ChemVA: Interactive visual analysis of chemical compound similarity in virtual screening

In the modern drug discovery process, medicinal chemists deal with the complexity of analysis of large ensembles of candidate molecules. Computational tools, such as dimensionality reduction (DR) and classification, are commonly used to efficiently process the multidimensional space of features. These underlying calculations often hinder interpretability of results and prevent experts from assessing the impact of individual molecular features on the resulting representations. To provide a solution for scrutinizing such complex data, we introduce ChemVA, an interactive application for the visual exploration of large molecular ensembles and their features. Our tool consists of multiple coordinated views: Hexagonal view, Detail view, 3D view, Table view, and a newly proposed Difference view designed for the comparison of DR projections. These views display DR projections combined with biological activity, selected molecular features, and confidence scores for each of these projections. This conjunction of views allows the user to drill down through the dataset and to efficiently select candidate compounds. Our approach was evaluated on two case studies of finding structurally similar ligands with similar binding affinity to a target protein, as well as on an external qualitative evaluation. The results suggest that our system allows effective visual inspection and comparison of different high-dimensional molecular representations. Furthermore, ChemVA assists in the identification of candidate compounds while providing information on the certainty behind different molecular representations.Fil: Sabando, María Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; ArgentinaFil: Ulbrich, Pavol. Masaryk University. Faculty of Sciences; República ChecaFil: Selzer, Matias Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; Argentina. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Laboratorio de Ciencias de la Imágenes; ArgentinaFil: Byska, Jan. Masaryk University. Faculty of Sciences; República ChecaFil: Mican, Jan. Masaryk University. Faculty of Sciences; República ChecaFil: Ponzoni, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; ArgentinaFil: Soto, Axel Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; ArgentinaFil: Ganuza, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Ciencias e Ingeniería de la Computación. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Instituto de Ciencias e Ingeniería de la Computación; Argentina. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación. Laboratorio de Ciencias de la Imágenes; ArgentinaFil: Kozlikova, Barbora. Masaryk University. Faculty of Sciences; República Chec

Genome-Wide and Functional Annotation of Human E3 Ubiquitin Ligases Identifies MULAN, a Mitochondrial E3 that Regulates the Organelle's Dynamics and Signaling

Specificity of protein ubiquitylation is conferred by E3 ubiquitin (Ub) ligases. We have annotated ∼617 putative E3s and substrate-recognition subunits of E3 complexes encoded in the human genome. The limited knowledge of the function of members of the large E3 superfamily prompted us to generate genome-wide E3 cDNA and RNAi expression libraries designed for functional screening. An imaging-based screen using these libraries to identify E3s that regulate mitochondrial dynamics uncovered MULAN/FLJ12875, a RING finger protein whose ectopic expression and knockdown both interfered with mitochondrial trafficking and morphology. We found that MULAN is a mitochondrial protein – two transmembrane domains mediate its localization to the organelle's outer membrane. MULAN is oriented such that its E3-active, C-terminal RING finger is exposed to the cytosol, where it has access to other components of the Ub system. Both an intact RING finger and the correct subcellular localization were required for regulation of mitochondrial dynamics, suggesting that MULAN's downstream effectors are proteins that are either integral to, or associated with, mitochondria and that become modified with Ub. Interestingly, MULAN had previously been identified as an activator of NF-κB, thus providing a link between mitochondrial dynamics and mitochondria-to-nucleus signaling. These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment

A virtual centre at the interface of basic and applied weather and climate research

The Hans-Ertel Centre for Weather Research is a network of German universities, research institutes and the German Weather Service (Deutscher Wetterdienst, DWD). It has been established to trigger and intensify basic research and education on weather forecasting and climate monitoring. The performed research ranges from nowcasting and short-term weather forecasting to convective-scale data assimilation, the development of parameterizations for numerical weather prediction models, climate monitoring and the communication and use of forecast information. Scientific findings from the network contribute to better understanding of the life-cycle of shallow and deep convection, representation of uncertainty in ensemble systems, effects of unresolved variability, regional climate variability, perception of forecasts and vulnerability of society. Concrete developments within the research network include dual observation-microphysics composites, satellite forward operators, tools to estimate observation impact, cloud and precipitation system tracking algorithms, large-eddy-simulations, a regional reanalysis and a probabilistic forecast test product. Within three years, the network has triggered a number of activities that include the training and education of young scientists besides the centre's core objective of complementing DWD's internal research with relevant basic research at universities and research institutes. The long term goal is to develop a self-sustaining research network that continues the close collaboration with DWD and the national and international research community

Connecting Artificial Brains to Robots in a Comprehensive Simulation Framework: The Neurorobotics Platform

