EADock : design of a new molecular docking algorithm and some of its applications

3 Summary 3. 1 English The pharmaceutical industry has been facing several challenges during the last years, and the optimization of their drug discovery pipeline is believed to be the only viable solution. High-throughput techniques do participate actively to this optimization, especially when complemented by computational approaches aiming at rationalizing the enormous amount of information that they can produce. In siiico techniques, such as virtual screening or rational drug design, are now routinely used to guide drug discovery. Both heavily rely on the prediction of the molecular interaction (docking) occurring between drug-like molecules and a therapeutically relevant target. Several softwares are available to this end, but despite the very promising picture drawn in most benchmarks, they still hold several hidden weaknesses. As pointed out in several recent reviews, the docking problem is far from being solved, and there is now a need for methods able to identify binding modes with a high accuracy, which is essential to reliably compute the binding free energy of the ligand. This quantity is directly linked to its affinity and can be related to its biological activity. Accurate docking algorithms are thus critical for both the discovery and the rational optimization of new drugs. In this thesis, a new docking software aiming at this goal is presented, EADock. It uses a hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with .the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 R around the center of mass of the ligand position in the crystal structure, and conversely to other benchmarks, our algorithms was fed with optimized ligand positions up to 10 A root mean square deviation 2MSD) from the crystal structure. This validation illustrates the efficiency of our sampling heuristic, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best-ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures in this benchmark could be explained by the presence of crystal contacts in the experimental structure. EADock has been used to understand molecular interactions involved in the regulation of the Na,K ATPase, and in the activation of the nuclear hormone peroxisome proliferatoractivated receptors a (PPARa). It also helped to understand the action of common pollutants (phthalates) on PPARy, and the impact of biotransformations of the anticancer drug Imatinib (Gleevec®) on its binding mode to the Bcr-Abl tyrosine kinase. Finally, a fragment-based rational drug design approach using EADock was developed, and led to the successful design of new peptidic ligands for the a5ß1 integrin, and for the human PPARa. In both cases, the designed peptides presented activities comparable to that of well-established ligands such as the anticancer drug Cilengitide and Wy14,643, respectively. 3.2 French Les récentes difficultés de l'industrie pharmaceutique ne semblent pouvoir se résoudre que par l'optimisation de leur processus de développement de médicaments. Cette dernière implique de plus en plus. de techniques dites "haut-débit", particulièrement efficaces lorsqu'elles sont couplées aux outils informatiques permettant de gérer la masse de données produite. Désormais, les approches in silico telles que le criblage virtuel ou la conception rationnelle de nouvelles molécules sont utilisées couramment. Toutes deux reposent sur la capacité à prédire les détails de l'interaction moléculaire entre une molécule ressemblant à un principe actif (PA) et une protéine cible ayant un intérêt thérapeutique. Les comparatifs de logiciels s'attaquant à cette prédiction sont flatteurs, mais plusieurs problèmes subsistent. La littérature récente tend à remettre en cause leur fiabilité, affirmant l'émergence .d'un besoin pour des approches plus précises du mode d'interaction. Cette précision est essentielle au calcul de l'énergie libre de liaison, qui est directement liée à l'affinité du PA potentiel pour la protéine cible, et indirectement liée à son activité biologique. Une prédiction précise est d'une importance toute particulière pour la découverte et l'optimisation de nouvelles molécules actives. Cette thèse présente un nouveau logiciel, EADock, mettant en avant une telle précision. Cet algorithme évolutionnaire hybride utilise deux pressions de sélections, combinées à une gestion de la diversité sophistiquée. EADock repose sur CHARMM pour les calculs d'énergie et la gestion des coordonnées atomiques. Sa validation a été effectuée sur 37 complexes protéine-ligand cristallisés, incluant 11 protéines différentes. L'espace de recherche a été étendu à une sphère de 151 de rayon autour du centre de masse du ligand cristallisé, et contrairement aux comparatifs habituels, l'algorithme est parti de solutions optimisées présentant un RMSD jusqu'à 10 R par rapport à la structure cristalline. Cette validation a permis de mettre en évidence l'efficacité de notre heuristique de recherche car des modes d'interactions présentant un RMSD inférieur à 2 R par rapport à la structure cristalline ont été classés premier pour 68% des complexes. Lorsque les cinq meilleures solutions sont prises en compte, le taux de succès grimpe à 78%, et 92% lorsque la totalité de la dernière génération est prise en compte. La plupart des erreurs de prédiction sont imputables à la présence de contacts cristallins. Depuis, EADock a été utilisé pour comprendre les mécanismes moléculaires impliqués dans la régulation de la Na,K ATPase et dans l'activation du peroxisome proliferatoractivated receptor a (PPARa). Il a également permis de décrire l'interaction de polluants couramment rencontrés sur PPARy, ainsi que l'influence de la métabolisation de l'Imatinib (PA anticancéreux) sur la fixation à la kinase Bcr-Abl. Une approche basée sur la prédiction des interactions de fragments moléculaires avec protéine cible est également proposée. Elle a permis la découverte de nouveaux ligands peptidiques de PPARa et de l'intégrine a5ß1. Dans les deux cas, l'activité de ces nouveaux peptides est comparable à celles de ligands bien établis, comme le Wy14,643 pour le premier, et le Cilengitide (PA anticancéreux) pour la seconde.

