Identité et filiation : enfants enlevés-appropriés, adultes restitués dans le contexte de la dernière dictature militaire en Argentine (1976-1983)

Durant la dernière dictature argentine (1976-1983), !a junte militaire organisa le vol de nourrissons, enfants de leurs ennemis, pour qu'ils puissent être élevés dans des familles proches du pouvoir. L'association « Grands-Mères de la Place de Mai » comptabilisa environ 409 vols. Au moment de l'exploration du terrain de récherche, en 2004, une quarantaine avaient été retrouvés dans des familles qui ne connaissaient pas leurs origines tandis qu'une vingtaine étaient dans des familles liées à la junte ; c'est à cette dernière catégorie que s'intéresse ce travail. Durant leur enfance ou à l'âge adulte, ces enfants apprirent un jour la vérité sur leurs origines biologiques et la justice la leur restitua ; c'est pourquoi ils sont dits « restitués ». Cette contribution vise à interroger l'identité individuelle comme une dynamique intime qui s'articule à la filiation et s'insère dans une collectivité, une société. Trois hypothèses l'ont organisée : une première concerne la connaissance des origines biologiques et ses conséquences psychologiques identitaires, qui passe nécessairement par la justice et la société. Une deuxième hypothèse explore les éventelles conséquences traumatiques de l'enlèvement des personnes restituées et de la restitution. Enfin, la troisième hypothèse interroge le rapport de la construction identitaire à la société, qu'elle se fasse par des investissements politiques et associatifs ou par les médias et l'Histoire. Ces hypothèses nourrissent un questionnement sur les liens entre restitution et travail de symbolisation des origines. Sept entretiens semi structurés avec des personnes restituées ont. été menés puis qualitativement analysés dans une perspective que l'on peut référer, de manière large, à une « anthropologique clinique », au croisement d'une psychologie clinique éclairée par la psychanalyse et de l'anthropologie. Au travers d'une analyse approfondie de leur parcours identitaire des personnes enlevées, adoptées et restituées, ce travail se livre à une recherche empirique sur la construction identitaire. Le concept de transmission se trouve mobilisé, qui concerne l'inscription de l'individu dans la subjectivité d'un couple avec le prénom, dans une lignée ou dans un collectif avec le choix professionnel ou les liens avec l'association « Grands-Mères de la Place Mai ». De plus, la thèse apporte une contribution à la compréhension des enjeux du clivage, des blessures primitive et narcissique, des processus d'affiliation et des secrets de famille et propose également de penser, en prolongement, les enjeux de la « défiliation » et de I'« amalgame ». La question du traumatisme, de sa répétition et de son élaboration, ainsi que celle des facteurs de resilience sont également discutées. Ce travail ouvre sur une réflexion plus large du concept d'identité. - During the last dictatorship in Argentina (1976-1983), the military junta organized the kidnapping of infants - children of its enemies - in order to raise them in families close to the authorities. The association "Mothers of the Plaza de Mayo" estimates that approximately 400 children have been kidnapped in this way. During their childhood, or as adults, they have come to learn the truth about their biological origins, restituted to them by justice: They are therefore known as "restituted" children. At the time of the field research in 2004, around 40 children had been found in families unaware of their origins. About 20 other came from families close to the junta. The present work is particularly interested in the latter category. This contribution investigates the individual identity as an intimate dynamics by examining its articulation with filiation and its insertion within a community, a society. It revolves around three hypotheses: the first concerns the knowledge - necessarily transmitted through justice and society - of biological origins and its psychological consequences on the identity. The second explores the eventually traumatic, consequences of kidnapping and restitution among the restituted persons. Finally, the third hypothesis questions the relation between identity construction and society, whether it is made through political and associative involvements, media or History. These hypotheses lead to the examination of affiliations between restitution and symbolization process of the origins. Seven semi-structured interviews with restituted persons have been conducted and qualitatively analyzed in a perspective that can, in a large sense, be referred to as "clinical anthropology": an approach/intersection between clinical psychology, psychoanalysis and anthropology. Through an in-depth analysis of the identity itinerary of the kidnapped, adopted and restituted persons, this work is conducted as an empirical research on identity construction. For that purpose, it uses the concept of transmission to describe an individual's affiliation with the subjectivity of a couple through the first name, with a lineage or a community through professional choices or through his/her connections with the association "Mothers of the Plaza de Mayo". Further, it makes a meaningful contribution to the understanding and implications of the notions of cleavage, of primal and narcissistic wounds, of processes of affiliation and of family secrets. In addition, it also proposes a reflection on and the implication of the notions of "deviation" and "amalgam". The question of trauma, its repetition and elaboration, and of resilience factors are aiso being discussed. This work concludes with results in a iarger consideration of the concept of identity.

