Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells.

Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.

Matrizes da linguagem e a organização virtual do conhecimento

Os signos e as linguagens foram investigados para a organização virtual do conhecimento por meio dos mecanismos de busca. Fundamentou-se na teoria das matrizes da linguagem-pensamento, postuladas por Santaella (2005), na qual se perscrutou as linguagens sonora, visual e verbal. O objetivo da investigação foi estabelecer uma categorização dos mecanismos de busca a partir da correspondência dessas matrizes da linguagem com a indexação virtual e o modus análogo de busca. Os resultados da investigação indicam ser adequada a categorização dos mecanismos de busca sob o critério dos paradigmas semiótico da linguagem em três matrizes, dado o seu modo de ser e sua operacionalidade, sendo eles baseados em conteúdos sonoros, visuais e verbais. Sinteticamente, a sintaxe é a representação do sonoro, a forma é a representação do visível e o discurso é a representação do conhecimento verbal.

Individual prediction of cognitive decline in mild cognitive impairment using support vector machine-based analysis of diffusion tensor imaging data.

Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPCPH). Institutions were retrospectively requested to irradiate their institutional phantom (INSTPH) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS: CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPCPH and INSTPH were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS: Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPCPH and INSTPH (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS: IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INSTPH measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPCPH and INSTPH comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Insularity and the evolution of melanism, sexual dichromatism and body size in the worldwide-distributed barn owl.

Abstract Island biogeography has provided fundamental hypotheses in population genetics, ecology and evolutionary biology. Insular populations usually face different feeding conditions, predation pressure, intraspecific and interspecific competition than continental populations. This so-called island syndrome can promote the evolution of specific phenotypes like a small (or large) body size and a light (or dark) colouration as well as influence the evolution of sexual dimorphism. To examine whether insularity leads to phenotypic differentiation in a consistent way in a worldwide-distributed nonmigratory species, we compared body size, body shape and colouration between insular and continental barn owl (Tyto alba) populations by controlling indirectly for phylogeny. This species is suitable because it varies in pheomelanin-based colouration from reddish-brown to white, and it displays eumelanic black spots for which the number and size vary between individuals, populations and species. Females are on average darker pheomelanic and display more and larger eumelanic spots than males. Our results show that on islands barn owls exhibited smaller and fewer eumelanic spots and lighter pheomelanic colouration, and shorter wings than on continents. Sexual dimorphism in pheomelanin-based colouration was less pronounced on islands than continents (i.e. on islands males tended to be as pheomelanic as females), and on small islands owls were redder pheomelanic and smaller in size than owls living on larger islands. Sexual dimorphism in the size of eumelanic spots was more pronounced (i.e. females displayed much larger spots than males) in barn owls living on islands located further away from a continent. Our study indicates that insular conditions drive the evolution towards a lower degree of eumelanism, smaller body size and affects the evolution of sexual dichromatism in melanin-based colour traits. The effect of insularity was more pronounced on body size and shape than on melanic traits.

Assessment of emotional reactivity produced by exposure to virtual environments in patients with eating disorders

The aim of this study was to assess the usefulness of virtual environments representing situations that are emotionally significant to subjects with eating disorders (ED). These environments may be applied with both evaluative and therapeutic aims and in simulation procedures to carry out a range of experimental studies. This paper is part of a wider research project analyzing the influence of the situation to which subjects are exposed on their performance on body image estimation tasks. Thirty female patients with eating disorders were exposed to six virtual environments: a living-room (neutral situation), a kitchen with highcalorie food, a kitchen with low-calorie food, a restaurant with high-calorie food, a restaurant with low-calorie food, and a swimming-pool. After exposure to each environment the STAI-S (a measurement of state anxiety) and the CDB (a measurement of depression) were administered to all subjects. The results show that virtual reality instruments are particularly useful for simulating everyday situations that may provoke emotional reactions such as anxiety and depression, in patients with ED. Virtual environments in which subjects are obliged to ingest high-calorie food provoke the highest levels of state anxiety and depression.

The future of patient safety: Surgical trainees accept virtual reality as a new training tool.

BACKGROUND: The use of virtual reality (VR) has gained increasing interest to acquire laparoscopic skills outside the operating theatre and thus increasing patients' safety. The aim of this study was to evaluate trainees' acceptance of VR for assessment and training during a skills course and at their institution. METHODS: All 735 surgical trainees of the International Gastrointestinal Surgery Workshop 2006-2008, held in Davos, Switzerland, were given a minimum of 45 minutes for VR training during the course. Participants' opinion on VR was analyzed with a standardized questionnaire. RESULTS: Fivehundred-twenty-seven participants (72%) from 28 countries attended the VR sessions and answered the questionnaires. The possibility of using VR at the course was estimated as excellent or good in 68%, useful in 21%, reasonable in 9% and unsuitable or useless in 2%. If such VR simulators were available at their institution, most course participants would train at least one hour per week (46%), two or more hours (42%) and only 12% wouldn't use VR. Similarly, 63% of the participants would accept to operate on patients only after VR training and 55% to have VR as part of their assessment. CONCLUSION: Residents accept and appreciate VR simulation for surgical assessment and training. The majority of the trainees are motivated to regularly spend time for VR training if accessible.

