http://hdl.handle.net/10900/42133 Tue, 14 Jul 2026 02:24:45 GMT 2026-07-14T02:24:45Z http://hdl.handle.net/10900/181459 Structure Elucidation and Biophysical Characterization of Hits from Designed Fragment Libraries Binding to Therapeutically Relevant Drug Targets Stahlecker, Wilhelm Jason Fragment-based drug discovery is an efficient approach to probe the chemical space of protein binding sites. Screening experiments can yield fragment hits that can be further investigated. By designing focused libraries one can try to shift binding modes towards underrepresented or unconventional binding interactions. One such underrepresented interaction is the σ-hole interaction of e.g., halogens or chalcogens. Halogen-containing molecules that play biologically or pharmaceutically relevant roles often have the halogen bound to either an aryl or alkyl group. Contrary to common perception, halogens (Cl, Br, and I) do not exhibit an isotropically distributed electron density, but rather an anisotropically distributed one. Along the C–X-axis a positive electrostatic potential is observed, while a negative electrostatic potential wraps around the bond. This phenomenon allows for halogens to closely interact with electronegative groups such as carbonyl oxygen atoms and many more. Previously, the group of Prof. Frank Böckler has designed such a halogen-focused library, called the halogen enriched fragment library (HEFLib). One important lesson that was learned from characterizing this fragment library was that the size of the σ-hole, given as the Vmax-value, correlates with hit rates. In addition, the knowledge about the exact atomic coordinates is fundamental to knowing the exact binding location on the protein, if a σ-hole interaction is present, if and how the hit can be optimized, or if a structural change in the protein occurred. X-ray crystallography is used to elucidate the binding mode of a ligand–protein complex by obtaining atomic coordinates. Herein, I present the design of a Vmax-value optimized halogen enriched fragment library (Vmax-Lib). Based on hits obtained from this and complementary designed libraries (HEFLib, Cov-Lib, and the Chalco-Lib) on multiple targets, I solved a total of 31 crystal structures with these ligands bound to the respective targets. These include ten structures of mutant p53, two of DYRK1a, 17 of JNK3 or JNK3-M115L, one of USP7 and one of cereblon. Further, I investigated reasons for selectivity between JNK2 and JNK3 and focused on the question if a methionine–methionine contact could be a major contributor. Additionally, some crystal structures have shown unexpected features that will be presented, such as a possible unreported NOS bond in JNK3 or a possible unique rescue mechanism for mutant p53-R282W. Finally, I explored if an expression and purification protocol for S6K2 in E. coli can be established. While expression of S6K2 was possible issues with solubility and aggregation did not allow for a successful purification, suggesting that other expression systems may be necessary. Future work in obtaining more ligand–protein complexes is important for rational drug design, and can identify binding modes suitable for fragment growing, merging or linking. More structures of ligands binding to both JNK3 and JNK3-M115L is necessary to better understand the effect of the Met–Met contact. All in all, the obtained structures enabled us to rationally pursue structure-activity relationship trials, confirmed halogen bonding and revealed unexpected features that paved the way for further investigation.; Die Dissertation ist gesperrt bis zum 09. Juni 2028 ! Fri, 09 Jun 2028 00:00:00 GMT http://hdl.handle.net/10900/181459 2028-06-09T00:00:00Z http://hdl.handle.net/10900/181446 The relationship between birds and the human psychological experience of nature Vanhöfen, Janina Ongoing urbanization and climate change threaten not only biodiversity but also human health, since being in nature is beneficial to human well-being - physically and mentally. However, the underlying mechanisms linking nature experiences and mental well-being are difficult to pinpoint. Many factors are theorized to play a role, which is why investigating the potential contribution of bird diversity to the mental well-being benefits of being in nature, is one of the key questions this dissertation aims to understand. In the first part of this dissertation, human mental well-being was surveyed and connected to local bird diversity, habitat heterogeneity, and landscape features. Results showed that