Dissertationen/Habilitationen
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Item type: Item , Deciphering Self-Assembly Mechanisms and Chemical Reactions of Organic Building Blocks on Metal Surfaces by Chemical Bond Imaging(2025-09-24) Wiche, MiguelIn recent years, the novel field of on-surface synthesis has been established as one of the main tools for constructing customized, low-dimensional organic nanostructures via bottom-up approaches on atomically flat metal substrates. The self-assembly of the molecular precursors, a process that often serves as pre-step of the on-surface reaction, determines the precise local arrangement of atoms and bonds in neighboring molecules, thus playing a decisive role in product formation. Thereby, intermolecular interactions between hydrogen and fluorine atoms have proven to be a valuable tool to steer molecular alignments. In this work, the mainly unexplored intermolecular hydrogen-fluorine interaction is systematically investigated on inert Au(111) and reactive Cu(111) substrates, using a linear, unilaterally fluorinated 1,2,10,11,12,14-hexafluoropentacene molecule as a model system. In the combined scanning tunneling microscopy and chemical bond imaging study, the local arrangement of hydrogen and fluorine atoms in neighboring molecules is determined in the picometer range and angular variations of a few degrees. While on Au(111) the intermolecular interactions between the molecules are the main contributor to the self-assembly, the higher reactivity of Cu(111) results in different adsorption geometries and molecular arrangements. The highly precise self-assembly study provides new insights into the on-surface interaction of hydrogen and fluorine atoms, thereby highlighting its significance for the field of on-surface synthesis. An on-surface reaction that solely takes place using halogenated precursors is the on-surface Ullmann coupling reaction, which enables the formation of covalent carbon-carbon bonds with the underlying metal surface as a catalyst. However, when applying Ullmann coupling reaction steps, complex self-assembly mechanisms can occur when halogenated precursors interact with the metal surface. Further, cleaved halogens adsorbed on the surface may potentially inhibit the reaction steps. Hence, there is a growing demand for halogen-free precursors for on-surface reactions. Recently, it has been demonstrated that halogen-free (6)Cycloparaphenylene ((6)CPP) molecules are suited to thermally induce a ring-opening polymerization reaction for the synthesis of graphene and biphenylene nanoribbons of confined widths. However, the mechanism of the ring-opening polymerization and the use of cycloparaphenylenes as precursors have not been investigated sufficiently. To contribute to the fundamental understanding of this remarkable reaction, in this thesis we systematically investigate the influence of the ring strain, which decreases with increasing ring size, using a set of cycloparaphenylenes of different sizes ((6)CPP vs. (8)CPP vs. (10)CPP). Our results demonstrate that the ring-opening polymerization is facilitated when using smaller, highly strained cycloparaphenylenes. For larger molecules with lower strain energies, the initial ring-opening is hampered, leading to only partial polymerization for (8)CPP and no polymerization in case of (10)CPP. Additionally, dehydrogenation of individual phenyl rings in intact molecules is observed for (8)CPP and (10)CPP, which further impedes the polymerization reaction.Item type: Item , The Effects of DNA Repair Pathway Engineering on CRISPR-Mediated Genome Editing in Neuronal Cells(2025) Alabudeeb, FatimahInherited retinal dystrophies are a group of genetically and clinically heterogeneous disorders that vary in their clinical presentation and progression, possibly leading to blindness. So far, about 332 genes, most expressed in photoreceptors, have been identified to be associated with these diseases. The relatively new genome editing field, particularly CRISPR-Cas9 mediated genome editing technology, which introduces DNA double-strand breaks (DSBs) that are subsequently repaired by the cells' repair systems, has recently drawn much attention. The major repair pathways are non-homologous end-joining (NHEJ) and homology-directed repair (HDR). One of the main obstacles to its application in the retina is the limited knowledge of DNA repair in photoreceptors. This work aims to analyze the DNA repair mechanisms, improve CRISPR Cas9 genome editing efficacy by modulating and engineering the DNA repair pathways in mature neurons using the human inducible Neurogenin iPS (iNGN) cell line, and validate it as an in vitro model system. These cells are human-induced pluripotent stem cells that differentiate into mature neurons within 4 days. In addition, the iNGN TET3KO cell line was also investigated to determine the impact of the TET3 protein at various differentiation stages. To achieve this, the iNGN cell lines and a control cell line, HEK293T cells, were transfected with BRET reporter assay plasmid using Cas9 and the inducible Cas systems (iCas). Promoter optimizations were done by replacing the CMV promoter, which can be silenced and suppressed in certain cell types, with a sustained EF1α promoter. Applying the Cas9 system, iNGN WT and iNGN TET3KO cells were tested throughout the differentiation process. Moreover, the modifications of PARP1 protein levels using PARP1 overexpression or knockout plasmids were necessary to study its influence on the DNA repair pathways of different cell lines. The BRET reporter assay was the primary quantitative technique used. The results showed decreased frameshift rates for the undifferentiated iNGN using the iCas system compared to the Cas9 system, and along with failure to use its timing control advantage, the Cas9 system was mainly used for the remaining experiments. The undifferentiated iNGN TET3KO cells' frameshift rates, as well as at the beginning of differentiation, were significantly higher than iNGN WT ones. Furthermore, the frameshift rate results of the TET3KO overexpressed cells resembled those of iNGN WT cells. After PARP1 modulation, the frameshift rates of PARP1 downregulation were greater throughout the differentiation process of the iNGNs, regardless of the HDR template addition. Interestingly, the results of the iNGN TET3KO cells were higher than those of the WT cells. For future assessment, the generation and application of iNGNs TLR3 cell lines is essential to verify the results obtained using the BRET reporter assay at the genomic level.Item type: Item , Charakterisierung des Down-Syndrom-Zelladhäsionsmoleküls Dscam in der angeborenen Immunantwort von Manduca sexta (L.)(2025) Speckmann, MartinDie Spezifität angeborener Immunmechanismen wird entscheidend von genetischer Diversifizierung und selektiver Anpassung in der Evolution von Wirt-Mikroben-Interaktionen beeinflusst. Angeborene Immunantworten von Insekten werden demnach allgemein als effizient, jedoch bedingt durch Keimbahn-kodierte Mustererkennungsrezeptoren (PRR) als eingeschränkt spezifisch beschrieben. In Zusammenhang mit exklusiver molekularer Diversität des Down-Syndrom-Zelladhäsionsmoleküls (Dscam) bei Vertretern der Pancrustacea verdichten sich Belege, die für eine Funktion als hypervariabler, Pathogen-spezifischer PRR der Immunglobulin-Superfamilie sprechen. Obwohl experimentelle Daten erregerspezifische Dscam-Spleißformen in Hämozyten von Insekten und Krebstieren sowie deren Beteiligung an In-vitro-Phagozytose von Mikroorganismen zeigen, sind Genexpressionsmuster in Hämozyten und deren Relevanz im Rahmen angeborener Immunantworten in vivo noch größtenteils unbekannt. Anhand eines In-vivo-Modells bakterieller Stimulation und monoklonaler Antikörper für spezifische Hämozytentypen wurden die Genaktivität und das Proteinmuster von Manduca sexta Dscam (MsDscam) in zirkulierenden, larvalen Hämozyten charakterisiert. Trotz geringer quantitativer Veränderungen der relativen mRNA-Level konnte eine qualitative Veränderung des differenziellen Transkriptionsmusters von MsDscam in Zusammenhang mit Hämocoel-Injektion von fixierten E. coli K12 festgestellt werden. In Abwesenheit von Immunstimulation ist MsDscam-Transkript ausschließlich in einer seltenen Population sphärischer Hämozyten mit exzentrischen Zellkernen lokalisiert. Prophenoloxidase (proPO) enthaltende Oenozytoide mit gleichen morphologischen Eigenschaften fallen unabhängig als einzige Population in Zirkulation mit membranassoziiertem MsDscam-Muster auf. Nach E. coli-Injektion ist der prozentuale Anteil von Hämozyten mit aktiver MsDscam-Transkription hingegen signifikant um das Zehnfache erhöht (p < 0,001), darunter auch Subpopulationen von Plasmatozyten und granulären Zellen. Damit vermittelt diese Dissertation zum ersten Mal in zwei Jahrzehnten immunologischer Dscam-Forschung ein fundiertes Bild immunstatusabhängiger Genaktivität in drei distinkten Hämozytentypen. Zusätzlich