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During the last decades, therapeutical proteins have risen to great significance in the pharmaceutical industry. As non-human proteins that are introduced into the human body cause a distinct immune system reaction that triggers their rapid clearance, most newly approved protein pharmaceuticals are shielded by modification with synthetic polymers to significantly improve their blood circulation time. All such clinically approved protein-polymer conjugates contain polyethylene glycol (PEG) and its conjugation is denoted as PEGylation. However, many patients develop anti-PEG antibodies which cause a rapid clearance of PEGylated molecules upon repeated administration. Therefore, the search for alternative polymers that can replace PEG in therapeutic applications has become important. In addition, although the blood circulation time is significantly prolonged, the therapeutic activity of some conjugates is decreased compared to the unmodified protein. The reason is that these conjugates are formed by the traditional conjugation method that addresses the protein's lysine side chains. As proteins have many solvent exposed lysines, this results in a somewhat uncontrolled attachment of polymer chains, leading to a mixture of regioisomers, with some of them eventually affecting the therapeutic performance.
This thesis investigates a novel method for ligating macromolecules in a site-specific manner, using enzymatic catalysis. Sortase A is used as the enzyme: It is a well-studied transpeptidase which is able to catalyze the intermolecular ligation of two peptides. This process is commonly referred to as sortase-mediated ligation (SML). SML constitutes an equilibrium reaction, which limits product yield. Two previously reported methods to overcome this major limitation were tested with polymers without using an excessive amount of one reactant.
Specific C- or N-terminal peptide sequences (recognition sequence and nucleophile) as part of the protein are required for SML. The complementary peptide was located at the polymer chain end. Grafting-to was used to avoid damaging the protein during polymerization. To be able to investigate all possible combinations (protein-recognition sequence and nucleophile-protein as well as polymer-recognition sequence and nucleophile-polymer) all necessary building blocks were synthesized. Polymerization via reversible deactivation radical polymerization (RDRP) was used to achieve a narrow molecular weight distribution of the polymers, which is required for therapeutic use.
The synthesis of the polymeric building blocks was started by synthesizing the peptide via automated solid-phase peptide synthesis (SPPS) to avoid post-polymerization attachment and to enable easy adaptation of changes in the peptide sequence. To account for the different functionalities (free N- or C-terminus) required for SML, different linker molecules between resin and peptide were used.
To facilitate purification, the chain transfer agent (CTA) for reversible addition-fragmentation chain-transfer (RAFT) polymerization was coupled to the resin-immobilized recognition sequence peptide. The acrylamide and acrylate-based monomers used in this thesis were chosen for their potential to replace PEG.
Following that, surface-initiated (SI) ATRP and RAFT polymerization were attempted, but failed. As a result, the newly developed method of xanthate-supported photo-iniferter (XPI) RAFT polymerization in solution was used successfully to obtain a library of various peptide-polymer conjugates with different chain lengths and narrow molar mass distributions.
After peptide side chain deprotection, these constructs were used first to ligate two polymers via SML, which was successful but revealed a limit in polymer chain length (max. 100 repeat units). When utilizing equimolar amounts of reactants, the use of Ni2+ ions in combination with a histidine after the recognition sequence to remove the cleaved peptide from the equilibrium maximized product formation with conversions of up to 70 %.
Finally, a model protein and a nanobody with promising properties for therapeutical use were biotechnologically modified to contain the peptide sequences required for SML. Using the model protein for C- or N-terminal SML with various polymers did not result in protein-polymer conjugates. The reason is most likely the lack of accessibility of the protein termini to the enzyme. Using the nanobody for C-terminal SML, on the other hand, was successful. However, a similar polymer chain length limit was observed as in polymer-polymer SML. Furthermore, in case of the synthesis of protein-polymer conjugates, it was more effective to shift the SML equilibrium by using an excess of polymer than by employing the Ni2+ ion strategy.
Overall, the experimental data from this work provides a good foundation for future research in this promising field; however, more research is required to fully understand the potential and limitations of using SML for protein-polymer synthesis. In future, the method explored in this dissertation could prove to be a very versatile pathway to obtain therapeutic protein-polymer conjugates that exhibit high activities and long blood circulation times.
Die Digitalisierung ist ein wesentlicher Bestandteil aktueller Verwaltungsreformen. Trotz der hohen Bedeutung und langjähriger Bemühungen bleibt die Bilanz der Verwaltungsdigitalisierung in Deutschland ambivalent. Diese Studie konzentriert sich auf drei erfolgreiche Digitalisierungsvorhaben aus dem Onlinezugangsgesetz (OZG) und analysiert mittels problemzentrierter Expertenbefragung Einflussfaktoren auf die Umsetzung von OZG-Vorhaben und den Einfluss des Managements in diesem Prozess. Die Analyse erfolgt theoriegeleitet basierend auf dem Ansatz der begrenzten Rationalität und der ökonomischen Theorie der Bürokratie. Die Ergebnisse zeigen, dass anzunehmen ist, dass die identifizierten Einflussfaktoren unterschiedlich auf Nachnutzbarkeit und Reifegrad von Verwaltungsleistungen wirken und als Folgen begrenzter Rationalität im menschlichen Problemlösungsprozess interpretiert werden können. Managerinnen unterstützen die operativen Akteure bei der Umsetzung, indem sie deren begrenzte Rationalität mit geeigneten Strategien adressieren. Dazu können sie Ressourcen bereitstellen, mit ihrer Expertise unterstützen, Informationen zugänglich machen, Entscheidungswege verändern sowie zur Konfliktlösung beitragen. Die Studie bietet wertvolle Einblicke in die tatsächliche Managementpraxis und leitet daraus Empfehlungen für die Umsetzung öffentlicher Digitalisierungsvorhaben sowie für die Steuerung öffentlicher Verwaltungen ab. Diese Studie liefert einen wichtigen Beitrag zum Verständnis des Einflusses des Managements in der Verwaltungsdigitalisierung. Die Studie unterstreicht außerdem die Notwendigkeit weiterer Forschung in diesem Bereich, um die Praktiken und Herausforderungen der Verwaltungsdigitalisierung besser zu verstehen und effektiv zu adressieren.
This thesis explores word order variability in verb-final languages. Verb-final languages have a reputation for a high amount of word order variability. However, that reputation amounts to an urban myth due to a lack of systematic investigation. This thesis provides such a systematic investigation by presenting original data from several verb-final languages with a focus on four Uralic ones: Estonian, Udmurt, Meadow Mari, and South Sámi. As with every urban myth, there is a kernel of truth in that many unrelated verb-final languages share a particular kind of word order variability, A-scrambling, in which the fronted elements do not receive a special information-structural role, such as topic or contrastive focus. That word order variability goes hand in hand with placing focussed phrases further to the right in the position directly in front of the verb. Variations on this pattern are exemplified by Uyghur, Standard Dargwa, Eastern Armenian, and three of the Uralic languages, Estonian, Udmurt, and Meadow Mari. So far for the kernel of truth, but the fourth Uralic language, South Sámi, is comparably rigid and does not feature this particular kind of word order variability. Further such comparably rigid, non-scrambling verb-final languages are Dutch, Afrikaans, Amharic, and Korean. In contrast to scrambling languages, non-scrambling languages feature obligatory subject movement, causing word order rigidity next to other typical EPP effects.