Chagas disease in Andean countries

The Andean Countries' Initiative (ACI) for controlling Chagas disease was officially created in 1997 within the framework of the Hipolito Unanue Agreement (UNANUE) between the Ministries of Health of Colombia, Ecuador, Peru, and Venezuela. Its objective was to interrupt transmission via vector and transfusion in the region, taking into account that there are 12.5 million people at risk in the four Andean countries forming the initiative in the area and around 3 million people are infected by Trypanosoma cruzi. The progress of control activities for the vector species present in the Andean sub-region, for different reasons, has been slow and control interventions have still not been installed in all geographical areas occupied by the target species. This has been partly due to lack of knowledge about these vector populations' biological characteristics, and consequent uncertainty about which are the appropriate control measures and strategies to be implemented in the region. The main vector species present important similarities in Venezuela and Colombia and in Ecuador and Northern Peru and they can be approached in a similar way throughout the whole regions, basing approaches on and adapting them to the current strategies being developed in Venezuela during the 1960s which have been progressively adopted in the Southern Cone and Central-American region. Additional measures are needed for keeping endemic areas free from Rhodnius prolixus silvatic populations, widely spread in the Orinoco region in Colombia and Venezuela. Regarding aetiological treatment, it is worth mentioning that (with the exception of Colombia) none of the other countries forming the ACI have registered medicaments available for treating infected young people. There are no suitable follow-up programmes in the sub-region or for treating cases of congenital Chagas disease. An integral and integrated programme encompassing all the aspects including transmission by transfusion which seems to have achieved extremely encouraging results in all countries, are urgently needed.

Mise en oeuvre de protocoles spatiaux pour analyser la modulation de processus cognitifs en fonction de la dimension émotionnelle chez le rongeur

