Structure-based drug design studies of the interactions ofent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparumsarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosawere tested in silico against the Plasmodium falciparumCa2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Use of Two-Part Regression Calibration Model to Correct for Measurement Error in Episodically Consumed Foods in a Single-Replicate Study Design: EPIC Case Study.

In epidemiologic studies, measurement error in dietary variables often attenuates association between dietary intake and disease occurrence. To adjust for the attenuation caused by error in dietary intake, regression calibration is commonly used. To apply regression calibration, unbiased reference measurements are required. Short-term reference measurements for foods that are not consumed daily contain excess zeroes that pose challenges in the calibration model. We adapted two-part regression calibration model, initially developed for multiple replicates of reference measurements per individual to a single-replicate setting. We showed how to handle excess zero reference measurements by two-step modeling approach, how to explore heteroscedasticity in the consumed amount with variance-mean graph, how to explore nonlinearity with the generalized additive modeling (GAM) and the empirical logit approaches, and how to select covariates in the calibration model. The performance of two-part calibration model was compared with the one-part counterpart. We used vegetable intake and mortality data from European Prospective Investigation on Cancer and Nutrition (EPIC) study. In the EPIC, reference measurements were taken with 24-hour recalls. For each of the three vegetable subgroups assessed separately, correcting for error with an appropriately specified two-part calibration model resulted in about three fold increase in the strength of association with all-cause mortality, as measured by the log hazard ratio. Further found is that the standard way of including covariates in the calibration model can lead to over fitting the two-part calibration model. Moreover, the extent of adjusting for error is influenced by the number and forms of covariates in the calibration model. For episodically consumed foods, we advise researchers to pay special attention to response distribution, nonlinearity, and covariate inclusion in specifying the calibration model.

Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

Let's talk: how communication affects contract design

We study experimentally how the ability to communicate affects the frequency and effectiveness of flexible and inflexible contracts in a bilateral trade context where sellers can adjust trade quality after observing a post-contractual cost shock and a discretionary buyer transfer. In the absence of communication, we find that rigid contracts are more frequent and lead to higher earnings for both buyer and seller. By contrast, in the presence of communication, flexible contracts are much more frequent and considerably more productive, both for buyers and sellers. Also, both buyer and seller earn considerably more from flexible with communication than rigid without communication. Our results show quite strongly that communication, a normal feature in contracting, can remove the potential cost of flexibility (disagreements caused by conflicting perceptions). We offer an explanation based on social norms.

Enterprise Architecture Management Design: Towards Understanding Organizational Contingencies, Design Principles and Effectiveness

Despite the increasing popularity of enterprise architecture management (EAM) in practice, many EAM initiatives either do not fully meet the expected targets or fail. Several frameworks have been suggested as guidelines to EA implementation, but companies seldom follow prescriptive frameworks. Instead, they follow very diverse implementation approaches that depend on their organizational contingencies and the way of adopting and evolving EAM over time. This research strives for a broader understanding of EAM by exploring context-dependent EAM adoption approaches as well as identifying the main EA principles that affect EA effectiveness. Based on two studies, this dissertation aims to address two main questions: (1) EAM design: Which approaches do companies follow when adopting EAM? (2) EA principles and their impact: What impact does EA principles have on EA effectiveness/quality? By utilizing both qualitative and quantitative research methods, this research contributes to exploring different EAM designs in different organizational contingencies as well as using EA principles as an effective means to achieve principle-based EAM design. My research can help companies identify a suitable EAM design that fits their organizational settings and shape their EA through a set of principles.

"Quitter le milieu" Une étude sociologique des processus de désaffiliation religieuse du milieu évangélique suisse

La thématique des désaffiliations religieuses du milieu évangélique est le parent pauvre des études faites jusqu'à ce jour sur ce courant religieux. En effet, l'accent est généralement mis sur son développement en termes d'affiliation faisant alors l'impasse sur les pertes qu'il connaît pourtant. De plus, la question des désaffiliations religieuses est un angle d'approche sociologique particulièrement fécond pour étudier les groupes religieux en permettant, entre autres, de cerner plus en profondeur leur identité, les mécanismes qui favorisent leur pérennisation, mais aussi leur rapport à la société environnante. Dans ce travail, qui s'inscrit en sociologie des religions et qui puise autant dans la littérature sur les désaffiliations religieuses que dans celle des désengagements militants, l'analyse s'est focalisée sur les processus de désengagement au niveau microsociologique : quels sont les motifs qui président les désaffiliations, comment se déroulent ces dernières, quels effets ont-elles sur l'individu en termes identitaires et comment sont-elles perçues par ceux qui restent ? Ces principales questions ont permis de (re] questionner des éléments constitutifs de l'engagement évangélique : les processus de socialisation ; la structuration des liens intragroupe développés par le milieu et son rapport à l'extérieur ; son système normatif; son système de représentation du monde et la démarche religieuse qu'il valorise, qui sont autant d'aspects qui jouent un rôle dans les processus de désaffiliation. Plus précisément, ces éléments agissent en tant que mécanismes de rétention tant sociaux que psychologiques compliquant ainsi le désengagement. Cette thèse s'est construite sur dix-sept entretiens semi directifs menés auprès de personnes ayant grandi pour la plupart dans une famille évangélique et qui ont décidé, un jour, de ne plus fréquenter ce milieu religieux. Pour élargir la perspective analytique et pour permettre de comprendre et d'expliquer les processus de désaffiliation en lien avec le groupe quitté, un ensemble de septante-huit entretiens semi directifs et de mille cent questionnaires standardisés de membres d'Eglises évangéliques a été mobilisé. Partant des logiques du désengagement, cette thèse affine les connaissances actuelles sur l'évangélisme dans le contexte de la modernité, grâce à l'éclairage inédit qu'elle lui donne. Elle développe également le champ des connaissances sur les désaffiliations religieuses en lui fournissant un nouvel exemple de cas tout en lui offrant une autre façon de théoriser les sorties de groupes religieux qui valorisent un engagement de type militant. - Religious disaffiliations from the evangelical milieu have not yet been investigated. Indeed, former studies have usually focused on the development of the milieu by looking at conversions. However, it appears that the study of the disaffiliation processes may not only give results on the reasons and experiences of those disaffiliating, but also shed light on the attributes and the development of the evangelical milieu itself. The main goal of this thesis was to fill this gap in the literature. From a microsociological approach, this thesis sought to answer the following central question : Why, how and with what effects do individuals leave the evangelical milieu and how is this phenomenon perceived, interpreted and managed by the individuals who leave the evangelical community and by the members of the evangelical milieu? These questions enabled me to investigate the functioning of the evangelical milieu : its processes of socialization ; internal and external relationships ; normative system ; belief system or its religious engagement. This set of aspects can influence and complicate the processes of disaffiliation. The analysis of religious disaffiliation was based on seventeen qualitative interviews with former members of evangelical chrurches who decided, one day, not to attend an evangelical church anymore and who question more or less strongly the « system of evangelical thought ». Seventy-eight qualitative interviews with members of evangelical free churches and a representative survey with members of evangelical free churches (N = 1100] completed the analysis and inserted the individual disengagement in the « milieu's logics ». This thesis complements and enriches the literature on evangelism as well as on religious disaffiliation in general.