The EPP is a defining feature of South Sámi clause structure in general. South Sámi exhibits a one-of-a-kind alternation between SOV and SAuxOV order that is captured by the assumption of the EPP and obligatory movement of auxiliaries but not lexical verbs. Other languages that allow for SAuxOV order either lack an alternation because the auxiliary is obligatorily present (Macro-Sudan SAuxOVX languages), or feature an alternation between SVO and SAuxOV (Kru languages; V2 with underlying OV as a fringe case). In the SVO–SAuxOV languages, both auxiliaries and lexical verbs move. Hence, South Sámi shows that the textbook difference between the VO languages English and French, whether verb movement is restricted to auxiliaries, also extends to OV languages. SAuxOV languages are an outlier among OV languages in general but are united by the presence of the EPP.
Word order variability is not restricted to the preverbal field in verb-final languages, as most of them feature postverbal elements (PVE). PVE challenge the notion of verb-finality in a language. Strictly verb-final languages without any clause-internal PVE are rare. This thesis charts the first structural and descriptive typology of PVE. Verb-final languages vary in the categories they allow as PVE. Allowing for non-oblique PVE is a pivotal threshold: when non-oblique PVE are allowed, PVE can be used for information-structural effects. Many areally and genetically unrelated languages only allow for given PVE but differ in whether the PVE are contrastive. In those languages, verb-finality is not at stake since verb-medial orders are marked. In contrast, the Uralic languages Estonian and Udmurt allow for any PVE, including information focus. Verb-medial orders can be used in the same contexts as verb-final orders without semantic and pragmatic differences. As such, verb placement is subject to actual free variation. The underlying verb-finality of Estonian and Udmurt can only be inferred from a range of diagnostics indicating optional verb movement in both languages. In general, it is not possible to account for PVE with a uniform analysis: rightwards merge, leftward verb movement, and rightwards phrasal movement are required to capture the cross- and intralinguistic variation.
Knowing that a language is verb-final does not allow one to draw conclusions about word order variability in that language. There are patterns of homogeneity, such as the word order variability driven by directly preverbal focus and the givenness of postverbal elements, but those are not brought about by verb-finality alone. Preverbal word order variability is restricted by the more abstract property of obligatory subject movement, whereas the determinant of postverbal word order variability has to be determined in the future.
The automotive industry is a prime example of digital technologies reshaping mobility. Connected, autonomous, shared, and electric (CASE) trends lead to new emerging players that threaten existing industrial-aged companies. To respond, incumbents need to bridge the gap between contrasting product architecture and organizational principles in the physical and digital realms. Over-the-air (OTA) technology, that enables seamless software updates and on-demand feature additions for customers, is an example of CASE-driven digital product innovation. Through an extensive longitudinal case study of an OTA initiative by an industrial- aged automaker, this dissertation explores how incumbents accomplish digital product innovation. Building on modularity, liminality, and the mirroring hypothesis, it presents a process model that explains the triggers, mechanisms, and outcomes of this process. In contrast to the literature, the findings emphasize the primacy of addressing product architecture challenges over organizational ones and highlight the managerial implications for success.
Human activities modify nature worldwide via changes in the environment, biodiversity and the functioning of ecosystems, which in turn disrupt ecosystem services and feed back negatively on humans. A pressing challenge is thus to limit our impact on nature, and this requires detailed understanding of the interconnections between the environment, biodiversity and ecosystem functioning. These three components of ecosystems each include multiple dimensions, which interact with each other in different ways, but we lack a comprehensive picture of their interconnections and underlying mechanisms. Notably, diversity is often viewed as a single facet, namely species diversity, while many more facets exist at different levels of biological organisation (e.g. genetic, phenotypic, functional, multitrophic diversity), and multiple diversity facets together constitute the raw material for adaptation to environmental changes and shape ecosystem functioning. Consequently, investigating the multidimensionality of ecosystems, and in particular the links between multifaceted diversity, environmental changes and ecosystem functions, is crucial for ecological research, management and conservation. This thesis aims to explore several aspects of this question theoretically.
I investigate three broad topics in this thesis. First, I focus on how food webs with varying levels of functional diversity across three trophic levels buffer environmental changes, such as a sudden addition of nutrients or long-term changes (e.g. warming or eutrophication). I observed that functional diversity generally enhanced ecological stability (i.e. the buffering capacity of the food web) by increasing trophic coupling. More precisely, two aspects of ecological stability (resistance and resilience) increased even though a third aspect (the inverse of the time required for the system to reach its post-perturbation state) decreased with increasing functional diversity. Second, I explore how several diversity facets served as a raw material for different sources of adaptation and how these sources affected multiple ecosystem functions across two trophic levels. Considering several sources of adaptation enabled the interplay between ecological and evolutionary processes, which affected trophic coupling and thereby ecosystem functioning. Third, I reflect further on the multifaceted nature of diversity by developing an index K able to quantify the facet of functional diversity, which is itself multifaceted. K can provide a comprehensive picture of functional diversity and is a rather good predictor of ecosystem functioning. Finally I synthesise the interdependent mechanisms (complementarity and selection effects, trophic coupling and adaptation) underlying the relationships between multifaceted diversity, ecosystem functioning and the environment, and discuss the generalisation of my findings across ecosystems and further perspectives towards elaborating an operational biodiversity-ecosystem functioning framework for research and conservation.
Homomorphisms are a fundamental concept in mathematics expressing the similarity of structures. They provide a framework that captures many of the central problems of computer science with close ties to various other fields of science. Thus, many studies over the last four decades have been devoted to the algorithmic complexity of homomorphism problems. Despite their generality, it has been found that non-uniform homomorphism problems, where the target structure is fixed, frequently feature complexity dichotomies. Exploring the limits of these dichotomies represents the common goal of this line of research.
We investigate the problem of counting homomorphisms to a fixed structure over a finite field of prime order and its algorithmic complexity. Our emphasis is on graph homomorphisms and the resulting problem #_{p}Hom[H] for a graph H and a prime p. The main research question is how counting over a finite field of prime order affects the complexity.