Résumé : Emotion et cognition sont deux termes généralement employés pour désigner des processus psychiques de nature opposée. C'est ainsi que les sciences cognitives se sont longtemps efforcées d'écarter la composante «chaude »des processus «froids »qu'elles visaient, si ce n'est pour montrer l'effet dévastateur de la première sur les seconds. Pourtant, les processus cognitifs (de collecte, maintien et utilisation d'information) et émotioAnels (d'activation subjective, physiologique et comportementale face à ce qui est attractif ou aversif) sont indissociables. Par l'approche neuro-éthologique, à l'interface entre le substrat biologique et les manifestations comportementales, nous nous sommes intéressés à une fonction cognitive essentielle, la fonction mnésique, classiquement exprimée chez le rongeur par l'orientation spatiale. Au niveau du substrat, McDonald et White (1993) ont montré la dissociation de trois systèmes de mémoire, avec les rôles de l'hippocampe, du néostriatum et de l'amygdale dans l'encodage des informations respectivement épisodiques, procédurales et émotionnelles. Nous nous sommes penchés sur l'interaction entre ces systèmes en fonction de la dimension émotionnelle par l'éclairage du comportement. L'état émotionnel de l'animal dépend de plusieurs facteurs, que nous avons tenté de contrôler indirectement en comparant leurs effets sur l'acquisition, dans diverses conditions, de la tâche de Morris (qui nécessite la localisation dans un bassin de la position d'une plate-forme submergée), ainsi que sur le style d'exploration de diverses arènes, ouvertes ou fermées, plus ou moins structurées par la présence de tunnels en plexiglas transparent. Nous avons d'abord exploré le rôle d'un composant du système adrénergique dans le rapport à la difficulté et au stress, à l'aide de souris knock-out pour le récepteur à la noradrénaline a-1 B dans un protocole avec 1 ou 4 points de départ dans un bassin partitionné. Ensuite, nous nous sommes penchés, chez le rat, sur les effets de renforcement intermittent dans différentes conditions expérimentales. Dans ces conditions, nous avons également tenté d'analyser en quoi la situation du but dans un paysage donné pouvait interférer avec les effets de certaines formes de stress. Finalement, nous avons interrogé les conséquences de perturbations passées, y compris le renforcement partiel, sur l'organisation des déplacements sur sol sec. Nos résultats montrent la nécessité, pour les souris cont~ô/es dont l'orientation repose sur l'hippocampe, de pouvoir varier les trajectoires, ce qui favoriserait la constitution d'une carte cognitive. Les souris a->B KO s'avèrent plus sensibles au stress et capables de bénéficier de la condition de route qui permet des réponses simples et automatisées, sous-tendues par l'activité du striatum. Chez les rats en bassin 100% renforcé, l'orientation apparaît basée sur l'hippocampe, relayée par le striatum pour le développement d'approches systématiques et rapides, avec réorientation efficace en nouvelle position par réactivation dépendant de l'hippocampe. A 50% de renforcement, on observe un effet du type de déroulement des sessions, transitoirement atténué par la motivation Lorsque les essais s'enchaînent sans pause intrasession, les latences diminuent régulièrement, ce qui suggère une prise en charge possible par des routines S-R dépendant du striatum. L'organisation des mouvements exploratoires apparaît dépendante du niveau d'insécurité, avec différents profils intermédiaires entre la différentiation maximale et la thigmotaxie, qui peuvent être mis en relation avec différents niveaux d'efficacité de l'hippocampe. Ainsi, notre travail encourage à la prise en compte de la dimension émotionnelle comme modulatrice du traitement d'information, tant en phase d'exploration de l'environnement que d'exploitation des connaissances spatiales. Abstract : Emotion and cognition are terms widely used to refer to opposite mental processes. Hence, cognitive science research has for a long time pushed "hot" components away from "cool" targeted processes, except for assessing devastating effects of the former upon the latter. However, cognitive processes (of information collection, preservation, and utilization) and emotional processes (of subjective, physiological, and behavioral activation roue to attraction or aversion) are inseparable. At the crossing between biological substrate and behavioral expression, we studied a chief cognitive function, memory, classically shown in animals through spatial orientation. At the substrate level, McDonald et White (1993) have shown a dissociation between three memory systems, with the hippocampus, neostriatum, and amygdala, encoding respectively episodic, habit, and emotional information. Through the behavior of laboratory rodents, we targeted the interaction between those systems and the emotional axis. The emotional state of an animal depends on different factors, that we tried to check in a roundabout way by the comparison of their effects on acquisition, in a variety of conditions, of the Morris task (in which the location of a hidden platform in a pool is required), as well as on the exploration profile in different apparatus, open-field and closed mazes, more or less organized by clear Plexiglas tunnels. We first tracked the role, under more or less difficult and stressful conditions, of an adrenergic component, with knock-out mice for the a-1 B receptor in a partitioned water maze with 1 or 4 start positions. With rats, we looked for the consequences of partial reinforcement in the water maze in different experimental conditions. In those conditions, we further analyzed how the situation of the goal in the landscape could interfere with the effect of a given stress. At last, we conducted experiments on solid ground, in an open-field and in radial mazes, in order to analyze the organization of spatial behavior following an aversive life event, such as partial reinforcement training in the water maze. Our results emphasize the reliance of normal mice to be able to vary approach trajectories. One of our leading hypotheses is that such strategies are hippocampus-dependent and are best developed for of a "cognitive map like" representation. Alpha-1 B KO mice appear more sensitive to stress and able to take advantage of the route condition allowing simple and automated responses, most likely striatum based. With rats in 100% reinforced water maze, the orientation strategy is predominantly hippocampus dependent (as illustrated by the impairment induced by lesions of this structure) and becomes progressively striatum dependent for the development of systematic and fast successful approaches. Training towards a new platform position requires a hippocampus based strategy. With a 50% reinforcement rate, we found a clear impairment related to intersession disruption, an effect transitorily minimized by motivation enhancement (cold water). When trials are given without intrasession interruption, latencies consistently diminish, suggesting a possibility for striatum dependent stimulus-response routine to occur. The organization of exploratory movements is shown to depend on the level of subjective security, with different intermediary profiles between maximum differentiation and thigmotaxy, which can be considered in parallel with different efficiency levels of the hippocampus dependent strategies. Thus, our work fosters the consideration of emotion as a cognitive treatment modulator, during spatial exploration as well as spatial learning. It leads to a model in which the predominance of hippocampus based exploration is challenged by training conditions of various nature.