participants’ perception of bird diversity in the study areas was relatively accurate. Positive determinants of mental well-being included perceived naturalness and perceived bird diversity, whereas a highly visible human impact and infrastructure were associated with lower mental well-being, place attachment, and perception. The perceived naturalness of study areas was positively related to present bird diversity and negatively to the human impact. Individual traits, such as positive perception of birds, a high birding specialization, and bird species knowledge were connected to a positive nature experience. For the second half of the dissertation, two experimental studies were designed. In a controlled, park-like environment, participants undertook an unguided 30-minute walk-through, with mental well-being and physiological stress parameters measured in a pre-post-test design. The treatment groups were designed to enhance the exposure to and/or awareness of birdsong. All groups experienced improved well-being and reduced physiological stress parameters. Increased awareness of participants' surroundings led to improved mental well-being, while additional birdsong did not. The group that was prompted visually to stop regularly on their walk and listen attentively reported the highest benefits, indicating a higher perceived restorativeness of ambient sound and birdsong compared to the group receiving a verbal cue instead. Furthermore, greater bird species knowledge and a positive nature experience led to better mental well-being, as did a positive perception of birds and higher estimated bird diversity. Finally, bird species characteristics of brightness, visual attractivity, beauty of song, and cuteness were calculated into one value and connected to the mental well-being of recreationists. Species with a high amount of these characteristics lead to a positive effect of satisfaction and place attachment, while birds exhibiting a lower value may even have negative effects. This result could help in understanding why studies on mental well-being and bird diversity often report mixed results. The characteristics of the bird species present in the study areas could have a bigger effect than previously believed. Going forward, this information can help planners improve urban green spaces, not only by creating habitats for birds but also by considering how those same birds may in turn influence the mental well-being of humans. While careful interpretation and further large-scale studies are needed, the present results offer a promising starting point, showing that bird species traits are indeed related to human experience in recreational areas. Building on these findings, practical implications emerge for designing recreational urban areas: enhancing perceived naturalness and positive nature experiences while reducing visible human impact together can promote human mental well-being. The results also highlight the potential of practical interventions like signage to enhance the nature awareness and mental well-being of recreationists, possibly even leading to more positive attitudes towards nature conservation.; Die fortschreitende Urbanisierung und der Klimawandel bedrohen nicht nur die Artenvielfalt, sondern auch die menschliche Gesundheit, da sich ein Aufenthalt in der Natur positiv auf das körperliche und geistige Wohlbefinden auswirkt. Die zugrunde liegenden Mechanismen, die Naturerlebnisse und geistiges Wohlbefinden miteinander verbinden, sind allerdings schwer festzustellen. Es gibt viele Faktoren, von denen angenommen wird, dass sie eine Rolle spielen, was die Forschung in eine interessante Richtung führt: die Untersuchung des potenziellen Beitrags der Vogelvielfalt zum psychischen Wohlbefinden durch den Aufenthalt in der Natur. Dies ist eine der Hauptfragen dieser Arbeit. Im ersten Teil dieser Dissertation wurde das psychische Wohlbefinden von Menschen an unterschiedlichen Orten untersucht und mit der lokalen Vogelvielfalt, der Heterogenität der Lebensräume und den vorhandenen Landschaftsmerkmalen in Verbindung gebracht. Die Ergebnisse zeigten, dass die Teilnehmenden die Vogelvielfalt in den Untersuchungsgebieten relativ genau einschätzen konnten. Determinanten des psychischen Wohlbefindens waren die wahrgenommene Natürlichkeit und Vogelvielfalt, während ein starker menschlicher Einfluss und viel Infrastruktur mit einem geringeren psychischen Wohlbefinden und einer geringeren Ortsverbundenheit verbunden waren. Die subjektiv empfundene Natürlichkeit der Gebiete stand in einem positiven