In the first part of this thesis, we tackle the research question in its generality and develop a framework for studying the complexity of counting problems based on category theory. In the absence of problem-specific details, results in the language of category theory provide a clear picture of the properties needed and highlight common ground between different branches of science. The proposed problem #Mor^{C}[B] of counting the number of morphisms to a fixed object B of C is abstract in nature and encompasses important problems like constraint satisfaction problems, which serve as a leading example for all our results. We find explanations and generalizations for a plethora of results in counting complexity. Our main technical result is that specific matrices of morphism counts are non-singular. The strength of this result lies in its algebraic nature. First, our proofs rely on carefully constructed systems of linear equations, which we know to be uniquely solvable. Second, by exchanging the field that the matrix is defined by to a finite field of order p, we obtain analogous results for modular counting. For the latter, cancellations are implied by automorphisms of order p, but intriguingly we find that these present the only obstacle to translating our results from exact counting to modular counting. If we restrict our attention to reduced objects without automorphisms of order p, we obtain results analogue to those for exact counting. This is underscored by a confluent reduction that allows this restriction by constructing a reduced object for any given object. We emphasize the strength of the categorial perspective by applying the duality principle, which yields immediate consequences for the dual problem of counting the number of morphisms from a fixed object.
In the second part of this thesis, we focus on graphs and the problem #_{p}Hom[H]. We conjecture that automorphisms of order p capture all possible cancellations and that, for a reduced graph H, the problem #_{p}Hom[H] features the complexity dichotomy analogue to the one given for exact counting by Dyer and Greenhill. This serves as a generalization of the conjecture by Faben and Jerrum for the modulus 2. The criterion for tractability is that H is a collection of complete bipartite and reflexive complete graphs. From the findings of part one, we show that the conjectured dichotomy implies dichotomies for all quantum homomorphism problems, in particular counting vertex surjective homomorphisms and compactions modulo p. Since the tractable cases in the dichotomy are solved by trivial computations, the study of the intractable cases remains. As an initial problem in a series of reductions capable of implying hardness, we employ the problem of counting weighted independent sets in a bipartite graph modulo prime p. A dichotomy for this problem is shown, stating that the trivial cases occurring when a weight is congruent modulo p to 0 are the only tractable cases. We reduce the possible structure of H to the bipartite case by a reduction to the restricted homomorphism problem #_{p}Hom^{bip}[H] of counting modulo p the number of homomorphisms between bipartite graphs that maintain a given order of bipartition. This reduction does not have an impact on the accessibility of the technical results, thanks to the generality of the findings of part one. In order to prove the conjecture, it suffices to show that for a connected bipartite graph that is not complete, #_{p}Hom^{bip}[H] is #_{p}P-hard. Through a rigorous structural study of bipartite graphs, we establish this result for the rich class of bipartite graphs that are (K_{3,3}\{e}, domino)-free. This overcomes in particular the substantial hurdle imposed by squares, which leads us to explore the global structure of H and prove the existence of explicit structures that imply hardness.
Among the different meanings carried by numerical information, cardinality is fundamental for survival and for the development of basic as well as of higher numerical skills. Importantly, the human brain inherits from evolution a predisposition to map cardinality onto space, as revealed by the presence of spatial-numerical associations (SNAs) in humans and animals. Here, the mapping of cardinal information onto physical space is addressed as a hallmark signature characterizing numerical cognition.
According to traditional approaches, cognition is defined as complex forms of internal information processing, taking place in the brain (cognitive processor). On the contrary, embodied cognition approaches define cognition as functionally linked to perception and action, in the continuous interaction between a biological body and its physical and sociocultural environment.
Embracing the principles of the embodied cognition perspective, I conducted four novel studies designed to unveil how SNAs originate, develop, and adapt, depending on characteristics of the organism, the context, and their interaction. I structured my doctoral thesis in three levels. At the grounded level (Study 1), I unfold the biological foundations underlying the tendency to map cardinal information across space; at the embodied level (Study 2), I reveal the impact of atypical motor development on the construction of SNAs; at the situated level (Study 3), I document the joint influence of visuospatial attention and task properties on SNAs. Furthermore, I experimentally investigate the presence of associations between physical and numerical distance, another numerical property fundamental for the development of efficient mathematical minds (Study 4).
In Study 1, I present the Brain’s Asymmetric Frequency Tuning hypothesis that relies on hemispheric asymmetries for processing spatial frequencies, a low-level visual feature that the (in)vertebrate brain extracts from any visual scene to create a coherent percept of the world. Computational analyses of the power spectra of the original stimuli used to document the presence of SNAs in human newborns and animals, support the brain’s asymmetric frequency tuning as a theoretical account and as an evolutionarily inherited mechanism scaffolding the universal and innate tendency to represent cardinality across horizontal space.
In Study 2, I explore SNAs in children with rare genetic neuromuscular diseases: spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). SMA children never accomplish independent motoric exploration of their environment; in contrast, DMD children do explore but later lose this ability. The different SNAs reported by the two groups support the critical role of early sensorimotor experiences in the spatial representation of cardinality.
In Study 3, I directly compare the effects of overt attentional orientation during explicit and implicit processing of numerical magnitude. First, the different effects of attentional orienting based on the type of assessment support different mechanisms underlying SNAs during explicit and implicit assessment of numerical magnitude. Secondly, the impact of vertical shifts of attention on the processing of numerical distance sheds light on the correspondence between numerical distance and peri-personal distance.
In Study 4, I document the presence of different SNAs, driven by numerical magnitude and numerical distance, by employing different response mappings (left vs. right and near vs. distant).
In the field of numerical cognition, the four studies included in the present thesis contribute to unveiling how the characteristics of the organism and the environment influence the emergence, the development, and the flexibility of our attitude to represent cardinal information across space, thus supporting the predictions of the embodied cognition approach. Furthermore, they inform a taxonomy of body-centred factors (biological properties of the brain and sensorimotor system) modulating the spatial representation of cardinality throughout the course of life, at the grounded, embodied, and situated levels.
If the awareness for different variables influencing SNAs over the course of life is important, it is equally important to consider the organism as a whole in its sensorimotor interaction with the world. Inspired by my doctoral research, here I propose a holistic perspective that considers the role of evolution, embodiment, and environment in the association of cardinal information with directional space. The new perspective advances the current approaches to SNAs, both at the conceptual and at the methodological levels.
Unveiling how the mental representation of cardinality emerges, develops, and adapts is necessary to shape efficient mathematical minds and achieve economic productivity, technological progress, and a higher quality of life.
Water stored in the unsaturated soil as soil moisture is a key component of the hydrological cycle influencing numerous hydrological processes including hydrometeorological extremes. Soil moisture influences flood generation processes and during droughts when precipitation is absent, it provides plant with transpirable water, thereby sustaining plant growth and survival in agriculture and natural ecosystems.
Soil moisture stored in deeper soil layers e.g. below 100 cm is of particular importance for providing plant transpirable water during dry periods. Not being directly connected to the atmosphere and located outside soil layers with the highest root densities, water in these layers is less susceptible to be rapidly evaporated and transpired. Instead, it provides longer-term soil water storage increasing the drought tolerance of plants and ecosystems.
Given the importance of soil moisture in the context of hydro-meteorological extremes in a warming climate, its monitoring is part of official national adaption strategies to a changing climate. Yet, soil moisture is highly variable in time and space which challenges its monitoring on spatio-temporal scales relevant for flood and drought risk modelling and forecasting.
