rst Transcriptional Activity Influences kirre mRNA Concentration in the Drosophila Pupal Retina during the Final Steps of Ommatidial Patterning

Background: Drosophila retinal architecture is laid down between 24-48 hours after puparium formation, when some of the still uncommitted interommatidial cells (IOCs) are recruited to become secondary and tertiary pigment cells while the remaining ones undergo apoptosis. This choice between survival and death requires the product of the roughest (rst) gene, an immunoglobulin superfamily transmembrane glycoprotein involved in a wide range of developmental processes. Both temporal misexpression of Rst and truncation of the protein intracytoplasmic domain, lead to severe defects in which IOCs either remain mostly undifferentiated and die late and erratically or, instead, differentiate into extra pigment cells. Intriguingly, mutants not expressing wild type protein often have normal or very mild rough eyes. Methodology/Principal Findings: By using quantitative real time PCR to examine rst transcriptional dynamics in the pupal retina, both in wild type and mutant alleles we showed that tightly regulated temporal changes in rst transcriptional rate underlie its proper function during the final steps of eye patterning. Furthermore we demonstrated that the unexpected wild type eye phenotype of mutants with low or no rst expression correlates with an upregulation in the mRNA levels of the rst paralogue kin-of-irre (kirre), which seems able to substitute for rst function in this process, similarly to their role in myoblast fusion. This compensatory upregulation of kirre mRNA levels could be directly induced in wild type pupa upon RNAi-mediated silencing of rst, indicating that expression of both genes is also coordinately regulated in physiological conditions. Conclusions/Significance: These findings suggest a general mechanism by which rst and kirre expression could be fine tuned to optimize their redundant roles during development and provide a clearer picture of how the specification of survival and apoptotic fates by differential cell adhesion during the final steps of retinal morphogenesis in insects are controlled at the transcriptional level.

Determination of temperature variation during the individual steps of the production of hospital diets of modified consistency

Background & aim: Many disease outbreaks of food origin are caused by foods prepared in Food Service and Nutrition Units of hospitals, affecting hospitalized patients who, in most cases, are immunocompromised and therefore at a higher risk of severe worsening of their clinical status. The aim of this study was to determine the variations in temperature and the time-temperature factor of hospital diets. Methods: The time and temperature for the preparation of 4 diets of modified consistency were determined on 5 nonconsecutive days in a hospital Diet and Nutrition Unit at the end of preparation and during the maintenance period, portioning and distribution at 3 sites, i.e., the first, the middle and the last to receive the diets. Results and discussion: All foods reached an adequate temperature at the end of cooking, but temperature varied significantly from the maintenance period to the final distribution, characterizing critical periods for microorganism proliferation. During holding, temperatures that presented a risk were reached by 16.7% of the meats and 59% of the salads of the general diet, by 16.7% of the garnishes in the bland diet and by 20% of the meats and garnishes in the viscous diet. The same occurred at the end of distribution for 100% of the hot samples and of the salads and for 61% of the desserts. None of the preparations remained at risk temperature for a time exceeding that established by law. Conclusion: The exposure to inadequate temperature did not last long enough to pose risks to the patient.

The first steps of a secondary school teacher: experiences and studies of a student-teacher

This dissertation aims at fostering the professional development of the EFL teacher. This document compiles two small scale empirical studies carried out during the practicum periods of the TED's course. The first one is based on the role of the teacher's talk in the EFL classroom and the second one focuses on students’ small group talk, analysing the impact of cooperative learning in the EFL classroom by examining students' conversation. The following section gathers the teacher's personal reflections upon the process of professionalization. The paper concludes with a summary of the major findings and further professional improvement proposals

Towards a system analysis of the early steps of infectious endocarditis pathogenesis