Should reproductively isolated populations of Lutzomyia longipalpis sensu lato receive taxonomically valid names?

A group of 18 research workers involved in different aspects of the biology of Lutzomyia longipalpis discussed whether or not it is important to give taxonomically valid names to populations that have been defined by biological, biochemical and molecular methods to be reproductively isolated. The type material of this medically important species has been lost and because of this it was recommended that a colony should be established from insects captured in the region of the type area and that their description should serve as the basis for future descriptions. It was pointed out that there is a lack of uniformity in the naming of closely related American sand flies and that some of the differences between populations of Lu. longipalpis are greater than those between accepted species. The majority of the participants agreed that the populations that have been defined in the literature as sibling species should be named.

All-around care for patients with Chagas disease: a challenge for the XXI century

In 1987, the University of Pernambuco's Oswaldo Cruz Hospital in Recife, Brazil opened its Chagas Disease and Heart Failure Outpatient Clinic with the aim of providing its patients all-around care through adoption of a biopsychosocial model of care. All-around care involves caring for the patient as a whole human being in the context of the biological, psychological and social factors present, which are an inherent part of the human condition. One prerequisite for the proposed model of care is the participation of a multidisciplinary team of trained technical staff committed to this framework. Although the main focus of the service is on care, teaching and research are also an important part of its work. The Pernambuco Association of Chagas Disease Patients is guided by the same model of care and has been carrying out educational activities relating to the disease, its treatment and support for patients and family members for several years. This Association plays an important role in advocating to public authorities on behalf of patients. The accumulated experience of the past 22 years has shown us that a broad vision of health care can help clinicians and policy makers to make decisions that are more in tune with the everyday reality of the patient, which in turn has a positive impact on adherence to treatment and quality of life.

Total hemoglobin mass--a new parameter to detect blood doping?

PURPOSE: All kinds of blood manipulations aim to increase the total hemoglobin mass (tHb-mass). To establish tHb-mass as an effective screening parameter for detecting blood doping, the knowledge of its normal variation over time is necessary. The aim of the present study, therefore, was to determine the intraindividual variance of tHb-mass in elite athletes during a training year emphasizing off, training, and race seasons at sea level. METHODS: tHb-mass and hemoglobin concentration ([Hb]) were determined in 24 endurance athletes five times during a year and were compared with a control group (n = 6). An analysis of covariance was used to test the effects of training phases, age, gender, competition level, body mass, and training volume. Three error models, based on 1) a total percentage error of measurement, 2) the combination of a typical percentage error (TE) of analytical origin with an absolute SD of biological origin, and 3) between-subject and within-subject variance components as obtained by an analysis of variance, were tested. RESULTS: In addition to the expected influence of performance status, the main results were that the effects of training volume (P = 0.20) and training phases (P = 0.81) on tHb-mass were not significant. We found that within-subject variations mainly have an analytical origin (TE approximately 1.4%) and a very small SD (7.5 g) of biological origin. CONCLUSION: tHb-mass shows very low individual oscillations during a training year (<6%), and these oscillations are below the expected changes in tHb-mass due to Herythropoetin (EPO) application or blood infusion (approximately 10%). The high stability of tHb-mass over a period of 1 year suggests that it should be included in an athlete's biological passport and analyzed by recently developed probabilistic inference techniques that define subject-based reference ranges.

