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Chemical exposures affect the environment and may lead to adverse outcomes in its organisms. Omics-based approaches, like standardised microarray experiments, have expanded the toolbox to monitor the distribution of chemicals and assess the risk to organisms in the environment. The resulting complex data have extended the scope of toxicological knowledge bases and published literature. A plethora of computational approaches have been applied in environmental toxicology considering systems biology and data integration. Still, the complexity of environmental and biological systems given in data challenges investigations of exposure-related effects. This thesis aimed at computationally linking chemical exposure to biological effects on the molecular level considering sources of complex environmental data. The first study employed data of an omics-based exposure study considering mixture effects in a freshwater environment. We compared three data-driven analyses in their suitability to disentangle mixture effects of chemical exposures to biological effects and their reliability in attributing potentially adverse outcomes to chemical drivers with toxicological databases on gene and pathway levels. Differential gene expression analysis and a network inference approach resulted in toxicologically meaningful outcomes and uncovered individual chemical effects — stand-alone and in combination. We developed an integrative computational strategy to harvest exposure-related gene associations from environmental samples considering mixtures of lowly concentrated compounds. The applied approaches allowed assessing the hazard of chemicals more systematically with correlation-based compound groups. This dissertation presents another achievement toward a data-driven hypothesis generation for molecular exposure effects. The approach combined text-mining and deep learning. The study was entirely data-driven and involved state-of-the-art computational methods of artificial intelligence. We employed literature-based relational data and curated toxicological knowledge to predict chemical-biomolecule interactions. A word embedding neural network with a subsequent feed-forward network was implemented. Data augmentation and recurrent neural networks were beneficial for training with curated toxicological knowledge. The trained models reached accuracies of up to 94% for unseen test data of the employed knowledge base. However, we could not reliably confirm known chemical-gene interactions across selected data sources. Still, the predictive models might derive unknown information from toxicological knowledge sources, like literature, databases or omics-based exposure studies. Thus, the deep learning models might allow predicting hypotheses of exposure-related molecular effects. Both achievements of this dissertation might support the prioritisation of chemicals for testing and an intelligent selection of chemicals for monitoring in future exposure studies.:Table of Contents ... I Abstract ... V Acknowledgements ... VII Prelude ... IX 1 Introduction 1.1 An overview of environmental toxicology ... 2 1.1.1 Environmental toxicology ... 2 1.1.2 Chemicals in the environment ... 4 1.1.3 Systems biological perspectives in environmental toxicology ... 7 Computational toxicology ... 11 1.2.1 Omics-based approaches ... 12 1.2.2 Linking chemical exposure to transcriptional effects ... 14 1.2.3 Up-scaling from the gene level to higher biological organisation levels ... 19 1.2.4 Biomedical literature-based discovery ... 24 1.2.5 Deep learning with knowledge representation ... 27 1.3 Research question and approaches ... 29 2 Methods and Data ... 33 2.1 Linking environmental relevant mixture exposures to transcriptional effects ... 34 2.1.1 Exposure and microarray data ... 34 2.1.2 Preprocessing ... 35 2.1.3 Differential gene expression ... 37 2.1.4 Association rule mining ... 38 2.1.5 Weighted gene correlation network analysis ... 39 2.1.6 Method comparison ... 41 Predicting exposure-related effects on a molecular level ... 44 2.2.1 Input ... 44 2.2.2 Input preparation ... 47 2.2.3 Deep learning models ... 49 2.2.4 Toxicogenomic application ... 54 3 Method comparison to link complex stream water exposures to effects on the transcriptional level ... 57 3.1 Background and motivation ... 58 3.1.1 Workflow ... 61 3.2 Results ... 62 3.2.1 Data preprocessing ... 62 3.2.2 Differential gene expression analysis ... 67 3.2.3 Association rule mining ... 71 3.2.4 Network inference ... 78 3.2.5 Method comparison ... 84 3.2.6 Application case of method integration ... 87 3.3 Discussion ... 91 3.4 Conclusion ... 99 4 Deep learning prediction of chemical-biomolecule interactions ... 101 4.1 Motivation ... 102 4.1.1Workflow ...105 4.2 Results ... 107 4.2.1 Input preparation ... 107 4.2.2 Model selection ... 110 4.2.3 Model comparison ... 118 4.2.4 Toxicogenomic application ... 121 4.2.5 Horizontal augmentation without tail-padding ...123 4.2.6 Four-class problem formulation ... 124 4.2.7 Training with CTD data ... 125 4.3 Discussion ... 129 4.3.1 Transferring biomedical knowledge towards toxicology ... 129 4.3.2 Deep learning with biomedical knowledge representation ...133 4.3.3 Data integration ...136 4.4 Conclusion ... 141 5 Conclusion and Future perspectives ... 143 5.1 Conclusion ... 143 5.1.1 Investigating complex mixtures in the environment ... 144 5.1.2 Complex knowledge from literature and curated databases predict chemical- biomolecule interactions ... 145 5.1.3 Linking chemical exposure to biological effects by integrating CTD ... 146 5.2 Future perspectives ... 147 S1 Supplement Chapter 1 ... 153 S1.1 Example of an estrogen bioassay ... 154 S1.2 Types of mode of action ... 154 S1.3 The dogma of molecular biology ... 157 S1.4 Transcriptomics ... 159 S2 Supplement Chapter 3 ... 161 S3 Supplement Chapter 4 ... 175 S3.1 Hyperparameter tuning results ... 176 S3.2 Functional enrichment with predicted chemical-gene interactions and CTD reference pathway genesets ... 179 S3.3 Reduction of learning rate in a model with large word embedding vectors ... 183 S3.4 Horizontal augmentation without tail-padding ... 183 S3.5 Four-relationship classification ... 185 S3.6 Interpreting loss observations for SemMedDB trained models ... 187 List of Abbreviations ... i List of Figures ... vi List of Tables ... x Bibliography ... xii Curriculum scientiae ... xxxix Selbständigkeitserklärung ... xliii