Implementación de GNU/Linux para una empresa de desarrollo de software

Trabajo que muestra, haciendo uso de tecnologías libres y basándonos en sistemas operativos abiertos, cómo es posible mantener un nivel alto de trabajo para una empresa que se dedica a implementar y realizar desarrollos en tecnologías de software libre. Se muestra el montaje de un laboratorio de desarrollo que nos va a permitir entender el funcionamiento y la implementación tanto de GNU/Linux como del software que se basa en él dentro de la infraestructura de la empresa.

Software for interpolation of vegetative growth of yerba mate plants in 3D

The objective of this work was to build mock-ups of complete yerba mate plants in several stages of development, using the InterpolMate software, and to compute photosynthesis on the interpolated structure. The mock-ups of yerba-mate were first built in the VPlants software for three growth stages. Male and female plants grown in two contrasting environments (monoculture and forest understory) were considered. To model the dynamic 3D architecture of yerba-mate plants during the biennial growth interval between two subsequent prunings, data sets of branch development collected in 38 dates were used. The estimated values obtained from the mock-ups, including leaf photosynthesis and sexual dimorphism, are very close to those observed in the field. However, this similarity was limited to reconstructions that included growth units from original data sets. The modeling of growth dynamics enables the estimation of photosynthesis for the entire yerba mate plant, which is not easily measurable in the field. The InterpolMate software is efficient for building yerba mate mock-ups.

Quantification of Myocardial Perfusion Using 13N-ammonia PET: a Cross-Comparison Study on Analysis Software Packages - Carimas, PMOD and FlowQuant

Aim. Several software packages (SWP) and models have been released for quantification of myocardial perfusion (MP). Although they all are validated against something, the question remains how well their values agree. The present analysis focused on cross-comparison of three SWP for MP quantification of 13N-ammonia PET studies. Materials & Methods. 48 rest and stress MP 13N-ammonia PET studies of hypertrophic cardiomyopathy (HCM) patients (Sciagrà et al., 2009) were analysed with three SW packages - Carimas, PMOD, and FlowQuant - by three observers blinded to the results of each other. All SWP implement the one-tissue-compartment model (1TCM, DeGrado et al. 1996), and first two - the two-tissue-compartment model (2TCM, Hutchins et al. 1990) as well. Linear mixed model for the repeated measures was fitted to the data. Where appropriate we used Bland-Altman plots as well. The reproducibility was assessed on global, regional and segmental levels. Intraclass correlation coefficients (ICC), differences between the SWPs and between models were obtained. ICC≥0.75 indicated excellent reproducibility, 0.4≤ICC<0.75 indicated fair to good reproducibility, ICC<0.4 - poor reproducibility (Rosner, 2010). Results. When 1TCM MP values were compared, the SW agreement on global and regional levels was excellent, except for Carimas vs. PMOD at RCA: ICC=0.715 and for PMOD vs. FlowQuant at LCX:ICC=0.745 which were good. In segmental analysis in five segments: 7,12,13, 16, and 17 the agreement between all SWP was excellent; in the remaining 12 segments the agreement varied between the compared SWP. Carimas showed excellent agreement with FlowQuant in 13 segments and good in four - 1, 5, 6, 11: 0.687≤ICCs≤0.73; Carimas had excellent agreement with PMOD in 11 segments, good in five_4, 9, 10, 14, 15: 0.682≤ICCs≤0.737, and poor in segment 3: ICC=0.341. PMOD had excellent agreement with FlowQuant in eight segments and substantial-to-good in nine_1, 2, 3, 5, 6,8-11: 0.585≤ICCs≤0.738. Agreement between Carimas and PMOD for 2TCM was good at a global level: ICC=0.745, excellent at LCX (0.780) and RCA (0.774), good at LAD (0.662); agreement was excellent for ten segments, fair-to-substantial for segments 2, 3, 8, 14, 15 (0.431≤ICCs≤0.681), poor for segments 4 (0.384) and 17 (0.278). Conclusions. The three SWP used by different operators to analyse 13N-ammonia PET MP studies provide results that agree well at a global level, regional levels, and mostly well even at a segmental level. Agreement is better for 1TCM. Poor agreement at segments 4 and 17 for 2TCM needs further clarification.