Combined efforts in the fields of neuroscience, computer science, and biology allowed to design biologically realistic models of the brain based on spiking neural networks. For a proper validation of these models, an embodiment in a dynamic and rich sensory environment, where the model is exposed to a realistic sensory-motor task, is needed. Due to the complexity of these brain models that, at the current stage, cannot deal with real-time constraints, it is not possible to embed them into a real-world task. Rather, the embodiment has to be simulated as well. While adequate tools exist to simulate either complex neural networks or robots and their environments, there is so far no tool that allows to easily establish a communication between brain and body models. The Neurorobotics Platform is a new web-based environment that aims to fill this gap by offering scientists and technology developers a software infrastructure allowing them to connect brain models to detailed simulations of robot bodies and environments and to use the resulting neurorobotic systems for in silico experimentation. In order to simplify the workflow and reduce the level of the required programming skills, the platform provides editors for the specification of experimental sequences and conditions, environments, robots, and brain–body connectors. In addition to that, a variety of existing robots and environments are provided. This work presents the architecture of the first release of the Neurorobotics Platform developed in subproject 10 “Neurorobotics” of the Human Brain Project (HBP).1 At the current state, the Neurorobotics Platform allows researchers to design and run basic experiments in neurorobotics using simulated robots and simulated environments linked to simplified versions of brain models. We illustrate the capabilities of the platform with three example experiments: a Braitenberg task implemented on a mobile robot, a sensory-motor learning task based on a robotic controller, and a visual tracking embedding a retina model on the iCub humanoid robot. These use-cases allow to assess the applicability of the Neurorobotics Platform for robotic tasks as well as in neuroscientific experiments.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604102 (Human Brain Project) and from the European Unions Horizon 2020 Research and Innovation Programme under Grant Agreement No. 720270 (HBP SGA1)

Estudo de um caso de deficiência do componente C3 do sistema complemento humano.

Uma criança brasileira (LAS) vítima de infecções recidivantes e vasculite, cujos pais são consangüíneos em segundo grau apresentou 0,15 µg/mL de C3 plasmático e atividades hemolíticas nulas pelas vias clássica e alternativa, já outras proteínas do complemento e Igs estavam normais (exceto IgG4, que foi indetectável). Diferentemente de sua mãe os fibroblastos da criança não foram capazes de sintetizar as cadeias a e b de C3, como observado por SDS-PAGE. O probando possui dois alelos C3S, assim como seu irmão mais novo e saudável, enquanto a mãe é FS. A migração de leucócitos, em resposta ao soro do probando ativado com LPS foi menor que a obtida com soro normal e estatisticamente semelhante àquela gerada por SHN inativado a 56oC (SHNi). A ingestão e a morte de C. albicans, opsonizadas por soro do probando, por fagócitos normais foram semelhantes às dos fungos opsonizados por SHNi. Nós concluimos que, em conseqüência da incapacidade de sintetizar C3, o probando não é capaz de exercer as funções imunológicas dependentes do complemento, resultando em uma maior susceptibilidade a infecções.A brasilian child (LAS) victim of recurrent infections whose parents have second degree consanguinity presented 0.15 µg/mL of serum C3 and no hemolytic activities either after activation of the classical or alternative pathways. His mother presented C3 alpha and beta chains of normal sizes, while LAS's fibroblasts did not secrete any C3 as observed by SDS-PAGE. The proband possesses two C3S alleles, like his younger and healthy brother whereas his mother is FS. Leukocyte migration across nitrocellulose membrane in response to the proband's LPS-activated serum was less intense than that obtained in response to normal serum. Phagocytosis and killing of C. albicans opsonized with the proband's serum was comparable to fungi opsonized with inactivated serum, incdicating that chemotactic and opsonic activities of the proband's serum are greatly diminished. We colclude that as a consequence of C3 deficiency the proband's complement system is uncapable of performing it's normal effector functions resulting in greater susceptibility to infections

Accuracy of Devereux and Teichholz formulas for left ventricular mass calculation in different geometric patterns: comparison with cardiac magnetic resonance imaging

Abstract Left ventricular (LV) myocardial mass is important in the evaluation of cardiac remodeling and requires accurate assessment when performed on linear measurements in two-dimensional echocardiography (Echo). We aimed to compare the accuracy of the Devereux formula (DEV) and the Teichholz formula (TEICH) in calculating LV myocardial mass in Echo using cardiac magnetic resonance (CMR) as the reference method. Based on preceding mathematical calculations, we identified primarily LV size rather than wall thickness as the main source of bias between DEV and TEICH in a retrospective derivation cohort (n = 1276). Although LV mass from DEV and TEICH were correlated with CMR, TEICH did not show a proportional bias as did DEV (− 2 g/m2 vs. + 22 g/m2). This could be validated in an independent prospective cohort (n = 226) with symptomatic non-ischemic heart failure. DEV systematically overestimated LV mass in all tiers of LV remodeling as compared to TEICH. In conclusion, the TEICH method accounts for the changes in LV geometry with increasing LV mass and thus better reflects the different pattern of LV remodeling than the DEV method. This has important clinical implications, as TEICH may be more appropriate for use in clinical practice, rather than DEV, currently recommended