Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces

An Internet portal accessible at www.gdb.unibe.ch has been set up to automatically generate color-coded similarity maps of the ChEMBL database in relation to up to two sets of active compounds taken from the enhanced Directory of Useful Decoys (eDUD), a random set of molecules, or up to two sets of user-defined reference molecules. These maps visualize the relationships between the selected compounds and ChEMBL in six different high dimensional chemical spaces, namely MQN (42-D molecular quantum numbers), SMIfp (34-D SMILES fingerprint), APfp (20-D shape fingerprint), Xfp (55-D pharmacophore fingerprint), Sfp (1024-bit substructure fingerprint), and ECfp4 (1024-bit extended connectivity fingerprint). The maps are supplied in form of Java based desktop applications called “similarity mapplets” allowing interactive content browsing and linked to a “Multifingerprint Browser for ChEMBL” (also accessible directly at www.gdb.unibe.ch) to perform nearest neighbor searches. One can obtain six similarity mapplets of ChEMBL relative to random reference compounds, 606 similarity mapplets relative to single eDUD active sets, 30 300 similarity mapplets relative to pairs of eDUD active sets, and any number of similarity mapplets relative to user-defined reference sets to help visualize the structural diversity of compound series in drug optimization projects and their relationship to other known bioactive compounds.

Visualization of cell microtubules in their native state.

BACKGROUND INFORMATION Over the past decades, cryo-electron microscopy of vitrified specimens has yielded a detailed understanding of the tubulin and microtubule structures of samples reassembled in vitro from purified components. However, our knowledge of microtubule structure in vivo remains limited by the chemical treatments commonly used to observe cellular architecture using electron microscopy. RESULTS We used cryo-electron microscopy and cryo-electron tomography of vitreous sections to investigate the ultrastructure of microtubules in their cellular context. Vitreous sections were obtained from organotypic slices of rat hippocampus and from Chinese-hamster ovary cells in culture. Microtubules revealed their protofilament ultrastructure, polarity and, in the most favourable cases, molecular details comparable with those visualized in three-dimensional reconstructions of microtubules reassembled in vitro from purified tubulin. The resolution of the tomograms was estimated to be approx. 4 nm, which enabled the detection of luminal particles of approx. 6 nm in diameter inside microtubules. CONCLUSIONS The present study provides a first step towards a description of microtubules, in addition to other macromolecular assemblies, in an unperturbed cellular context at the molecular level. As the resolution appears to be similar to that obtainable with plunge-frozen samples, it should allow for the in vivo identification of larger macromolecular assemblies in vitreous sections of whole cells and tissues.

Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state.

The cell envelope of mycobacteria, which include the causative agents of tuberculosis and leprosy, is crucial for their success as pathogens. Despite a continued strong emphasis on identifying the multiple chemical components of this envelope, it has proven difficult to combine its components into a comprehensive structural model, primarily because the available ultrastructural data rely on conventional electron microscopy embedding and sectioning, which are known to induce artifacts. The existence of an outer membrane bilayer has long been postulated but has never been directly observed by electron microscopy of ultrathin sections. Here we have used cryo-electron microscopy of vitreous sections (CEMOVIS) to perform a detailed ultrastructural analysis of three species belonging to the Corynebacterineae suborder, namely, Mycobacterium bovis BCG, Mycobacterium smegmatis, and Corynebacterium glutamicum, in their native state. We provide new information that accurately describes the different layers of the mycobacterial cell envelope and challenges current models of the organization of its components. We show a direct visualization of an outer membrane, analogous to that found in gram-negative bacteria, in the three bacterial species examined. Furthermore, we demonstrate that mycolic acids, the hallmark of mycobacteria and related genera, are essential for the formation of this outer membrane. In addition, a granular layer and a low-density zone typifying the periplasmic space of gram-positive bacteria are apparent in CEMOVIS images of mycobacteria and corynebacteria. Based on our observations, a model of the organization of the lipids in the outer membrane is proposed. The architecture we describe should serve as a reference for future studies to relate the structure of the mycobacterial cell envelope to its function.

