads in a aßy ENaC complex. On Western blot, the ENaC subunits show typical post-translation modifications associated with a functional channel. Using differentially tagged ENaC subunits, we could demonstrate that 2 different a ENaC co- purify with ß and y subunits, whereas only one single ß and y are detected in the ENaC complex. Comparison of the mass of the aßy ENaC complex on Western blot under non reducing conditions with different ENaC dimeric, trimmeric and tetratemeric concatamers indicate that the ENaC channel complex is a heterotetramer made of 2a-, lß-, and ly ENaC subunits. Our result will certainly not provide the last words on the subunit stoichiometry of the ENaC/ASIC channels, but hopefully will promote the réévaluation of the cASICl crystal structure for its functional relevance. -- Le canal épithélial sodique ENaC est responsable de la réabsorption du sodium dans les cellules principales du tubule collecteur rénal et joue un rôle important dans le maintien de l'homéostasie sodique et le maintien de la pression artérielle. Ce canal est régulé par des hormones telles que l'aldostérone ou la Vasopressine mais également par des sérines protéases. ENaC est un canal multimerique constitué des trois sous-unités homologues a, ß and y. De nombreuses études fonctionnelles et biochimiques ont montré que le canal ENaC fonctionnel exprimé à la surface cellulaire est un canal formé de 4 sous unités avec une stoichiometric préférentielle de 2 sous-unités a, 1 sous-unité ß et 1 sous-unité y. Récemment, la cristallisation du canal sodique sensible au pH acide, ASIC, un autre membre de la famille ENaC/Deg, a mis en évidence un canal homotrimérique. Cette divergence dans la composition en sous-unités formant les complexes ENaC et ASIC, deux canaux de la même famille de gènes, nous a motivé à réinvestiguer le problème de l'oligomérisation du complexe fonctionnel ENaC après purification. Dans ce but le complexe ENaC fait des sous-unités aßy marquées par un épitope His 6 ont été exprimées dans l'ovocyte de Xenopus leavis. Les trois sous-unités aßy du complexe ENaC peuvent être co-purifiées sur des billes d'agarose Ni+2-NTA et montrent les modifications post-traductionnelles attendues pour le complexe fonctionnel ENaC exprimé en surface. Nous avons pu démontrer que ce complexe ENaC fonctionnel, est formé de deux sous-unités a différentes, mais de une seule sous-unité ß et une seule sous-unité y, suggérant un complexe ENaC formé de plus de trois sous-unités. L'estimation de la masse du complexe fonctionnel ENaC par Western blot, en comparaison avec des constructions concatemériques de ENaC faites de 2, 3, ou 4 sous-unités indique que le complexe aßy ENaC fonctionnel est une hétérotétramère composé de 2 sous-unités a, une ß et une y. Ces expériences ne représentent pas le fin d'une controverse quant à la structure des canaux ENaC et ASIC, mais soulèvent la question de la relevance fonctionnelle de la structure tridimentionelle du canal ASIC révélée par crystallographie.

