Étude de la toxicité causée par le gène C9orf72 dans la Sclérose Latérale Amyotrophique

La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative qui affecte les neurones moteurs. 10% des cas sont des cas familiaux et l’étude de ces familles a mené à la découverte de plusieurs gènes pouvant causer la SLA, incluant SOD1, TARDBP et FUS. L’expansion de la répétition GGGGCC dans le gène C9orf72 est, à ce jour, la cause la plus connue de SLA. L’impact de cette expansion est encore méconnu et il reste à déterminer si la toxicité est causée par un gain de fonction, une perte de fonction ou les deux. Plusieurs gènes impliqués dans la SLA sont conservés entre le nématode Caenorhabditis elegans et l’humain. C. elegans est un vers transparent fréquemment utilisé pour des études anatomiques, comportementales et génétiques. Il possède une lignée cellulaire invariable qui inclue 302 neurones. Aussi, les mécanismes de réponse au stress ainsi que les mécanismes de vieillissement sont très bien conservés entre ce nématode et l’humain. Donc, notre groupe, et plusieurs autres, ont utilisé C. elegans pour étudier plusieurs aspects de la SLA. Pour mieux comprendre la toxicité causée par l’expansion GGGGCC de C9orf72, nous avons développé deux modèles de vers pour étudier l’impact d’une perte de fonction ainsi que d’un gain de toxicité de l’ARN. Pour voir les conséquences d’une perte de fonction, nous avons étudié l’orthologue de C9orf72 dans C. elegans, alfa-1 (ALS/FTD associated gene homolog). Les vers mutants alfa-1(ok3062) développent des problèmes moteurs causant une paralysie et une dégénérescence spécifique des neurones moteurs GABAergiques. De plus, les mutants sont sensibles au stress osmotique qui provoque une dégénérescence. D’autre part, l’expression de la séquence d’ARN contenant une répétition pathogénique GGGGCC cause aussi des problèmes moteurs et de la dégénérescence affectant les neurones moteurs. Nos résultats suggèrent donc qu’un gain de toxicité de l’ARN ainsi qu’une perte de fonction de C9orf72 sont donc toxiques pour les neurones. Puisque le mouvement du vers peut être rapidement évalué en cultivant les vers dans un milieu liquide, nous avons développé un criblage de molécules pouvant affecter le mouvement des vers mutants alfa-1 en culture liquide. Plus de 4 000 composés ont été évalués et 80 ameliore la mobilité des vers alfa-1. Onze molécules ont aussi été testées dans les vers exprimant l’expansion GGGGCC et huit diminuent aussi le phénotype moteur de ces vers. Finalement, des huit molécules qui diminent la toxicité causée par la perte de fonction de C9orf72 et la toxicité de l’ARN, deux restaurent aussi l’expression anormale de plusieurs transcrits d’ARN observée dans des cellules dérivées de patient C9orf72. Avec ce projet, nous voulons identifier des molécules pouvant affecter tous les modes de toxicité de C9orf72 et possiblement ouvrir de nouvelles avenues thérapeutiques

Techniques en appui des formats de modulation avancés pour les futurs réseaux optiques

