Large-scale analysis of orthologs and paralogs under covarion-like and constant-but-different models of amino acid evolution.

Functional divergence between homologous proteins is expected to affect amino acid sequences in two main ways, which can be considered as proxies of biochemical divergence: a "covarion-like" pattern of correlated changes in evolutionary rates, and switches in conserved residues ("conserved but different"). Although these patterns have been used in case studies, a large-scale analysis is needed to estimate their frequency and distribution. We use a phylogenomic framework of animal genes to answer three questions: 1) What is the prevalence of such patterns? 2) Can we link such patterns at the amino acid level with selection inferred at the codon level? 3) Are patterns different between paralogs and orthologs? We find that covarion-like patterns are more frequently detected than "constant but different," but that only the latter are correlated with signal for positive selection. Finally, there is no obvious difference in patterns between orthologs and paralogs.

Reaching for the Holy Grail: insights from infection/cure models on the prospects for vaccines for Trypanosoma cruziinfection

Prevention of Trypanosoma cruzi infection in mammals likely depends on either prevention of the invading trypomastigotes from infecting host cells or the rapid recognition and killing of the newly infected cells byT. cruzi-specific T cells. We show here that multiple rounds of infection and cure (by drug therapy) fails to protect mice from reinfection, despite the generation of potent T cell responses. This disappointing result is similar to that obtained with many other vaccine protocols used in attempts to protect animals from T. cruziinfection. We have previously shown that immune recognition ofT. cruziinfection is significantly delayed both at the systemic level and at the level of the infected host cell. The systemic delay appears to be the result of a stealth infection process that fails to trigger substantial innate recognition mechanisms while the delay at the cellular level is related to the immunodominance of highly variable gene family proteins, in particular those of the trans-sialidase family. Here we discuss how these previous studies and the new findings herein impact our thoughts on the potential of prophylactic vaccination to serve a productive role in the prevention of T. cruziinfection and Chagas disease.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Neuronal in vitro models for the estimation of acute systemic toxicity.

The objective of the EU funded integrated project "ACuteTox" is to develop a strategy in which general cytotoxicity, together with organ-specific endpoints and biokinetic features, are taken into consideration in the in vitro prediction of oral acute systemic toxicity. With regard to the nervous system, the effects of 23 reference chemicals were tested with approximately 50 endpoints, using a neuronal cell line, primary neuronal cell cultures, brain slices and aggregated brain cell cultures. Comparison of the in vitro neurotoxicity data with general cytotoxicity data generated in a non-neuronal cell line and with in vivo data such as acute human lethal blood concentration, revealed that GABA(A) receptor function, acetylcholine esterase activity, cell membrane potential, glucose uptake, total RNA expression and altered gene expression of NF-H, GFAP, MBP, HSP32 and caspase-3 were the best endpoints to use for further testing with 36 additional chemicals. The results of the second analysis showed that no single neuronal endpoint could give a perfect improvement in the in vitro-in vivo correlation, indicating that several specific endpoints need to be analysed and combined with biokinetic data to obtain the best correlation with in vivo acute toxicity.

Two-sided learning in new keynesian models: dynamics, (lack of) convergence and the value of information

This paper investigates the role of learning by private agents and the central bank (two-sided learning) in a New Keynesian framework in which both sides of the economy have asymmetric and imperfect knowledge about the true data generating process. We assume that all agents employ the data that they observe (which may be distinct for different sets of agents) to form beliefs about unknown aspects of the true model of the economy, use their beliefs to decide on actions, and revise these beliefs through a statistical learning algorithm as new information becomes available. We study the short-run dynamics of our model and derive its policy recommendations, particularly with respect to central bank communications. We demonstrate that two-sided learning can generate substantial increases in volatility and persistence, and alter the behavior of the variables in the model in a signifficant way. Our simulations do not converge to a symmetric rational expectations equilibrium and we highlight one source that invalidates the convergence results of Marcet and Sargent (1989). Finally, we identify a novel aspect of central bank communication in models of learning: communication can be harmful if the central bank's model is substantially mis-specified

Probabilistic models to assist maintenance of multiple instruments

The paper discusses maintenance challenges of organisations with a huge number of devices and proposes the use of probabilistic models to assist monitoring and maintenance planning. The proposal assumes connectivity of instruments to report relevant features for monitoring. Also, the existence of enough historical registers with diagnosed breakdowns is required to make probabilistic models reliable and useful for predictive maintenance strategies based on them. Regular Markov models based on estimated failure and repair rates are proposed to calculate the availability of the instruments and Dynamic Bayesian Networks are proposed to model cause-effect relationships to trigger predictive maintenance services based on the influence between observed features and previously documented diagnostics