Introduced over a decade ago, Cosmic-Ray Neutron Sensing (CRNS) is a noninvasive geophysical method that allows for the estimation of soil moisture at relevant spatio-temporal scales of several hectares at a high, subdaily temporal resolution. CRNS relies on the detection of secondary neutrons above the soil surface which are produced from high-energy cosmic-ray particles in the atmosphere and the ground. Neutrons in a specific epithermal energy range are sensitive to the amount of hydrogen present in the surroundings of the CRNS neutron detector. Due to same mass as the hydrogen nucleus, neutrons lose kinetic energy upon collision and are subsequently absorbed when reaching low, thermal energies. A higher amount of hydrogen therefore leads to fewer neutrons being detected per unit time. Assuming that the largest amount of hydrogen is stored in most terrestrial ecosystems as soil moisture, changes of soil moisture can be estimated through an inverse relationship with observed neutron intensities.
Although important scientific advancements have been made to improve the methodological framework of CRNS, several open challenges remain, of which some are addressed in the scope of this thesis. These include the influence of atmospheric variables such as air pressure and absolute air humidity, as well as, the impact of variations in incoming primary cosmic-ray intensity on observed epithermal and thermal neutron signals and their correction. Recently introduced advanced neutron-to-soil moisture transfer functions are expected to improve CRNS-derived soil moisture estimates, but potential improvements need to be investigated at study sites with differing environmental conditions. Sites with strongly heterogeneous, patchy soil moisture distributions challenge existing transfer functions and further research is required to assess the impact of, and correction of derived soil moisture estimates under heterogeneous site conditions. Despite its capability of measuring representative averages of soil moisture at the field scale, CRNS lacks an integration depth below the first few decimetres of the soil. Given the importance of soil moisture also in deeper soil layers, increasing the observational window of CRNS through modelling approaches or in situ measurements is of high importance for hydrological monitoring applications.
By addressing these challenges, this thesis aids to closing knowledge gaps and finding answers to some of the open questions in CRNS research. Influences of different environmental variables are quantified, correction approaches are being tested and developed. Neutron-to-soil moisture transfer functions are evaluated and approaches to reduce effects of heterogeneous soil moisture distributions are presented. Lastly, soil moisture estimates from larger soil depths are derived from CRNS through modified, simple modelling approaches and in situ estimates by using CRNS as a downhole technique. Thereby, this thesis does not only illustrate the potential of new, yet undiscovered applications of CRNS in future but also opens a new field of CRNS research. Consequently, this thesis advances the methodological framework of CRNS for above-ground and downhole applications. Although the necessity of further research in order to fully exploit the potential of CRNS needs to be emphasised, this thesis contributes to current hydrological research and not least to advancing hydrological monitoring approaches being of utmost importance in context of intensifying hydro-meteorological extremes in a changing climate.
Overcoming natural biomass limitations in gram-negative bacteria through synthetic carbon fixation
(2024)
The carbon demands of an ever-increasing human population and the concomitant rise in net carbon emissions requires CO2 sequestering approaches for production of carbon-containing molecules. Microbial production of carbon-containing products from plant-based sugars could replace current fossil-based production. However, this form of sugar-based microbial production directly competes with human food supply and natural ecosystems. Instead, one-carbon feedstocks derived from CO2 and renewable energy were proposed as an alternative. The one carbon molecule formate is a stable, readily soluble and safe-to-store energetic mediator that can be electrochemically generated from CO2 and (excess off-peak) renewable electricity. Formate-based microbial production could represent a promising approach for a circular carbon economy. However, easy-to-engineer and efficient formate-utilizing microbes are lacking. Multiple synthetic metabolic pathways were designed for better-than-nature carbon fixation. Among them, the reductive glycine pathway was proposed as the most efficient pathway for aerobic formate assimilation. While some of these pathways have been successfully engineered in microbial hosts, these synthetic strains did so far not exceed the performance of natural strains. In this work, I engineered and optimized two different synthetic formate assimilation pathways in gram-negative bacteria to exceed the limits of a natural carbon fixation pathway, the Calvin cycle.
The first chapter solidified Cupriavidus necator as a promising formatotrophic host to produce value-added chemicals. The formate tolerance of C. necator was assessed and a production pathway for crotonate established in a modularized fashion. Last, bioprocess optimization was leveraged to produce crotonate from formate at a titer of 148 mg/L.
In the second chapter, I chromosomally integrated and optimized the synthetic reductive glycine pathway in C. necator using a transposon-mediated selection approach. The insertion methodology allowed selection for condition-specific tailored pathway expression as improved pathway performance led to better growth. I then showed my engineered strains to exceed the biomass yields of the Calvin cycle utilizing wildtype C. necator on formate. This demonstrated for the first time the superiority of a synthetic formate assimilation pathway and by extension of synthetic carbon fixation efforts as a whole.
In chapter 3, I engineered a segment of a synthetic carbon fixation cycle in Escherichia coli. The GED cycle was proposed as a Calvin cycle alternative that does not perform a wasteful oxygenation reaction and is more energy efficient. The pathways simple architecture and reasonable driving force made it a promising candidate for enhanced carbon fixation. I created a deletion strain that coupled growth to carboxylation via the GED pathway segment. The CO2 dependence of the engineered strain and 13C-tracer analysis confirmed operation of the pathway in vivo.
In the final chapter, I present my efforts of implementing the GED cycle also in C. necator, which might be a better-suited host, as it is accustomed to formatotrophic and hydrogenotrophic growth. To provide the carboxylation substrate in vivo, I engineered C. necator to utilize xylose as carbon source and created a selection strain for carboxylase activity. I verify activity of the key enzyme, the carboxylase, in the decarboxylative direction. Although CO2-dependent growth of the strain was not obtained, I showed that all enzymes required for operation of the GED cycle are active in vivo in C. necator.
I then evaluate my success with engineering a linear and cyclical one-carbon fixation pathway in two different microbial hosts. The linear reductive glycine pathway presents itself as a much simpler metabolic solution for formate dependent growth over the sophisticated establishment of hard-to-balance carbon fixation cycles. Last, I highlight advantages and disadvantages of C. necator as an upcoming microbial benchmark organism for synthetic metabolism efforts and give and outlook on its potential for the future of C1-based manufacturing.
Skepticism
(2022)
This dissertation offers new and original readings of three major texts in the history of Western philosophy: Descartes’s “First Meditation,” Kant’s “Transcendental Deduction,” and his “Refutation of Idealism.” The book argues that each text addresses the problem of skepticism and posits that they have a hitherto underappreciated, organic relationship to one another. The dissertation begins with an analysis of Descartes’ “First Meditation,” which I argue offers two distinct and independent skeptical arguments that differ in both aim and scope. I call these arguments the “veil of ideas” argument and the “author of my origin” argument. My reading counters the standard interpretation of the text, which sees it as offering three stages of doubt, namely the occasional fallibility of the senses, the dream hypothesis, and the evil demon hypothesis. Building on this, the central argument of the dissertation is that Kant’s “Transcendental Deduction” actually transforms and radicalizes Descartes’s Author of My Origin argument, reconceiving its meaning within the framework of Kant’s own transcendental idealist philosophy. Finally, I argue that the Refutation of Idealism offers a similarly radicalized version of Descartes’s Veil of Ideas argument, albeit translated into the framework of transcendental idealism.