Rules of origin : from analysis to reform

General Introduction This thesis can be divided into two main parts :the first one, corresponding to the first three chapters, studies Rules of Origin (RoOs) in Preferential Trade Agreements (PTAs); the second part -the fourth chapter- is concerned with Anti-Dumping (AD) measures. Despite wide-ranging preferential access granted to developing countries by industrial ones under North-South Trade Agreements -whether reciprocal, like the Europe Agreements (EAs) or NAFTA, or not, such as the GSP, AGOA, or EBA-, it has been claimed that the benefits from improved market access keep falling short of the full potential benefits. RoOs are largely regarded as a primary cause of the under-utilization of improved market access of PTAs. RoOs are the rules that determine the eligibility of goods to preferential treatment. Their economic justification is to prevent trade deflection, i.e. to prevent non-preferred exporters from using the tariff preferences. However, they are complex, cost raising and cumbersome, and can be manipulated by organised special interest groups. As a result, RoOs can restrain trade beyond what it is needed to prevent trade deflection and hence restrict market access in a statistically significant and quantitatively large proportion. Part l In order to further our understanding of the effects of RoOs in PTAs, the first chapter, written with Pr. Olivier Cadot, Celine Carrère and Pr. Jaime de Melo, describes and evaluates the RoOs governing EU and US PTAs. It draws on utilization-rate data for Mexican exports to the US in 2001 and on similar data for ACP exports to the EU in 2002. The paper makes two contributions. First, we construct an R-index of restrictiveness of RoOs along the lines first proposed by Estevadeordal (2000) for NAFTA, modifying it and extending it for the EU's single-list (SL). This synthetic R-index is then used to compare Roos under NAFTA and PANEURO. The two main findings of the chapter are as follows. First, it shows, in the case of PANEURO, that the R-index is useful to summarize how countries are differently affected by the same set of RoOs because of their different export baskets to the EU. Second, it is shown that the Rindex is a relatively reliable statistic in the sense that, subject to caveats, after controlling for the extent of tariff preference at the tariff-line level, it accounts for differences in utilization rates at the tariff line level. Finally, together with utilization rates, the index can be used to estimate total compliance costs of RoOs. The second chapter proposes a reform of preferential Roos with the aim of making them more transparent and less discriminatory. Such a reform would make preferential blocs more "cross-compatible" and would therefore facilitate cumulation. It would also contribute to move regionalism toward more openness and hence to make it more compatible with the multilateral trading system. It focuses on NAFTA, one of the most restrictive FTAs (see Estevadeordal and Suominen 2006), and proposes a way forward that is close in spirit to what the EU Commission is considering for the PANEURO system. In a nutshell, the idea is to replace the current array of RoOs by a single instrument- Maximum Foreign Content (MFC). An MFC is a conceptually clear and transparent instrument, like a tariff. Therefore changing all instruments into an MFC would bring improved transparency pretty much like the "tariffication" of NTBs. The methodology for this exercise is as follows: In step 1, I estimate the relationship between utilization rates, tariff preferences and RoOs. In step 2, I retrieve the estimates and invert the relationship to get a simulated MFC that gives, line by line, the same utilization rate as the old array of Roos. In step 3, I calculate the trade-weighted average of the simulated MFC across all lines to get an overall equivalent of the current system and explore the possibility of setting this unique instrument at a uniform rate across lines. This would have two advantages. First, like a uniform tariff, a uniform MFC would make it difficult for lobbies to manipulate the instrument at the margin. This argument is standard in the political-economy literature and has been used time and again in support of reductions in the variance of tariffs (together with standard welfare considerations). Second, uniformity across lines is the only way to eliminate the indirect source of discrimination alluded to earlier. Only if two countries face uniform RoOs and tariff preference will they face uniform incentives irrespective of their initial export structure. The result of this exercise is striking: the average simulated MFC is 25% of good value, a very low (i.e. restrictive) level, confirming Estevadeordal and Suominen's critical assessment of NAFTA's RoOs. Adopting a uniform MFC would imply a relaxation from the benchmark level for sectors like chemicals or textiles & apparel, and a stiffening for wood products, papers and base metals. Overall, however, the changes are not drastic, suggesting perhaps only moderate resistance to change from special interests. The third chapter of the thesis considers whether Europe Agreements of the EU, with the current sets of RoOs, could be the potential model for future EU-centered PTAs. First, I have studied and coded at the six-digit level of the Harmonised System (HS) .both the old RoOs -used before 1997- and the "Single list" Roos -used