L'endocardite infectieuse (EI) est une maladie potentiellement mortelle qui doit être prévenue dans toute la mesure du possible. Au cours de ces dernières 50 années, les recommandations Américaines et Européennes pour la prophylaxie de PEI proposaient aux patients à risques de prendre un antibiotique, préventif avant de subir une intervention médico-chirurgicale susceptible d'induire une bactériémie transitoire. Cependant, des études épidémiologiques récentes ont montré que la plupart des EI survenaient en dehors de tous actes médico-chirurgicaux, et indépendamment de la prise ou non de prophylaxie antibiotique . L'EI pourrait donc survenir suite à la cumulation de bactériémies spontanées de faibles intensités, associées à des activités de la vie courante telle que le brossage dentaire pour le streptocoques, ou à partir de tissus colonisés ou de cathéters infectés pour les staphylocoques. En conséquence, les recommandations internationales pour la prophylaxie de PEI ont été revues et proposent une diminution drastique de l'utilisation d'antibiotiques. Cependant, le risque d'EI représenté par le cumul de bactériémies de faibles intensités n'a pas été démontré expérimentalement. Nous avons développé un nouveau modèle d'EI expérimentale induite par une inoculation en continu d'une faible quantité de bactéries, simulant le cumul de bactériémies de faibles intensités chez l'homme, et comparé l'infection de Streptococcus gordonii et de Staphylococcus aureus dans ce modèle avec celle du modèle d'IE induite par une bactériémie brève, mais de forte intensité. Nous avons démontré, après injection d'une quantité égale de bactéries, que le nombre de végétations infectées était similaire dans les deux types d'inoculations. Ces résultats expérimentaux ont confirmé l'hypothèse qu'une exposition cumulée à des bactériémies de faibles intensités, en dehors d'une procédure médico-chirurgicale, représentait un risque pour le développement d'une El, comme le suggéraient les études épidémiologiques. En plus, ces résultats ont validé les nouvelles recommandations pour la prophylaxie de l'El, limitant drastiquement l'utilisation d'antibiotiques. Cependant, ces nouvelles recommandations laissent une grande partie (> 90%) de cas potentiels d'EI sans alternatives de préventions, et des nouvelles stratégies prophylactiques doivent être investiguées. Le nouveau modèle d'EI expérimentale représente un modèle réaliste pour étudier des nouvelles mesures prophylactiques potentielles appliquées à des expositions cumulées de bactériémies de faible nombre. Dans un contexte de bactériémies spontanées répétitives, les antibiotiques ne peuvent pas résoudre le problème de la prévention de l'EI. Nous avons donc étudié la une alternative de prévention par l'utilisation d'agents antiplaquettaires. La logique derrière cette approche était basée sur le fait que les plaquettes sont des composants clés dans la formation des végétations cardiaques, et le fait que les bactéries capables d'interagir avec les plaquettes sont plus enclines à induire une El. Les agents antiplaquettaires utilisés ont été l'aspirine (inhibiteur du COX1), la ticlopidine (inhibiteur du P2Y12, le récepteur de l'ADP), et l'eptifibatide et Pabciximab, deux inhibiteurs du GPIIb/IIIa, le récepteur plaquettaire pour le fibrinogène. Les anticoagulants étaient le dabigatran etexilate, inhibant lathrombine et l'acenocumarol, un antagoniste de la vitamine K. L'aspirine, la ticlopidine ou l'eptifibatide seuls n'ont pas permis de prévenir l'infection valvulaire (> 75% animaux infectés). En revanche, la combinaison d'aspirine et de ticlopidine, aussi bien que l'abciximab, ont protégé 45% - 88% des animaux de l'EI par S. gordonii et par S. aureus. L'antithrombotique dabigatran etexilate à protégé 75% des rats contre l'EI par S. aureus, mais pas (< 30% de protection) par S. gordonii. L'acenocoumarol n'a pas eu d'effet sur aucun des deux organismes. En général, ces résultats suggèrent un possible rôle pour les antiplaquettaires et du dabigatran etexilate dans la prophylaxie de l'EI dans un contexte de bactériémies récurrentes de faibles intensités. Cependant, l'effet bénéfique des antiplaquettaires doit être soupesé avec le risque d'hémorragie inhérent à ces molécules, et le fait que les plaquettes jouent un important rôle dans les défenses de l'hôte contre les infections endovasculaires. En plus, le double effet bénéfique du dabigatran etexilate devrait être revu chez les patients porteurs de valves prothétiques, qui ont besoin d'une anticoagulation à vie, et chez lesquels l'EI à S. aureus est associée avec une mortalité de près de 50%. Comme l'approche avec des antiplaquettaires et des antithrombotiques pourrait avoir des limites, une autre stratégie prophylactique pourrait être la vaccination contre des adhésines de surfaces des pathogènes. Chez S. aureus, la protéine de liaison au fibrinogène, ou dumping factor A (ClfA), et la protéine de liaison à la fibronectine (FnbpA) sont des facteurs de virulence nécessaires à l'initiation et l'évolution de PEI. Elles