The metabolization of drugs as a factor in the development of adverse drug reactions

When medicines cause side effects, we often assume that the original active substance is responsible for this. However, after ingestion, the active substance is processed (metabolized) by enzymes or attached to polar compounds in order to accelerate its excretion from the body. The original active substance undergoes chemical changes and drug metabolites are formed. These drug metabolites have their own characteristics and can also cause side effects. Recognizing, predicting and preventing these side effects requires knowledge of the metabolism of the parent drug, the formation of metabolites and their effects in the body.In this thesis we investigated the knowledge about the role of drug metabolization and metabolites on side effects. Various data sources have been explored and used for this purpose. Phenoconversion has also been investigated as a method to intervene in drug metabolization and prevent the formation of unwanted metabolites.It appears that the role of drug metabolism and the formation of drug metabolites in side effects is well recognized, but the available information is not yet fully exploited. For example, knowledge about certain chemical structures in medicines can be included more often in the recognition and prediction of known and unknown side effects.Once the role of drug metabolism and the formation of the drug metabolites in the development of the side effect is recognized, action can be taken to prevent side effects. Phenoconversion appears to be a suitable method to prevent the formation of unwanted metabolites and could be investigated and possibly be applied more often

G-quadruplexes at play:DNA changes, chromatin deposition, and gene transcription

In addition to the classical double helix structure, DNA can also take on other forms. An example is the G-quadruplex (G4). A G4 looks a bit like a mini-apartment building and can form from a single guanine-rich DNA strand. Despite posing an obstacle during the replication of DNA molecules, sequences with the potential to form G4s are present in many key regions of our genomes, suggesting G4s may be of functional importance. Hence, our research has focused on the genome-wide relationship between G4s and various processes in the cell. We evaluated the potential role of G4s in gene expression regulation in cells of patients with Bloom Syndrome, a rare disease caused by absence of the BLM enzyme. BLM can resolve G4s, but our results indicate that BLM's interaction with the ribosomal DNA locus may be of much greater importance to healthy cells. Furthermore, we investigated how G4s affect the distribution of the “packaging” proteins that help to organize the DNA strands. Using our newly developed technique called double-click-seq, we show that the deposition of the packaging proteins onto replicated DNA is a non-random process that clearly deviates at G4 sites. Lastly, we have explored how the sequences of human G4s mutate over time.Together, our findings contribute to a better understanding of the cellular effects of genome-wide G4 stabilization. In doing so, we hope to advance the development of future medical treatments as new studies focus on using G4s as a therapeutic target in cancer treatment strategies

A Multi-Agent Mah Jong Playing System: Towards Real-Time Recognition of Graphic Units in Graphic Representations

In architectural design, sketching is an important means to explore the first conceptual developments in the design process. It is necessary to understand the conventions of depiction and encoding in sketches and drawings if we want to support the architect in the sketching activity. The theory of graphic units provides a comprehensive list of conventions of depiction and encoding that are widely used among architects. These graphic units form useful building blocks to understand design drawings. We investigate whether it is possible to build a system that can recognize graphic units. The technology we are looking at is multi-agent systems. It was chosen for the following reasons: agents can specialize in graphic units, a multi-agent system can deal with ambiguity through negotiation and conflict resolution, and multi-agent systems function in dynamically changing environments. Currently there is no general approach or technology available for multi-agent systems. Therefore, in our research we first set out to make such a multi-agent system. In order to keep the complexity low, we first aim to make a system that can do something simple: playing Mah Jong solitary. The Mah Jong solitary system shares the following important features with a multi-agent system that can recognize graphic units: (1) specialized agents for moves; (2) negotiation between agents to establish the best move; (3) a dynamically changing environment; and (4) search activity for more advanced strategies. The paper presents the theoretical basis of graphic units and multi-agents systems, followed by a description of the multi-agent framework and its implementation. A number of systems that can play Mah Jong at various degrees of competence and accordingly degrees of complexity of multi-agent system, are distinguished. Finally, the paper demonstrates how the findings are informative for a system that can recognize graphic units

A multi-agent Mah Jong playing system : towards real-time recognition of graphic units in graphic representations

In architectural design, sketching is an important means to explore the first conceptual developments in the design process. It is necessary to understand the conventions of depiction and encoding in sketches and drawings if we want to support the architect in the sketching activity. The theory of graphic units provides a comprehensive list of conventions of depiction and encoding that are widely used among architects. These graphic units form useful building blocks to understand design drawings. We investigate whether it is possible to build a system that can recognize graphic units. The technology we are looking at is multi-agent systems. It was chosen for the following reasons: agents can specialize in graphic units, a multi-agent system can deal with ambiguity through negotiation and conflict resolution, and multi-agent systems function in dynamically changing environments. Currently there is no general approach or technology available for multi-agent systems. Therefore, in our research we first set out to make such a multi-agent system. In order to keep the complexity low, we first aim to make a system that can do something simple: playing Mahjong solitary. The Mahjong solitary system shares the following important features with a multi-agent system that can recognize graphic units: (1) specialized agents for moves; (2) negotiation between agents to establish the best move; (3) a dynamically changing environment; and (4) search activity for more advanced strategies. The paper presents the theoretical basis of graphic units and multi-agents systems, followed by a description of the multi-agent framework and its implementation. A number of systems that can play Mah Jong at various degrees of competence and accordingly degrees of complexity of multi-agent system, are distinguished. Finally, the paper demonstrates how the findings are informative for a system that can recognize graphic units