Die immer schneller steigenden Energiepreise haben in der jüngsten Vergangenheit eine breite Diskussion über Energieeffizienz und alternative Erzeugungsverfahren ausgelöst. Von besonderer Bedeutung ist dies für den Gebäudesektor und die darin installierte Anlagentechnik, da in Deutschland ca. 30 % des Energieverbrauches hier anfallen. Eine Minderung dieses Verbrauches kann nur durch eine Vielzahl von Maßnahmen erreicht werden, die schon bei der Planung berücksichtigt werden müssen. Vor diesem Hintergrund wird in diesem Artikel die Anordnung von freien Heizflächen im Raum untersucht sowie energetische und wärmephysiologische Ergebnisse aufgezeigt. Die beschriebenen Analysen wurden für eine repräsentative Raumgeometrie vorgenommen, wodurch es möglich ist, die Aussagen auf eine Vielzahl von Räumen zu übertragen. / The steady rise in energy prices has recently triggered a broad discussion on energy efficiency and alternative methods of generation. Since approximately 30 % of the total energy consumption is attributable to HVAC installations (Heating, Ventilation and Air Conditioning), this sector is acutely relevant for the building industry and for building services. Reduction of the building energy consumption can be achieved only by applying a wide range of measures across the whole process from planning to the realisation stage. Considering the aforementioned, the influence on thermal comfort and energy consumption of different radiator positions within a room is described in the following paper. The analysis was carried out for a representative room geometry, which allows the results to be applied to a broad spectrum of real room configurations.

Vor dem Hintergrund des heutigen Verständnisses der biologischen Psychologie zur Entstehung von Farbempfindung als selbstregulierende Energiewandlung und -wirkung wird der Beitrag gewürdigt, den Wilhelm Ostwald vor über 100 Jahren mit seiner ‚biologischen Energetik’ einbrachte. Energetische Intentionen und Interpretationen bestimmten auch dessen ,Psychologische Farbenlehre’ als das erklärte Kernstück einer modernen Farbenlehre. Obwohl im Sinne einer kritischen Rezeption auch Grenzen jener Farbenlehre aufgezeigt werden, offenbart sich aber Ostwalds energetische Konzeption durchaus als visionäre Vorleistung, die sich in vielen Aspekten mit heutigen einschlägigen Wissensbeständen deckt. Aus der Perspektive enger Beziehungen zwischen Wissenschaft und Kunst wird zudem auf befruchtende Wechselwirkungen, insbesondere die Ausstrahlung der Ostwald’schen ‚Energetik’ auf die visuellen Künste im 20. Jahrhundert hingewiesen. / With today's understanding of colour perception as a self-regulating process of energy transformation and effects, biological psychology honours the contribution made by Wilhelm Ostwald over 100 years ago with his concept of ’biological energetics’. Energy considerations and interpretations determined also his ’psychological theory of colour’, the declared core of modern colour science. Even if critical reception has revealed also the limitations of this colour theory, Ostwald's energetic concept can certainly be seen as a pioneering vision, retaining its validity in many aspects in today's scientific knowledge base. In the context of close relationships between science and art, furthermore, attention must be drawn to fertile interactions, in particular in the influences of Ostwald’s ’energetics’ on the visual arts in the 20th century.

Jahresinhaltsverzeichnis

Given the large variety of existing logical formalisms it is of utmost importance to select the most adequate one for a specific purpose, e.g. for representing the knowledge relevant for a particular application or for using the formalism as a modeling tool for problem solving. Awareness of the nature of a logical formalism, in other words, of its fundamental intrinsic properties, is indispensable and provides the basis of an informed choice. One such intrinsic property of logic-based knowledge representation languages is the context-dependency of pieces of knowledge. In classical propositional logic, for example, there is no such context-dependence: whenever two sets of formulas are equivalent in the sense of having the same models (ordinary equivalence), then they are mutually replaceable in arbitrary contexts (strong equivalence). However, a large number of commonly used formalisms are not like classical logic which leads to a series of interesting developments. It turned out that sometimes, to characterize strong equivalence in formalism L, we can use ordinary equivalence in formalism L0: for example, strong equivalence in normal logic programs under stable models can be characterized by the standard semantics of the logic of here-and-there. Such results about the existence of characterizing logics has rightly been recognized as important for the study of concrete knowledge representation formalisms and raise a fundamental question: Does every formalism have one? In this thesis, we answer this question with a qualified “yes”. More precisely, we show that the important case of considering only finite knowledge bases guarantees the existence of a canonical characterizing formalism. Furthermore, we argue that those characterizing formalisms can be seen as classical, monotonic logics which are uniquely determined (up to isomorphism) regarding their model theory. The other main part of this thesis is devoted to argumentation semantics which play the flagship role in Dung’s abstract argumentation theory. Almost all of them are motivated by an easily understandable intuition of what should be acceptable in the light of conflicts. However, although these intuitions equip us with short and comprehensible formal definitions it turned out that their intrinsic properties such as existence and uniqueness, expressibility, replaceability and verifiability are not that easily accessible. We review the mentioned properties for almost all semantics available in the literature. In doing so we include two main axes: namely first, the distinction between extension-based and labelling-based versions and secondly, the distinction of different kind of argumentation frameworks such as finite or unrestricted ones.

