http://hdl.handle.net/10900/42126 2026-06-17T04:28:21Z http://hdl.handle.net/10900/180876 Response to PD-1 based immunotherapy in patients with preexisting autoimmune diseases receiving active immunosuppression; Ansprechen auf eine PD-1-basierte Immuntherapie bei Patient:innen mit vorbestehenden Autoimmunerkran- kungen, die eine aktive Immunsuppression erhalten Sattler, Jens Sören In this study, we retrospectively examined 89 patients with stage IV malignant melanoma and pre-existing autoimmune disease with and without active immunosuppression regard- ing their response to PD-1 based immunotherapy. In this univariate analysis, the type of first-line therapy was significantly associated with longer overall survival (PD-1 monotherapy: mOS 79.5 months; p=0.010). Active immu- nosuppression was significantly associated with longer progression-free survival (PFS1 with immunosuppression: 4.1 months vs. 2.4 months without; p=0.028). Interestingly, established indicators of poor prognosis — elevated LDH and S100 serum levels and the presence of liver and brain metastases — did not show a significant impact on survival in PAD patients. Systemic treatment of metastatic melanomas with mono- or combined ICI therapy seems to be a viable and safe option for patients with PAD. Immune related adverse events did not generally occur more often or more severely than in patients without PAD. Current data suggest that immune checkpoint inhibitors can be used safely and effectively in patients with PAD, achieving response rates comparable to those reported in studies of patients without PAD. Further prospective studies should be conducted and clinical guidelines adapted accordingly. 2026-06-16T00:00:00Z http://hdl.handle.net/10900/180875 3D Genome Organization in Brown Algae Liu, Pengfei The three-dimensional (3D) organization of the genome plays a crucial role in gene regulation and epigenetic states. In animal genomes, core 3D genome features like topologically associated domains (TADs) and chromatin loops have been extensively characterized, whereas in plants such higher order structures are less pronounced. Beyond animals and plants, however, relatively little is known about the 3D genome organization evolution. This thesis explores the evolution of 3D genome organization in brown algae by comparing species differing in genome size, sexual systems (dioicous and monoicous), and morphological complexity. By substantially improving chromosomal-level assemblies, I demonstrated that brown algal genomes exhibit a high degree of linear conservation relative to the outgroup species, with only moderate rates of interchromosomal rearrangement. Examining interspecies variations in 3D chromatin organization revealed distinct patterns of nuclear architecture in brown algae shaped by evolutionary history. Comparative analysis suggests that 3D genome architecture is broadly conserved over approximately 11 million years of brown algae evolution. Notably, sex chromosomes and sex homologs display divergent interactions profiles distinct from autosomes. Consistent non-Rabl chromosome folding patterns were identified, which enabled the characterization of “centromere interaction clusters” and “telomere interaction clusters”. Identification of the centromeric regions revealed longterm co-evolution with a specific lineage of “centrophilic” LTR retrotransposons, which are uniquely present at the centromeres in most brown algal species and likely constitute the centromeric repeat. This study presents the first comparative analysis of 3D chromatin organization across six phylogenetically diverse brown algal species and one outgroup, offering new insights into 3D genome architecture within the eukaryotic lineage through the integration of high-resolution Hi-C data, gene expression profiling, centromere characterization, and ancestral genome reconstruction. 2026-06-16T00:00:00Z http://hdl.handle.net/10900/180799 Adaptation of Agriculture Systems to Metal(loid) and Climate Change Stressors Pieńkowska, Aleksandra The accumulation and mobility of essential and harmful metal(loid)s in agroecosystems greatly influence crop yields, nutritional quality and the stability of soil prokaryotic communities. Agricultural management, particularly through fertilization, represents a major source of metal(loid)s in agriculture soils. However, its long-term effects on metal(loid) mobility and bioavailability under realistic field conditions remain poorly understood. Climate change further complicates these dynamics by altering biogeochemical processes, which govern metal(loid) mobilization in soil and crop physiology, raising critical concerns about potential impacts on nutritional quality. Additional uncertainty arises from the methodological approaches used in climate incubation studies, which often compare present-day soils under current and projected climate conditions. In reality, future soils will already have been shaped by long-term exposure to those climates. This raises a critical question: do incubations using today’s soils provide valid predictions of future biogeochemical responses? This thesis investigates how agricultural management and climate change jointly shape the mobility, accumulation, and biological effects of essential and harmful metal(loid)s in agroecosystems. It aims to: i) assess metal(loid) transfer from soil to crops under different long-term fertilization regimes, including the use of 87Sr/86Sr isotopes as potential tracers for fertilizer-derived metal(loid)s; ii) evaluate the resistance and resilience of soil prokaryotic communities to metal stress across long-term fertilization histories; iii) determine how future climate conditions affect metal(loid) accumulation in crops; iv) assess the extent to which organic farming practices mandated under EU regulations mitigate climate-induced shifts in metal(loid) accumulation and crop productivity; v) evaluate whether climate incubation experiments using present-day soils provide accurate predictions of future biogeochemical responses. This study focuses on both essential (Fe, Zn, Mg, Mn, V) and harmful (Cd, As, Pb) metal(loid)s. To address the research objectives, it integrates long-term field trials, greenhouse climate simulations, and laboratory microcosm incubations with interdisciplinary approaches