Increased eotaxin in tears of patients wearing contact lenses

Résumé Introduction : La conjonctivite giganto-papillaire chez des patients porteurs de lentilles de contact survient lors d'une intolérance et/ou d'une allergie aux lentilles de contact. L'éotaxine est un CC chémokine produisant un puissant effet chémotactique sur les éosinophiles, qui sont impliqués dans les allergies. Le but de cette étude est de mesurer le taux d'éotaxine dans les larmes de patients porteurs de lentilles de contact et de le comparer à celui de sujets normaux. Les taux d'éotaxine sont également corrélés avec le degré de conjonctivite giganto-papillaire. Méthode : Environ 10 Ill de larmes ont été collectés avec une rnicropipette en verre chez 16 patients porteurs de lentilles de contact et chez 10 volontaires normaux. La conjonctivite giganto-papillaire a été évaluée selon une échelle de 0 à 4 en référence à des images photographiques de la paupière supérieure réalisées à la lampe à fente. La concentration de l'éotaxine dans les larmes a été mesurée par un ELISA utilisant un anticorps d'éotaxine de souris dirigé contre l'anticorps humain. Pour l'analyse statistique des résultats, le test de Wilcox/Kruskal-Wallis a été utilisé. Résultats : La concentration moyenne d'éotaxine était de 2698 +233 (SEM) pg/ml chez les patients porteurs de lentilles de contact et de 1498 139 pg/ml chez les sujets normaux. La différence était statistiquement significative avec P = 0.0004. Le score moyen des papilles était de 1.75 ±0.19 chez les patients porteurs de lentilles de contact et de 0.2 +0.13 chez les sujets normaux (P <0.0001). Le grading des papilles a pu être mis en relation avec le taux d'éotaxine dans les larmes (R2- 0.6562 avec P <0.0001). Conclusion : Une augmentation du taux d'éotaxine dans les larmes a été mesurée chez les patients porteurs de lentilles de contact. Les taux d'éotaxine ont été corrélés avec la sévérité de la conjonctivite giganto-papillaire. Ces données suggèrent que l'éotaxine pourrait jouer un rôle important dans la formation des papilles. Abstract : Purpose: Giant papillary conjunctivitis in patients wearing contact lenses occurs after intolerance and/or allergy to contact lenses. Eotaxin is a CC chemokine with a potent and specific chemotactic effect for eosinophils, which are involved in allergies. The purpose of this study is to measure the eotaxin levels in tears of patients wearing contact lenses and in normal subjects. Eotaxin levels were also correlated with the grade of giant papillary conjunctivitis. Methods: Around 10µL of tears were collected with glass capillaries in 16 patients wearing contact lenses and in 10 normal volunteers. Giant papillary conjunctivitis was graded from 0 to 4 by reference to standard slit-lamp photographs of the superior tarsal conjunctiva. Eotaxin concentration in tears was measured by ELSA using mouse anti-human eotaxin monoclonal antibodies. For the statistical analysis of the results, the paired Wilcoxon/Kruskai-Wallis test was used. Results: The mean concentration of eotaxin was 2698 ± 233 (SEM) pg/mL in patients wearing contact lenses and 1498 ± 139 pg/mL normal subjects. The difference was statistically significant (P =0.0004). The mean score of papilla grade was 1.75 ± 0.19 in patients wearing contact lenses and 01 ± 0.13 in normal subjects (P < 0.0001). Papilla grade could be correlated to the eotaxin level in tears (R2 = 0.6562 and P< 0.0001), Conclusion: An increase of eotaxin levels in tears was measured in patients wearing contact lenses. Eotaxin levels correlated with the severity of giant papillary conjunctivitis. These data suggest that eotaxin could play a role in papilla formation.

