Open Access

In dem Werk wird die Synthese von bisher unbekannten SIRT2-Inhibitoren mit 2-Naphthol- und partiell hydriertem Indolgrundkörpern beschrieben. Am Ende ist es gelungen potente und SIRT2-selektive Inhibitoren mit unterer mikromolarer Hemmkonzentration zu synthetisieren.

There is an increasingly urgent need to understand and predict how organisms will cope with the environmental consequences of global climate change. Adaptation in any form can be mediated by genetic adaptation and/or by phenotypic plasticity. Disentangling these two adaptive processes is critical in understanding and predicting adaptive responses to environmental change. Usually, disentangling genetic adaptation from phenotypic plasticity requires common garden experiments conducted under controlled laboratory conditions. While these experiments are powerful, it is often difficult to translate the results into natural populations and extrapolate to naturally occurring phenotypic variation. One solution to this problem is provided by the many examples of invasive species that exhibit wide phenotypic variation and that reproduce asexually. Besides selecting the appropriate in situ model, one must carefully choose a relevant trait to investigate. Ecomorphology has been a central theme in evolutionary biology because it reflects how organisms can adapt to their environment through their morphology. Intraspecific ecomorphological studies are especially well suited to identify adaptive pressures and provide insights into the microevolutionary mechanisms leading to the phenotypic differentiation. One excellent candidate for an intraspecific ecomorphological study aiming to understand adaptation through genetic adaptation and phenotypic plasticity is the invasive New Zealand mudsnail Potamopyrgus antipodarum Gray (1853). This ovoviviparous snail features high variability in shell morphology and has successfully invaded a wide range of fresh- and brackish water habitats around the world. The evolutionary and ecological situations in this species’ native and invasive ranges is drastically different. In New Zealand, P. antipodarum’s native range, sexual and asexual individuals coexist and experience selective pressure by sterilizing endoparasites. By contrast, only a few asexual lineages have been established in invaded regions around the globe, where parasite infection is extremely rare. Here, we took advantage of the low genetic diversity among asexually reproducing European individuals in an attempt to characterize the relative contribution of genetic variation and phenotypic plasticity to the wide variation in shell morphology of this snail. Analysing the ecomorphology of 425 European P. antipodarum in a geometric-morphometric framework, using brood size as proxy for fecundity, and mtDNA and nuclear SNPs to account for relatedness and identify reproductive mode, we hypothesized that 1) shell variation in the invasive range should be adaptive with respect to colonization of novel habitats, and 2) at least some of the variation might be caused by phenotypic plasticity. We then expanded our ecomorphological scope by analysing 996 native specimens, expecting 1) genetic and morphological diversity to be higher in the native range compared to invaded regions; 2) morphological diversity to be higher in sexual compared to asexual individuals according to the frozen niche hypothesis; and 3) shell morphology to be habitat specific, hence adaptative. In a last part, we used computational fluid dynamics simulations to calculate relative drag and lift forces of three shell morphologies (globular, intermediate, and slender). Here, we tested the overall hypothesis that shell morphology in gastropods is an adaptation against dislodgement through lift rather than drag forces, which would explain the counterintuitive presence of wider shells with shorter spires in lotic environments. With a final flow tank experiment, we tested the specific hypothesis that the dislocation velocity of living snails is positively linked to foot size, and that the latter can be predicted by shell morphology, in particular the aperture area as assumed by several authors. As expected, we found genetic and morphological diversity to be higher in native than in invasive snails, but surprisingly no higher morphological diversity in sexual versus asexual individuals. The relationships between shell morphology, habitat, and fecundity were complex. Shape variation was primarily linked to genetic relatedness, but specific environmental factors including flow rate induced similar shell shapes. By contrast, shell size was largely explained by environmental factors. Fecundity was correlated with size, but showed trade-offs with shape in increasingly extreme conditions. With increasing flow and in smaller habitats such as springs, the trend of shell shape becoming wider was reversed, i.e. snails with slender shells were brooding more embryos. This increase in fitness was explained by our CFD simulations: in lotic habitats, slender shells experience less drag and lift forces compared to globular shells. We found no correlation between foot size and shell shape or aperture area showing that the assumed aperture/foot area correlation should be used with caution and cannot be generalized for all aquatic gastropod species. Finally, shell morphology and foot size were not related to dislodgement speed in our flow tank experiment. We concluded that the relationship of shell morphology and flow velocity is more complex than assumed. Hence, other traits must play a major role in decreasing dislodgement risk in stream gastropods, e.g. specific behaviours or pedal mucus stickiness. Although we did not find that globular shells are adaptations decreasing dislodgement risk, we cannot rule out that they are still flow related adaptations. For instance, globular shells are more crush-resistant and might therefore represent a flow adaptation in terms of diminishing damage caused by tumbling after dislodgement or against lotic specific crush-type predators. At this point, we can conclude that shell morphology in P. antipodarum varies at least in part as an adaptation to specific environmental factors. This study shows how essential it is to reveal how plastic, genetically as well as phenotypically, adaptive traits in species can be and to identify the causal factors and how these adaptations affect the fitness in order to better predict how organisms will cope with changing environmental conditions.