ergeben sich kumulative Hinweise, die eher für funktionelle Relevanz von MsDscam im Rahmen einer zweiten Immunantwort sprechen als in der Akutphase-Immunantwort nach erstmaliger mikrobieller Stimulation. Dementsprechend liefert diese Arbeit erstmals eine Grundlage für die Analyse Dscam-basierter molekularer Diversität in proPO-produzierenden Hämozyten, was zu einem erweiterten Verständnis von Oenozytoide als immunologische Masterregulatoren in Manduca beitragen kann. Typspezifische Transkriptomanalyse von Manduca-Hämozyten in Homöostase und Immunstimulation kann somit nicht nur zur Validierung der Hypothese von funktioneller Relevanz von Dscam beim Immunpriming in Insekten, sondern auch zur Aufklärung der immer noch unbekannten Regulation zellulärer Dscam-Spleißsignaturen beitragen.Item type: Item , Microbes in bee-plant networks: Composition characterization and their ecological implications(2025) Shi, HaoranHoney bees are vital pollinators in ecosystems around the world, and microbes play key roles in connecting bees and plants. Collectively, microbes, bees and plants form intricate tripartite interactions networks. Through a co-evolution, many bee- and plant-associated microbes have developed functions that benefit their hosts, including promoting growth, enhancing pathogen resistance, and aiding digestion. Microbiome associated with different hosts tend to be specific, and within bee-microbe-plant networks, both beneficial and pathogenic microbes are dynamically transmitted among hosts. In the current study, honey bee corbicular samples were collected over a two-year period from beehives at Justus-Liebig-University Giessen. Corbicular pollen is able to reflect both microbes and plants encountered by honey bees during foraging activity. Plant and microbial communities in honey bee corbicular pollen were profiled using 16S rRNA gene and plant ITS2 metabarcoding. The results indicated that the corbicular pollen microbiome exhibited clear seasonal variations, and was affected by multiple environmental factors as well as choices of forage plants. Co-occurrence network analysis further revealed specific plant-microbe associations and identified several hub plant taxa that may serve as hotspots for microbial transmissions. Following this study, we characterized bacterial and fungal microbiome of flowers from a highly insect-visited hub plant, bramble (genus Rubus), using 16S rRNA gene and fungal ITS2 metabarcoding. The data showed that insect visitation increased microbial loads on flowers and enriched specific microbial groups including fermentative and pathogenic microbes, highlighting the role of bramble flowers as hotspots for microbial transmission. In addition, insect visitation altered floral microbiome structure, potentially through the introduction of several hub microbial taxa and by increasing the centralization of the microbial interaction networks. Honey bees were collected from beehives, and common bacterial, fungal and viral honey bee pathogens were screened. The expression levels of several immunity-related genes (defensin-1, lysozyme-like, vitellogenin, glucose oxidase) and the composition of the bee microbiome were examined to assess honey bee health status. Black queen cell virus (BQCV) was detected in almost all individuals, while Vairimorpha pathogens were only partially detected. Paenibacillus larvae, Melissococcus plutonius, Kashmir bee virus (KBV), Acute Bee Paralysis Virus (ABPV), Chronic bee paralysis virus (CBPV), Deformed Wing Virus (DWV), and Sacbrood bee virus (SBV) were not detected in the samples. The data indicated that BQCV and Vairimorpha infections had no significant impact on the expression of immunity-related gene. Since the microbiome composition was assessed at the hive level and BQCV was present in every hive, its potential influence on the microbiome remains to be further clarified. In addition, a bacterial isolate from birch pollen was phenotypically, genotypically, and chemotaxonomically characterized using a polyphasic approach. Based on 16S rRNA gene phylogeny and comparative genomic analysis, the isolate was identified as a novel species of the genus Robbsia. The bacterium was rod-shaped, non-motile, facultative anaerobic and grew optimally at 28 °C and pH 6–7. Unlike its closest relative Robbsia andropogonis, which is a known phytopathogen, the isolate exhibited no phytopathogenic traits such as flagellum formation, rhizobitoxine production, or induction of plant hypersensitive response. The proposed and accepted name of the isolate is Robbsia betulipollinis Bb-Pol-6T.Item type: Item , Multiparametrische MR-Bildgebung als nicht-invasiver Biomarker für Meniskus-Degenerationen beim Hund(2025) Bunzendahl-Först, LenaDie Osteoarthrose des Kniegelenkes ist sowohl beim Menschen, als auch beim Hund, unabhändig von der genauen Genese, ein weit verbreitetes Erkrankungsbild. Sie kann je nach Schweregrad zu deutlichen Einschränkungen in der Lebensqualität betroffener Patienten führen. Eine Heilung bzw. das Verhindern des Voranschreitens der Degenerationen ist nach aktuellem Stand nicht möglich. Behoben werden können im Bereich der Tiermedizin mehr oder weniger die auslösenden Faktoren, wie beisielsweise ein vorderer Kreuzbandriss oder eine Patellaluation beim Hund. Das Auftreten einer Osteoarthrose nach einer solchen Gelenkserkrankung zu verhindern, ist jedoch nicht möglich. Aktuelle Therapien können im besten Fall Symptome lindern und das Voranschreiten der Erkrankung verlangsamen. Die Menisken des Kniegelenkes spielen als mandarinenförmige Faserknorpelscheiben eine äußerst wichtige Rolle zur Gesunderhaltung des Gelenkes. Sie gleichen die Inkongruenz zwischen den Gelenkflächen des Femurs und der Tibia aus und minimieren Stoß- und Druckbelastungen. Aufgrund dieser anspruchsvollen mechanischen Funktion sind die Menisken häufig von Degenerationen betroffen. Meniskusschäden entstehen beispielsweise häufig im Zusammenhang mit einer Kreuzbandruptur und sie können das Entstehen bzw. das Ausmaß der Osteoarthrose stark beeinflussen. Daher kommt ihnen im Rahmen wissenschaftlicher Studien zur Pathogenese und Therapie der Arthrose eine wichtige Bedeutung zu. Zur Abklärung von Meniskusschäden ist die MRT v.a. in der Humanmedizin das Mittel der ersten Wahl. Als nicht invasive Technik ermöglicht sie eine sehr gute Darstellung der Menisken. Die konventionelle qualitative MR-Bildgebung weist jedoch Defizite auf, wenn es um die Darstellung mikrostruktureller Veränderungen der Menisken geht. Sie kann nur Pathologien detektieren, die zu morphologischen Veränderungen des Gewebes führen. Da aber gerade im Rahmen der Arthroseentstehung eine frühzeitige Erkennung die besten Aussichten auf eine erfolgreiche Therapie hat, kommen zunehmend MR-Sequenzen zum Einsatz, die (mikro-)strukturelle Veränderungen des Gewebes detektieren können. Auch für andere Anwendungsgebiete, wie z.B. die Überprüfung von verschiedenen therapeutischen Maßnahmen, kann diese Art der Bildgebung sinnvoll sein. Das Ziel dieser Studie war es, die T1-, T2-, T2*-Relaxationszeit und den Magnetisierungsransfer in Form der MTR und des MTsat als Biomarker für frühe Meniskusdegenerationen zu untersuchen. Dazu wurden in einem ex vivo Studiendesign die Menisken älterer Hunde mittels verschiedener MR-Kontraste untersucht. Im Anschluss erfolgte die histologische Untersuchung der Menisken zur Beurteilung von Zellularität, Kollagenorganisation, Kollagen-gehalt und Proteoglykangehalt. In der ersten Studie zur Untersuchung der T2-Relaxationszeit wurden 16 Gelenk von 8 mittelgroßen, älteren Hunden untersucht. Durchgeführt wurden die MRT-Untersuchung der Kniegelenke mit manueller Segmentierung der Menisken und deren anschließender histolgischer Untersuchung. Die T2-Relaxationszeit lag im Mittel bei 18,3ms. Die medialen Menisken wiesen im Mittel eine T2-Relaxationszeit von 17,7ms auf, die lateralen Menisken eine T2-Relaxationszeit von 19,0ms. Wir konnten keinen signifikanten Unterschied zwischen den medialen und lateralen Menisken feststellen. Außerdem fand sich keine Korrelation zwischen T2-Relaxation und Alter und Geschlecht der untersuchten Hunde. In der histologischen Untersuchung fanden wir einen signifikant höheren Degenerationsgrad in den medialen Menisken (Score 4,75 (medial) vs. 3,75 (lateral)). Zwischen den histologischen Ergebnissen und der T2-Relaxations der Menisken konnte keine signifikante Korrelation festgestellt werden. In der zweiten Studie musste aufgrund technischer Fehler ein Gelenk von der Auswertung ausgeschlossen werden. Es wurden somit ingesamt 30 Menisken von 15 Gelenken untersucht. Die Ergebnisse der histologischen Untersuchungen wurden von der vorangegangen Studie übernommen und um einige bildgebenden Parameter (T1, T2*, Magnetisierungstransfer) ergänzt. Auch hier konnten nur vereinzelt Zusammenhänge zwischen histologischen und bildgebenden Parametern gefunden werden. Die T1-Relaxation sank mit steigendem Proteoglykangehalt