Breast cancer prognostic classification in the molecular era: the role of histological grade.

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

Validation d'une version abrégée du TCI (TCI-56) sur un échantillon de jeunes fumeurs et non-fumeurs

Introduction: The psychobiological seven-factor model proposed by Cloninger et al. (1993) takes into account temperament and character dimensions to describe personality. Four of the dimensions are linked with biological, genetic and neuroanatomic structures, whereas the three other dimensions are related to the degree of individual, social and spiritual development. A study conducted by Wills et al. (1994) with adolescents showed that substance abuse was associated with high scores on Novelty Seeking and low scores on Harm Avoidance and Reward Dependence. The aim of the present study was, firstly, to create a short form of Cloninger's (1993) Temperament and Character Inventory (TCI) and, secondly, to study the impact of nicotine dependence as well as demographic variables on a sample of young adults. Method: We created a short form of the TCI containing 56 items (TCI-56), 8 for each scale. Responses are made on a five-point Likert type scale. A Swiss sample (n=211), of 116 women and 95 men, aged from 15 to 30 years, participated in this study. Our population was divided into a group of 81 smokers and another of 130 non-smokers, according to their scores on the Fagerstörm test for nicotine dependence (1999). Results: The structural validation consisted of two separate factor analysis with varimax rotations, one for the temperamental items, and the other, for the character ones. The first factor analysis conducted on the items of the temperament scales allowed to extract 4 factors explaining 40.7% of the variance. The correlations between factors and scales are the following: r=.71 for Novelty Seeking, r=.69 for Persistence, r=.95 for Harm Avoidance, r=.94 for Reward Dependence. The second factor analysis conducted on the items of the character scales allowed to extract 3 factors explaining 41.5% of the variance. The correlations between factors and scales are the following: r=.94 for Self-Directedness, r=.91 for Cooperativeness and r=.99 for Self-Transcendence. The internal consistencies range from α=.65 to α=.75 for the temperament scales, and from α=.71 to α=.83 for the three character scales. Concerning, the impact of the nicotine dependence, we observed that smokers have significantly higher scores for Novelty seeking, than non-smokers (p=.01). We found no difference for Harm Avoidance and Reward Dependence. Nevertheless, smokers seem to have the tendency to score higher on Transcendence (p=.06). Moreover, people having smoked more than 100 cigarettes in their life have significantly higher scores on this scale (p.04) and the correlation between Transcendence and the Fagerstörm test is significant (r=.19). We also found gender differences: the women (N=116) obtain significantly higher scores for Harm Avoidance (p<.001), for Reward Dependence (p<.001) and for Cooperation (p=.01). We further found a significant correlation between age and Self-Directedness, r=.34. We observed no interaction between gender and smoking or age and smoking on the dimensions of the TCI-56. Discussion: The TCI short form (TCI-56) seems to be a valid and useful inventory to assess personality differences. Confirming the results of others about the relation between addiction and personality, we found that smokers have significantly higher scores for Novelty seeking, than non-smokers. But we were not able to find any significant differences for Harm Avoidance and Reward Dependence. This might be due to our sample that was made of young adults. This study also shows that Transcendence could be an interesting dimension for studies on Tobacco smoking to consider. Concerning the impact of demographic variables, we observed that age and gender have specific and coherent influence on personality.

Malaria vector species in Colombia: a review

Here we present a comprehensive review of the literature on the vectorial importance of the major Anopheles malaria vectors in Colombia. We provide basic information on the geographical distribution, altitudinal range, immature habitats, adult behaviour, feeding preferences and anthropophily, endophily and infectivity rates. We additionally review information on the life cycle, longevity and population fluctuation of Colombian Anopheles species. Emphasis was placed on the primary vectors that have been epidemiologically incriminated in malaria transmission: Anopheles darlingi, Anopheles albimanus and Anopheles nuneztovari. The role of a selection of local, regional or secondary vectors (e.g., Anopheles pseudopunctipennis and Anopheles neivai) is also discussed. We highlight the importance of combining biological, morphological and molecular data for the correct taxonomical determination of a given species, particularly for members of the species complexes. We likewise emphasise the importance of studying the bionomics of primary and secondary vectors along with an examination of the local conditions affecting the transmission of malaria. The presence and spread of the major vectors and the emergence of secondary species capable of transmitting human Plasmodia are of great interest. When selecting control measures, the anopheline diversity in the region must be considered. Variation in macroclimate conditions over a species' geographical range must be well understood and targeted to plan effective control measures based on the population dynamics of the local Anopheles species.