Zusammenhang mit der vorhandenen Vogelvielfalt und in einem negativen Zusammenhang mit dem Einfluss des Menschen. Individuelle Merkmale wie eine positive Einstellung zu Vögeln, eine hohe Spezialisierung auf die Vogelbeobachtung und viel vorhandenes Wissen über Vogelarten standen ebenfalls in Zusammenhang mit einer positiven Naturerfahrung. Für die zweite Hälfte der Dissertation wurden zwei experimentelle Studien konzipiert: In einer kontrollierten, parkähnlichen Umgebung unternahmen die Teilnehmenden allein einen 30-minütigen Spaziergang, wobei psychisches Wohlbefinden und physiologische Stressparameter in einem Vorher-Nachher-Test gemessen wurden. Die Behandlungsgruppen wurden so eingeteilt, dass das Vorhandensein von Vogelgesang und/oder das Bewusstsein für Vogelgesang verstärkt wurde. Alle Gruppen verzeichneten ein verbessertes Wohlbefinden und eine reduzierte physiologische Stressantwort. Ein gesteigertes Bewusstsein für die Umgebung der Teilnehmenden führte zu einem verbesserten psychischen Wohlbefinden, während zusätzlicher Vogelgesang dies nicht bewirkte. Die Gruppe, die visuell dazu aufgefordert wurde, regelmäßig anzuhalten und zu lauschen, schätzte den positiven Effekt am stärksten ein. Dies weist auf eine höhere wahrgenommene Erholungswirkung von Umgebungsgeräuschen und Vogelgesang hin. Darüber hinaus führten höheres ornithologisches Wissen und eine positive Naturerfahrung zu einem besseren psychischen Wohlbefinden, ebenso wie eine positive Wahrnehmung von Vögeln und eine höhere geschätzte Vogelvielfalt. Zuletzt wurden die Merkmale der Vogelarten hinsichtlich Farbpracht, visueller Attraktivität, Schönheit des Gesangs und Niedlichkeit zu einem Wert zusammengefasst und mit dem psychischen Wohlbefinden der Teilnehmenden der ersten Studie in Verbindung gebracht. Vogelarten mit vielen dieser Merkmale führten zu einem positiven Effekt auf die Zufriedenheit und die Bindung an den Ort, während Vögel mit einem niedrigeren Wert dementsprechend sogar negative Auswirkungen haben könnten. Dieses Ergebnis könnte zur Klärung der Frage beitragen, warum Studien zum psychischen Wohlbefinden und zur Vogelvielfalt oft zu unterschiedlichen Ergebnissen kommen. Die Eigenschaften der in den Untersuchungsgebieten vorkommenden Vogelarten könnten einen größeren Einfluss haben als bisher angenommen. Dies könnte planenden Personen helfen, städtische Grünflächen zu verbessern und nicht nur Lebensräume für Vögel zu schaffen, sondern auch zu verstehen, wie sich Vögel möglicherweise auf das psychische Wohlbefinden des Menschen auswirken. Die vorliegenden Ergebnisse müssen jedoch in weiteren Studien auf eine größere Skala übertragen und zusätzlich im kulturellen Kontext sorgfältig interpretiert werden. Dennoch sind die Ergebnisse ein vielversprechender Anfang, der zeigt, dass die Artenmerkmale von Vögeln tatsächlich mit der menschlichen Erfahrung in Erholungsgebieten zusammenhängen. Die Erkenntnisse der vorliegenden Dissertation haben praktische Auswirkungen auf die Gestaltung städtischer Erholungsgebiete, da eine Steigerung der wahrgenommenen Natürlichkeit und positiver Naturerlebnisse bei gleichzeitiger Verringerung sichtbarer menschlicher Einflüsse das psychische Wohlbefinden der Menschen in diesen Gebieten fördern kann. Die Ergebnisse unterstreichen auch das Potenzial praktischer Maßnahmen wie Beschilderungen, um das Naturbewusstsein und das psychische Wohlbefinden von Erholungssuchenden zu verbessern, was möglicherweise zu einer positiveren Einstellung gegenüber dem Naturschutz führen kann. Mon, 13 Jul 2026 00:00:00 GMT http://hdl.handle.net/10900/181446 2026-07-13T00:00:00Z http://hdl.handle.net/10900/181439 Machine Learning Solutions for Small Data Prediction Problems in Virology Arslan-Jirasek, Nurhan Machine learning methods are increasingly used across a wide range of scientific disciplines, including health-related and biomedical research, where data are often high dimensional, heterogeneous, and limited in sample size. In health-related virology, clinical datasets often combine patient-level information with high-dimensional viral sequence data, while the number of available samples is constrained by ethical and privacy considerations, clinical practice, and the cost of data collection. These characteristics lead to machine learning problems in high-dimensional, low-sample-size settings, in which model selection, data handling, and evaluation require particular care to avoid overfitting and misleading conclusions. This thesis examines the application of machine learning methods to three