und stieg mit zunehmender Zellularität an. Die mittlere T1-Relaxation der medialen Menisken lag bei 517ms, die der lateralen Menisken bei 536ms. Die MTsat-Werte waren dahingegen in Menisken mit höherem Proteoglykanscore erhöht. Der Mittelwert von MTsat lag für die medialen Menisken bei 0,08ms und für die lateralen Menisken bei 0,08ms. Der Proteoglykan- und Kollagengehalt zeigten in unseren Ergebnissen einen gegensätzlichen Effekt auf MTsat zu haben. Um dies weitergehend betrachten zu können, wurde zusätzlich das Verhältnis von Kollagen- und Proteoglykanscore gebildet. Dabei zeigte sich, dass MTsat bei höherem „Kollagen-zu-Proteoglykan-Verhältnis“ signifikant niedriger war (p<0,002). Eine Korrelation zwischen dem histologischen Gesamtscore und den einzelnen MR-Parametern konnte auch hier nicht gefunden werden. Bei unabhängiger Analyse der medialen und lateralen Menisken konnte eine leichte negative Korrelation zwischen MTR und dem Histoscore der medialen Menisken gefunden werden. Diese Korrelation ist jedoch nur als Tendenz anzusprechen, da sie keine statistische Signifikanz erreichte (p=0,08). Desweiteren konnte gezeigt werden, dass MTR tendenziell niedriger in den medialen Menisken war (p=0,059). Die histologische Untersuchung der Menisken ergab einen signifikant höhren Proteoglykanscore der medialen Menisken bei zugleich größerer Variabiltät innerhalb der einzelnen Proben (p=0,006). Daraus könnte geschlossen werden, dass MTR indirekt mit dem Proteoglykanscore in Zusammenhang steht. Die Ergebnisse dieser Studien zeigen, dass grundsätzlich geringe histologische Veränderungen in den Menisken älterer, klinisch unauffälliger Hunde nachweisbar sind. Keiner der untersuchten MR-Kontraste wies eine hohe Spezifität oder Sensitivität bezüglich geringgradiger histologischer Meniskusveränderungen auf. Die gezeigten Zusammenhänge von MTsat und T1-Relaxationszeit mit dem Proteoglykangehalt bzw. der Zellularität sprechen dafür, dass einige dieser Parameter vielversprechende Kandidaten sein könnten, um mikrostrukturelle Gewebeveränderungen zu detektieren. Gleichzeitig zeigen die Studien aber auch, dass die Darstellung von geringgradigen Meniskusdegenerationen sehr herausfordernd ist. Die semi-quantitative Bildgebung muss v.a. im Bereich der Tiermedizin erst noch etabliert werden. Sie bietet jedoch grundsätzlich ein hohes Potential für die Früherkennung von strukturellen Meniskusveränderungen und kann somit sowohl in der Forschung als auch in der klinischen Anwendung wertvolle Informationen liefern.Item type: Item , Towards a deeper understanding of genetics of dermatitis digitalis in dairy cows through the consideration of housing characteristics, climate and barn emissions in alternative statistical modelling approaches(2025) Sölzer, NiklasClaw disorders are one of the main reasons for the culling of dairy cows. Due to the lameness that often follows in the herd, the feed intake and, not least, the milk yield of the affected animals decrease. These indirect costs are further increased by the also decreasing fertility of affected animals. In addition, there are the direct costs of veterinary treatment, medication and the need for more care of the lame animals. One of the most frequent claw disorders in this area, occurring worldwide, is dermatitis digitalis, usually better known as Mortellaro's disease. Dermatitis digitalis (DD) is a multifactorial disease in which both the housing environment and the genetics of the animals play a role. In recent years, several studies have been published to clarify the genetic background of claw disorders in general and DD in particular. In this context, genome-wide association studies (GWAS) have been conducted and potential candidate genes associated with claw disorders have been annotated. However, it is still unclear how specific environmental effects influence the estimation of variance components and GWAS. Climatic conditions in particular have changed in recent years and will continue to have an increasing impact on the productivity and welfare of cattle in the future. The Temperature-Humidity Index (THI) is a scientifically proven tool in this context. Heat stress (HS) for cattle begins at a THI > 68. The wide availability of data from weather stations near farms enables appropriate management. In order to identify possible correlations with claw health, SNP x heat stress (HS) interactions for claw disorders were analysed in the first part of this study. This showed that specific SNPs and their annotated candidate genes were only significant under HS or thermoneutral conditions. In the second part of this study, the aspect of interaction effects was taken up again. Here, SNP x housing system interactions were estimated for three DD traits in the housing systems of cubicle housing and compost bedded pack barn. However, very similar genetic parameters were found for the same traits in different environments. As well as negligible genotype x housing system interactions. This indicates that the housing system has only a minor effect on the genetic evaluation of a DD disease. Since cattle farming must adapt to the negative consequences of climate change, on the one hand, and is mentioned as a contributor to climate change, on the other, these aspects should also be reflected in the study design. Therefore, on the one hand, climate influences (wind speed, temperature and humidity) were recorded, and on the other hand, the emissions of ammonia, nitrous oxide, carbon dioxide and methane were measured in the barn. A special ‘climate gas trolley’ was built for this purpose. Using this, it was possible to measure the effects of climate and emissions at the same time in different areas of the barn. In the third part of this study, the effects of the housing environment, cow phenotypes and genomics were placed in an overall context. This approach has been used very rarely in animal breeding to date and not at all in relation to a DD disorder. Structural equation modelling (SEM) was used to address this issue. These models can incorporate both measurable and non-measurable variables into the analyses and have mostly been used in psychology until now. In this study, the models allow for the simultaneous consideration of environmental and genetic effects. The SEM showed that the housing environment has a greater influence on DD than genetic parameters, for example. In summary, the results of this study contribute to a better understanding of the genetic background of claw disorders in general and DD in particular. The results also provide an important contribution to a better understanding and further clarification of genotype-environment interactions. To provide a general introduction to the subject of the dissertation, Chapter 1 will take a closer look at the disease DD. On the one hand, the general course of the disease with its clinical symptoms, therapy and prevention is discussed, but on the other hand, economic aspects and the complexity of possible causes of the disease are also mentioned. The following part of the chapter deals with the housing systems of conventional cubicle housing and compost bedded housing. The chapter ends with various possibilities for modelling and the current knowledge on breeding for disease resistance. Chapter 2 aims at a deeper genomic analysis of the three claw disorders DD, hyperplasia interdigitalis (HYP) and Sole ulcer (SU), as well as their genetic association with other important breeding goal traits. Finally, possible SNP x heat stress interactions for claw disorders are analysed. The study design included 17,264 genotyped, first-lactating Holstein Friesian cows from 50 herds in northeast Germany. The heritabilities of the three claw disorders were estimated using linear and threshold models and were 0.04 and 0.08 for DD, 0.03 and 0.10 for SU and 0.03 and 0.23 for HYP. Genetic correlations estimated in bivariate linear models were consistently positive with the selected conformation traits. This indirectly indicates the need for selection on conformation traits to improve claw health. Genetic correlations with other breeding goal traits showed reduced fertility, poorer udder health and productivity in diseased cows. Genetic correlations were observed between the claw disorders, suggesting a closer genetic relationship. Furthermore, disease-specific candidate genes and genetic associations based on the surrounding SNPs were estimated, which in some cases differed from the genetic correlations. For the SNP x heat stress interactions, significant SNPs were identified on BTA 2,4,5,7,8,9,13,22,25 and 28. The results suggest gene-specific mechanisms for claw disorders only in specific environments. In Chapter 3, a detailed phenotypic characterisation of the claw disorder DD in the two housing environments (conventional cubicle barn and compost bedded pack barn) was carried out to determine possible genotype x housing system interactions. In total, the data set comprised 