The experience of premenstrual syndrome (PMS) affects up to 90% of individuals with an active menstrual cycle and involves a spectrum of aversive physiological and psychological symptoms in the days leading up to menstruation (Tschudin et al., 2010). Despite its high prevalence, the precise origins of PMS remain elusive, with influences ranging from hormonal fluctuations to cognitive, social, and cultural factors (Hunter, 2007; Matsumoto et al., 2013).
Biologically, hormonal fluctuations, particularly in gonadal steroids, are commonly believed to be implicated in PMS, with the central factor being varying susceptibilities to the fluctuations between individuals and cycles (Rapkin & Akopians, 2012). Allopregnanolone (ALLO), a neuroactive steroid and progesterone metabolite, has emerged as a potential link to PMS symptoms (Hantsoo & Epperson, 2020). ALLO is a positive allosteric modulator of the GABAA receptor, influencing inhibitory communication (Rupprecht, 2003; Andréen et al., 2006). Different susceptibility to ALLO fluctuations throughout the cycle may lead to reduced GABAergic signal transmission during the luteal phase of the menstrual cycle.
The GABAergic system's broad influence leads to a number of affected physiological systems, including a consistent reduction in vagally mediated heart rate variability (vmHRV) during the luteal phase (Schmalenberger et al., 2019). This reduction in vmHRV is more pronounced in individuals with high PMS symptoms (Baker et al., 2008; Matsumoto et al., 2007). Fear conditioning studies have shown inconsistent associations with cycle phases, suggesting a complex interplay between physiological parameters and PMS-related symptoms (Carpenter et al., 2022; Epperson et al., 2007; Milad et al., 2006).
The neurovisceral integration model posits that vmHRV reflects the capacity of the central autonomous network (CAN), which is responsible for regulatory processes on behavioral, cognitive, and autonomous levels (Thayer & Lane, 2000, 2009). Fear learning, mediated within the CAN, is suggested to be indicative of vmHRV's capacity for successful
VI
regulation (Battaglia & Thayer, 2022). Given the GABAergic mediation of central inhibitory functional connectivity in the CAN, which may be affected by ALLO fluctuations, this thesis proposes that fluctuating CAN activity in the luteal phase contributes to diverse aversive symptoms in PMS.
A research program was designed to empirically test these propositions. Study 1 investigated fear discrimination during different menstrual cycle phases and its interaction with vmHRV, revealing nuanced effects on acoustic startle response and skin conductance response. While there was heightened fear discrimination in acoustic startle responses in participants in the luteal phase, there was an interaction between menstrual cycle phase and vmHRV in skin conductance responses. In this measure, heightened fear discrimination during the luteal phase was only visible in individuals with high resting vmHRV; those with low vmHRV showed reduced fear discrimination and higher overall responses.
Despite affecting the vast majority of menstruating people, there are very limited tools available to reliably assess these symptoms in the German speaking area. Study 2 aimed at closing this gap, by translating and validating a German version of the short version of the Premenstrual Assessment Form (Allen et al., 1991), providing a reliable tool for future investigations, which closes the gap in PMS questionnaires in the German-speaking research area.
Study 3 employed a diary study paradigm to explore daily associations between vmHRV and PMS symptoms. The results showed clear simultaneous fluctuations between the two constructs with a peak in PMS and a low point in vmHRV a few days before menstruation onset. The association between vmHRV and PMS was driven by psychological PMS symptoms.
Based on the theoretical considerations regarding the neurovisceral perspective on PMS, another interesting construct to consider is attentional control, as it is closely related to functions of the CAN. Study 4 delved into attentional control and vmHRV differences between menstrual cycle phases, demonstrating an interaction between cycle phase and PMS symptoms. In a pilot, we found reduced vmHRV and attentional control during the luteal phase only in participants who reported strong PMS.
While Studies 1-4 provided evidence for the mechanisms underlying PMS, Studies 5 and 6 investigated short- and long-term intervention protocols to ameliorate PMS symptomatology. Study 5 explored the potential of heart rate variability biofeedback (HRVB) in alleviating PMS symptoms and a number of other outcome measures. In a waitlist-control design, participants underwent a 4-week smartphone-based HRVB intervention. The results revealed positive effects on PMS, with larger effect sizes on psychological symptoms, as well as on depressive symptoms, anxiety/stress and attentional control.
Finally, Study 6 examined the acute effects of HRVB on attentional control. The study found positive impact but only in highly stressed individuals.
The thesis, based on this comprehensive research program, expands our understanding of PMS as an outcome of CAN fluctuations mediated by GABAA receptor reactivity. The results largely support the model. These findings not only deepen our understanding of PMS but also offer potential avenues for therapeutic interventions. The promising results of smartphone-based HRVB training suggest a non-pharmacological approach to managing PMS symptoms, although further research is needed to confirm its efficacy.
In conclusion, this thesis illuminates the complex web of factors contributing to PMS, providing valuable insights into its etiological underpinnings and potential interventions. By elucidating the relationships between hormonal fluctuations, CAN activity, and psychological responses, this research contributes to more effective treatments for individuals grappling with the challenges of PMS. The findings hold promise for improving the quality of life for those affected by this prevalent and often debilitating condition.
Der Semi-Parlamentarismus beschreibt das Regierungssystem, in dem die Regierung von einem Teil des Parlaments gewählt wird und abberufen werden kann, von einem anderen Teil des Parlaments aber unabhängig ist. Beide Kammern müssen dabei der Gesetzgebung zustimmen. Dieses von Steffen Ganghof klassifizierte System ergänzt gängige Regierungssystemtypologien, wie sie beispielsweise von David Samuels und Matthew Shugart genutzt werden. Der Semi-Parlamentarismus ist der logische Gegenpart zum Semi-Präsidentialismus, bei dem nur ein Teil der Exekutive von der Legislative abhängt, während im Semi-Parlamentarismus die Exekutive von nur einem Teil der Legislative abhängt. Der Semi-Parlamentarismus verkörpert so ein System der Gewaltenteilung ohne einen exekutiven Personalismus, wie er durch die Direktwahl und Unabhängigkeit der Regierungchef:in im Präsidentialismus hervorgerufen wird. Dadurch ist der Semi-Parlamentarismus geeignet, Unterschiede zwischen Parlamentarismus und Präsidentialismus auf den separaten Einfluss der Gewaltenteilung und des exekutiven Personalismus zurückzuführen. Die Untersuchung des Semi-Parlamentarismus ist daher für die Regierungssystemliteratur insgesamt von Bedeutung. Der Semi-Parlamentarismus ist dabei kein rein theoretisches Konstrukt, sondern existiert im australischen Bundesstaat, den australischen Substaaten und Japan.