since 1997. Second, using a Constant Elasticity Transformation function where CEEC exporters smoothly mix sales between the EU and the rest of the world by comparing producer prices on each market, I have estimated the trade effects of the EU RoOs. The estimates suggest that much of the market access conferred by the EAs -outside sensitive sectors- was undone by the cost-raising effects of RoOs. The chapter also contains an analysis of the evolution of the CEECs' trade with the EU from post-communism to accession. Part II The last chapter of the thesis is concerned with anti-dumping, another trade-policy instrument having the effect of reducing market access. In 1995, the Uruguay Round introduced in the Anti-Dumping Agreement (ADA) a mandatory "sunset-review" clause (Article 11.3 ADA) under which anti-dumping measures should be reviewed no later than five years from their imposition and terminated unless there was a serious risk of resumption of injurious dumping. The last chapter, written with Pr. Olivier Cadot and Pr. Jaime de Melo, uses a new database on Anti-Dumping (AD) measures worldwide to assess whether the sunset-review agreement had any effect. The question we address is whether the WTO Agreement succeeded in imposing the discipline of a five-year cycle on AD measures and, ultimately, in curbing their length. Two methods are used; count data analysis and survival analysis. First, using Poisson and Negative Binomial regressions, the count of AD measures' revocations is regressed on (inter alia) the count of "initiations" lagged five years. The analysis yields a coefficient on measures' initiations lagged five years that is larger and more precisely estimated after the agreement than before, suggesting some effect. However the coefficient estimate is nowhere near the value that would give a one-for-one relationship between initiations and revocations after five years. We also find that (i) if the agreement affected EU AD practices, the effect went the wrong way, the five-year cycle being quantitatively weaker after the agreement than before; (ii) the agreement had no visible effect on the United States except for aone-time peak in 2000, suggesting a mopping-up of old cases. Second, the survival analysis of AD measures around the world suggests a shortening of their expected lifetime after the agreement, and this shortening effect (a downward shift in the survival function postagreement) was larger and more significant for measures targeted at WTO members than for those targeted at non-members (for which WTO disciplines do not bind), suggesting that compliance was de jure. A difference-in-differences Cox regression confirms this diagnosis: controlling for the countries imposing the measures, for the investigated countries and for the products' sector, we find a larger increase in the hazard rate of AD measures covered by the Agreement than for other measures.

The pattern of health care use of older prisoners in Switzerland.

Introduction: Population ageing is a worldwide phenomenon that forces us to make radical changes on multiple levels of society. So far, studies have concluded that the health, both physical and mental, of prisoners in general and older prisoners in particular is worse than that of the general population. Prisoners are reported to age faster as compared to adults in the community. However, to date, very little is known about the actual healthcare conditions of older prisoners and almost no substantial knowledge is available concerning their patterns of healthcare use. Method: A quantitative study was conducted in four prisons for male prisoners in Switzerland, including two open and two closed prisons situated in different cantons. In this study, medical records of older prisoners (50+) were obtained from the respective authority upon consent and total anonymity was ensured. Data gathered from all available medical records included basic demographic information, education and prison sentencing. Healthcare data obtained were extensive in nature encompassing data related to illness types, number of visits to different health care providers and hospitals. The corresponding reasons for visits and outcomes of these visits were extracted. All data are analysed using statistical software SPSS 20.0. Results: Data were extracted for a total of 50 older prisoners living in Switzerland. The chosen prisons are located in German-speaking cantons. Preliminary results show that the age average was 56 years. For more than half, this was their first imprisonment. Nevertheless, a third of them were sentenced to measures (Art. 64 Swiss Criminal Code) which means that the length of the detention is indefinite and while release is possible it is in most cases not very likely. This entails that these prisoners will grow old in prison and some will even spend their remaining years there. Concerning their health, a third of the sample reported respiratory and cardiovascular illnesses and half reported suffering from some form of musculoskeletal related pain. Older prisoners were prescribed on average only 3.5 medications, which is significantly fewer than the number of medication prescribed to younger prisoners, whose data were also sampled. Conclusion: Access to healthcare is a right given to all prisoners through the principle of equivalence which is generally exercised in Switzerland. Prisoners growing old in prison will represent a challenge for prison health care services.