2,980 observations for the three traits DD-sick, DD-acute and DD-chronic from 1,311 Holstein-Friesian and 399 Simmental cows, 926 of these animals were available for the genomic studies. In total 899 cows were housed in the compost bedded pack barn (1,530 observations) and 811 were housed in the conventional cubicle barn (1,450 observations). The disease prevalence was higher in the cubicle barn than in the compost bedded pack barn. The heritabilities over the entire data set were 0.16 for DD-sick, 0.14 for DD-acute and 0.11 for DD-chronic. A slight increase in heritabilities and genetic variances was observed in the housing environment of the cubicle barn compared to the compost bedded pack barn. Genetic correlations between the same DD traits in the different housing environments were close to 0.80, indicating obvious genotype x housing system interactions. The genetic correlations between the three DD traits ranged from 0.58 to 0.81. The SNP main effects and SNP x housing system interactions were estimated using genome-wide association studies. Some common candidate genes were identified for DD-sick and DD-acute. The genes had direct or indirect effects on disease resistance or immunological processes. The genes ASXL1 and NOL4L were annotated for the SNP x housing system interactions for DD-sick and DD-acute. Chapter 4 analyses the effects of the environmental factors, cow phenotypes and genomics in more detail for the DD traits discussed in Chapter 3. The most relevant housing characteristics were analysed in linear models. The last-squares means for the infection probability were generally lower in the compost bedded pack barn than in the cubicle barn. The genome-wide association studies showed similar Manhattan plots for DD-sick and DD-acute and similar potential candidate genes in each case. Five SNPs were significantly associated with either DD-acute and DD-sick or with DD-chronic and DD-sick. These significant SNPs were then related to phenotypic and genetic estimated breeding values for the DD traits, as well as to production data and housing environmental factors in structural equation models. This showed that the housing environment had a greater influence on the risk of DD infection than genetic parameters, for example. Finally, some important aspects of this work are discussed again in chapter 5. In particular, genomic aspects of claw disorders, the influence of the housing environment and the economic weight of claw disorders in the total breeding value are considered here.Item type: Item , New Classes of Radial Basis Functions for Quasi-Interpolation(2025) Ortmann, MathisRadial basis functions (RBFs) are considered an important tool in numerical mathematics for approximating functions based on scattered data. They are often used as an interpolation method. In this process, a system of linear equations has to be solved. The size of the linear system is determined by the number of interpolation points. As the number of interpolation points increases, the solution tends to become numerically unstable, which results in the approximation of the function based on the scattered data becoming inaccurate. One possible approach to avoid this problem is provided by quasi-interpolation using RBFs. Quasi-interpolation is an efficient approximation method that does not require a system of linear equations to be solved. Just like interpolation with RBFs, quasi-interpolation is applied in arbitrary dimensions. Since many problems in industry and science are based on the approximation of scattered data, efficient approximation is regarded as a central task. With a rapidly increasing amount of available data, quasi-interpolation is gaining importance compared to classical interpolation. To compute the quasi-interpolation, a RBF has to be selected in advance. The approximation quality is affected by the selected RBF. The determination of an optimal RBF for a given approximation problem is considered an open research challenge. In this work, two new classes of RBFs are presented that are used to improve approximation by quasi-interpolation. The quality of an approximation is determined by the approximation order. A statement about the approximation order is provided by the Strang and Fix conditions. For their application, the asymptotic behavior of the distributional Fourier transform of the RBF is required. In addition to the two new classes of RBFs, a new class of non-RBFs is also introduced for use in quasi-interpolation. The analysis of approximation orders between RBFs and non-RBFs is fundamentally distinguished, and new approaches for further non-RBFs in quasi-interpolation are opened up. The results are shown to yield excellent convergence properties with low computational effort. The theoretical results presented are verified by numerical examples.Item type: Item , Development of a novel conditional gene expression system in the global pest Drosophila suzukii(2025) Jaffri, Syeda Azka SeharThe invasive pest D. suzukii causes significant economic losses to soft fruit crops worldwide. This study aims to improve the Sterile Insect Technique (SIT), an ecofriendly pest management approach, by establishing the Q system in D. suzukii. The Q system provides regulated expression of any gene of interest and it allows the generation of transgenic lines with the ability to induce female-specific lethality. The objectives of this study were to isolate and characterize the endogenous pro-apoptotic and pre-embryonic genes of D. suzukii; to analyze gene expression profiles by RT-qPCR; to test the efficacy of pro-apoptotic genes, and embryonic promoters in S2 cells, both independently and in conjunction with Q system components; and to generate the transgenic D. suzukii strains carrying Q system elements for conditional lethality induction. The results of this study provide insights into the potential of pro-apoptotic genes and early embryonic promoter that can be used in conditional expression systems to control pest populations. Notably, transgenic lines of QUAS (the effector element) were successfully generated. However, the attempts to develop any transgenic lines with QF (the activation factor) were failed in D. suzukii. This may pose a very serious obstacle towards the viability of the Q system in this species.Item type: Item , Chromatic and luminance processing during eye movements in human early visual cortex(2025) Zhang, YuanHuman vision is not a passive process. Rather, our visual perception of the world emerges from a dynamic and adaptive interplay between sensory input and motor action, whereby perception continually guides movements, and these movements in turn reshape perceptual experience. Eye movements are essential for acquiring clear visual input in natural viewing. Despite substantial progress in understanding how eye movements are generated, controlled, and functionally organized, fundamental questions remain about how early visual processing is modulated by natural viewing behaviors, and how different types of eye movements influence neural mechanisms encoding color and luminance. This dissertation addresses these questions by combining precise neurophysiological measurement techniques with carefully controlled behavioral paradigms. Our eyes move frequently to keep objects of interest projected onto the fovea for a clear image. Among these movements, saccades are rapid, ballistic shifts of gaze that move the eyes from one location to another, while smooth pursuit keeps a moving target within the foveal region through continuous, slow eye rotations that closely match the target’s speed and direction. When the gaze is relatively stable and directed at a single point, the eye is in a state of fixation. These three types of eye movements are fundamental for acquiring visual information from the environment. Visual scenes are encoded by the L, M, and S cones in the retina and then relayed via three pathways: the magnocellular pathway (L+M, luminance), the parvocellular pathway (L–M, red-green opponency), and the koniocellular pathway (S–[L+M], blue-yellow opponency). These pathways transmit information in parallel up to the primary visual cortex (V1), where their signals are subsequently processed through partially distinct yet interacting cortical circuits (for reviews, see Gegenfurtner, 2003; S. H. C. Hendry & Reid, 2000; Nassi & Callaway, 2009). Given that V1 is the first cortical site where luminance and chromatic signals converge and begin to interact, a key unresolved question is how these signals are modulated by different types of eye movements during natural viewing. To explore the neural mechanisms underlying these processes, this thesis employed steady-state visual evoked potentials (SSVEPs) to track neural responses in the early visual cortex. SSVEPs are brain oscillations elicited by periodic visual stimulation (Adrian & Matthews, 1934; for review, see Norcia et al., 2015), originating primarily from V1 (Di Russo et al., 2007; Müller et al., 1997). SSVEPs possess high temporal resolution and exhibit narrowband spectral responses locked precisely to the stimulation frequency, making them highly resistant to eye movement artifacts (e.g., J. Chen et al., 2017a, 2017b; J. Chen, Valsecchi, et al., 2019). Those properties make SSVEPs a reliable tool for studying visual processing in the human early visual cortex during eye movements. In Study 1, we investigated the effect of chromatic (L–M) adaptation during prolonged fixation. Results showed that SSVEP responses to chromatic stimuli progressively decrease as stimulation duration increased, following an exponential decay with a half-life of approximately 20 seconds. In contrast, responses to luminance stimuli did not show any systematic adaptation. After characterizing this sustained visual adaptation, Study 2 then investigated transient modulations of visual cortical responses induced by saccadic eye movements. Results demonstrated comparable saccadic suppression effects on SSVEP responses to both chromatic (L–M) and luminance stimuli. Further modeling of contrast response functions revealed that saccades selectively reduced response gain without altering contrast gain, suggesting that visual attenuation involves a multiplicative mechanism operating similarly within both the parvocellular and magnocellular pathways. To enhance the quality of SSVEP data, the third study evaluated various EEG referencing methods and introduced the Laplacian reference as an optimal strategy for signal derivation. Results showed that the Laplacian reference significantly improved the signal-to-noise ratio (SNR) and reliability of neural measurements, while also being straightforward to implement across different experimental settings. Taken together, these findings underscore the critical role of eye movements in modulating both luminance and chromatic signals within the early visual cortex. This work demonstrates that perception is dynamically shaped by the continuous interplay between sensory input and oculomotor behavior, offering new insights into how active vision operates under natural viewing conditions.Item type: Item , Können Plaqueindizes die tatsächliche Plaquemenge abbilden?(2025) Eilert, FranziskaFür die zahnmedizinische Prävention spielen plaquereduzierende Maßnahmen eine zentrale Rolle. Um einschätzen zu können, ob Mundhygienemaßnahmen effektiv sind und inwieweit sie die mikrobielle Besiedlung der Zahnoberflächen reduzieren, kommen heute verschiedene Methoden der Plaquequantifizierung zum Einsatz. Die zwei gängigsten Verfahren sind die Plaqueplanimetrie und der Einsatz von Plaqueindizes, wobei sich Letztere in ihren Differenzierungsgraden teils deutlich unterscheiden. Folglich wird die vorhandene Plaquemenge indexabhängig unterschiedlich abgebildet, was wiederum einen Einfluss auf die Vergleichbarkeit zwischen Studienergebnissen hinsichtlich der ermittelten Effektgröße und statistischen Signifikanz nimmt. Bei der Planimetrie hingegen wird die vorhandene Plaque objektiv durch eine Computersoftware als prozentualer Anteil an der Gesamtoberfläche errechnet. Ziel der vorliegenden Arbeit war es herauszufinden, inwiefern verschiedene Indizes in der Lage sind, die planimetrisch gemessene, tatsächliche Plaquebedeckung, auch zu unterschiedlichen Zeitpunkten der Mundhygiene, darzustellen. Der Erkenntnisgewinn diente unter anderem der kritischen Auseinandersetzung mit der Aussagekraft von vorherigen klinischen Studien. Hierzu wurden Intraoralscans von 30 Probanden zu jeweils drei unterschiedlichen Zeitpunkten der Mundhygiene angefertigt. Der erste Termin repräsentierte dabei die habituelle Mundhygiene (T1). Beim zweiten Termin stellten sich die Probanden nach 72 Stunden ohne Mundhygiene vor (T2), wurden anschließend dazu aufgefordert ihre Zähne wie gewohnt zu putzen und unterzogen sich dann dem dritten Intraoralscan (T3). Vor jeder Datenerfassung wurden die vorhandenen mikrobiellen Beläge durch einen Plaquerevelator (Mira-2-Ton®) sichtbar gemacht. Anhand der ermittelten 3D-Scans wurden standardisierte Screenshots der Vestibulär- und Oralflächen der Ramfjordzähne erstellt und die Plaquemenge mithilfe eines Grids hinsichtlich vier verschiedener Indizes ausgewertet (T-QHI, RMNPI, RMNPI nach Bretz, marginaler Plaqueindex). Im Anschluss erfolgte die Messung der tatsächlichen Plaquebedeckung mithilfe der Planimetrie. Es konnte gezeigt werden, dass zwar alle Indizes Plaquemengenveränderungen widerspiegeln können, diese aber in einer deutlich abweichenden Effektgröße repräsentiert werden. Die Indexwerte fielen immer signifikant niedriger als die planimetrisch erhobenen Messergebnisse aus, zudem bestand ein nichtlinearer Zusammenhang. Insgesamt lieferte der T-QHI noch die zuverlässigsten Ergebnisse, kann aber auch nur eingeschränkt einen Anhalt auf die tatsächliche Plaquemenge geben. Schlussfolgernd ist es also nicht sicher möglich Effektgrößen mithilfe von Plaqueindizes auszudrücken.Item type: Item , Unraveling the role of heterotrophic feeding in coral tolerance to ocean warming and microplastic pollution(2025) López Hernández, María Antonieta PanamáCoral reefs harbor the highest biodiversity of all marine ecosystems and support the livelihoods of nearly 500 million people worldwide. Yet, they are increasingly threatened by global warming. Marine heatwaves disrupt the symbiosis between corals and Symbiodiniaceae algae, leading to coral bleaching. As these algae provide up to 90% of coral energy requirements, their loss results in energy deficits that compromise coral health, reducing growth and reproduction, increasing disease susceptibility, and often leading to mortality. Heterotrophic feeding, as a secondary pathway of energy acquisition in reef-building corals, can sustain up to 100% of their metabolic demands under stress, thereby enhancing survival and resilience to bleaching caused by ocean warming. Consequently, trophic plasticity, i.e., the ability to modulate trophic strategies in response to environmental change, has emerged as a key trait distinguishing potential “winners” under climate change. However, trophic plasticity varies among species and may be compromised by emerging stressors such as microplastic pollution, which can interfere with coral feeding. Despite the importance of heterotrophy in coral resilience, there are still knowledge gaps regarding the role of food type and food availability on coral physiology, and how these interact with pollutants such as microplastic, particularly in an ocean warming context. These uncertainties are further compounded by a lack of field-based data. This thesis addresses these knowledge gaps through two controlled laboratory experiments and the first in situ application of compound-specific isotope analysis of amino acids during a natural bleaching event. Five coral species (Galaxea fascicularis, Porites lobata, Stylophora pistillata, Ctenactis echinata, and Pocillopora verrucosa) were assessed for key physiological traits (photophysiology, growth, energy reserves, δ¹⁵N and δ¹3C), providing a comparative framework of heterotrophic strategies. Results indicated that complex diets enhanced the benefits of heterotrophy across coral species. Although these benefits varied among species when symbiotic, all bleached corals exhibited positive responses to more complex food sources. Physiological rates were consistently higher in symbiotic fragments compared to their bleached counterparts, with the magnitude of these differences increasing alongside the baseline productivity of the species, from G. fascicularis to P. lobata and S. pistillata. Food treatments did not affect respiration or photosynthetic rates, suggesting that growth gains were driven primarily by enhanced heterotrophic nutrient supply. In situ bleaching was associated with δ¹⁵N enrichment in the trophic amino acids alanine (ALA), glutamic acid (GLU), isoleucine (ISO), proline (PRO), and valine (VAL), suggesting alterations in nitrogen acquisition and processing under stress. The trophic position (TP) of the symbiotic host and symbionts of C. echinata was 1.3, consistent with a mixotrophic diet. In contrast, P. verrucosa exhibited TP values of 1.2 for the host and 1.0 for the symbionts, indicating a stronger reliance on autotrophy. Under bleaching, C. echinata maintained a TP of 1.4, reflecting a stable mixotrophic strategy, whereas P. verrucosa shifted to a TP of 1.5, suggesting an increased reliance I on heterotrophy. These findings suggest higher heterotrophic plasticity in P. verrucosa compared to C. echinata. Microplastics (MPs) exposure significantly decreased the energy reserves of P. verrucosa, although it increased photosynthesis and respiration. High food availability partially mitigated the loss of tissue energy content observed while maintaining photosynthesis and respiration rates comparable to control conditions. S. pistillata was not affected by MP exposure alone, but