représentent donc des cibles potentielles pour le développement de vaccins contre cette infection. Récemment, des nombreuses publications ont décrit que la bactérie Lactococcus lactis pouvait être utilisée comme vecteur pour la diffusion d'antigènes bactériens in vivo, et que cette approche pourrait être une stratégie de vaccination contre les infections bactériennes. Nous avons exploré l'effet de l'immunisation par des recombinant de L. lactis exprimant le ClfA, la FnbpA, ou le ClfA ensemble avec et une forme tronquée de la FnbpA (Fnbp, comprenant seulement le domaine de liaison à la fibronectine mais sans le domaine A de liaison au fibrinogène [L. lactis ClfA/Fnbp]), dans la prophylaxie de PIE expérimentale à S. aureus. L. lactis ClfA a été utilisés comme agent d'immunisation contre la souche S. aureus Newman (qui a particularité de n'exprimer que le ClfA, mais pas la FnbpA). L. lactis ClfA, L. lactis FnbpA, et L. lactis ClfA/Fnbp, ont été utilisé comme agents d'immunisation contre une souche isolée d'une IE, S. aureus P8 (exprimant ClfA et FnbpA). L'immunisation avec L. lactis ClfA a généré des anticorps anti-ClfA fonctionnels, capables de bloquer la liaison de S. aureus Newman au fibrinogène in vitro et protéger 13/19 (69%) animaux d'une El due à S. aureus Newman (P < 0.05 comparée aux contrôles). L'immunisation avec L. lactis ClfA, L. lactis FnbpA, ou L. lactis ClfA/Fnbp, a généré des anticorps contre chacun de ces antigènes. Cependant, ils n'ont pas permis de bloquer l'adhésion de S. aureus P8 au fibrinogène et à la fibronectine in vitro. De plus, l'immunisation avec L. lactis ClfA ou L. lactis FnbpA s'est avérée inefficace in vivo (< 10% d'animaux protégés d'une El) et l'immunisation avec L. lactis ClfA/Fnbp a fourni une protection limitée de l'EI (8/23 animaux protégés; P < 0.05 comparée aux contrôles) après inoculation avec S. aureus P8. Dans l'ensemble, ces résultats indiquent que L. lactis est un système efficace pour la présentation d'antigènes in vivo et potentiellement utile pour la prévention de PEI à S. aureus. Cependant, le répertoire de protéines de surface de S. aureus capable d'évoquer une panoplie d'anticorps efficace reste à déterminer.. En résumé, notre étude a démontré expérimentalement, pour la première fois, qu'une bactériémie répétée de faible intensité, simulant la bactériémie ayant lieu, par exemple, lors des activités de la vie quotidienne, est induire un taux d'EI expérimentale similaire à celle induite par une bactériémie de haute intensité suite à une intervention médicale. Dans ce contexte, où l'utilisation d'antibiotiques est pas raisonnable, nous avons aussi montré que d'autres mesures prophylactiques, comme l'utilisation d'agents antiplaquettaires ou antithrombotiques, ou la vaccination utilisant L. lactis comme vecteur d'antigènes bactériens, sont des alternatives prometteuses qui méritent d'être étudiées plus avant. Thesis Summary Infective endocarditis (IE) is a life-threatening disease that should be prevented whenever possible. Over the last 50 years, guidelines for IE prophylaxis proposed the use of antibiotics in patients undergoing dental or medico-surgical procedures that might induce high, but transient bacteremia. However, recent epidemiological studies indicate that IE occurs independently of medico-surgical procedures and the fact that patients had taken antibiotic prophylaxis or not, i.e., by cumulative exposure to random low-grade bacteremia, associated with daily activities (e.g. tooth brushing) in the case of oral streptococci, or with a colonized site or infected device in the case of staphylococci. Accordingly, the most recent American and European guidelines for IE prophylaxis were revisited and updated to drastically restrain antibiotic use. Nevertheless, the relative risk of IE represented by such cumulative low-grade bacteremia had never been demonstrated experimentally. We developed a new model of experimental IE due to continuous inoculation of low-grade bacteremia, mimicking repeated low-grade bacteremia in humans, and compared the infectivity of Streptococcus gordonii and Staphylococcus aureus in this model to that in the model producing brief, high-level bacteremia. We demonstrated that, after injection of identical bacterial numbers, the rate of infected vegetations was similar in both types of challenge. These experimental results support the hypothesis that cumulative exposure to low-grade bacteremia, outside the context of procedure-related bacteremia, represents a genuine risk of IE, as suggested by human epidemiological studies. In addition, they validate the newer guidelines for IE prophylaxis, which drastic limit the procedures in which antibiotic prophylaxis is indicated. Nevertheless, these refreshed guidelines leave the vast majority (> 90%) of potential IE cases without alternative propositions of prevention, and novel strategies must be considered to propose effective alternative and "global" measures to prevent IE initiation. The more realistic experimental model of IE induced by low-grade