classification problems in health-related virology under such data constraints, with a focus on Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). All three problems are characterized by low-sample-size settings, and the first two additionally involve high-dimensional data. The first part of the thesis focuses on developing machine learning models to distinguish the HCV 2k/1b recombinant variant from subtype 1b using sequence data from three non-structural proteins. This distinction is challenging for standard genotyping assays because the recombination breakpoint lies outside of the commonly analyzed genomic regions. The resulting models are integrated into the open access geno2phenoHCV web tool, enabling genotype prediction based on sequence data that is routinely measured for drug resistance determination instead of more expensive whole-genome sequencing data, and supporting molecular epidemiological analyses. The second part of the thesis addresses the early prediction of multidrug class resistance in HIV using viral sequence data. The prediction problem is formulated under multiple settings that differ with respect to both the level of pre-existing drug class resistance and the time interval between sample collection and the onset of multidrug class resistance. To evaluate model behavior across these settings, feature importance analysis is used to identify amino acid positions and mutations that contribute most strongly to the predictions, including both previously reported and newly identified ones. The third part of the thesis examines HLA footprint analysis by applying binomial generalized linear mixed models to next-generation viral sequencing data from HIV-infected patients. Several model formulations are considered, differing in their inclusion of demographic vari- ables, individual-level HLA allele indicators, and HLA escape mutation pair information, while the group structure capturing phylogenetic relatedness is kept fixed across models. In the absence of a ground-truth set, model behavior is evaluated using a subsampling strategy that assesses the effects of limited sample size, incomplete HLA representation, and variable read depth.; Die Dissertation ist gesperrt bis zum 29. April 2028 ! Sat, 29 Apr 2028 00:00:00 GMT http://hdl.handle.net/10900/181439 2028-04-29T00:00:00Z http://hdl.handle.net/10900/181412 Long-Term Human–Environment Interactions and Ecological Variability on the Lebanese Coast Russo, Gabriele The Levantine corridor represents a key biogeographic interface linking Africa, Europe, and Asia, yet paleoecological and behavioral models of the region have been disproportionately shaped by evidence from the southern Levant. This geographical bias has limited our understanding of environmental variability and human adaptation across the broader eastern Mediterranean. This dissertation addresses this gap by investigating long-term human–environment interactions in the central Levant through the analysis of legacy faunal assemblages from coastal Lebanon. Focusing on material from the Paleolithic sites of Naame, Nahr Ibrahim, Ras el-Kelb, and the Late Epipaleolithic site of Antelias Cave, the study integrates zooarchaeological and taphonomic analyses, dental wear proxies (mesowear and microwear), enamel stable carbon and oxygen isotope data, and GIS-based spatial modelling. This multiproxy approach enables the reconstruction of herbivore community structure, vegetation patterns, and hominin subsistence strategies across multiple phases of the Pleistocene. The results demonstrate the long-term persistence of Mediterranean woodland and ecotonal environments along the Lebanese coastal corridor over nearly 400,000 years. Faunal, dental wear, and isotopic evidence consistently indicate herbivore communities structured around C3-dominated vegetation and stable habitat mosaics, despite glacial–interglacial climatic fluctuations. Across this period, hominin populations repeatedly exploited these environments, focusing primarily on large-bodied, high-ranked prey while maintaining flexible subsistence strategies adapted to heterogeneous landscapes. Analysis of the Late Epipaleolithic assemblage from Antelias Cave further reveals locally structured patterns of resource use within a compact and topographically diverse landscape, highlighting continuity in flexible, mosaic-based subsistence strategies into the terminal Pleistocene.; Die Dissertation ist gesperrt bis zum 19. Mai 2028 Fri, 19 May 2028 00:00:00 GMT http://hdl.handle.net/10900/181412 2028-05-19T00:00:00Z