Die vorliegende Dissertation untersucht erstmals umfassend die Gesetzgebung der semi-parlamentarischen Staaten als solchen. Der Fokus liegt dabei auf den zweiten Kammern, da diese durch die Unabhängigkeit von der Regierung der eigentliche Ort der Gesetzgebung sind. Die Gesetzgebung in Parlamentarismus und Präsidentialismus unterscheidet sich insbesondere in der Geschlossenheit der Parteien, der Koalitionsbildung und dem legislativen Erfolg der Regierungen. Diese Punkte sind daher auch von besonderem Interesse bei der Analyse des Semi-Parlamentarismus. Die semi-parlamentarischen Staaten unterscheiden sich auch untereinander teilweise erheblich in der institutionellen Ausgestaltung wie den Wahlsystemen oder den verfügbaren Mitteln zur Überwindung von Blockadesituationen. Die Darstellung und die Analyse der Auswirkungen dieser Unterschiede auf die Gesetzgebung ist neben dem Vergleich des Semi-Parlamentarismus mit anderen Systemen das zweite wesentliche Ziel dieser Arbeit.
Als Fundament der Analyse habe ich einen umfangreichen Datensatz erhoben, der alle Legislaturperioden der australischen Staaten zwischen 1997 und 2019 umfasst. Wesentliche Bestandteile des Datensatzes sind alle namentlichen Abstimmungen beider Kammern, alle
eingebrachten und verabschiedeten Gesetzen der Regierung sowie die mit Hilfe eines Expert-Surveys erhobenen Parteipositionen in den relevanten Politikfeldern auf substaatlicher Ebene.
Hauptsächlich mit der Hilfe von Mixed-Effects- und Fractional-Response-Analysen kann ich so zeigen, dass der Semi-Parlamentarismus in vielen Aspekten eher parlamentarischen als präsidentiellen Systemen gleicht. Nur die Koalitionsbildung erfolgt deutlich flexibler und unterscheidet sich daher von der typischen parlamentarischen Koalitionsbildung. Die Analysen legen nahe, dass wesentliche Unterschiede zwischen Parlamentarismus und Präsidentialismus eher auf den exekutiven Personalismus als auf die Gewaltenteilung zurückzuführen sind.
Zwischen den semi-parlamentarischen Staaten scheinen vor allem die Kontrolle des Medians beider Parlamentskammern durch die Regierung und die Möglichkeit der Regierung, die zweite Kammer mitaufzulösen, zu entscheidenden Unterschieden in der Gesetzgebung zu führen. Die Kontrolle des Medians ermöglicht eine flexible Koalitionsbildung und führt zu höheren legislativen Erfolgsraten. Ebenso führt eine möglichst leichte Auflösungsmöglichkeit der zweiten Kammern zu höheren legislativen Erfolgsraten. Die Parteigeschlossenheit ist unabhängig von diesen Aspekten in beiden Kammern der semi-parlamentarischen Parlamente sehr hoch.
Deep learning has seen widespread application in many domains, mainly for its ability to learn data representations from raw input data. Nevertheless, its success has so far been coupled with the availability of large annotated (labelled) datasets. This is a requirement that is difficult to fulfil in several domains, such as in medical imaging. Annotation costs form a barrier in extending deep learning to clinically-relevant use cases. The labels associated with medical images are scarce, since the generation of expert annotations of multimodal patient data at scale is non-trivial, expensive, and time-consuming. This substantiates the need for algorithms that learn from the increasing amounts of unlabeled data. Self-supervised representation learning algorithms offer a pertinent solution, as they allow solving real-world (downstream) deep learning tasks with fewer annotations. Self-supervised approaches leverage unlabeled samples to acquire generic features about different concepts, enabling annotation-efficient downstream task solving subsequently.
Nevertheless, medical images present multiple unique and inherent challenges for existing self-supervised learning approaches, which we seek to address in this thesis: (i) medical images are multimodal, and their multiple modalities are heterogeneous in nature and imbalanced in quantities, e.g. MRI and CT; (ii) medical scans are multi-dimensional, often in 3D instead of 2D; (iii) disease patterns in medical scans are numerous and their incidence exhibits a long-tail distribution, so it is oftentimes essential to fuse knowledge from different data modalities, e.g. genomics or clinical data, to capture disease traits more comprehensively; (iv) Medical scans usually exhibit more uniform color density distributions, e.g. in dental X-Rays, than natural images. Our proposed self-supervised methods meet these challenges, besides significantly reducing the amounts of required annotations.
We evaluate our self-supervised methods on a wide array of medical imaging applications and tasks. Our experimental results demonstrate the obtained gains in both annotation-efficiency and performance; our proposed methods outperform many approaches from related literature. Additionally, in case of fusion with genetic modalities, our methods also allow for cross-modal interpretability. In this thesis, not only we show that self-supervised learning is capable of mitigating manual annotation costs, but also our proposed solutions demonstrate how to better utilize it in the medical imaging domain. Progress in self-supervised learning has the potential to extend deep learning algorithms application to clinical scenarios.
Arctic climate change is marked by intensified warming compared to global trends and a significant reduction in Arctic sea ice which can intricately influence mid-latitude atmospheric circulation through tropo- and stratospheric pathways. Achieving accurate simulations of current and future climate demands a realistic representation of Arctic climate processes in numerical climate models, which remains challenging.
Model deficiencies in replicating observed Arctic climate processes often arise due to inadequacies in representing turbulent boundary layer interactions that determine the interactions between the atmosphere, sea ice, and ocean. Many current climate models rely on parameterizations developed for mid-latitude conditions to handle Arctic turbulent boundary layer processes.
This thesis focuses on modified representation of the Arctic atmospheric processes and understanding their resulting impact on large-scale mid-latitude atmospheric circulation within climate models. The improved turbulence parameterizations, recently developed based on Arctic measurements, were implemented in the global atmospheric circulation model ECHAM6. This involved modifying the stability functions over sea ice and ocean for stable stratification and changing the roughness length over sea ice for all stratification conditions. Comprehensive analyses are conducted to assess the impacts of these modifications on ECHAM6's simulations of the Arctic boundary layer, overall atmospheric circulation, and the dynamical pathways between the Arctic and mid-latitudes.
Through a step-wise implementation of the mentioned parameterizations into ECHAM6, a series of sensitivity experiments revealed that the combined impacts of the reduced roughness length and the modified stability functions are non-linear. Nevertheless, it is evident that both modifications consistently lead to a general decrease in the heat transfer coefficient, being in close agreement with the observations.
Additionally, compared to the reference observations, the ECHAM6 model falls short in accurately representing unstable and strongly stable conditions.
The less frequent occurrence of strong stability restricts the influence of the modified stability functions by reducing the affected sample size. However, when focusing solely on the specific instances of a strongly stable atmosphere, the sensible heat flux approaches near-zero values, which is in line with the observations. Models employing commonly used surface turbulence parameterizations were shown to have difficulties replicating the near-zero sensible heat flux in strongly stable stratification.