when combined with high feeding, photosynthesis decreased below that of the Control. When exposed to short-term heat stress, all corals bleached severely, however, both species bleached less in the MP treatment suggesting that MPs may also disrupt the relationship between energy balance and thermal resilience. Overall, this thesis provides evidence supporting the central role of heterotrophic feeding in modulating coral tolerance to the combined pressures of ocean warming and microplastic pollution, while emphasizing the need to integrate trophic plasticity and interspecific variability into future conservation and management strategies.Item type: Item , Predictive Modelling with Machine Learning in Plant Breeding(2025) Heilmann, Philipp GeorgGenomic prediction, originally proposed as a solution to the limitations of marker-assisted selection for complex traits, has become the standard for estimating breeding values in both inbred and hybrid crops. While linear models such as GBLUP and RR-BLUP remain effective in many cases, especially when assuming an additive genetic architecture, recent years have seen a growing interest in applying machine learning (ML) methods to overcome some of their constraints, including their limited capacity to model non-additive effects and nonlinear interactions. This thesis explored the influence of three key aspects on the success of genomic prediction: The choice of input features, the statistical model used, and the target trait or crop.
In terms of input features, marker data was compared to minimalist parentage-based models, haplotype blocks, and features generated using autoencoders. It was shown that even simple ML models using parentage-based information can rival marker-based GBLUP under certain conditions, which holds potential for small breeding programs with large amounts of historical, but ungenotyped, records. At the same time, dimensionality reduction techniques, especially a novel haplotype-based autoencoder that was developed during this thesis, were introduced to compress genomic data while preserving prediction accuracy and successfully accelerated model training.
Concerning the model aspect, a variety of ML algorithms were benchmarked using different approaches for hyperparameter tuning. Although no single model outperformed others across all traits and crops, ensemble approaches typically performed better than the individual models they were based on. Support vector machines seemed to be relatively unstable when compared to other ML based algorithms, such as tree-based models.
Finally, results showed that the accuracy of the genomic predictions was strongly dependent on differences between traits, crops with different breeding schemes, and different populations. For hybrids, ML performed well when SCA was more important for determining the hybrid yield than GCA. Large differences were observed for different fungal diseases in wheat, while differences among methods for the same disease were relatively similar.
While ML has not yet provided a significant improvement over traditional methods in many scenarios, its flexibility and potential for multi-modal data integration remain promising. The development of plant breeding-specific model architectures, such as haplotype-based autoencoders, may represent a more promising path than the general application of standard ML models.Item type: Item , Impact of compressive force on macrophages and cementoblasts and the possible interrelation with orthodontically induced inflammatory root resorption(2025) Wang, YaoThis study analyzes the impacts of orthodontic compressive force on both innate immune responses and cementum homeostasis (Figure 22). In macrophages, compressive force induces chromatin rearrangement, nuclear shrinkage, and polarization. Two distinct mechanotransduction pathways were identified: 1. Histone H3 hyperacetylation: This mediates M2 polarization during the late stage of the immune response. 2. Lamin A/C downregulation: Orthodontic compressive force transiently reduces lamin A/C levels, compromising the nuclear envelope and increasing nuclear permeability to YAP1. This facilitates enhanced force-induced cytokine expression and proliferative inhibition. Concurrently, it reduces force-induced IRF4 expression, DNA damage, and phagocytosis enhancement, likely due to LINC complex disruption. These opposing effects of lamin A/C deficiency jointly regulate cellular behavior under compressive force. Furthermore, cementoblasts respond directly to compressive force but do not respond to macrophage-conditioned medium, suggesting that excessive orthodontic force, rather than macrophage activation, is the primary driver of OIIRR. Mechanistically, Piezo1 activation under force mediates enhanced hypoxia and suppressed mineralization in a Ca2+-independent manner. Lastly, LMCD1 and POSTN were identified as downstream mediators of Piezo1, representing potential therapeutic targets for OIIRR.Item type: Item , Speckle Tracking zur Detektion von Liquorzirkulationsstörungen: Deformationsanalyse des dritten Hirnventrikels anhand transkranieller Ultraschallvideos(2025) Radder, MarkusEinleitung: Die intrakranielle Dynamik beschreibt das komplexe Zusammenspiel aus pulsatilen Blut-, Liquor- und Hirnparenchymbewegungen, die den Gesetzmäßigkeiten der Monroe-Kellie-Doktrin unterliegen. Liquorzirkulationsstörungen wie der nicht-kommunizierende Hydrozephalus gehen mit einem erhöhten intrakraniellen Druck (ICP) einher, dessen Überwachung bislang nur mittels invasiver Methoden möglich ist. Ausgehend von der Annahme, dass pulsatile Bewegungen der Wandstrukturen des dritten Ventrikels biomechanisch eng mit der intrakraniellen (Liquor-)Dynamik und somit auch mit dem ICP gekoppelt sind, wurde in dieser Arbeit untersucht, ob die ultraschallbasierte Methode des Speckle Trackings zur Gewebsdeformationsanalyse als nicht-invasives Verfahren geeignet ist, Veränderungen in der intrakraniellen (Liquor-)Dynamik nachzuweisen, die zukünftig Rückschlüsse auf den ICP ermöglichen könnten. Material und Methoden: Bei allen Studienteilnehmern wurden transkranielle Ultraschallvideos aufgenommen und anschließend die relative Deformation des dritten Ventrikels mithilfe einer Speckle-Tracking-Software analysiert. Die Studie erfolgte in zwei Phasen: In Phase 1 wurde ein Normalkollektiv aus 25 gesunden Probanden untersucht und die physiologische relative Deformation des dritten Ventrikels quantifiziert. Aus 9 Messpositionen im dritten Ventrikel wurde eine optimale Messposition für die Methode ermittelt. In Phase 2 wurde ein Kollektiv aus sechs Patienten mit nicht-kommunizierendem Hydrozephalus prä- und postoperativ untersucht und deren (pathologisch) veränderte relative Deformation des dritten Ventrikels aufgezeigt. Ergebnisse: Die optimale Messposition für eine zuverlässige Analyse konnte mithilfe eines Mixed-Effects-Modells identifiziert werden. Die Speckle-Tracking-Analyse zeigte Unterschiede in den Deformationsmustern zwischen gesunden Probanden und Patienten mit Hydrozephalus. Bei einigen Hydrozephalus-Patienten waren postoperative Veränderungen der Deformationsmuster erkennbar, die sich teilweise dem physiologischen Zustand annäherten. Diskussion: Die ermittelten Deformationsmuster lassen sich in die Erkenntnisse anderer Arbeitsgruppen zur intrakraniellen Dynamik einordnen. Der Vergleich zwischen Normal- und Patientenkollektiv zeigt, dass Speckle Tracking pathologische Veränderungen in den Pulsationsmustern des dritten Ventrikels erkennen kann. Dies unterstreicht das Potenzial dieser Methode als nicht-invasives Verfahren zur Erkennung und Überwachung von Liquorzirkulationsstörungen im klinischen Alltag. In Zukunft könnten hieraus Rückschlüsse auf den ICP gezogen werden. Weitere Studien sind erforderlich, um die klinische Anwendbarkeit und den diagnostischen Nutzen des Speckle Trackings des dritten Ventrikels umfassend zu bestätigen.Item type: Item , Retrospektive Analyse des GC-MS Harnsteroidmetaboloms bei Säuglingen und Kleinkindern mit 21-Hydroxylase-Mangel(2024) Friedrich, ClemensHintergrund: Das Adrenogenitale Syndrom, ausgelöst durch eine Mutation im CYP21A2-Gen, ist eine gravierende Erkrankung. Insbesondere wenige Wochen nach Geburt sind potenziell lebensgefährliche Verläufe mit schweren Elektrolytentgleisungen bis hin zum Schock möglich. Auch die schwerwiegenden Auswirkungen der Erkrankung, gerade bei ausbleibender bzw. insuffizienter Therapie, verdeutlichen die Gefahren dieser Erkrankung. Die adäquate Therapie mittels Fludrocortison und Hydrocortison ist aufgrund des schmalen Grades zwischen Unter- und Überbehandlung, gerade bei sehr jungen Patienten, schwierig. Zusätzlich ist der Therapieerfolg bei aktuell fehlenden verlässlichen Monitoring-Parametern zum großen Teil vom Behandler abhängig. Die Intention dieser Arbeit bestand darin, das Patientenkollektiv anhand einer retrospektiven Metabotypisierung in einzelne Behandlungsgruppen einzuteilen, das Wachstum