Umfeldwahrnehmung stellt eine Grundvoraussetzung für den sicheren und komfortablen Betrieb automatisierter Fahrzeuge dar. Insbesondere bewegte Verkehrsteilnehmer in der unmittelbaren Fahrzeugumgebung haben dabei große Auswirkungen auf die Wahl einer angemessenen Fahrstrategie. Dies macht ein System zur Objektwahrnehmung notwendig, welches eine robuste und präzise Zustandsschätzung der Fremdfahrzeugbewegung und -geometrie zur Verfügung stellt. Im Kontext des automatisierten Fahrens hat sich das Box-Geometriemodell über die Zeit als Quasistandard durchgesetzt. Allerdings stellt die Box aufgrund der ständig steigenden Anforderungen an Wahrnehmungssysteme inzwischen häufig eine unerwünscht grobe Approximation der tatsächlichen Geometrie anderer Verkehrsteilnehmer dar. Dies motiviert einen Übergang zu genaueren Formrepräsentationen. In der vorliegenden Arbeit wird daher ein probabilistisches Verfahren zur gleichzeitigen Schätzung von starrer Objektform und -bewegung mittels Messdaten eines LiDAR-Sensors vorgestellt. Der Vergleich dreier Freiform-Geometriemodelle mit verschiedenen Detaillierungsgraden (Polygonzug, Dreiecksnetz und Surfel Map) gegenüber dem einfachen Boxmodell zeigt, dass die Reduktion von Modellierungsfehlern in der Objektgeometrie eine robustere und präzisere Parameterschätzung von Objektzuständen ermöglicht. Darüber hinaus können automatisierte Fahrfunktionen, wie beispielsweise ein Park- oder Ausweichassistent, von einem genaueren Wissen über die Fremdobjektform profitieren. Es existieren zwei Einflussgrößen, welche die Auswahl einer angemessenen Formrepräsentation maßgeblich beeinflussen sollten: Beobachtbarkeit (Welchen Detaillierungsgrad lässt die Sensorspezifikation theoretisch zu?) und Modell-Adäquatheit (Wie gut bildet das gegebene Modell die tatsächlichen Beobachtungen ab?). Auf Basis dieser Einflussgrößen wird in der vorliegenden Arbeit eine Strategie zur Modellauswahl vorgestellt, die zur Laufzeit adaptiv das am besten geeignete Formmodell bestimmt. Während die Mehrzahl der Algorithmen zur LiDAR-basierten Objektverfolgung ausschließlich auf Punktmessungen zurückgreift, werden in der vorliegenden Arbeit zwei weitere Arten von Messungen vorgeschlagen: Information über den vermessenen Freiraum wird verwendet, um über Bereiche zu schlussfolgern, welche nicht von Objektgeometrie belegt sein können. Des Weiteren werden LiDAR-Intensitäten einbezogen, um markante Merkmale wie Nummernschilder und Retroreflektoren zu detektieren und über die Zeit zu verfolgen. Eine ausführliche Auswertung auf über 1,5 Stunden von aufgezeichneten Fremdfahrzeugtrajektorien im urbanen Bereich und auf der Autobahn zeigen, dass eine präzise Modellierung der Objektoberfläche die Bewegungsschätzung um bis zu 30%-40% verbessern kann. Darüber hinaus wird gezeigt, dass die vorgestellten Methoden konsistente und hochpräzise Rekonstruktionen von Objektgeometrien generieren können, welche die häufig signifikante Überapproximation durch das einfache Boxmodell vermeiden.

On Monday, March 12 at 14:30 UTC, 2018, the sounding rocket REXUS 24 was launched from Esrange Space Center. After T+8:9 s, the payload separated unintentionally from the motor. The payload impacted 2km North east of the launcher. The thrusting motor continued to fly down range. All objects were contained within safe areas, causing no damage on human beings or property. The methodical approach of the conducted failure Investigation is introduced and the most probable failure cause is identified. A summary of performed studies is given and it is described how the most probable failure cause was deduced. Finally, recommendations and restrictions referring technical and procedural aspects are covered which are planned to be applied in future campaigns.

Pathological yawning is rarely observed in cerebral or spinal diseases. A 67-year-old woman was admitted with a seven-day progressive hemisyndrome with left-sided limb ataxia and hypesthesia. The patient yawned with a high frequency, partially in salve-like episodes. MRI showed a cervical myelitis over more than three vertebral segments up to the lower medulla and Aquaporin-4-antibodies were positive (diagnostic criteria for a Neuromyelitis optica spectrum disorder were fulfilled). Under treatment with methylprednisolone, followed by plasmapheresis and immunoadsorption, clinical symptoms were regressive and the frequency of yawning completely normalized. When observing pathological yawning, even in the absence of other cerebral or brainstem symptoms, one should be aware of NMOSD as a possible cause.