bacteremia provides an accurate experimental setting to study new preventive measures applying to cumulative exposure to low bacterial numbers. Since in a context of spontaneous low-grade bacteremia antibiotics are unlikely to solve the problem of IE prevention, we addressed the role of antiplatelet and anticoagulant agents for the prophylaxis of experimental IE induced by S. gordonii and S. aureus. The logic of this approach was based on the fact that platelets are key players in vegetation formation and vegetation enlargement, and on the fact that bacteria capable of interacting with platelets are more prone to induce IE. Antiplatelet agents included the COX1 inhibitor aspirin, the inhibitor of the ADP receptor P2Y12 ticlopidine, and two inhibitors of the platelet fibrinogen receptor GPIIb/IIIa, eptifibatide and abciximab. Anticoagulants included the thrombin inhibitor dabigatran etexilate and the vitamin K antagonist acenocoumarol. Aspirin, ticlopidine or eptifibatide alone failed to prevent aortic infection (> 75% infected animals). In contrast, the combination of aspirin with ticlopidine, as well as abciximab, protected 45% to 88% of animals against IE due to S. gordonii and S. aureus. The antithrombin dabigatran etexilate protected 75% of rats against IE due to S. aureus, but failed (< 30% protection) against S. gordonii. Acenocoumarol had no effect against any bacteria. Overall, these results suggest a possible role for antiplatelet agents and dabigatran etexilate in the prophylaxis of IE in humans in a context of recurrent low- grade bacteremia. However, the potential beneficial effect of antiplatelet agents should be balanced against the risk of bleeding and the fact that platelets play an important role in the host defenses against intravascular infections. In addition, the potential dual benefit of dabigatran etexilate might be revisited in patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality rate. Because the antiplatelet and anticoagulant approach might be limited in the context of S. aureus bacteremia, other prophylactic strategies for the prevention of S. aureus IE, like vaccination with anti-adhesion proteins was tested. The S. aureus surface proteins fibrinogen-binding protein clumping-factor A (ClfA) and the fibronectin-binding protein A (FnbpA) are critical virulence factors for the initiation and development of IE. Thus, they represent key targets for vaccine development against this disease. Recently, numerous reports have described that the harmless bacteria Lactococcus lactis can be used as a bacterial vector for the efficient delivery of antigens in vivo, and that this approach is a promising vaccination strategy against bacterial infections. We therefore explored the immunization capacity of non- living recombinant L. lactis ClfA, L. lactis FnbpA, or L. lactis expressing ClfA together with Fnbp (a truncated form of FnbpA with only the fibronectin-binding domain but lacking the fibrinogen-binding domain A [L. lactis ClfA/Fnbp]), to protect against S. aureus experimental IE. L. lactis ClfA was used as immunization agent against the laboratory strain S. aureus Newman (expressing ClfA, but lacking FnbpA). L. lactis ClfA, L. lactis FnbpA, as well as L. lactis ClfA/Fnbp, were used as immunization agents against the endocarditis isolate S. aureus P8 (expressing both ClfA and FnbpA). Immunization with L. lactis ClfA produced anti-ClfA functional antibodies, which were able to block the binding of S. aureus Newman to fibrinogen in vitro and protect 13/19 (69%) animals from IE due to S. aureus Newman (P < 0.05 compared to controls). Immunization with L. lactis ClfA, L. lactis FnbpA or L. lactis ClfA/Fnbp, produced antibodies against each antigen. However, they were not sufficient to block S. aureus P8 binding to fibrinogen and fibronectin in vitro. Moreover, immunization with L. lactis ClfA or L. lactis FnbpA was ineffective (< 10% protected animals) and immunization with L. lactis ClfA/Fnbp conferred limited protection from IE (8/23 protected animals; P < 0.05 compared to controls) after challenge with S. aureus P8. Together, these results indicate that L. lactis is an efficient delivering antigen system potentially useful for preventing S. aureus IE. They also demonstrate that expressing multiple antigens in L. lactis, yet to be elucidated, will be necessary to prevent IE due to clinical S. aureus strains fully equipped with virulence determinants. In summary, our study has demonstrated experimentally, for the first time, the hypothesis that low-grade bacteremia, mimicking bacteremia occurring outside of a clinical intervention, is equally prone to induce experimental IE as high-grade bacteremia following medico-surgical procedures. In this context, where the use of antibiotics for the prophylaxis of IE is limited, we showed that other prophylactic measures, like the use of antiplatelets, anticoagulants, or vaccination employing L. lactis as delivery vector of bacterial antigens, are reasonable alternatives that warrant to be further investigated.