In vitro antimicrobial assessment of Cuban propolis extracts

Propolis is a resinous mixture of different plant exudates collected by honeybees. Currently, propolis is widely used as a food supplement and in folk medicine. We have evaluated 20 Cuban propolis extracts of different chemical types, brown (BCP), red and yellow (YCP), with respect to their in vitro antibacterial, antifungal and antiprotozoal properties. The extracts inhibited the growth of Staphylococcus aureus and Trichophyton rubrum at low µg/mL concentrations, whereas they were not active against Escherichia coli and Candida albicans. The major activity of the extracts was found against the protozoa Leishmania, Trypanosoma and Plasmodium, although cytotoxicity against MRC-5 cells was also observed. The BCP-3, YCP-39 and YCP-60 extracts showed the highest activity against P. falciparum, with 50% of microbial growth (IC50) values of 0.2 µg/mL. A positive correlation between the biological activity and the chemical composition was observed for YCP extracts. The most promising antimicrobial activity corresponds to YCP subtype B, which contains acetyl triterpenes as the main constituents. The present in vitro study highlights the potential of propolis against protozoa, but further research is needed to increase selectivity towards the parasite. The observed chemical composition-activity relationship of propolis can contribute to the identification of the active principles and standardisation of this bee product.

Characterization of SKI-1/S1P-mediated processing of Arenavirus glycoprotein precursors