Pulse-shaping assisted multidimensional coherent electronic spectroscopy

Understanding nuclear and electronic dynamics of molecular systems has advanced considerably by probing their nonlinear responses with a suitable sequence of pulses. Moreover, the ability to control crucial parameters of the excitation pulses, such as duration, sequence, frequency, polarization, slowly varying envelope, or carrier phase, has led to a variety of advanced time-resolved spectroscopic methodologies. Recently, two-dimensional electronic spectroscopy with ultrashort pulses has become a more and more popular tool since it allows to obtain information on energy and coherence transfer phenomena, line broadening mechanisms, or the presence of quantum coherences in molecular complexes. Here, we present a high fidelity two-dimensional electronic spectroscopy setup designed for molecular systems in solution. It incorporates the versatility of pulse-shaping methods to achieve full control on the amplitude and phase of the individual exciting and probing pulses. Selective and precise amplitude- and phase-modulation is shown and applied to investigate electronic dynamics in several reference molecular systems.

Timely Reporting and Interactive Visualization of Animal Health and Slaughterhouse Surveillance Data in Switzerland

The reporting of outputs from health surveillance systems should be done in a near real-time and interactive manner in order to provide decision makers with powerful means to identify, assess, and manage health hazards as early and efficiently as possible. While this is currently rarely the case in veterinary public health surveillance, reporting tools do exist for the visual exploration and interactive interrogation of health data. In this work, we used tools freely available from the Google Maps and Charts library to develop a web application reporting health-related data derived from slaughterhouse surveillance and from a newly established web-based equine surveillance system in Switzerland. Both sets of tools allowed entry-level usage without or with minimal programing skills while being flexible enough to cater for more complex scenarios for users with greater programing skills. In particular, interfaces linking statistical softwares and Google tools provide additional analytical functionality (such as algorithms for the detection of unusually high case occurrences) for inclusion in the reporting process. We show that such powerful approaches could improve timely dissemination and communication of technical information to decision makers and other stakeholders and could foster the early-warning capacity of animal health surveillance systems.

MO visualization of Pi Orbitals

In the spirit of trying to convert people to understanding atomic orbitals centered elsewhere than the origin, we continue the discussion of visualizing molecular orbitals, so called LCAO-MO, using various plotting tricks in Maple.

Renal Cryoablation: Investigation of Periprocedural Visualization Tools and Treatment Response Quantification

Cryoablation for small renal tumors has demonstrated sufficient clinical efficacy over the past decade as a non-surgical nephron-sparing approach for treating renal masses for patients who are not surgical candidates. Minimally invasive percutaneous cryoablations have been performed with image guidance from CT, ultrasound, and MRI. During the MRI-guided cryoablation procedure, the interventional radiologist visually compares the iceball size on monitoring images with respect to the original tumor on separate planning images. The comparisons made during the monitoring step are time consuming, inefficient and sometimes lack the precision needed for decision making, requiring the radiologist to make further changes later in the procedure. This study sought to mitigate uncertainty in these visual comparisons by quantifying tissue response to cryoablation and providing visualization of the response during the procedure. Based on retrospective analysis of MR-guided cryoablation patient data, registration and segmentation algorithms were investigated and implemented for periprocedural visualization to deliver iceball position/size with respect to planning images registered within 3.3mm with at least 70% overlap and a quantitative logit model was developed to relate perfusion deficit in renal parenchyma visualized in verification images as a result of iceball size visualized in monitoring images. Through retrospective study of 20 patient cases, the relationship between likelihood of perfusion loss in renal parenchyma and distance within iceball was quantified and iteratively fit to a logit curve. Using the parameters from the logit fit, the margin for 95% perfusion loss likelihood was found to be 4.28 mm within the iceball. The observed margin corresponds well with the clinically accepted margin of 3-5mm within the iceball. In order to display the iceball position and perfusion loss likelihood to the radiologist, algorithms were implemented to create a fast segmentation and registration module which executed in under 2 minutes, within the clinically-relevant 3 minute monitoring period. Using 16 patient cases, the average Hausdorff distance was reduced from 10.1mm to 3.21 mm with average DSC increased from 46.6% to 82.6% before and after registration.