The GTPase RalA regulates different steps of the secretory process in pancreatic beta-cells.

BACKGROUND: RalA and RalB are multifuntional GTPases involved in a variety of cellular processes including proliferation, oncogenic transformation and membrane trafficking. Here we investigated the mechanisms leading to activation of Ral proteins in pancreatic beta-cells and analyzed the impact on different steps of the insulin-secretory process. METHODOLOGY/PRINCIPAL FINDINGS: We found that RalA is the predominant isoform expressed in pancreatic islets and insulin-secreting cell lines. Silencing of this GTPase in INS-1E cells by RNA interference led to a decrease in secretagogue-induced insulin release. Real-time measurements by fluorescence resonance energy transfer revealed that RalA activation in response to secretagogues occurs within 3-5 min and reaches a plateau after 10-15 min. The activation of the GTPase is triggered by increases in intracellular Ca2+ and cAMP and is prevented by the L-type voltage-gated Ca2+ channel blocker Nifedipine and by the protein kinase A inhibitor H89. Defective insulin release in cells lacking RalA is associated with a decrease in the secretory granules docked at the plasma membrane detected by Total Internal Reflection Fluorescence microscopy and with a strong impairment in Phospholipase D1 activation in response to secretagogues. RalA was found to be activated by RalGDS and to be severely hampered upon silencing of this GDP/GTP exchange factor. Accordingly, INS-1E cells lacking RalGDS displayed a reduction in hormone secretion induced by secretagogues and in the number of insulin-containing granules docked at the plasma membrane. CONCLUSIONS/SIGNIFICANCE: Taken together, our data indicate that RalA activation elicited by the exchange factor RalGDS in response to a rise in intracellular Ca2+ and cAMP controls hormone release from pancreatic beta-cell by coordinating the execution of different events in the secretory pathway.