und das Harnsteroidmetabolom zu analysieren und mittels konkreter Biomarker das Therapiemonitoring im Sinne einer möglichst individualisierten Therapie zu verbessern. Methoden: Die Studie nutzte, bei hoher Spezifität und Nicht-Selektivität, das Verfahren der GC-MS zur Analyse der Harnsteroidprofile in Kombination mit einer Clusteranalyse zur Metabotypisierung derer. Ergebnisse: Anhand der in der Arbeit ausgewerteten Daten konnte einerseits gezeigt werden, dass die Patienten mit einem Jahr über ein vermindertes Wachstum verfügten und somit in den ersten Lebensmonaten überbehandelt waren. Mit Hilfe der in dieser Studie durchgeführten Clusteranalyse war es außerdem möglich, die Probanden in drei verschiedene Cluster, für unter-, über- und adäquat behandelte Patienten, einzuteilen. Es stellten sich die 11-oxygenierten Androgene, allen voran 11β-Hydroxyandrosteron, als die dominierenden Androgene bei Patienten im Alter von 0 bis 4 Jahren mit AGS heraus. Es zeigte sich, dass 11β-Hydroxyandrosteron und 11-Ketopregnanetriol die wichtigsten Differenzierungsmerkmale zwischen den Clustern bildeten und daher perspektivisch als Biomarker zum Therapiemonitoring genutzt werden könnten. Schlussfolgerung: Die mittels Metabotypisierung erfolgte Einteilung in unter-, über- und adäquat behandelte Patienten ermöglicht eine differenzierte Therapiekontrolle und ein individualisiertes diagnostisches und therapeutisches Vorgehen. Es bedarf jetzt weiterer Forschung, um auf Grundlage dessen noch spezifischere Handlungsanweisungen für die klinische Praxis zu schaffen und das Therapie-Outcome von Patienten mit AGS zu verbessern.
Background: Congenital adrenal hyperplasia (CAH), due to a mutation in the CYP21A2 gene, is a serious disease. Especially in the first few weeks after birth, potentially life-threatening courses with severe electrolyte imbalances and even shock are possible. The serious consequences of the disease, particularly in the absence of or insufficient therapy, illustrate its dangers. Adequate therapy with fludrocortisone and hydrocortisone is challenging, especially in very young patients, due to the fine balance between under-treatment and over-treatment. Additionally, in the absence of reliable monitoring parameters, the success of therapy currently relies very much on the practitioner's expertise. The aim of this study was to divide the group of patients into individual treatment groups through retrospective metabotyping, to analyze growth and the urinary steroid metabolome, and to improve therapy monitoring by identifying concrete biomarkers to enable the most individualized therapy possible. Methods: The study utilized the method of GC-MS, known for its high specificity and non-selectivity, to analyze the urinary steroid profiles. This was combined with cluster analysis to metabotype the profiles. Results: Based on the data analysed in the paper, it was shown that, on the one hand, the patients had reduced growth at one year of age and were also over-treated in the first months of life. On the other hand, the 11-oxygenated androgens, foremost 11β-hydroxyandrosterone, turned out to be the dominant androgens in patients aged 0 to 4 years with AGS. With the help of the GC-MS-based cluster analysis performed in this study, it was possible to divide the subjects into three different clusters, for under-, over-and adequately treated patients. It was shown that 11β-hydroxyandrosterone and 11-ketopregnanetriol were the most important differentiating features between the clusters and could therefore be used in the future as biomarkers for therapy monitoring. Conclusion: The classification into under-, over-, and adequately treated patients by means of metabotyping enables differentiated therapy monitoring and an individualised diagnostic as well as therapeutic approach. Further research is now needed to create even more specific guidelines for clinical practice and to improve the therapy outcome of patients with AGS.Item type: Item , Soziale Innovationen und transformative Gemeinschaften – Eine qualitative Untersuchung deutscher Ernährungsräte(2025) Gehron, Anna-KatharinaAngesichts der zahlreichen negativen Auswirkungen derzeit dominierender Ernährungssysteme und der damit verbundenen Herausforderungen bedarf es einer Transformation des Ernährungssystems. Um lokale Ernährungssysteme nachhaltiger, demokratischer, lokaler, fairer und resilienter zu gestalten, entwickeln zivilgesellschaftliche Akteure soziale Innovationen. Diese nehmen eine wichtige Rolle in Wandlungsprozessen ein. In Deutschland werden soziale Innovationen für eine Transformation des Ernährungssystems unter anderem im Rahmen von Ernährungsräten entwickelt. Ernährungsräte gewinnen zunehmend an Relevanz und Sichtbarkeit. Die Forschung zu deutschen Ernährungsräten ist jedoch noch eingeschränkt. Bisherige Untersuchungen fokussierten sich vorwiegend auf die politische Arbeit von Ernährungsräten und ihren Beitrag zur Ernährungsdemokratie, weniger auf die sozialen Innovationen, die unter ihrem Dach entstehen. Um diese Forschungslücke zu schließen und zur Entwicklung von Transformationsstrategien beizutragen, widmet sich diese Dissertation der Entstehung sozialer Innovationen im Rahmen von Ernährungsräten. Das Ziel ist es, das Wissen über Ernährungsräte und soziale Innovationen zu erweitern, die Dynamiken der sozialen Innovationsprozesse zu verstehen und somit zur Realisierung einer Transformation des Ernährungssystems beizutragen. Anhand von vier Fallbeispielen werden aus der Perspektive der Transformationsforschung und mithilfe des qualitativen Forschungsansatzes der Innovationsbiografie Erkenntnisse über die Entwicklungsprozesse von sozialen Innovationen gesammelt. Dazu wird ein Methodenmix aus Dokumentenanalysen, narrativen Interviews, qualitativen egozentrischen Netzwerkanalysen, Raum-Zeit-Pfaden und teilnehmender Beobachtung verwendet. Um die sozialen Innovationen darüber hinaus aus einem neuen Blickwinkel zu betrachten und die sie begleitenden internen Prozesse und sozialen Dynamiken fokussieren zu können, werden diese als transformative Gemeinschaften untersucht. Diese Dissertation zeigt, dass die Entwicklung der sozialen Innovation durch interne Schlüsselakteure, diverse lokale Akteure sowie Ernährungsräte als Inkubatoren positiv und durch ehrenamtliche Strukturen sowie fehlende Ressourcen negativ beeinflusst wird. Des Weiteren wird festgestellt, dass Eigenschaften transformativer Gemeinschaften sich positiv auf die Mitgliederzahlen, die Zusammenarbeit und somit auf die Entwicklung sozialer Innovationen auswirken. Darüber hinaus wird deutlich, dass sich je nach Vision und Ziel der sozialen Innovation Unterschiede in der Entwicklung ergeben. Mit diesen Ergebnissen betont die Dissertation zum einen, dass es sich bei Transformationsprozessen, um eine gemeinschaftliche Aufgabe handelt, die nicht ohne ausreichende Ressourcen funktionieren kann. Zum anderen hebt sie die Relevanz von Ernährungsräten sowie den Einfluss sozialer Dynamiken und interner Prozesse auf Transformationsprozesse und das soziale Potenzial sozialer Innovationen für eine Ernährungswende hervor. Damit tragen die Ergebnisse zur Entwicklung von Transformationsstrategien bei.Item type: Item , Cell-type-specific efferocytosis restricts the functional plasticity of alveolar macrophages to prioritize resolution of inflammation over antibacterial defense(2025-08-21) Better, JulianResolution of lung injuries is vital to maintain gas exchange and restore homeostasis. Concurrently, there is an increased risk of secondary bacterial pneumonia. Alveolar macrophages (AMs) are crucial to not only initiate inflammation and clear bacteria but also promote resolution. However, environmental cues that switch these seemingly opposing functional phenotypes of AMs remain elusive. Resolution of lung inflammation requires efferocytosis of alveolar epithelial cells (AECs) and neutrophils (PMNs). Here, we discovered an incapacity of AMs to mount an effective immune response to bacteria during resolution of inflammation. Efferocytosis of both cell types led to an anti-inflammatory phenotype in AMs. Intriguingly though, only efferocytosis of PMNs reprogrammed mitochondrial metabolism of AMs to restrict functional plasticity during resolution of inflammation. PMN-derived Myeloperoxidase (MPO) fueled canonical glutaminolysis through Uncoupling protein 2 (UCP2) resulting in decreased mitochondrial reactive oxygen species (mtROS)-dependent killing of bacteria and secretion of pro-inflammatory cytokines. Instead, MPO-mediated stabilization of UCP2 inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. In contrast, efferocytosis of AECs resulted in a distinct anti-inflammatory phenotype in AMs maintaining phenotypic plasticity towards bacteria. Overall, uptake of apoptotic neutrophils switches AMs to prioritize resolution of inflammation over antibacterial responses and likewise affects human AMs. Key message: MPO activates an immunometabolic