Les systèmes de communication optique avec des formats de modulation avancés sont actuellement l’un des sujets de recherche les plus importants dans le domaine de communication optique. Cette recherche est stimulée par les exigences pour des débits de transmission de donnée plus élevés. Dans cette thèse, on examinera les techniques efficaces pour la modulation avancée avec une détection cohérente, et multiplexage par répartition en fréquence orthogonale (OFDM) et multiples tonalités discrètes (DMT) pour la détection directe et la détection cohérente afin d’améliorer la performance de réseaux optiques. Dans la première partie, nous examinons la rétropropagation avec filtre numérique (DFBP) comme une simple technique d’atténuation de nonlinéarité d’amplificateur optique semiconducteur (SOA) dans le système de détection cohérente. Pour la première fois, nous démontrons expérimentalement l’efficacité de DFBP pour compenser les nonlinéarités générées par SOA dans un système de détection cohérente porteur unique 16-QAM. Nous comparons la performance de DFBP avec la méthode de Runge-Kutta quatrième ordre. Nous examinons la sensibilité de performance de DFBP par rapport à ses paramètres. Par la suite, nous proposons une nouvelle méthode d’estimation de paramètre pour DFBP. Finalement, nous démontrons la transmission de signaux de 16-QAM aux taux de 22 Gbaud sur 80km de fibre optique avec la technique d’estimation de paramètre proposée pour DFBP. Dans la deuxième partie, nous nous concentrons sur les techniques afin d’améliorer la performance des systèmes OFDM optiques en examinent OFDM optiques cohérente (CO-OFDM) ainsi que OFDM optiques détection directe (DDO-OFDM). Premièrement, nous proposons une combinaison de coupure et prédistorsion pour compenser les distorsions nonlinéaires d’émetteur de CO-OFDM. Nous utilisons une interpolation linéaire par morceaux (PLI) pour charactériser la nonlinéarité d’émetteur. Dans l’émetteur nous utilisons l’inverse de l’estimation de PLI pour compenser les nonlinéarités induites à l’émetteur de CO-OFDM. Deuxièmement, nous concevons des constellations irrégulières optimisées pour les systèmes DDO-OFDM courte distance en considérant deux modèles de bruit de canal. Nous démontrons expérimentalement 100Gb/s+ OFDM/DMT avec la détection directe en utilisant les constellations QAM optimisées. Dans la troisième partie, nous proposons une architecture réseaux optiques passifs (PON) avec DDO-OFDM pour la liaison descendante et CO-OFDM pour la liaison montante. Nous examinons deux scénarios pour l’allocations de fréquence et le format de modulation des signaux. Nous identifions la détérioration limitante principale du PON bidirectionnelle et offrons des solutions pour minimiser ses effets.

Accessible Immersion Metrics (AIM) for Second Language Acquisition : A Constructivist Innovation for the ESL Classroom

Abstract: This study was designed to validate a constructivist learning framework, herein referred to as Accessible Immersion Metrics (AIM), for second language acquisition (SLA) as well as to compare two delivery methods of the same framework. The AIM framework was originally developed in 2009 and is proposed as a “How to” guide for the application of constructivist learning principles to the second language classroom. Piloted in 2010 at Champlain College St-Lambert, the AIM model allows for language learning to occur, free of a fixed schedule, to be socially constructive through the use of task-based assessments and relevant to the learner’s life experience by focusing on the students’ needs rather than on course content.||Résumé : Cette étude a été principalement conçu pour valider un cadre d'apprentissage constructiviste, ci-après dénommé Accessible Immersion Metrics - AIM, pour l'acquisition d'une langue seconde - SLA. Le cadre de l'AIM est proposé comme un mode d'emploi pour l'application des principes constructivistes à l'apprentissage d’une langue seconde. Créé en 2009 par l'auteur, et piloté en 2010 au Collège Champlain St-Lambert, le modèle de l'AIM permet l'apprentissage des langues à se produire, sans horaire fixe et socialement constructive grâce à l'utilisation des évaluations alignées basées sur des tâches pertinentes à l'expérience de vie de l'étudiant en se concentrant sur les besoins des élèves plutôt que sur le contenu des cours.

Interview with Dana L. Roth

An interview in four sessions, January and February 2014, with longtime Caltech chemistry librarian Dana L. Roth. Roth received his undergraduate education at Pasadena City College and UCLA (BS in chemistry, 1962). In 1965, he received master’s degrees in chemistry from Caltech and in library science from UCLA; that summer, he became Caltech’s chemistry librarian. After consolidation of Caltech’s division libraries in Millikan Library in 1967, he undertook various administrative responsibilities at Millikan over the years, along with his continuing duties as chemistry librarian. Active in the chemistry division of the Special Libraries Association. In 2008, inducted into the SLA Hall of Fame. That year he also received the Thomas W. Schmitt Staff Prize, presented to a Caltech staff member whose contributions “embody the values and spirit that enable the institute to achieve excellence in research and education.” Retired April 2013. In this interview he discusses his initial education as a chemist, including his graduate education at Caltech, and his switch to library science. He traces the development of library science in general and at Caltech—from the card-catalog days to the growth of the electronic Caltech Library system and the present state of online access and databases.