I also found that these limited changes in surface layer turbulence parameterizations have a statistically significant impact on the temperature and wind patterns across multiple pressure levels, including the stratosphere, in both the Arctic and mid-latitudes. These significant signals vary in strength, extent, and direction depending on the specific month or year, indicating a strong reliance on the background state.
Furthermore, this research investigates how the modified surface turbulence parameterizations may influence the response of both stratospheric and tropospheric circulation to Arctic sea ice loss.
The most suitable parameterizations for accurately representing Arctic boundary layer turbulence were identified from the sensitivity experiments. Subsequently, the model's response to sea ice loss is evaluated through extended ECHAM6 simulations with different prescribed sea ice conditions.
The simulation with adjusted surface turbulence parameterizations better reproduced the observed Arctic tropospheric warming in vertical extent, demonstrating improved alignment with the reanalysis data. Additionally, unlike the control experiments, this simulation successfully reproduced specific circulation patterns linked to the stratospheric pathway for Arctic-mid-latitude linkages. Specifically, an increased occurrence of the Scandinavian-Ural blocking regime (negative phase of the North Atlantic Oscillation) in early (late) winter is observed. Overall, it can be inferred that improving turbulence parameterizations at the surface layer can improve the ECHAM6's response to sea ice loss.
The wide distribution of location-acquisition technologies means that large volumes of spatio-temporal data are continuously being accumulated. Positioning systems such as GPS enable the tracking of various moving objects' trajectories, which are usually represented by a chronologically ordered sequence of observed locations. The analysis of movement patterns based on detailed positional information creates opportunities for applications that can improve business decisions and processes in a broad spectrum of industries (e.g., transportation, traffic control, or medicine). Due to the large data volumes generated in these applications, the cost-efficient storage of spatio-temporal data is desirable, especially when in-memory database systems are used to achieve interactive performance requirements.
To efficiently utilize the available DRAM capacities, modern database systems support various tuning possibilities to reduce the memory footprint (e.g., data compression) or increase performance (e.g., additional indexes structures). By considering horizontal data partitioning, we can independently apply different tuning options on a fine-grained level. However, the selection of cost and performance-balancing configurations is challenging, due to the vast number of possible setups consisting of mutually dependent individual decisions.
In this thesis, we introduce multiple approaches to improve spatio-temporal data management by automatically optimizing diverse tuning options for the application-specific access patterns and data characteristics. Our contributions are as follows:
(1) We introduce a novel approach to determine fine-grained table configurations for spatio-temporal workloads. Our linear programming (LP) approach jointly optimizes the (i) data compression, (ii) ordering, (iii) indexing, and (iv) tiering. We propose different models which address cost dependencies at different levels of accuracy to compute optimized tuning configurations for a given workload, memory budgets, and data characteristics. To yield maintainable and robust configurations, we further extend our LP-based approach to incorporate reconfiguration costs as well as optimizations for multiple potential workload scenarios.
(2) To optimize the storage layout of timestamps in columnar databases, we present a heuristic approach for the workload-driven combined selection of a data layout and compression scheme. By considering attribute decomposition strategies, we are able to apply application-specific optimizations that reduce the memory footprint and improve performance.
(3) We introduce an approach that leverages past trajectory data to improve the dispatch processes of transportation network companies. Based on location probabilities, we developed risk-averse dispatch strategies that reduce critical delays.
(4) Finally, we used the use case of a transportation network company to evaluate our database optimizations on a real-world dataset. We demonstrate that workload-driven fine-grained optimizations allow us to reduce the memory footprint (up to 71% by equal performance) or increase the performance (up to 90% by equal memory size) compared to established rule-based heuristics.
Individually, our contributions provide novel approaches to the current challenges in spatio-temporal data mining and database research. Combining them allows in-memory databases to store and process spatio-temporal data more cost-efficiently.
This thesis presents an attempt to use source code synthesised from Coq formalisations of device drivers for existing (micro)kernel operating systems, with a particular focus on the Linux Kernel.
In the first part, the technical background and related work are described. The focus is here on the possible approaches to synthesising certified software with Coq, namely the extraction to functional languages using the Coq extraction plugin and the extraction to Clight code using the CertiCoq plugin. It is noted that the implementation of CertiCoq is verified, whereas this is not the case for the Coq extraction plugin. Consequently, there is a correctness guarantee for the generated Clight code which does not hold for the code being generated by the Coq extraction plugin. Furthermore, the differences between user space and kernel space software are discussed in relation to Linux device drivers. It is elaborated that it is not possible to generate working Linux kernel module components using the Coq extraction plugin without significant modifications. In contrast, it is possible to produce working user space drivers both with the Coq extraction plugin and CertiCoq. The subsequent parts describe the main contributions of the thesis.
In the second part, it is demonstrated how to extend the Coq extraction plugin to synthesise foreign function calls between the functional language OCaml and the imperative language C. This approach has the potential to improve the type-safety of user space drivers. Furthermore, it is shown that the code being synthesised by CertiCoq cannot be used in kernel space without modifications to the necessary runtime. Consequently, the necessary modifications to the runtimes of CertiCoq and VeriFFI are introduced, resulting in the runtimes becoming compatible components of a Linux kernel module. Furthermore, justifications for the transformations are provided and possible further extensions to both plugins and solutions to failing garbage collection calls in kernel space are discussed.
The third part presents a proof of concept device driver for the Linux Kernel. To achieve this, the event handler of the original PC Speaker driver is partially formalised in Coq. Furthermore, some relevant formal properties of the formalised functionality are discussed. Subsequently, a kernel module is defined, utilising the modified variants of CertiCoq and VeriFFI to compile a working device driver. It is furthermore shown that it is possible to compile the synthesised code with CompCert, thereby extending the guarantee of correctness to the assembly layer. This is followed by a performance evaluation that compares a naive formalisation of the PC speaker functionality with the original PC Speaker driver pointing out the weaknesses in the formalisation and possible improvements. The part closes with a summary of the results, their implications and open questions being raised.
The last part lists all used sources, separated into scientific literature, documentations or reference manuals and artifacts, i.e. source code.
This thesis focuses on the molecular evolution of Macroscelidea, commonly referred to as sengis. Sengis are a mammalian order belonging to the Afrotherians, one of the four major clades of placental mammals. Sengis currently consist of twenty extant species, all of which are endemic to the African continent. They can be separated in two families, the soft-furred sengis (Macroscelididae) and the giant sengis (Rhynchocyonidae). While giant sengis can be exclusively found in forest habitats, the different soft-furred sengi species dwell in a broad range of habitats, from tropical rain-forests to rocky deserts.