Lipoxygenase 2 and the early steps of jasmonic acid biosynthesis in "Arabidopsis thaliana"

Résumé Les oxylipines, telles que l'acide jasmonique (AJ ou jasmonate), jouent un rôle central en réponse à la blessure et à la pathogenèse. De nombreuses études ont montré l'importance de la voie canonique du jasmonate lors de la défense des plantes. De plus, un précurseur cyclopentenone de l'AJ, l'acide oxo-phyto-dienoic (OPDA), a été impliqué comme jouant le rôle d'une molécule signal lors de la défense contre certains pathogènes. En utilisant des mutants bloqués dans la biosynthèse de l'acide jasmonique (aos) ou dans sa perception (coi1-1), nous avons cherché à définir dans quelle mesure l'OPDA joue un rôle de signal induisant l'expression génétique en réponse à la blessure chez Arabidopsis. A l'aide de puces à ADN (microarray), nous avons montré que les transcriptomes d'aos et de coi1-1 sont très semblables après blessure, ce qui suggère que les produits d'AOS sont tous perçus via COI1. Pourtant, lorsqu'on analyse les métabolites présents chez ces mutants, une différence est visible, puisque aos n'accumule pas d'AJ, alors que coi1-1 en accumule encore rapidement après blessure. Nous avons étudié la possibilité qu'un mécanisme de régulation post-traductionnelle sur la voie de biosynthèse du jasmonate explique l'accumulation d'AJ chez coi1-1 après blessure. La lipoxygenase 2 (LOX2) est la première enzyme impliquée dans la biosynthèse de l'AJ et est donc une cible potentielle d'un tel mécanisme. Un indice sur la manière dont l'activité LOX pourrait être régulée vient du mutant fou2 (pour fatty acid oxygenation upregcilated 2) dans lequel l'activité LOX ainsi que le niveau d'AJ sont constitutivement élevés. Cette mutation implique un flux de cation dans la régulation de la production de l'AJ. De plus, il a été montré que plusieurs LOXs, dans des organismes autres que des plantes, peuvent lier le calcium. Nous montrons que l'activité LOX requiert l'addition de cations divalents pour être maximale in vitro, et que non seulement le calcium mais aussi le magnésium joue ce rôle. De plus, nous caractérisons un mutant récessif de LOX2 chez Arabidopsis (lox2-1). Ces plantes sont fertiles, et une analyse quantitative montre qu'elles accumulent toujours un peu d'AJ après blessure. Ceci suggère que LOX2 n'est pas la seule LOX impliquée dans la synthèse d'AJ. Aussi les plantes lox2-1 ne sont pas plus sensibles que les plantes de type sauvage lorsqu'elles sont infectées par la moisissure Botrytis cinerea ou lorsqu'elles sont exposées à un détritivore, néanmoins elles sont plus sensibles lorsqu'elles sont offertes en nourriture à un insecte herbivore. Les insectes et les plantes ont co-évolué conjointement, ainsi une plante ne contenant qu'un niveau réduit d'AJ favorise l'insecte. La disponibilité d'un mutant avec un niveau intermédiaire d'AJ va permettre de mieux comprendre pourquoi les plantes produisent autant de jasmonate. Abstract Oxylipins such as jasmonic acid (JA) play central roles in the wound response and during pathogenesis and many studies have confirmed the important role of the canonical jasmonate pathway in plant defense. Moreover, the cyclopentenone precursor of JA, oxo-phytodienoic acid (OPDA), is also thought to function as a signaling molecule in defense towards some pathogens. Its action was reported to depend on a different signal pathway to JA. By using mutants blocked in the biosynthesis (aos) or perception (coil-1) of JA, we investigated to which extend OPDA works as signaling molecule to trigger gene expression in the wound response of Arabidopsis. Using microarrays, we showed that aos and coil-1 transcriptome are similar in response to wounding, suggesting that products of AOS are all perceived by COI1. However, we found a difference between the two mutants at the metobolomic level, since aos is devoid of JA, but coil-1 can still rapidly accumulate JA upon wounding. We investigated the possibility that the post-translational activation of JA biosynthesis could explain the fast accumulation of JA in coil-1 plants upon wounding. Lipoxygenase (LOX) 2 is the first enzyme implicated in JA synthesis and was thus chosen as a potential target for posttranslational regulation. A clue as to how LOX activity might be regulated came from the fatty acid oxygenation upregulated 2 (foul) mutant in which LOX activity and JA levels are elevated. The foul mutant implicates cations flux in the regulation of JA production, and several LOXs in organisms other than plants have been shown to bind calcium. We showed that Arabidopsis LOX requires divalent cations for full activity in vitro, and that not only calcium but also magnesium can play this role. Moreover, a single recessive mutant of AtLOX2 was characterized. These plants are fully fertile. Quantitative oxylipin analysis showed that lox2-1 can still accumulate some JA after wounding, which suggests that LOX2 is not the only LOX involved in JA biosynthesis. lox2-1 plants do not show altered susceptibility to the fungus Botrytis cinerea or to a detritivore, however, they are more susceptible to an insect herbivore. The insect and plants are closely co-evolved and a reduced ability to synthesize JA favors the insect. The availability of a lox2-1 mutant with intermediate JA levels will further help understanding why plants produce elevated JA levels.

Endogenous depth of reasoning

We introduce a model of strategic thinking in games of initial response. Unlike standard level-k models, in this framework the player's `depth of reasoning' is endogenously determined, andit can be disentangled from his beliefs over his opponent's cognitive bound. In our approach,individuals act as if they follow a cost-benefit analysis. The depth of reasoning is a function ofthe player's cognitive abilities and his payoffs. The costs are exogenous and represent the gametheoretical sophistication of the player; the benefit instead is related to the game payoffs. Behavioris in turn determined by the individual's depth of reasoning and his beliefs about the reasoningprocess of the opponent. Thus, in our framework, payoffs not only affect individual choices inthe traditional sense, but they also shape the cognitive process itself. Our model delivers testableimplications on players' chosen actions as incentives and opponents change. We then test themodel's predictions with an experiment. We administer different treatments that vary beliefs overpayoffs and opponents, as well as beliefs over opponents' beliefs. The results of this experiment,which are not accounted for by current models of reasoning in games, strongly support our theory.Our approach therefore serves as a novel, unifying framework of strategic thinking that allows forpredictions across games.