Arenaviruses are rodent-born world-wide distributed negative strand RNA viruses that comprise a number of important human pathogens including Lassa virus (LASV) which causes more than 3 00'000 infections annually in Western Africa. Lymphocytic choriomeningitis virus (LCMV) is the prototypic member of the arenavirus family, which is divided in two major subgroups according to serological properties and geographical distribution, the Old World and New World arenaviruses. The envelope glycoprotein precursors (GPCs) of arenaviruses have to undergo proteolytic processing to acquire biological function and to be incorporated into progeny virions. A cellular enzyme is responsible for this processing: the Subtilisin Kexin Isozyme-1 or Site-1 protease (SKI- 1/S1P). In this thesis we have studied the relationship between SKI-1/S1P and the envelope GPs of arenaviruses. In a first project, we investigated the molecular interactions between SKI-1/SIP and arenavirus GPCs. Using SKI-1/SIP mutants, we confirmed previously published observations locating LCMV GPC and LASV GPC processing in the Late Golgi/TGN and ER/cis-Golgi, respectively. A single mutation in the cleavage site of LCMV was sufficient to re-locate SKI- 1/SIP-mediated processing from the late Golgi/TGN to the ER/cis-Golgi. We then demonstrated that the transmembrane domain, the C-terminal tail and the phosphorylation sites of SKI-1/S1P are dispensable for GPC processing. Additionally we identified a SKI- 1/S1P mutant defective for autoprocessing at site Β, B' that was selectively impaired in processing of viral GPCs but not cellular substrates. We also showed that a soluble variant of SKI-1/SIΡ was unable to cleave envelope GPs at the cell surface when added in the culture medium. This study highlighted a new target for small molecule inhibitors that would specifically impair GPC but not cellular substrate processing. In a second project, we identified and characterized two residues: LASV GPC Y253 and SKI-1/S1P Y285 that are important for the SKI-1/SIP-mediated LASV GPC cleavage. An alignment of GPC sequences revealed a conserved aromatic residue in P7 position in the GPCs of Old World and Clade C of New World arenaviruses. Mutations in GPC at position P7 impaired processing efficiency. In SKI-1/S1P, mutating Y285 into A negatively affected processing of substrates containing aromatic residues in P7, without affecting others. This property could be used to develop specific drugs targeting SKI-1/SIP-mediated cleavage of LASV GPC without affecting cellular substrates. As a third project we studied the role of the SKI-1/SIP-mediated processing and the unusual stable signal peptide (SSP) for the folding and secretion of soluble forms of the ectodomain of LASV and LCMV glycoproteins. We provide evidence that the transmembrane domain and the cytosolic tail are crucial for the stability of the prefusion conformation of arenavirus GP and that the SSP is required for transport and processing of full-length GP, but not the soluble ectodomain per se. Taken together, these results will lead to a better understanding of the complex interactions between arenavirus GPCs and SKI-1/S IP, paving the avenue for the development of novel anti-arenaviral therapeutics. - Les Arenavirus sont des virus à ARN négatif distribués mondialement et portés par les rongeurs. Cette famille de virus comprend des virus hautement pathogènes pour l'homme comme le virus de Lassa (LASV) qui cause plus de 300Ό00 infections par année en Afrique de l'Ouest. Le virus de la chorioméningite lymphocytaire (LCMV) est le représentant de cette famille qui est divisée en deux sous-groupes selon des critères sérologiques et de distributions géographiques: arenavirus du Nouveau et de l'Ancien monde. Les glycoprotéines d'enveloppe de ces virus (GPCs) doivent être clivées pour être incorporées dans le virus et ainsi lui permettre d'être infectieux. Une enzyme cellulaire est responsable de ce clivage : la Subtilisin Kexin Isozyme-1 ou protéase Site-1 (SKI-l/SlP). Dans cette thèse, nous avons étudié la relation entre cette enzyme cellulaire et les GPs des arenavirus. Dans un premier temps, nous avons étudié les interactions moléculaires entre SKI- 1/S1P et GPC. A l'aide de mutants de SKI-l/SlP, nous avons confirmé des résultats précédemment publiés montrant que les glycoprotéines d'enveloppe de LASV sont clivés dans le réticulum endoplasmique/cis-Golgi alors que celles de LCMV sont clivées dans le Golgi tardif/TGN. Une seule mutation dans le site de clivage de la glycoprotéine de LCMV est suffisante pour changer le compartiment cellulaire dans lequel est clivée cette glycoprotéine. Ensuite, nous avons démontré que le domaine transmembranaire, la partie cytosolique C-terminale ainsi que les sites de phosphorylations de cette enzyme ne sont pas indispensables pour permettre le clivage de GPC. De plus, nous avons identifié un mutant de SKI-l/SlP dans lequel Γ autoprocessing au site B,B' est impossible, incapable de cliver GPC mais toujours pleinement fonctionnelle envers ses substrats cellulaires. Nous avons également démontré qu'une forme soluble de SKI-l/SlP ajoutée dans le milieu de culture n'est pas capable de couper GPC à la surface de la cellule. Cette étude a défini une nouvelle cible potentielle pour un médicament qui inhiberait le clivage des glycoprotéines des arenavirus sans affecter les processus normaux de la cellule. Dans un second project, nous avons identifié deux acides aminés, LASV GPC Y253 et SKI-l/SlP Y285, qui sont important pour le clivage de LASV GPC. Un alignement des séquences de clivage des GPCs a montré qu'un résidu aromatique est conservé en position P7 du site de clivage chez tous les arenavirus de l'Ancien monde et dans le clade C des arenavirus du Nouveau monde. Une mutation de cet acide aminée dans GPC réduit l'efficacité de clivage par SKI-l/SlP. Mutation de la tyrosine 285 de SKI-l/SlP en alanine affecte négativement le clivage des substrats contenant un résidu aromatique en position P7 sans affecter les autres. Cette propriété pourrait être utilisée pour le développement de médicaments spécifiques ciblant le clivage de GPC. Finalement, nous avons étudié le rôle du processing accomplit par SKI-l/SlP et du signal peptide pour le pliage et la sécrétion de formes solubles des glycoprotéines de LASV et LCMV. Nous avons montré que le domaine transmembranaire et la partie cytosolique de GP sont crucials pour la stabilité de la conformation pre-fusionnelle des GPs et que SSP est nécessaire pour le transport et le processing de GP, mais pas de son ecto-domaine soluble. En conclusion, les résultats obtenus durant cette thèse permettrons de mieux comprendre les interactions complexes entre SKI-l/SlP et les glycoprotéines des arenavirus, ouvrant le chemin pour le développement de nouveaux médicaments anti-arénaviraux.