Study of infectious haematopoietic necrosis disease in some hatcheries and farmed rainbow trout in Iran using immunohistochemical technique and to comparing the obtained results with the PCR works

To detect rainbow trout hatcheries for infectious hematopoietic necrosis virus, samples of kidney, liver, spleen, muscle, intestine, heart and gills of trout larvae were obtained from a number of trout hatcheries from different provinces. Also tissue samples were obtained for molecular works using RT- PCR procedure. Tissue samples were processed using standard histotechnique and the obtained sections were stained using immunohistochemical procedure. From 100 examined samples 35 were positive for IHN by immunohistochemical test. Also, from 100 samples examined, 43 were positive in RT- PCR studies. The obtained results show that some rainbow trout hatcheries are contaminated in different regions of country. Therefore, a definition of prevention and eradication criteria are now critical to protect the unaffected areas within the country.

Levels of salivary immunoglobulin A under psychological stress and its relationship with rumination and five personality traits in medical students

Background and Objectives: The measurement of salivary immunoglobulin A is a useful and non-invasive method for measuring stress. Personality traits and rumination act as possible mediators in the relationship between psychological stressors and the immune system. This study was aimed to evaluate the levels of salivary IgA under psychological stress and its relationship with rumination and five personality traits in medical students. Methods: In this cross- sectional study, 45 medical students who intended to participate in the final exam were selected by simple random sampling. Two months before the exam, in the basal conditions, the NEO Personality Inventory-Short Form and Emotional Control Questionnaire (ECQ) were completed. Saliva samples were taken from students in both the basal conditions and exam stress conditions. Salivary IgA was measured by an ELISA test. Data was analyzed using paired samples T-test, Pearson correlation analysis, and stepwise regression. Results: A significant reduction of salivary IgA levels was found in exam stress conditions. Also, a significant negative correlation was found between traits of neuroticism and rumination with salivary IgA, as well as a significant positive correlation between of openness to experience and emotional inhibition with salivary IgA. Openness to experience and emotional inhibition may predict a substantial variance (34%) of salivary IgA under exam stress. Conclusions: Salivary IgA is reduced in response to exam stress. In addition, the rumination and personality traits may reduce or increase stress effects on the immune system, particularly the salivary IgA.

On L2 grammar and processing: the case of oblique relative clauses and the Null-Prep phenomenon

This dissertation investigates the acquisition of oblique relative clauses in L2 Spanish by English and Moroccan Arabic speakers in order to understand the role of previous linguistic knowledge and its interaction with Universal Grammar on the one hand, and the relationship between grammatical knowledge and its use in real-time, on the other hand. Three types of tasks were employed: an oral production task, an on-line self-paced grammaticality judgment task, and an on-line self-paced reading comprehension task. Results indicated that the acquisition of oblique relative clauses in Spanish is a problematic area for second language learners of intermediate proficiency in the language, regardless of their native language. In particular, this study has showed that, even when the learners’ native language shares the main properties of the L2, i.e., fronting of the obligatory preposition (Pied-Piping), there is still room for divergence, especially in production and timed grammatical intuitions. On the other hand, reaction time data have shown that L2 learners can and do converge at the level of sentence processing, showing exactly the same real-time effects for oblique relative clauses that native speakers had. Processing results demonstrated that native and non-native speakers alike are able to apply universal processing principles such as the Minimal Chain Principle (De Vincenzi, 1991) even when the L2 learners still have incomplete grammatical representations, a result that contradicts some of the predictions of the Shallow Structure Hypothesis (Clahsen & Felser, 2006). Results further suggest that the L2 processing and comprehension domains may be able to access some type of information that it is not yet available to other grammatical modules, probably because transfer of certain L1 properties occurs asymmetrically across linguistic domains. In addition, this study also explored the Null-Prep phenomenon in L2 Spanish, and proposed that Null-Prep is an interlanguage stage, fully available and accounted within UG, which intermediate L2 as well as first language learners go through in the development of pied-piping oblique relative clauses. It is hypothesized that this intermediate stage is the result of optionality of the obligatory preposition in the derivation, when it is not crucial for the meaning of the sentence, and when the DP is going to be in an A-bar position, so it can get default case. This optionality can be predicted by the Bottleneck Hypothesis (Slabakova, 2009c) if we consider that these prepositions are some sort of functional morphology. This study contributes to the field of SLA and L2 processing in various ways. First, it demonstrates that the grammatical representations may be dissociated from grammatical processing in the sense that L2 learners, unlike native speakers, can present unexpected asymmetries such as a convergent processing but divergent grammatical intuitions or production. This conclusion is only possible under the assumption of a modular language system. Finally, it contributes to the general debate of generative SLA since in argues for a fully UG-constrained interlanguage grammar.