Towards smart user models in open environments

Our work is concerned with user modelling in open environments. Our proposal then is the line of contributions to the advances on user modelling in open environments thanks so the Agent Technology, in what has been called Smart User Model. Our research contains a holistic study of User Modelling in several research areas related to users. We have developed a conceptualization of User Modelling by means of examples from a broad range of research areas with the aim of improving our understanding of user modelling and its role in the next generation of open and distributed service environments. This report is organized as follow: In chapter 1 we introduce our motivation and objectives. Then in chapters 2, 3, 4 and 5 we provide the state-of-the-art on user modelling. In chapter 2, we give the main definitions of elements described in the report. In chapter 3, we present an historical perspective on user models. In chapter 4 we provide a review of user models from the perspective of different research areas, with special emphasis on the give-and-take relationship between Agent Technology and user modelling. In chapter 5, we describe the main challenges that, from our point of view, need to be tackled by researchers wanting to contribute to advances in user modelling. From the study of the state-of-the-art follows an exploratory work in chapter 6. We define a SUM and a methodology to deal with it. We also present some cases study in order to illustrate the methodology. Finally, we present the thesis proposal to continue the work, together with its corresponding work scheduling and temporalisation

Le contact Gondwana - péri-Gondwana dans le Zanskar oriental (Ladakh-Himalaya)

A l'Est du fleuve Zanskar (Ladakh), la zone de suture de l'Indus sépare les nappes de la bordure nord-indienne du Gondwana (Haut-Himalaya, nappes du Zanskar, cristallin de Tso Morari) des éléments péri·gondwaniens du Trans-himalaya. Des recherches géologiques entreprises entre l'Indus el la Tsarap ont montré que: - la molasse autochlone du Ladakh est surmontée par un édifice de flysch et molasses tertiaires, rétrocharrié vers le NordEst et coiffé par les conglomérats post· éocène moyen du Stok Kangri et une formation eontinentale de molasse rouge; - - la zone de suture comprend deux unités. principales : a) au Nord et au Nord-Ouest, l'unité volcano-sédimentaire de Dras-Nindam avec des conglomérats et flysch crétacés, des brèches massives à radiolarHes et roches vertes; cette unité est accompagnée d'un mélange coloré à roches ultra-basiques, blocs exoti(Iues divers et une méga lentille de brèche carbonatée polygénique à grands Foraminifères (Nummulites ?) ; b) au Sud, l'unité de la Markha, un flysch à lentilles de calcaires plus ou moins marmoréens datée de la base du Jurassique moyen et que nons corrélons avec le Oysch de Lamayuru ; - l'unité complexe de Nimaling représente la terminaison occidentale du crist allin de Rupshn (Tso MOI'ari) ; il comprend un socle gneissique, des roches vert.es et une couverture de schistes quartzitiques, quartzites el dolomies. Cet ensemble est intrudé pal' un granite porphyrique et il est surmonté, en contact tectonique, par une épaisse série métamorphique de calcschistes, shales et grès de faciès schistes lustrés, d'âge inconnu; dans ce tte série, on note au moins trois phases de fortes déformaljons superposées (linéations replissées) ; le long de la vallée de la Markha, le style st.ructural évoque, avec des plis isoclinaux de 2" phase à axes verticaux, une « zone de racine" et pourrait également témoigner de mouvements horizontaux importants; - l'édifice des napp es du Zanskar a été subdivisé en trois unités; il surmonte vers le Nord-Est les schistes lustrés du groupe de Langtang et vient buter vers le Sud-Ouest, le long d'un aceident chevauchant, contre la nappe de Zangla (Haut Himalaya). Les séries sédimentaires (Trias - Crétacé supérieur) sont d'affinité téthysienne. De nouvelles datations sont apportées et nous mettons en évidence, directement à l'Est du fleuve Zanskar, la présence de Crétacé sous faciès calcaires multicolores à microfaune planctique ; transgressif sur les grès de Giumal, ce faciès calcaire déhut.e déjà dans l'Alhien supérieur, c'est-à-dire nellement plus tôt que dans les régions plus orientales de l 'Himalaya; - les nappes du Haut Himalaya comprennent du Nord-Est vers le Sud-Ouest la nappe de Zangla qui chevauche par l'intermédiaire d'une semelle de « Panjal Traps » des témoins écaillés de Paléozoïque inférieur, puis la nappe de cristallin. La nappe de Zangla correspond à l'unité qui, à l 'Ouest du Zanskar supporte la klippe ophiolitique de Spongtang.