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

DNA methylation is a crucial, abundant mechanism of gene regulation in vertebrates. It is less prevalent in many other metazoan organisms and completely absent in some key model species, such as D. melanogaster and C. elegans. In this thesis we report on a comprehensive study of the pres- ence and absence of DNA methyltransferases (DNMTs) in 138 Ecdysozoa covering Arthropoda, Nematoda, Priapulida, Onychophora, and Tardigrada. We observe that loss of individual DNMTs independently occured multiple times across ecdysozoan phyla. In several cases, this resulted in a loss of DNA methylation. In vertebrates, however, there is no single species known which lost DNA methylation. Actually, DNA methylation was greatly expanded after the 1R/2R whole genome duplication (WGD) and became a genome-wide phe- nomena. In our study of vertebrates we are not looking for losses of DNA methyltransferases and DNA methylation but are rather interested in the gain of additional DNA methyltransferase genes. In vertebrates there were a number of WGD. Most vertebrates only underwent two WGD but in the teleost lineage a third round of WGD occured and in some groups, e.g. Salmoniformes and some Cypriniformes even a forth WGD occured. The Carp-specific WGD (4R) is one of the most recent vertebrate WGD and is estimated to have occured 12.4 mya. We performed the most comprehen- sive analysis of the evolution of DNA methyltransferases after vertebrate whole-genome duplications (WGD) so far. We were able to show that the conservation of duplicated DNMT3 genes in Salmoniformes is more diverse than previously believed. We were also able to identify DNA methyltrans- ferases in Cypriniformes which have, due to their recent WGD, quite com- plex genomes. Our results show that the patterns of retained and lost DNA methyltransferases after a forth round of WGD differ between Cypriniformes and Salmoniformes. We also proposed a new nomenclature for teleost DNMT genes which correctly represents the orthology of DNMT genes for all teleost species. Next to these purely computational projects we collaborated with the Aluru lab to investigate the effects of different disturbances on zebrafish DNA methylation. One disturbance is the inactivation of DNMT3aa and DNMT3ab as single knockouts as well as a double knockout. This was the first double knockout of DNMT genes in zebrafish which was ever generated. It allows us to study the subfunctionalization of the two DNMT3a genes their effect on genome-wide DNA methylation. Given our results we hypothesize that DNMT3aa and DNMT3ab can compensate for each other to a high de- gree. DNMT3a genes have likely been subfuntionalized but their loss can be compensated by DNMT3b genes. This compensation by DNMT3b genes works well enough that no notable phenotype can be observed in double knockout zebrafish but a difference is notable on the epigenome level. The second disturbance we studied is the exposure of zebrafish to the toxic chemi- cal PCB126. We detected a moderate level of DNA methylation changes and a much larger effect on gene expression. Similar to previous reports we find little correlation between DNA methylation and gene expression changes. Therefore, while PCB126 exposure has a negative effect on DNA methyla- tion it is likely that other gene regulatory mechanisms play a role as well, possibly even a greater one. How do genes evolve and how are genes regulated are two of the main questions of modern molecular biology. In this thesis we have tried to shed more light on both questions. we have broadly expanded the phylogenetic range of species with a manually curated set of DNA methyltransferases. We have done this for ecdysozoan species which have lost all DNA methylating enzymes as well as for teleost fish which acquired more than ten copies of the, originally, two genes. We were also able to generate new insight into the subfunctionalization of the DNA methylation machinery in zebrafish and how it reacts to environmental effects.:1 Introduction 1.1 Biological introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.2 Detecting DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . 7 2 Evolution of DNA methylation across Ecdysozoa 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 3 Evolution of DNA methyltransferases after vertebrate whole genome duplications 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 3.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 3.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 4 The effect of DNMT3aa and DNMT3ab knockout on DNA methyla- tion in zebrafish 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 4.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 5 Role of DNA methylation in altered testis gene expression patterns in adult zebrafish exposed to Pentachlorobiphenyl 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 5.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 5.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 5.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 6 Conclusions 6.1 Evolution of DNA methylation across Ecdysozoa . . . . . . . . . . . . . 95 6.2 Evolution of DNA methyltransferases after vertebrate whole genome duplications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 6.3 Role of DNA methylation in altered testis gene expression patterns in adult zebrafish (Danio rerio) exposed to Pentachlorobiphenyl (PCB 126). . . 107 6.4 Knockout of DNMT3aa and DNMT3ab in zebrafish (Danio rerio) . . . . . . 108 Bibliography 119

Bericht über die UB Leipzig in der Pandemie, Aktivitäten im digitalen Raum, Personal, Drittmittelgestützte Projekte, Veröffentlichungen der UB Leipzig, die UB Leipzig in der Öffentlichkeit mit einen Ausblickund der UB Leipzig in Zahlen im Jahr 2020.:1. Die UB Leipzig in der Pandemie 2. Aktivitäten im digitalen Raum 3. Personal 4. Drittmittelgestützte Projekte 5. Veröffentlichungen der UB Leipzig 6. Die UB Leipzig in der Öffentlichkeit 7. Ausblick 8. Die UB Leipzig in Zahlen

Ziel des Seminars ist es, ein besseres Verständnis für diese Vielfalt von Systembegriffen zu gewinnen und dabei die Zugänge verschiedener Systemtheorien als Gegenstand einer Systemwissenschaft zu analysieren.

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