rheostat to restrict functional plasticity of macrophages to enhance resolution of inflammation at the expense of bacterial control.Item type: Item , Evaluation Point-of-Care gesteuerter, faktorenbasierter Gerinnungstherapie bei kinderherzchirurgischen Operationen unter extrakorporaler Zirkulation : Eine retrospektive Kohortenstudie(2025) Hofmann, JohannesDie Ergebnisse der vorliegenden Untersuchung weisen ein geringes Patientinnenalter, zyanotische Herzfehler, intraoperative Hypothermie, lange Bypassdauer und hohe Komplexität des chirurgischen Eingriffs als Risikofaktoren für postoperative Nachblutungen nach. Eine präemptive, algorithmus-basierte Gerinnungstherapie nach CPB ist in einer kinderkardiochirurgischen Patientinnenkohorte möglich. Der Algorithmus ermöglicht das Erreichen intraoperativ normwertiger POC Gerinnungsparameter ohne additiven Zeit- und Blutverlust, wie er bei einem reaktiven Ansatz zu erwarten wäre. Ein persistierender Verbrauch von Gerinnungsfaktoren könnte eine zentrale Rolle bei den aufgetretenen postoperativen Nachblutungen darstellen. Thema zukünftiger Forschung muss es sein, nicht untersuchte Bestandteile des Gerinnungssystems, wie die Thrombozytenfunktion, nach Eingriffen mit CPB bei Kindern zu analysieren. Die Dosierung von Gerinnungskonzentraten (speziell im neonatologischen Bereich) sollte, vor allem in Hinsicht auf die Inzidenz von thrombembolischen Komplikationen prospektiv untersucht werden.Item type: Item , Impact of Anthropogenic and Natural Disturbances on Biodiversity Patterns of Macroinvertebrates at different Taxonomic Levels in African Freshwater Systems(2025) Dusabe, Marie ClaireAfrican freshwater ecosystems are subject to both natural and anthropogenic pressures that affect habitat quality, biodiversity, and ecosystem functioning. Macroinvertebrates have been used in routine bioassessments to detect disturbances for decades. However, it is unclear how accurately they reflect disturbances at different taxonomic levels. This thesis investigates the environmental impact of disturbances in selected East African freshwater ecosystems, and how macroinvertebrates respond to these changes at different temporal and spatial scales. The effects of dam construction and the effectiveness of family-level bioindication for detecting them were tested on the Ruzizi River. Multimetric indices (MMIs) were used in Lake Kivu to assess their ability to identify and distinguish between various environmental pressures. Mollusc community indices were used to assess long-term environmental changes in six Albertine volcanic lakes. Additionally, the freshwater snail Gabbiella was tested as a model taxon to reconstruct historical hydrological shifts and water level fluctuations across the African Great Lakes, major connected river systems, and the crater lakes of western Uganda based on phylogenetic and biogeographical analyses. Finally, an eDNA index was used at Lake Albert to test its applicability in biodiversity surveys and use in African freshwater biomonitoring systems. The results showed that on the Ruzizi River, family-level indi-cators did not adequately capture the impact of the dams, while on Lake Kivu multimetric indices more effectively distinguished between stressed and reference sites. Pollution patterns varied across the lake, with greater impacts in the northern basin than in the central and southern basins. Phylogenetic and biogeography indices proved useful in detecting historical disturbances. The diversification of Gabbiella mirrored earlier water-level changes, a trend also reported in other African molluscs and fish groups. A series of vicariance and dispersal events shaped the biogeographic history of Gabbiella humerosa, and allowed tracing historical drainage changes during the Pleistocene. However, eDNA analysis yielded limited records of macroinvertebrates, as plankton dominated because only surface water was sampled. The lack of a reference library makes it difficult to accurately assign eDNA sequences. Nevertheless, the results underscore the potential of using aquatic eDNA for taxonomy-free biomonitoring in tropical regions. The results of the historical molluscan biodiversity change in the six volcanic barrier lakes studied in this thesis show that new species have emerged and others have disappeared over time. Invasive taxa were common, with crayfish and non-native snails among those displacing native species. The biogeography of most Albertine volcanic barrier lakes exhibits a Nilotic affinity, except for invasive species and other taxa with wide distributions. The current findings provide a useful basis for conservation efforts and inform strategies to slow the ongoing loss of biodiversity.Item type: Item , Medic responses to water deficit alone or combined to salinity, evaluation of their yield and priming effects(2025) Gharred, JihedThis thesis investigates the responses of two forage species, M. ciliaris and M. polymorpha, to water deficit, both alone and in combination with salinity. Additionally, it explores strategies to enhance their productivity under these challenging conditions, focusing on approaches such as seed priming and the incorporation of biochar into the culture medium. In Medicago ciliaris, drought (36% water holding capacity) led to a significant reduction in plant growth and an increase in the root/shoot ratio. The growth response was accompanied by a decreased stomatal conductance and a reduction of the net CO2 assimilation rate and water use efficiency. The associated higher risk of ROS production was indicated by a high level of lipid peroxidation, high antioxidant activities, and high proline accumulation. Soil amendment with biochar (2%) enhanced the growth significantly and supported the photosynthetic apparatus of Medicago ciliaris species by boosting chlorophyll content and Anet both under well-watered and insufficiently watered plants and water use efficiency in case of water shortage. This increase in water use efficiency was correlated with the biochar-mediated decrease of the MDA and proline contents in the leaves, buffering the impact of drought on photosynthetic apparatus by increasing the activity of enzymatic antioxidants SOD, APX, GPOX, and GR and non-enzymatic antioxidants, such as AsA and DHAsA, giving the overall picture of a moderate stress response. These results confirmed the hypothesis that biochar application significantly reduces both the degree of stress and the negative impact of oxidative stress on Medicago ciliaris plants. These results implied that this species could be suitable as a cash pasture plant in the development of agriculture on dry wasteland in a future world of water shortages. This study aimed to evaluate the extent to which seed priming with ascorbic acid (0.2 mM) enhances the performance of M. polymorpha L. under osmotic stress induced by 50 mM NaCl (salinity) or 100 g/L PEG. Parameters related to growth and photosynthesis were assessed to understand the impact. Both NaCl-induced salinity and PEG-mediated osmotic stress significantly reduced plant biomass (-30% and -40%, respectively), leaf and ramification numbers, stem length, net CO₂ assimilation, and leaf water content. However, both treatments, particularly PEG, increased the root/shoot ratio and leaf proline content. Interestingly, seed priming with ascorbic acid alleviated these stress-induced effects, improving CO2/H2O gas-exchange and increasing plant biomass production. Water relations also improved, as indicated by reduced leaf osmotic potential, enhanced proline accumulation, and higher leaf water content. Additionally, ascorbic acid seed priming increased leaf carotenoid content by 65% and chlorophyll content by 45%, thereby enhancing photosynthetic activity. These improvements collectively contributed to better plant performance, particularly under salinity stress. Seed priming with ascorbic acid is an easy, cost-effective, and promising approach to mitigate the impact of osmotic stresses like drought and salinity, especially by improving plant water relations and photosynthetic efficiency. The effects of salinity, soil drying, and their interaction on the two forage species Medicago ciliaris and M. polymorpha were investigated. The results revealed that salinity and drought applied individually adversely affected growth, photosynthesis, and leaf water and potassium content in both species. However, the combined effects of both constraints were not significantly additive. Salinity affected the growth of both species to a similar extent. The major advantage of M. ciliaris under dry or saline conditions seems to be its higher water use efficiency and its corresponding positive impact on the ROS risk. Compared to M. polymorpha, M. ciliaris demonstrated superior biomass production under drought, salinity, and combined stresses, making it a strong candidate for forage production and soil rehabilitation in arid and semi-arid salinized regions.