An?lisis semi?tico - discursivo de tres obras de la colecci?n "de diez obras sobre la violencia" del maestro Enrique Grau [recurso electr?nico]

Para esta investigaci?n el arte pict?rico se presenta desde la dimensi?n dial?gica intersubjetiva bajtiniana, en donde la obra de arte se compone de un objeto est?tico (contenido) y forma art?stica (forma), en la cual se evidencia como la posici?n en el mundo que asume el artista, en relaci?n con las valoraciones, el conocimiento y el hecho ?tico que plasma en la obra, determina su discurso. La posesi?n en el mundo del autor-artista y de su tarea art?stica pueden y deben entenderse en relaci?n con todos los valores del conocimiento y del hecho ?tico: no es el material el que se unifica, se individualiza, se completa, se a?sla y se concluye. (Bajt?n, 1992, p. 37). De igual manera, el arte pict?rico, desde la perspectiva de la semi?tica en Lotman (2011), se considera como un tipo de lenguaje con el cual se explicitan diferentes juicios de valor, en los cuales el artista y el espectador demuestran la organizaci?n de un sistema de comunicaci?n que emplea signos para su materializaci?n. Lotman (2011) contempla que el estudio de la cultura, del arte mismo pierde sentido si se separa del problema del contenido, en la medida en que la significaci?n proviene de la relaci?n que sostiene la estructura del texto con nociones puramente intuitivas de los significados que ?ste refleja. Toda estructura o sistema de codificaci?n en el que est? definido el texto observado requiere de las valoraciones de quien las produce y quien las interpreta.

Oxidative stress and its haemodynamic consequences in chronic kidney disease

Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.

Perfil de memória e ativação de linfócitos T na leishmaniose visceral

Visceral leishmaniasis (VL) in Brazil is a disease caused by Leishmania infantum chagasi (L.i.chagasi). The clinical evolution post-infection depends on the vertebrate host immune response, which is genetically mediated. This study aimed to evaluate the immune response of individuals living in endemic area for VL in the state of the Rio Grande do Norte, considering individuals with VL under treatment (n = 9), recovered VL <1 year post treatment (n = 10), > 10 years posttreatment (n = 9), uninfected individuals living in endemic areas (n = 7), individuals that lost DTH response (n=6) and asymptomatic individuals for VL (n=9). Peripheral blood cells were evaluated in the presence and absence of soluble Leishmania antigens (SLA) and ex vivo, to determine activation, presence of regulatory cells and memory cells. The Leishmania parasitemia and anti-Leishmania antibodies were determined respectively by qPCR and ELISA. Cells from individuals with VL under treatment showed less cell activation after stimulation with SLA for the markers CD4/CD69, CD8/CD69 and CD8/CD25 compared with VL post treatment treatment (p <0.001). Apparently uninfected individuals have a higher cell activation than symptomatic VL (p <0.001), with the exception of CD8/CD25 marker (p = 0.6662). On the other hand, in the ex-vivo group, significant differences were observed for CD4/CD69, CD8/CD69 and CD8/CD25 between the 4 groups due to increased cell activation present in cells of individuals symptomatic LV (p <0.001). VL cells under treatment, ex vivo, have a lower percentage of memory cells (CD4/CD45RO and CD8/CD45RO) than individuals VL post-treatment or control group (p = <0.01). Likewise, individuals with symptomatic VL have fewer regulatory cells when stimulated by SLA [CD4/CD25 (p = 0.0022) and CD4/FOXP3 (p = 0.0016)] and in the ex-vivo group (p = 0.0017). Finally, DNA isolated from recovered VL contained Leishmania DNA, supporting the hypothesis of non-sterile clinical cure for Leishmania infection. Recovered VL, even 10 years after treatment have high levels of memory cells, which may be due to the presence of stimulation, either by reexposure to Leishmania or non-sterile cure