The new final Clinical Skills examination in human medicine in Switzerland: Essential steps of exam development, implementation and evaluation, and central insights from the perspective of the national Working Group.

OBJECTIVE: Since 2011, the new national final examination in human medicine has been implemented in Switzerland, with a structured clinical-practical part in the OSCE format. From the perspective of the national Working Group, the current article describes the essential steps in the development, implementation and evaluation of the Federal Licensing Examination Clinical Skills (FLE CS) as well as the applied quality assurance measures. Finally, central insights gained from the last years are presented. METHODS: Based on the principles of action research, the FLE CS is in a constant state of further development. On the foundation of systematically documented experiences from previous years, in the Working Group, unresolved questions are discussed and resulting solution approaches are substantiated (planning), implemented in the examination (implementation) and subsequently evaluated (reflection). The presented results are the product of this iterative procedure. RESULTS: The FLE CS is created by experts from all faculties and subject areas in a multistage process. The examination is administered in German and French on a decentralised basis and consists of twelve interdisciplinary stations per candidate. As important quality assurance measures, the national Review Board (content validation) and the meetings of the standardised patient trainers (standardisation) have proven worthwhile. The statistical analyses show good measurement reliability and support the construct validity of the examination. Among the central insights of the past years, it has been established that the consistent implementation of the principles of action research contributes to the successful further development of the examination. CONCLUSION: The centrally coordinated, collaborative-iterative process, incorporating experts from all faculties, makes a fundamental contribution to the quality of the FLE CS. The processes and insights presented here can be useful for others planning a similar undertaking.

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

BACKGROUND: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. RESULTS: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. CONCLUSIONS: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.

Digital evidence, 'absence' of data and ambiguous patterns of reasoning

In this paper we discuss the use of digital data by the Swiss Federal Criminal Court in a recent case of attempted homicide. We use this case to examine drawbacks for the defense when the presentation of scientific evidence is partial, especially when the only perspective mentioned is that of the prosecution. We tackle this discussion at two distinct levels. First, we pursue an essentially non-technical presentation of the topic by drawing parallels between the court's summing up of the case and flawed patterns of reasoning commonly seen in other forensic disciplines, such as DNA and particle traces (e.g., gunshot residues). Then, we propose a formal analysis of the case, using elements of probability and graphical probability models, to justify our main claim that the partial presentation of digital evidence poses a risk to the administration of justice in that it keeps vital information from the defense. We will argue that such practice constitutes a violation of general principles of forensic interpretation as established by forensic science literature and current recommendations by forensic science interest groups (e.g., the European Network of Forensic Science Institutes). Finally, we posit that argument construction and analysis using formal methods can help replace digital evidence appropriately into context and thus support a sound evaluation of the evidence.

Steps of Memorial Hall, Chapman College, Orange

Students on the entrance steps of Memorial Hall, Chapman College, Orange.

Steps of Waltmar Theatre, Moulton Hall, Chapman College, Orange, California

Steps of Waltmar Theatre, Moulton Hall, Chapman College, Orange, California. Completed in 1975 (2 floors, 44,592 sq.ft.), Moulton Hall is named in memory of an artist and patroness of the arts, Nellie Gail Moulton. Within this structure are the departments of Art, Communications, and Theatre/Dance as well as the Guggenheim Gallery and Waltmar Theatre. Waltmar Theatre was a gift from the late Walter and Margaret Schmid.

Photograph - Charles W. Band, Jessie Shaw Band and a child sitting on the Steps of a House

A photograph of Charles W. Band, Jessie Shaw Band , and a child sitting together on the steps of a house.

Effectiveness of 'Reasoning and rehabilitation' in reducing reoffending. 'La eficacia del programa 'Razonamiento y Rehabilitaci??n' en la reducci??n de la reincidencia'

Resumen tomado de la publicaci??n