White spruce (Picea glauca (Moench) Voss) is one of the most common conifers in Alaska and various treelines mark the species distribution range. Because treelines positions are driven by climate and because climate change is estimated to be strongest in northern latitudes, treeline shifts appear likely. However, species range shifts depend on various species parameters, probably most importantly on phenotypic plasticity, genetic adaptation and dispersal. Due to their long generation cycles and their immobility, trees evolved to endure a wide variety of climatic conditions. In most locations, interannual climate variability is larger than the expected climate change until 2100. Thus treeline position is typically thought of as the integrated effect of multiple years and to lag behind gradual climate change by several decades. Past dendrochronological studies revealed that growth of white spruce in Alaska can be limited by several climatic variables, in particular water stress and low temperatures. Depending on how the intensity of climate warming, this could result in a leading range edge at treelines limited by low temperatures and trailing treelines where soil moisture is or becomes most limiting. Climate-growth correlations are the dendrochronological version of reaction norms and describe the relationship between an environmental variable and traits like tree-ring parameters (e.g. ring width, wood density, wood anatomy). These correlations can be used to explore potential effects of climate change on a target species. However, it is known that individuals differ with respect to multiple variables like size, age, microsite conditions, competition status or their genome. Such individual differences could be important because they can modulate climate-growth relationships and consequently also range shifts and growth trends. Removing individual differences by averaging tree-ring parameters of many individuals into site chronologies could be an oversimplification that might bias estimates of future white spruce performance. Population dynamics that emerge from the interactions of individuals (e.g. competition) and the range of reactions to the same environmental drivers can only be studied via individual tree analyses. Consequently, this thesis focuses on factors that might alter individual white spruce’ climate sensitivity and methods to assess such effects. In particular, the research articles included explore three topics: 1. First, clones were identified via microsatellites and high-frequency climate signals of clones were compared to that of non-clonal individuals. Clonal and non-clonal individuals showed similar high-frequency climate signals which allows to use clonal and non-clonal individuals to construct mean site chronologies. However, clones were more frequently found under the harsher environmental conditions at the treelines which could be of interest for the species survival strategy at alpine treelines and is further explored in the associated RESPONSE project A5 by David Würth. 2. In the second article, methods for the exploration and visualization of individual-tree differences in climate sensitivity are described. These methods represent a toolbox to explore causes for the variety of different climate sensitivities found in individual trees at the same site. Though, overlaying gradients of multiple factors like temperature, tree density and/or tree height can make it difficult to attribute a single cause to the range of reaction norms (climate growth correlations). 3. Lastly, the third article attempts to disentangle the effect of age and size on climate-growth correlations. Multiple past studies found that trees of different Ages responded differently to climatic drivers. In contrast, other studies found that trees do not age like many other organisms. Age and size of a trees are roughly correlated, though there are large differences in the growth rate of trees, which can lead to smaller trees that are older than taller trees. Consequently, age is an imperfect Proxy for size and in contrast to age, size has been shown to affect wood anatomy and thus tree physiology. The article compares two tree-age methods and one tree-size method based on cumulative ring width. In line with previous research on aging and Wood anatomy, tree size appeared to be the best predictor to explain ontogenetic changes in white spruce’ climate sensitivity. In particular, tallest trees exhibited strongest correlations with water stress in previous year July. In conclusion, this thesis is about factors that can alter climate-growth relationships (reaction norms) of white spruce. The results emphasize that interactions between climate variables and other factors like tree size or competition status are important for estimates of future tree growth and potential treeline shifts. In line with previous studies on white spruce in Alaska, the results of this thesis underline the importance of water stress for white spruce. Individuals that are taller and that have more competitors for water appear to be most susceptible to the potentially drier future climate in Alaska. While tree ring based growth trends estimates of white spruce are difficult to derive due to multiple overlaying low frequency (>10 years) signals, all investigated treeline sites showed highest growth at the treeline edge. This could indicate expanding range edges. However, a potential bottleneck for treeline advances and retreats could be seedling establishment, which should be explored in more detail in the future.

The synthesis of pterin-dithiolene ligands was achieved by employing the radical nucleophilic substitution, i.e. the so-called “Minisci- Reaction”1. This protocol was used for the first time by Professor W. Pfleiderer on pterin substrates2 and proved a powerful method for the preparation of 6 acyl-pterins in course of this work. Subsequent construction of the dithiolene ring facilitates the synthesis of pterin-dithiolene ligands with completely unprotected pterin moieti. The molybdenum cofactor is probably one of the most relevant discoveries in the recent history of pterin chemistry and biochemistry. Many efforts have been made for the preparation of compounds able to mimic the features of the Moco ligand system called "Molybdopterin". In fact, the study of MPT models enables a deeper understanding of the “mechanism of function” of this cofactor and most importantly, lays the foundation for a potential treatment for the Moco related diseases MoCOD and iSOD.

Unter Verwendung von rekombinanten Schweineleberesterasen wurden zwei Chemoenzymatische Prozesse sukkzessive etabliert, optmiert und im Maßstab vergößert. Es wurden zwei chirale Synthesebausteine beispielhaft hergestellt und charakterisiert. Die Arbeit gibt einen Einblick in die Prozessoptimierung von chemoenzymatischen Syntheserouten unter ökonomischen Aspekten.