Estado nutricional e efeito da vitamina A na resposta imune frente à infecção por Leishmania Infantum

Nutritional status is an important determinant to the response against Leishmania infection, although few studies have characterized the molecular basis for the association found between malnutrition and the disease. Vitamin A supplementation has long been used in developing countries to prevent mortality by diarrheal and respiratory diseases, but there are no studies on the role of vitamin A in Leishmania infection, although we and others have found vitamin A deficiency in visceral Leishmaniasis (VL). Regulatory T cells are induced in vitro by vitamin A metabolites and are considered important cells implicated T CD4+ cell suppression in human VL. This work aimed to examine the correlation of nutritional status and the effect of vitamin A in the response against Leishmania infantum infection. A total of 179 children were studied: 31 had active VL, 33 VL history, 44 were DTH+ and 71 were DTH- and had negative antibody to Leishmania (DTH-/Ac-). Peripheral blood monuclear cells were isolated in a subgroup of 10 active VL and 16 DTH-/Ac- children and cultivated for 20h under 5 different conditions: 1) Medium, 2) Soluble promastigote L. infantum antigens (SLA), 3) All-trans retinoic acid (ATRA), 4) SLA + ATRA and 5) Concanavalin A. T CD4+CD25highFoxp3+, T CD4+CD25-Foxp3- and CD14+ monocytes were stained and studied by flow cytometry for IL-10, TGF-β and IL-17 production. Nutritional status was compromised in VL children, which presented lower BMI/Age and retinol concentrations when compared to healthy controls. We found a negative correlation between nutritional status (measured by BMI/Age and serum retinol) and anti-Leishmania antibodies and acute phase proteins. There was no correlation between nutritional status and parasite load. ATRA presented a dual effect in Treg cells and monocytes: In healthy children (DTH-/Ac-), it induced a regulatory response, increasing IL-10 and TGF-β production; in VL children it modulated the immune response, preventing increased IL-10 production after SLA stimulation. Furthermore, we found a positive correlation between BMI/Age and IL-17 production and negative correlation between serum retinol and IL-10 and TGF-β production in T CD4+CD25highFoxp3+ cells after SLA stimulus. Our results show a potential dual role of vitamin A in the immune system: improvement of regulatory profile during homeostasis and down modulation of IL-10 in Treg cells and monocytes during symptomatic VL. Therefore, the use of vitamin A concomitant to VL therapy might improve recovery from disease status in Leishmania infantum infection

Prevalence of Barrett Esophagus in Adolescents and Young Adults With Esophageal Atresia

International audience

Étude de la toxicité causée par le gène C9orf72 dans la Sclérose Latérale Amyotrophique