Robust effect sizes and their confidence intervals for group difference between trajectories in hierarchical linear growth model

Hierarchical linear growth model (HLGM), as a flexible and powerful analytic method, has played an increased important role in psychology, public health and medical sciences in recent decades. Mostly, researchers who conduct HLGM are interested in the treatment effect on individual trajectories, which can be indicated by the cross-level interaction effects. However, the statistical hypothesis test for the effect of cross-level interaction in HLGM only show us whether there is a significant group difference in the average rate of change, rate of acceleration or higher polynomial effect; it fails to convey information about the magnitude of the difference between the group trajectories at specific time point. Thus, reporting and interpreting effect sizes have been increased emphases in HLGM in recent years, due to the limitations and increased criticisms for statistical hypothesis testing. However, most researchers fail to report these model-implied effect sizes for group trajectories comparison and their corresponding confidence intervals in HLGM analysis, since lack of appropriate and standard functions to estimate effect sizes associated with the model-implied difference between grouping trajectories in HLGM, and also lack of computing packages in the popular statistical software to automatically calculate them. ^ The present project is the first to establish the appropriate computing functions to assess the standard difference between grouping trajectories in HLGM. We proposed the two functions to estimate effect sizes on model-based grouping trajectories difference at specific time, we also suggested the robust effect sizes to reduce the bias of estimated effect sizes. Then, we applied the proposed functions to estimate the population effect sizes (d ) and robust effect sizes (du) on the cross-level interaction in HLGM by using the three simulated datasets, and also we compared the three methods of constructing confidence intervals around d and du recommended the best one for application. At the end, we constructed 95% confidence intervals with the suitable method for the effect sizes what we obtained with the three simulated datasets. ^ The effect sizes between grouping trajectories for the three simulated longitudinal datasets indicated that even though the statistical hypothesis test shows no significant difference between grouping trajectories, effect sizes between these grouping trajectories can still be large at some time points. Therefore, effect sizes between grouping trajectories in HLGM analysis provide us additional and meaningful information to assess group effect on individual trajectories. In addition, we also compared the three methods to construct 95% confident intervals around corresponding effect sizes in this project, which handled with the uncertainty of effect sizes to population parameter. We suggested the noncentral t-distribution based method when the assumptions held, and the bootstrap bias-corrected and accelerated method when the assumptions are not met.^

Estilos de desarrollo, ideología e Intervención antrópica en Misiones (Argentina): Un análisis multidimensional y comparativo. 16H201

Esta es una continuación del Programa ECIS (Estudio Comparativo de los Impactos Sociales de los Grandes Proyectos de Desarrollo), constituído a partir del 2005 en el Programa de Ecología Humana (PEH). Los ejes convocantes para esta nueva etapa, son, en primer lugar, la compleción del análisis del Proyecto Yacyretá, que en el período anterior concretó la publicación de un volumen. Una segunda vertiente remite a la ideología de los movimientos sociales opuestos a la construcción de represas y a la concepción de desarrollo explícitas o implícitas en sus propuestos y su comparación con otros movimientos ecologistas (Córdoba). Asimismo, nos proponemos realizar estudios de campo de las prácticas agrícolas de los colonos asentados en áreas de la provincia incluidas en el proyecto de "corredor verde", con el objeto de analizar su compatibilidad o no con los modelos de "explotación sustentable" que se vienen manejando, así como analizar otros desarrollos recientes en el agro misionero. Finalmente, se contemplan estudios comparativos sobre desarrollo socioeconómico de minorías en la Patagonia argentina.

Estilos de desarrollo, ideologia e intervención antropica en misiones (argentina): un análisis multidimensional y comparativo. Programa de Ecología Humana. PIP CONICET 11220080101659. 16H288

Actividades desarrolladas durante el período: se continuó con la sistematización y clasificación de los datos sobre la represa de Yacyreta. y con la preparación del libro, para lo cual se cuenta con la colaboracón de la Lic. María del Rosario Millán. Se sistematizaron los datos recopilados hasta este momento; Durante el año 2009 nos ocupamos específicamente del análisis de distintas asambleas ambientales que desarrollan sus actividades en la provincia de Córdoba. Entre otras reivindicaciones, cabe destacar la relevancia de las luchas llevadas a cabo por asambleas movilizadas para lograr la prohibición de la explotación minera a cielo abierto en todo el territorio provincial. Se realizaron registros bibliográficos, se recogió y analizó diversas folletería, observaciones, se participó de diversos eventos (reuniones, marchas, congreso, etc,) y se realizaron entrevistas en profundidad; análisis las prácticas y representaciones de los productores rurales sobre el ambiente. Se estudiaron los proyectos, discursos y actores ambientalistas que circulan en la región y que, de manera creciente, están influyendo sobre la manera en que los productores rurales se relacionan con el ambiente. De manera que en segundo lugar se estudió la expansión de discursos, actores y prácticas ambientalistas en la provincia de Misiones.