A Tool for optimum design of Waste Water Treatment Plants under uncertainty

L’objectiu principal és presentar un nou prototipus d’eina per al disseny de les plantes de tractament d’aigües residuals utilitzant models mecànics dinàmics quantificant la incertesa

Processus de communautarisation et société-monde. En partant de Tönnies, Weber et Luhmann

Les notions de « Gemeinschaft und Gesellschaft », « Communauté et société » ont fait leur apparition dans les sciences sociales germanophones du XIXe siècle grâce à l'ouvrage de Ferdinand Tönnies portant ces deux concepts dans le titre. Lors de la première édition de « Gemeinschaft und Gesellschaft » en 1887, le sous-titre de l'ouvrage porte encore sur l'« Abhandlung des Kommunismus und Sozialismus als empirische Kulturformen », mettant alors l?accent sur le communisme et le socialisme en tant que formes culturelles empiriques. Dans les éditions ultérieures, le nouveau sous-titre « Grundbegriffe der reinen Soziologie » est le résultat d'une réflexion profonde sur la nécessité de dépasser l?antagonisme entre une école historique et une école rationnelle. Optant pour une approche organique dans son ouvrage de 1931, Tönnies développe l'idée selon laquelle la Communauté représente la source dont jaillit la Société, tout en gardant l'espoir que la force de la Communauté subsiste à l'intérieur de la Société, demeurant ainsi la réalité de la vie sociale. Parmi les sociologues contemporains germanophones qui s'intéressent aux processus de sociétisation, Rudolf Stichweh, élève de Niklas Luhmann, cherche à démontrer que la « Weltgesellschaft », la société-monde, aboutit d'une part à une croissante pluralisation des solidarités et d'autre part à une institutionnalisation de ces dernières.

RTM mould design and construction for a DN 50 PN 16 flansch

The objective of this project consists of designing and constructing a RTM mould for a loose flange of glass fibre reinforced plastic (GRP). The design phase has the mission to realise a quality and simple design of the RTM mould, with the objective to obtain an easy and economic phase of construction and the more possible great characteristics of the loose flange. In fact this RTM mould will be a mould prototype, which will be developed in the future to obtain an RTM mould able to support a loose flange production. Therefore when more steps are developed in this project, then the future objective will be near

SwissBioisostere: a database of molecular replacements for ligand design.

The SwissBioisostere database (http://www.swissbioisostere.ch) contains information on molecular replacements and their performance in biochemical assays. It is meant to provide researchers in drug discovery projects with ideas for bioisosteric modifications of their current lead molecule, as well as to give interested scientists access to the details on particular molecular replacements. As of August 2012, the database contains 21 293 355 datapoints corresponding to 5 586 462 unique replacements that have been measured in 35 039 assays against 1948 molecular targets representing 30 target classes. The accessible data were created through detection of matched molecular pairs and mining bioactivity data in the ChEMBL database. The SwissBioisostere database is hosted by the Swiss Institute of Bioinformatics and available via a web-based interface.

Analysis and Design of a secure WLAN solution for Cobre Las Cruces

Cobre Las Cruces is a renowned copper mining company located in Sevilla, with unexpected problems in wireless communications that have a direct affectation in production. Therefore, the main goals are to improve the WiFi infrastructure, to secure it and to detect and prevent from attacks and from the installation of rogue (and non-authorized) APs. All of that integrated with the current ICT infrastructure.This project has been divided into four phases, although only two of them have been included into the TFC; they are the analysis of the current situation and the design of a WLAN solution.Once the analysis part was finished, some weaknesses were detected. Subjects such as lack of connectivity and control, ignorance about installed WiFi devices and their localization and state and, by and large, the use of weak security mechanisms were some of the problems found. Additionally, due to the fact that the working area became larger and new WiFi infrastructures were added, the first phase took more time than expected.As a result of the detailed analysis, some goals were defined to solve and it was designed a centralized approach able to cope with them. A solution based on 802.11i and 802.1x protocols, digital certificates, a probe system running as IDS/IPS and ligthweight APs in conjunction with a Wireless LAN Controller are the main features.

Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.

We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.