La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative qui affecte les neurones moteurs. 10% des cas sont des cas familiaux et l’étude de ces familles a mené à la découverte de plusieurs gènes pouvant causer la SLA, incluant SOD1, TARDBP et FUS. L’expansion de la répétition GGGGCC dans le gène C9orf72 est, à ce jour, la cause la plus connue de SLA. L’impact de cette expansion est encore méconnu et il reste à déterminer si la toxicité est causée par un gain de fonction, une perte de fonction ou les deux. Plusieurs gènes impliqués dans la SLA sont conservés entre le nématode Caenorhabditis elegans et l’humain. C. elegans est un vers transparent fréquemment utilisé pour des études anatomiques, comportementales et génétiques. Il possède une lignée cellulaire invariable qui inclue 302 neurones. Aussi, les mécanismes de réponse au stress ainsi que les mécanismes de vieillissement sont très bien conservés entre ce nématode et l’humain. Donc, notre groupe, et plusieurs autres, ont utilisé C. elegans pour étudier plusieurs aspects de la SLA. Pour mieux comprendre la toxicité causée par l’expansion GGGGCC de C9orf72, nous avons développé deux modèles de vers pour étudier l’impact d’une perte de fonction ainsi que d’un gain de toxicité de l’ARN. Pour voir les conséquences d’une perte de fonction, nous avons étudié l’orthologue de C9orf72 dans C. elegans, alfa-1 (ALS/FTD associated gene homolog). Les vers mutants alfa-1(ok3062) développent des problèmes moteurs causant une paralysie et une dégénérescence spécifique des neurones moteurs GABAergiques. De plus, les mutants sont sensibles au stress osmotique qui provoque une dégénérescence. D’autre part, l’expression de la séquence d’ARN contenant une répétition pathogénique GGGGCC cause aussi des problèmes moteurs et de la dégénérescence affectant les neurones moteurs. Nos résultats suggèrent donc qu’un gain de toxicité de l’ARN ainsi qu’une perte de fonction de C9orf72 sont donc toxiques pour les neurones. Puisque le mouvement du vers peut être rapidement évalué en cultivant les vers dans un milieu liquide, nous avons développé un criblage de molécules pouvant affecter le mouvement des vers mutants alfa-1 en culture liquide. Plus de 4 000 composés ont été évalués et 80 ameliore la mobilité des vers alfa-1. Onze molécules ont aussi été testées dans les vers exprimant l’expansion GGGGCC et huit diminuent aussi le phénotype moteur de ces vers. Finalement, des huit molécules qui diminent la toxicité causée par la perte de fonction de C9orf72 et la toxicité de l’ARN, deux restaurent aussi l’expression anormale de plusieurs transcrits d’ARN observée dans des cellules dérivées de patient C9orf72. Avec ce projet, nous voulons identifier des molécules pouvant affecter tous les modes de toxicité de C9orf72 et possiblement ouvrir de nouvelles avenues thérapeutiques

Sémaphore, suivi de services opérationnels

L’unité IDM fournit des services opérationnels utilisés par différents utilisateurs des scientifiques, des partenaires mais également le grand public. L’unité IDM souhaite mieux connaitre ses utilisateurs et évaluer la performance de ses services, afin : . D’améliorer le service rendu . D’effectuer du reporting mensuel/annuel . De répondre aux engagements de service (SLA) Pour cela, il faut utiliser différentes sources d’informations : Monitoring : permet de surveiller les services opérationnels et de connaitre l’état actuel et déterminer le taux de disponibilité . Logs d’activité o Logs serveurs (http, ftp, … ) : permet de connaître l’activité réelle des utilisateurs o Logs applicatifs : permet de récupérer des informations plus précise sur les différentes briques logicielles des services opérationnels L’objectif IDM, à travers cette alternance est de mettre en place une infrastructure commune à l’ensemble des systèmes d’informations.

THE ROLE OF RULES, EXAMPLES AND INDIVIDUAL DIFFERENCES IN THE ACQUISITION OF DECLARATIVE AND PROCEDURAL SECOND LANGUAGE KNOWLEDGE

The relevance of explicit instruction has been well documented in SLA research. Despite numerous positive findings, however, the issue continues to engage scholars worldwide. One issue that was largely neglected in previous empirical studies - and one that may be crucial for the effectiveness of explicit instruction - is the timing and integration of rules and practice. The present study investigated the extent to which grammar explanation (GE) before practice, grammar explanation during practice, and individual differences impact the acquisition of L2 declarative and procedural knowledge of two grammatical structures in Spanish. In this experiment, 128 English-speaking learners of Spanish were randomly assigned to four experimental treatments and completed comprehension-based task-essential practice for interpreting object-verb (OV) and ser/estar (SER) sentences in Spanish. Results confirmed the predicted importance of timing of GE: participants who received GE during practice were more likely to develop and retain their knowledge successfully. Results further revealed that the various combinations of rules and practice posed differential task demands on the learners and consequently drew on language aptitude and WM to a different extent. Since these correlations between individual differences and learning outcomes were the least observed in the conditions that received GE during practice, we argue that the suitable integration of rules and practice ameliorated task demands, reducing the burden on the learner, and accordingly mitigated the role of participants’ individual differences. Finally, some evidence also showed that the comprehension practice that participants received for the two structures was not sufficient for the formation of solid productive knowledge, but was more effective for the OV than for the SER construction.