Análisis económico de la brecha tecnológica en la producción de uva de mesa sanjuanina

Este estudio se realizó en una zona productora de uva de mesa de la provincia de San Juan, que incluyó los departamentos Zonda, Ullum, Albardón, Pocito, Caucete, 25 de Mayo, San Martín y 9 de Julio. De 335 explotaciones existentes, según la base obtenida a partir del CNA 2002, se tomó una muestra de 83 casos, para 2 sigmas de intervalo de confianza y 10 % de error. Los objetivos planteados fueron: determinar el nivel tecnológico para este rubro productivo, medir el grado de severidad de un grupo de restricciones asociadas a la incorporación de tecnología y estimar el beneficio económico alcanzado por el cierre de la brecha tecnológica. De este modo, se plantearon tres dimensiones de estudio, evaluando oportunamente las variables asociadas, de acuerdo a los estudios preeliminares. Los datos fueron procesados con el programa SPSS 11. Se realizó, para el estudio de la primera dimensión, análisis de componentes principales, escalamiento multidimensional y análisis de conglomerados no jerárquicos y en dos fases. En el caso de la segunda dimensión, se utilizaron tablas de contingencia con los estadísticos chi-cuadrado y t de student. Para estimar el beneficio económico alcanzado por el cierre de la brecha tecnológica, se utilizó un programa de simulación SIGMA 2.0. Se encontró la existencia de dos niveles tecnológicos dentro del rubro productivo uva de mesa de exportación, en donde existen inconvenientes referidos a la carencia de infraestructura, falta de rentabilidad asociada a los ingresos de la alternativa tecnológica, incompatibilidad entre los intereses al crédito que se puede acceder y las ganancias de la alternativa tecnológica y, por último, falta de planificación empresarial. Del cierre de la brecha tecnológica, en un escenario positivo, de cinco años, se concluye que el beneficio social medido como excedente bruto de la producción, puede ascender a casi $ 27 millones.

Hacia una aproximación multidimensional e innovadora de los pilares de la orientación vocacional

Se estudian cuestiones relativas a la elección de una carrera universitaria por alumnos que finalizan la educación secundaria. La hipótesis es que una complementación de enfoques que recupere dimensiones presentes en la teoría y en los instrumentos derivados, algunos de vieja data, permite anticipar una elección profesional satisfactoria. El objetivo general es analizar la viabilidad de conjugar principios y recursos de diferente origen psicológico-epistemológico, en una perspectiva holística y con proyección al plano aplicado. Para alcanzarlo se abordan cuali y cuantitativamente: intereses vocacionales y personalidad, globalmente considerados (variables independientes) en su relación con la elección de una carrera y se estima la capacidad de anticipar “una buena elección", medida por permanencia en la carrera, satisfacción y convicción de que se la volvería a elegir (variables dependientes). La fuente son registros documentales de procesos de Orientación y una entrevista de seguimiento habiendo transcurrido entre dos y seis años desde la elección. Es un estudio descriptivo, comparativo y en algunas instancias analiza correspondencias. Los resultados corroboran que la complementación de perspectivas e instrumentos sustenta una decisión vocacional que se caracteriza por la satisfacción con la elección, la permanencia en la carrera y la convicción de que se la volvería a elegir. Como corolario se resignifica la conceptualización de Orientación Vocacional sobre bases etimológicas y empíricas, en tanto proceso que realiza “quien se orienta" en cierta dirección.

Ordenaciones de material genético a partir de información multidimensional

Nuevas biotecnologías permiten obtener información para caracterizar materiales genéticos a partir de múltiples marcadores, ya sean éstos moleculares y/o morfológicos. La ordenación del material genético a través de la exploración de patrones de variabilidad multidimensionales se aborda mediante diversas técnicas de análisis multivariado. Las técnicas multivariadas de reducción de dimensión (TRD) y la representación gráfica de las mismas cobran sustancial importancia en la visualización de datos multivariados en espacios de baja dimensión ya que facilitan la interpretación de interrelaciones entre las variables (marcadores) y entre los casos u observaciones bajo análisis. Tanto el Análisis de Componentes Principales, como el Análisis de Coordenadas Principales y el Análisis de Procrustes Generalizado son TRD aplicables a datos provenientes de marcadores moleculares y/o morfológicos. Los Árboles de Mínimo Recorrido y los biplots constituyen técnicas para lograr representaciones geométricas de resultados provenientes de TRD. En este trabajo se describen estas técnicas multivariadas y se ilustran sus aplicaciones sobre dos conjuntos de datos, moleculares y morfológicos, usados para caracterizar material genético fúngico.