spanning soil chemistry, crop metal(loid) uptake, and prokaryotic ecology. This thesis demonstrates that agricultural management is a major factor shaping metal(loid) fate in soils and crops. Long-term mineral fertilization significantly increased Cd and As concentrations in wheat grains, with Cd content up by 70% compared with crops harvested from unfertilized control soils. This treatment also reduced the resistance and resilience of soil prokaryotic communities to additional inputs of Cd, Zn, and Pb, impairing prokaryote-mediated nutrient cycling. In contrast, organic fertilization with manure lowered Cd and As accumulation in wheat grains and supported stable prokaryotic communities under further metal stress. Combined mineral–organic treatments buffered negative effects of mineral fertilization on both grain nutritional quality and soil prokaryotic community stability. The 87Sr/86Sr ratios in wheat grains corresponded with those of the fertilizers used, validating their use as tracers for identifying fertilizer sources. In a separate field experiment, EU-certified organic farming reduced the accumulation of both essential Fe and Zn, as well as harmful Cd and As in wheat and barley grains by up to 24%, resulting in mixed effects on grain nutritional quality. This thesis shows that climate change alters metal(loid) dynamics in soils and crops, with outcomes that vary by environmental and experimental context. In a greenhouse experiment simulating future conditions with a substantial 3.4°C increase in atmospheric temperature, a 290 ppmv rise in CO2 concentration, and a 2-percentage-point decrease in soil moisture, spinach accumulated up to 54% more Cd, while Zn, Mg, and Mn responses were crop variety and soil type specific. These effects were linked to shifts in soil carbon composition and prokaryotic communities that particularly increased Cd mobility in soil. In contrast, a long-term field experiment was conducted under milder future conditions, including a +0.55°C increase in mean annual temperature, a 10% increase in spring and autumn precipitation, and a 20% decrease in summer precipitation. These smaller changes had no significant effects on Fe, Zn, Cd, or As concentrations in wheat and barley grains. However, organic farming did buffer climate-induced yield losses in wheat under this scenario. Climate incubation experiments using present-day soils without prior climate adaptation generally captured the direction of future biogeochemical responses, supporting their validity. Yet, without climate adaptation, the extent and timing of these responses may be misestimated due to inherited geochemical and microbial traits. This thesis demonstrated that metal(loid) dynamics in agroecosystems, and their subsequent effects on crop nutritional quality and soil prokaryotic stability, are governed by complex interactions among soil, crop, and prokaryotic processes. These interactions can be intensified under more severe climate conditions, particularly for harmful elements like Cd and As. Agricultural management might play a dual role in this challenge. While intensive conventional farming with mineral fertilization increases metal(loid) stress on agroecosystems, organic approaches offer promising mitigation strategies. As coupled climate change and metal(loid) contamination increasingly transform global croplands, science-based approaches to managing soil–crop–prokaryote systems will be critical for securing food safety, soil fertility and agroecosystem sustainability. 2027-11-25T00:00:00Z http://hdl.handle.net/10900/180788 7dSh – a Natural Sugar from Cyanobacteria as a Sustainable Herbicide Aries von Manteuffel, Nathan Matthias The use of herbicides over the last 80 years has been a constant driver of global food production. Specifically, the development of glyphosate-containing herbicides, most notably Roundup®, has significantly impacted global food security. Glyphosate is a selective inhibitor of the essential shikimate pathway in plants, bacteria, and fungi. With increasing critical research into the safety of glyphosate and the emergence of glyphosate-resistant weeds, the search for alternative herbicides has intensified in recent years. Since herbicides are essential to global food production and security, finding alternatives to glyphosate is of great importance. A promising candidate in this search is the bioactive sugar 7-deoxy-sedoheptulose (7dSh). 7dSh is naturally produced by Synechococcus elongatus and Streptomyces setonensis. It has been identified as an inhibitor of the shikimate pathway in plants and cyanobacteria, just like glyphosate. These findings have positioned 7dSh as a promising alternative to glyphosate. However, questions remain about additional working mechanisms and more economical and efficient methods of 7dSh production. In this work, Streptomyces setonensis was used to produce 7dSh in 20 L bioreactors, achieving concentrations of up to 1 g/l. A novel purification protocol was developed that yields 7dSh with high purity using cost-effective, scalable methods. The development of an economically scalable production of 7dSh ensures sufficient supply for future work and provides a basis for the development of potential industrial applications. A mutant in the highly sensitive strain Trichormus variabilis was found to show no sensitivity to 7dSh. Multi-sequence alignment revealed mutations in genes previously not linked to 7dSh activity. Although further research is needed, these findings open new avenues for investigating 7dShs' working mechanisms. Furthermore, it was shown that 7dSh must be phosphorylated after uptake to be bioactive. Work on chlorotic cells revealed that 7dSh is a potent inhibitor of both glycogen production and consumption. Furthermore, CO2 flux measurements showed that 7dSh inhibits CO2 fixation as early as 100 minutes after application. Lastly, 7dSh was shown to strongly influence glutamate pools in chlorotic and vegetative cells. These findings cannot be attributed to inhibition of the shikimate pathway and therefore must result from yet unknown working mechanisms. Based on these findings, this work suggests that 7dSh is not a selective inhibitor of the shikimate pathway alone, but rather a potent disruptor of central carbohydrate and nitrogen metabolism. 2026-06-15T00:00:00Z