Educació virtual : Els dispositius mòbils com a eina d'ensenyament-aprenentatge

Aquest treball pretén aprofundir en com es poden aprofitar les noves eines tecnològiques per millorar l'entorn educatiu. Analitzarem de quina manera els dispositius mòbils poden ajudar a incrementar la motivació, la curiositat i la cooperació dels alumnes i, en definitiva, l'aprentatge.

Improvement of a fully distributed decision making protocol for CRN

Abstract¿La deteción del espectro libre para las comunicaciones inalámbricas en un momento puntual es una tarea compleja cuyo desarrollo se simplica al realizarse de forma distribuida por una red de radio cognitiva. Sin embargo existes dificultades y vulnerabilidades de seguridad que han de ser tenidas en cuenta y solventadas a la hora de autenticar y validar los nodos de la red. Este artículo presenta una propuesta de mejora del protocolo fully distributed decision making protocol for CRN con el fin de llevar a cabo esta tarea de detección del espectro de una manera eficiente y segura.

Du capitalisme familial au capitalisme financier? : le cas de l'industrie suisse des machines, de l'électrotechnique et de la métallurgie au 20e siècle

L'objectif principal de cette thèse consiste à mettre en évidence la persistance du capitalisme familial en Suisse au cours du 20e siècle, et sa résistance aux capitalismes managérial et financier qui sont censés lui avoir succédé. Pour ce faire, nous avons retenu vingt-deux grandes entreprises du secteur des machines, de l'électrotechnique et de la métallurgie - principale branche de l'industrie suisse pour la période considérée -, pour lesquelles ont été recensés les membres des conseils d'administration et les principaux dirigeants exécutifs pour cinq dates- repère couvrant le siècle (1910, 1937, 1957, 1980 et 2000). Cette thèse s'inscrit dans une démarche pluridisciplinaire qui relève à la fois de l'histoire d'entreprise et de la sociologie des dirigeants, et fait appel à différentes méthodes telles que l'analyse de réseau et l'analyse prosopographique. Elle s'articule autour de trois axes de recherche principaux : le premier vise à mettre en évidence l'évolution des modes de gouvernance dans notre groupe d'entreprises, le second investit la question de la coordination patronale et le troisième a pour but de dresser un portrait collectif des élites à la tête de nos vingt-deux firmes. Nos résultats montrent que durant la majeure partie du siècle, la plupart de nos entreprises sont contrôlées par des familles et fonctionnent sur un mode de coordination hors marché qui repose notamment sur un réseau dense de liens interfirmes, le profil des dirigeants restant dans l'ensemble stable. Si la fin du siècle est marquée par plusieurs changements qui confirment l'avènement d'un capitalisme dit financier ou actionnarial et la mise en place de pratiques plus concurrentielles parmi les firmes et les élites industrielles, le maintien du contrôle familial dans plusieurs entreprises et la persistance de certains anciens mécanismes de coopération nous incitent cependant à nuancer ce constat. - The main objective of this research is to highlight the persistence of family capitalism in Switzerland during the 20th century and its resistance to managerial and financial capitalisms that succeeded. For this purpose, we focus on twenty- two big companies of the machine, electrotechnical and metallurgy sector - the main branch of the Swiss industry for the considered period - whose boards of directors and executive managers have been identified for five benchmarks across the century (1910, 1937, 1957, 1980 and 2000). This thesis relates to business history and elites sociology, and uses different methods such as network analysis and prosopography. It is articulated around three main parts. The aim of the first one is to identify the evolution of corporate governance in our twenty-two enterprises, the second part concentrates on interfirms coordination and the objective of the last one is to highlight the profile of the corporate elite leading our firms. Our results show that during the main part of the century, most of the companies were controlled by families and were characterized by non-market mechanisms of coordination such as interlocking directorates ; moreover, the profile of the corporate elite remained very stable. Although some major changes that took place by the end of the century confirmed a transition towards financial capitalism and more competitive interaction among firms and the corporate elite, the persistence of family control in several companies and the maintaining of some former mechanisms of coordination allow us to put this evolution into perspective.

Machine learning for spatial environmental data. Theory, applications and software

The book presents the state of the art in machine learning algorithms (artificial neural networks of different architectures, support vector machines, etc.) as applied to the classification and mapping of spatially distributed environmental data. Basic geostatistical algorithms are presented as well. New trends in machine learning and their application to spatial data are given, and real case studies based on environmental and pollution data are carried out. The book provides a CD-ROM with the Machine Learning Office software, including sample sets of data, that will allow both students and researchers to put the concepts rapidly to practice.