Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach

Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification of toxicant-induced changes of the cellular proteostasis, or of its underlying transcriptome network. Therefore, the 'human embryonic stem cell (hESC)- derived novel alternative test systems (ESNATS)' European commission research project established RT tests based on defined differentiation protocols of hESC and their progeny. Valproic acid (VPA) and methylmercury (MeHg) were used as positive control compounds to address the following fundamental questions: (1) Does transcriptome analysis allow discrimination of the two compounds? (2) How does analysis of enriched transcription factor binding sites (TFBS) and of individual probe sets (PS) distinguish between test systems? (3) Can batch effects be controlled? (4) How many DNA microarrays are needed? (5) Is the highest non-cytotoxic concentration optimal and relevant for the study of transcriptome changes? VPA triggered vast transcriptional changes, whereas MeHg altered fewer transcripts. To attenuate batch effects, analysis has been focused on the 500 PS with highest variability. The test systems differed significantly in their responses (\20 % overlap). Moreover, within one test system, little overlap between the PS changed by the two compounds has been observed. However, using TFBS enrichment, a relatively large 'common response' to VPA and MeHg could be distinguished from 'compound-specific' responses. In conclusion, the ESNATS assay battery allows classification of human DNT/RT toxicants on the basis of their transcriptome profiles.EU/FP7/ESNATSDFGDoerenkamp-Zbinden Foundatio

Visual steering to support decision making in Visdom

Zsfassung in dt. SpracheComputer-Simulationen werden häufig zur Untersuchung von natürlichen Prozessen herangezogen. Durch gezielte Änderung von Simulationsparametern ist es möglich, ein Verständnis komplexer Zusammenhänge zu gewinnen. Eine Software, mit der sich verschiedene Szenarien durchspielen und vergleichen lassen, kann sinnvoll als Entscheidungshilfe eingesetzt werden. Die Entwicklung leistungsstarker Simulationskomponenten ist eng mit einer steigenden Komplexität verbunden, welche durch die Präsenz einer Vielzahl heterogener Parameter gekenngezeichnet ist. Die Steuerung einer Simulation kann durch Verwendung visueller Interaktion stark vereinfacht werden, allerdings gibt es nur wenige Ansätze, die eine gezielte Verküpfung von Simulation und Visualisierung in einer Software anstreben. In der vorliegenden Arbeit werden die grundlegenden Komponenten der Visdom-Applikation vorgestellt, welche Simulation, Steuerung und interaktive, visuelle Analyse der Ergebnisse in einer einzigen Anwendung verbindet. Dadurch können die Auswirkungen alternativer Entscheidungen untersucht werden, ohne Details über die zugrundelegende Simulationstechnik wissen zu müssen. Visdom bietet zu diesem Zweck die interaktive World-Lines-Darstellung, die zur Erzeugung und Verwaltung mehrerer Simulationsläufe herangezogen wird. Die Methode verwendet bekannte Metaphern aus der multimedialen Welt zur Visualisierung von Simulationsläufen als sogenannte Tracks. Interaktiv können Benutzer neue Entscheidungen einfliessen lassen, welche in der World-Lines-Ansicht als Verzweigungen dargestellt werden. Darüberhinaus können Parameterstudien erstellt werden, die sich zur Berücksichtigung von statistischen Unsicherheiten eignen. Mithilfe mehrerer Positionszeiger werden gekoppelte Visualisierungen sowohl in der Zeit als auch zwischen alternativen Lösungen navigiert. Auf diese Weise ermöglicht das System die vergleichende Analyse mehrerer Simulationsläufe. Da der Simulationsprozess eine Vielzahl heterogener Daten erzeugt, stellen wir einen genetischen Algorithmus zur Verfügung, der die AnwenderInnen bei der Suche nach Erklärungen unterstützt. Im Kern der Applikation steht ein Datenflussmodel, welches einen hohen Grad an Modularität gewährleistet. Über einen flexiblen Kontrollfluss, welcher intern und visuell vom eigentlichen Datenfluss getrennt ist, werden die Parameter von World Lines zu den relevanten Modulen übertragen. Dabei verwenden wir dynamische Visualisierung innerhalb des Flussdiagrams, um auf relevante Steuerungsvorgänge aufmerksam zu machen. Die Anwendbarkeit des Systems wird in Fallstudien aus dem Hochwassermanagement überprüft. In einem virtuellen Dammbruchszenario besteht die Aufgabe darin, mit einer möglichst geringen Anzahl von Sandsäcken Schutzdämme zu entwerfen, die dem steigenden Wasserspiegel standhalten um eine Siedlung zu schützen.Computer simulation has become an ubiquitous tool to investigate the nature of systems. When steering a simulation, users modify parameters to study their impact on the simulation outcome. The ability to test alternative options provides the basis for interactive decision making. Increasingly complex simulations are characterized by an intricate interplay of many heterogeneous input and output parameters. A steering concept that combines simulation and visualization within a single, comprehensive system is largely missing. This thesis targets the basic components of a novel integrated steering system called Visdom to support the user in the decision making process. The proposed techniques enable users to examine alternative scenarios without the need for special simulation expertise. To accomplish this, we propose World Lines as a management strategy for multiple, related simulation runs. In a dedicated view, users create and navigate through many simulation runs.New decisions are included through the concept of branching. To account for uncertain knowledge about the input parameters, we provide the ability to cover full parameter distributions. Via multiple cursors, users navigate a system of multiple linked views through time and alternative scenarios. In this way, the system supports comparative visual analysis of many simulation runs. Since the steering process generates a huge amount of information, we employ the machine to support the user in the search for explanations inside the computed data. Visdom is built on top of a data-flow network to provide a high level of modularity. A decoupled meta-flow is in charge of transmitting parameter changes from World Lines to the affected data-flow nodes. To direct the user attention to the most relevant parts, we provide dynamic visualization inside the flow diagram. The usefulness of the presented approach is substantiated through case studies in the field of flood management. The Visdom application enables the design of a breach closure by dropping sandbags in a virtual environment.13

Annotations for Geospatial Decision Support Systems

In virtual 3D environments, it is easy to lose orientation while navigating or changing the view with zooming and panning operations. In the real world, annotated maps are an established tool to orient oneself in large and unknown environments. The use of annotations and landmarks in traditional maps can also be transferred to virtual environments. But occlusions by three-dimensional structures have to be taken into account as well as performance considerations for an interactive real-time application. Furthermore, annotations should be discreetly integrated into the existing 3D environment and not distract the viewer’s attention from more important features. In this paper we present an implementation of automatic annotations based on open data to improve the spatial orientation in the highly interactive and dynamic decision support system Visdom. We distinguish between line and area labels for object-specific labeling, which facilitates a direct association of the labels with their corresponding objects or regions. The final algorithm provides clearly visible, easily readable and dynamically adapting annotations with continuous levels of detail integrated into an interactive real-time application

Multiverse data-flow control

In this paper we present a data-flow system which supports comparative analysis of time-dependent data and interactive simulation steering. In such a system data is created on-the-fly and the user can introduce branching events to investigate multiple scenarios. The novel data-flow model automatically generates the required data for user requests without further interaction. In particular, we generalize the notion of capabilities, jobs and settings of a node which steer the data-flow execution. Based on a notion of scope and validity it becomes straightforward for the user to specify settings which vary over time or scenarios. Intuitive navigation concepts let the user select what he wants to see, the decision which data is required throughout the data-flow is then handled automatically. The approach is based on a graph-based model of a topologically sorted data-flow. Based on that we show that the notion of a scope allows to describe the computation of jobs and validity using set intersections and set unions. We demonstrate the approach by discussing two small case studies