Additive functions in boolean models of gene regulatory network modules.

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate.

Could radiotherapy effectiveness be enhanced by electromagnetic field treatment?

One of the main goals in radiobiology research is to enhance radiotherapy effectiveness without provoking any increase in toxicity. In this context, it has been proposed that electromagnetic fields (EMFs), known to be modulators of proliferation rate, enhancers of apoptosis and inductors of genotoxicity, might control tumor recruitment and, thus, provide therapeutic benefits. Scientific evidence shows that the effects of ionizing radiation on cellular compartments and functions are strengthened by EMF. Although little is known about the potential role of EMFs in radiotherapy (RT), the radiosensitizing effect of EMFs described in the literature could support their use to improve radiation effectiveness. Thus, we hypothesized that EMF exposure might enhance the ionizing radiation effect on tumor cells, improving the effects of RT. The aim of this paper is to review reports of the effects of EMFs in biological systems and their potential therapeutic benefits in radiotherapy.

Domains of p85cdc10 required for function of the fission yeast DSC-1 factor.

p85cdc10 is a component of the S.pombe DSC-1 complex, which is thought to mediate periodic transcription of genes in late G1. In order to understand the role of p85cdc10 in the function of this complex, we have analysed which domains of p85cdc10 are required for biological activity and the formation of a stable DSC-1 complex in vitro, both in cdc10 temperature sensitive and null backgrounds. No DSC-1 activity is found in the absence of p85cdc10 and the activity of the complex is reduced or absent in all cdc10ts mutants tested. Full biological activity and rescue of a cdc10::ura4+ null allele requires the N-terminal domain, the cdc10/SWI6 repeats and the helical C-terminal region. In the absence of p85cdc10, both the C-terminal and cdc10/SWI6 repeat domains are required for DSC-1 activity in vitro. In a cdc10ts background, rescue of DSC-1 activity and complementation of mutants, requires only expression of the C-terminal domain, though the presence of the cdc10/SWI6 motifs enhances its activity. The N-terminal domain, alone, or in combination with the cdc10/SWI6 motifs, does not have biological activity, and does not restore DSC-1 activity. We conclude that both the C-terminal domain of p85cdc10 is critical for formation of the DSC-1 complex and that the cdc10/SWI6 motifs also play a role, perhaps by stabilizing the complex. Our data also suggest that the S.pombe DSC-1 complex contains more than one molecule of p85cdc10.

A novel method for automated classification of epileptiform activity in the human electroencephalogram-based on independent component analysis.

Diagnosis of several neurological disorders is based on the detection of typical pathological patterns in the electroencephalogram (EEG). This is a time-consuming task requiring significant training and experience. Automatic detection of these EEG patterns would greatly assist in quantitative analysis and interpretation. We present a method, which allows automatic detection of epileptiform events and discrimination of them from eye blinks, and is based on features derived using a novel application of independent component analysis. The algorithm was trained and cross validated using seven EEGs with epileptiform activity. For epileptiform events with compensation for eyeblinks, the sensitivity was 65 +/- 22% at a specificity of 86 +/- 7% (mean +/- SD). With feature extraction by PCA or classification of raw data, specificity reduced to 76 and 74%, respectively, for the same sensitivity. On exactly the same data, the commercially available software Reveal had a maximum sensitivity of 30% and concurrent specificity of 77%. Our algorithm performed well at detecting epileptiform events in this preliminary test and offers a flexible tool that is intended to be generalized to the simultaneous classification of many waveforms in the EEG.