DnaSP v5: A software for comprehensive analysis of DNA polymorphism data

DnaSP is a software package for a comprehensive analysis of DNA polymorphism data. Version 5 implements a number of new features and analytical methods allowing extensive DNA polymorphism analyses on large datasets. Among other features, the newly implemented methods allow for: (i) analyses on multiple data files; (ii) haplotype phasing; (iii) analyses on insertion/deletion polymorphism data; (iv) visualizing sliding window results integrated with available genome annotations in the UCSC browser.

Lawyer-info : Software de atención al cliente para despachos de abogados en dispositivos móviles Android

Este trabajo desarrolla una aplicación basada en la tecnología Android para la atención de clientes en despachos de abogados.

Centre d'Atenció a l'Usuari (CAU) : Implantació i adaptació de GLPI en un entorn universitari

A partir dels requeriments, definits per la Universitat de Lleida, es proposa una implementació d'una eina de suport basada en un producte de programari lliure anomenat GLPI. El procés d'implementació passa per la parametrització de GLPI al model requerit, mirant d'evitar la necessitat de modificar el codi del sistema escollit.

Baseline Results of an Acute Ischemic Stroke Registry Including Acute Multimodal Imaging (ASTRAL)

Background: The DEFUSE (n_74) and EPITHET (n_101) studies have in common that a baseline MRI was obtained prior to treatment (tPA in DEFUSE; tPA or placebo in EPITHET) in the 3-6 hour time-window. There were however important methodological differences between the studies. A standardized reanalysis of pooled data was undertaken to determine the effect of these differences on baseline characteristics and study outcomes. Methods: To standardize the studies 1) the DWI and PWI source images were reprocessed and segmented using automated image processing software (RAPID); 2) patients were categorized according to their baseline MRI profile as either Target Mismatch (PWITmax_6/DWI ratio_ 1.8 and an absolute mismatch _15mL), Malignant (DWI or PWITmax_10 lesion _ 100 mL), or No Mismatch. 3) favorable clinical response was defined as NIHSS score of 0-1 or a _8 points improvement on the NIHSSS at day 90. Results: Prior to standardization there was no difference in the proportion of Target Mismatch patients between EPITHET and DEFUSE (54% vs 49%, p_0.6), but the EPITHET study had more patients with the Malignant profile than DEFUSE (35% vs 9%, p_0.01) and fewer patients that had No Mismatch (11% vs 42%, p_0.01). These differences in baseline MRI profiles between EPITHET and DEFUSE were largely eliminated by standardized processing of PWI and DWI images with RAPID software (Target Mismatch 49% vs 48%; Malignant 15% vs 8%; No Mismatch 36% vs 25%; p_NS for all comparisons) Reperfusion was strongly associated with a favorable clinical response in mismatch patients (figure). This relationship was not affected by the standardization procedures (pooled odds ratio of 8.8 based on original data and 6.6 based on standardized data). Conclusion: Standardization of image analyses procedures in acute stroke is important as non-standardized techniques introduce significant variability in DWI and PWI imaging characteristics. Despite methodological differences, the DEFUSE and EPITHET studies show a consistent and robust association between reperfusion and favorable clinical response in Target Mismatch patients regardless of standardization. These data support an RCT of iv tPA in the 3-6 hour time-window for Target Mismatch patients identified using RAPID.

Science 2.0 : The use of social networking in research.

REBIUN study on Science 2.0 and social web applications for research. There are three categories: share research, share resources and share results. Describes the applications and selected resources of interest: scientific social networks, scientific databases, research platforms, surveys, concept maps, file sharing, bibliographic management, social bookmarking, citation indexes, blogs and wikis, science news, open access. The services are evaluated and the report describes his interest to libraries.