Application of the european customer satisfaction index to postal services. Structural equation models versus partial least squars

Customer satisfaction and retention are key issues for organizations in today’s competitive market place. As such, much research and revenue has been invested in developing accurate ways of assessing consumer satisfaction at both the macro (national) and micro (organizational) level, facilitating comparisons in performance both within and between industries. Since the instigation of the national customer satisfaction indices (CSI), partial least squares (PLS) has been used to estimate the CSI models in preference to structural equation models (SEM) because they do not rely on strict assumptions about the data. However, this choice was based upon some misconceptions about the use of SEM’s and does not take into consideration more recent advances in SEM, including estimation methods that are robust to non-normality and missing data. In this paper, both SEM and PLS approaches were compared by evaluating perceptions of the Isle of Man Post Office Products and Customer service using a CSI format. The new robust SEM procedures were found to be advantageous over PLS. Product quality was found to be the only driver of customer satisfaction, while image and satisfaction were the only predictors of loyalty, thus arguing for the specificity of postal services

Networks of PhD Students and Academic Performance: A Comparison across Countries

In this article we compare regression models obtained to predict PhD students’ academic performance in the universities of Girona (Spain) and Slovenia. Explanatory variables are characteristics of PhD student’s research group understood as an egocentered social network, background and attitudinal characteristics of the PhD students and some characteristics of the supervisors. Academic performance was measured by the weighted number of publications. Two web questionnaires were designed, one for PhD students and one for their supervisors and other research group members. Most of the variables were easily comparable across universities due to the careful translation procedure and pre-tests. When direct comparison was notpossible we created comparable indicators. We used a regression model in which the country was introduced as a dummy coded variable including all possible interaction effects. The optimal transformations of the main and interaction variables are discussed. Some differences between Slovenian and Girona universities emerge. Some variables like supervisor’s performance and motivation for autonomy prior to starting the PhD have the same positive effect on the PhD student’s performance in both countries. On the other hand, variables like too close supervision by the supervisor and having children have a negative influence in both countries. However, we find differences between countries when we observe the motivation for research prior to starting the PhD which increases performance in Slovenia but not in Girona. As regards network variables, frequency of supervisor advice increases performance in Slovenia and decreases it in Girona. The negative effect in Girona could be explained by the fact that additional contacts of the PhD student with his/her supervisor might indicate a higher workload in addition to or instead of a better advice about the dissertation. The number of external student’s advice relationships and social support mean contact intensity are not significant in Girona, but they have a negative effect in Slovenia. We might explain the negative effect of external advice relationships in Slovenia by saying that a lot of external advice may actually result from a lack of the more relevant internal advice

From deep seated slope deformation to rock avalanche: Destabilization and transportation models of the Sierre landslide (Switzerland)

Sackung is a widespread post-glacial morphological feature affecting Alpine mountains and creating characteristic geomorphological expression that can be detected from topography. Over long time evolution, internal deformation can lead to the formation of rapidly moving phenomena such as a rock-slide or rock avalanche. In this study, a detailed description of the Sierre rock-avalanche (SW Switzerland) is presented. This convex-shaped postglacial instability is one of the larger rock-avalanche in the Alps, involving more than 1.5 billion m3 with a run-out distance of about 14 km and extremely low Fahrböschung angle. This study presents comprehensive analyses of the structural and geological characteristics leading to the development of the Sierre rock-avalanche. In particular, by combining field observations, digital elevation model analyses and numerical modelling, the strong influence of both ductile and brittle tectonic structures on the failure mechanism and on the failure surface geometry is highlighted. The detection of pre-failure deformation indicates that the development of the rock avalanche corresponds to the last evolutionary stage of a pre-existing deep seated gravitational slope instability. These analyses accompanied by the dating and the characterization of rock avalanche deposits, allow the proposal of a destabilization model that clarifies the different phases leading to the development of the Sierre rock avalanche.

Bayesian nash equilibrium in ''linear'' cournot models with private information about costs

Calculating explicit closed form solutions of Cournot models where firms have private information about their costs is, in general, very cumbersome. Most authors consider therefore linear demands and constant marginal costs. However, within this framework, the nonnegativity constraint on prices (and quantities) has been ignored or not properly dealt with and the correct calculation of all Bayesian Nash equilibria is more complicated than expected. Moreover, multiple symmetric and interior Bayesianf equilibria may exist for an open set of parameters. The reason for this is that linear demand is not really linear, since there is a kink at zero price: the general ''linear'' inverse demand function is P (Q) = max{a - bQ, 0} rather than P (Q) = a - bQ.