Cooperación y teoría de juegos, el software libre o el #15m, dos ejemplos para la universidad

Xerrada de cloenda de la Setmana internacional d'accés obert 2011 a la UOC, a càrrec de l'advocat Josep Jover. Per què les estratègies altruistes guanyen les egoistes en el programari lliure i en el #15m? El moviment #15m, igual que el programari, a diferència dels béns materials, no es pot posseir, ja que en pot gaudir (formant-ne part) un nombre indeterminat de persones sense que per això hagi de privar ningú de tenir-lo al seu torn. I això porta a girar com un mitjó la manera com manegen la informació les universitats, i quina és la missió de la universitat en la nova societat. En el futur immediat, valorarem les universitats no per la informació que guarden, que fora sempre serà millor i més extensa, sinó per la capacitat de crear masses crítiques, sia de recerca de coneixement, de capacitació humana, d'enllaç entre iguals... Les universitats hauran d'implantar el model o quedaran relegades.

Cooperation and game theory, free software or the #15m movement: Two examples for universities

Closing talk of the Open Access Week 2011 at the UOC, by Josep Jover. Why do altruistic strategies beat selfish ones in the spheres of both free software and the #15m movement? The #15m movement, like software but unlike tangible goods, cannot be owned. It can be used (by joining it) by an indeterminate number of people without depriving anyone else of the chance to do the same. And that turns everything on its head: how universities manage information and what their mission is in this new society. In the immediate future, universities will be valued not for the information they harbour, which will always be richer and more extensive beyond their walls, but rather for their capacity to create critical masses, whether of knowledge research, skill-building, or networks of peers... universities must implement the new model or risk becoming obsolete.

Extending Learning Objects by Means of Social Networking

Learning objects have been the promise of providing people with high quality learning resources. Initiatives such as MIT Open-CourseWare, MERLOT and others have shown the real possibilities of creating and sharing knowledge through Internet. Thousands of educational resources are available through learning object repositories. We indeed live in an age of content abundance, and content can be considered as infrastructure for building adaptive and personalized learning paths, promoting both formal and informal learning. Nevertheless, although most educational institutions are adopting a more open approach, publishing huge amounts of educational resources, the reality is that these resources are barely used in other educational contexts. This paradox can be partly explained by the dificulties in adapting such resources with respect to language, e-learning standards and specifications and, finally, granularity. Furthermore, if we want our learners to use and take advantage of learning object repositories, we need to provide them with additional services than just browsing and searching for resources. Social networks can be a first step towards creating an open social community of learning around a topic or a subject. In this paper we discuss and analyze the process of using a learning object repository and building a social network on the top of it, with respect to the information architecture needed to capture and store the interaction between learners and resources in form of learning object metadata.

Monitoring of noninvasive ventilation by built-in software of home bilevel ventilators: a bench study.

BACKGROUND: Current bilevel positive-pressure ventilators for home noninvasive ventilation (NIV) provide physicians with software that records items important for patient monitoring, such as compliance, tidal volume (Vt), and leaks. However, to our knowledge, the validity of this information has not yet been independently assessed. METHODS: Testing was done for seven home ventilators on a bench model adapted to simulate NIV and generate unintentional leaks (ie, other than of the mask exhalation valve). Five levels of leaks were simulated using a computer-driven solenoid valve (0-60 L/min) at different levels of inspiratory pressure (15 and 25 cm H(2)O) and at a fixed expiratory pressure (5 cm H(2)O), for a total of 10 conditions. Bench data were compared with results retrieved from ventilator software for leaks and Vt. RESULTS: For assessing leaks, three of the devices tested were highly reliable, with a small bias (0.3-0.9 L/min), narrow limits of agreement (LA), and high correlations (R(2), 0.993-0.997) when comparing ventilator software and bench results; conversely, for four ventilators, bias ranged from -6.0 L/min to -25.9 L/min, exceeding -10 L/min for two devices, with wide LA and lower correlations (R(2), 0.70-0.98). Bias for leaks increased markedly with the importance of leaks in three devices. Vt was underestimated by all devices, and bias (range, 66-236 mL) increased with higher insufflation pressures. Only two devices had a bias < 100 mL, with all testing conditions considered. CONCLUSIONS: Physicians monitoring patients who use home ventilation must be aware of differences in the estimation of leaks and Vt by ventilator software. Also, leaks are reported in different ways according to the device used.