Our knowledge on the evolutionary history of sengis is largely incomplete. The high level of superficial morphological resemblance among different sengi species (especially the soft-furred sengis) has for example led to misinterpretations of phylogenetic relationships, based on morphological characters. With the rise of DNA based taxonomic inferences, multiple new genera were defined and new species described. Yet, no full taxon molecular phylogeny exists, hampering the answering of basic taxonomic questions. This lack of knowledge can be to some extent attributed to the limited availability of fresh-tissue samples for DNA extraction. The broad African distribution, partly in political unstable regions and low population densities complicate contemporary sampling approaches. Furthermore, the DNA information available usually covers only short stretches of the mitochondrial genome and thus a single genetic locus with limited informational content.
Developments in DNA extraction and library protocols nowadays offer the opportunity to access DNA from museum specimens, collected over the past centuries and stored in natural history museums throughout the world. Thus, the difficulties in fresh-sample acquisition for molecular biological studies can be overcome by the application of museomics, the research field which emerged from those laboratory developments.
This thesis uses fresh-tissue samples as well as a vast collection museum specimens to investigate multiple aspects about the macroscelidean evolutionary history. Chapter 4 of this thesis focuses on the phylogenetic relationships of all currently known sengi species. By accessing DNA information from museum specimens in combination of fresh tissue samples and publicly available genetic resources it produces the first full taxon molecular phylogeny of sengis. It confirms the monophyly of the genus Elephantulus and discovers multiple deeply divergent lineages within different species, highlighting the need for species specific approaches. The study furthermore focuses on the evolutionary time frame of sengis by evaluating the impact of commonly varied parameters on tree dating. The results of the study show, that the mitochondrial information used in previous studies to temporal calibrate the Macroscelidean phylogeny led to an overestimation of node ages within sengis. Especially soft-furred sengis are thus much younger than previously assumed. The refined knowledge of nodes ages within sengis offer the opportunity to link e.g. speciation events to environmental changes.
Chapter 5 focuses on the genus Petrodromus with its single representative Petrodromus tetradactylus. It again exploits the opportunities of museomics and gathers a comprehensive, multi-locus genetic dataset of P. tetradactylus individuals, distributed across most the known range of this species. It reveals multiple deeply divergent lineages within Petrodromus, whereby some could possibly be associated to previously described sub-species, at least one was formerly unknown. It underscores the necessity for a revision of the genus Petrodromus through the integration of both molecular and morphological evidence. The study, furthermore identifies changing forest distributions through climatic oscillations as main factor shaping the genetic structure of Petrodromus.
Chapter 6 uses fresh tissue samples to extent the genomic resources of sengis by thirteen new nuclear genomes, of which two were de-novo assembled. An extensive dataset of more than 8000 protein coding one-to-one orthologs allows to further refine and confirm the temporal time frame of sengi evolution found in Chapter 4. This study moreover investigates the role of gene-flow and incomplete lineage sorting (ILS) in sengi evolution. In addition it identifies clade specific genes of possible outstanding evolutionary importance and links them to potential phenotypic traits affected. A closer investigation of olfactory receptor proteins reveals clade specific differences. A comparison of the demographic past of sengis to other small African mammals does not reveal a sengi specific pattern.
Die Zusammenarbeit zwischen Lehr- und anderen Fachkräften stellt in Modellen inklusiver Schul- und Unterrichtsentwicklung sowie Schuleffektivität ein wichtiges Element dar. Wenngleich Kooperation als bedeutsam postuliert wird, so belegen Studien, dass diese bisher überwiegend in autonomieerhaltenden Formen praktiziert wird. Als entwicklungsförderlich gelten jedoch v.a. komplexere Formen der Zusammenarbeit. Vor dem Hintergrund inklusiver Bildung und dem Anspruch einer bestmöglichen individuellen Entwicklung der Schüler*innen stellt die Zusammenarbeit von Lehr- und Fachkräften folglich ein sehr bedeutsames Thema dar. Es ist zu hinterfragen, wie sich die Zusammenarbeit zwischen Lehr- und Fachkräften im Primar- wie Sekundarstufenbereich an inklusiven Schulen gestaltet, welche Faktoren diese beeinflussen und welche Relevanz die unterschiedlichen Formen der Zusammenarbeit im Prozess inklusiver Schulentwicklung einnehmen. Bestehende Forschungsdesiderata aufgrei-fend, fokussiert die vorliegende Dissertation auf die realisierte Zusammenarbeit von Lehr- und Fachkräften im Primar- und Sekundarstufenbereich inklusiver Schulen, am Beispiel des Landes Brandenburg. Neben den realisierten Formen der Zusammenarbeit, stehen insbesondere die Identifikation von Kooperationsmustern von Lehr- und Fachkräften sowie von Schulen, und deren Zusammenhänge mit der Leistungsentwicklung von Schüler*innen im Kern des Forschungsinteresses.
Die vorliegende Dissertation bearbeitet insgesamt sechs Forschungsfragen, welche in drei Teilstudien adressiert werden: Zunächst werden mittels deskriptiver Analysen sowie Mehrebenenmodellierungen die Ausgangslage multiprofessioneller Kooperation (erste Forschungsfrage) sowie deren Rahmenbedingungen (zweite Forschungsfrage) im Primar- wie Sekundarstufenbereich erfasst (Teilstudie 1). Lehr- und Fachkräfte kooperierten überwiegend in autonomieerhaltenden, austauschbasierten Formen. Weiterhin zeigte sich, dass insbesondere die individuelle Offenheit zur Zusammenarbeit sowie die subjektiv wahrgenommene Unterstützung durch die Schulleitung bedeutsame Faktoren für die Realisierung multiprofessioneller Kooperation darstellten. Die Fragestellungen drei und vier befassen sich mit der Identifikation von Mustern im Kooperationsverhalten (Teilstudie 2). Zum einen geht es hierbei um personenbezogene Profile von Lehr- und Fachkräften (dritte Forschungsfrage), zum anderen um schulbezogene Profile (vierte Forschungsfrage), welche mittels des personenzentrierten Ansatzes der latenten Profilanalysen unter Berücksichtigung der Mehrebenenstruktur identifiziert werden. Hinsichtlich des individuellen Kooperationsverhaltens konnten vier Profile eruiert werden, bzgl. des schulspezifischen Kooperationsverhaltens drei. Die Mehrheit der Lehr- und Fachkräfte konnte im „regularly“-Profil verortet werden, d.h. nach eigener Einschätzung kooperierten diese überdurchschnittlich häufig im Austausch miteinander und arbeitsteilig, aber auch regelmäßig kokonstruktiv. Auf Schulebene zeigte sich, dass etwa jede zweite inklusive Schule im Land Brandenburg über eine hoch ausgeprägte Kooperationskultur verfügte. Im Fokus der Teilstudie 3 wird den Fragen nachgegangen, in welchem Zusammenhang die schulspezifischen Kooperationskulturen mit der Leistungsentwicklung von Schüler*innen in der Primar- wie Sekundarstufe steht. Mittels autoregressiver Mehrebenenanalysen wird einerseits der Zusammenhang mit der Leistungsentwicklung aller Schüler*innen (fünfte Forschungsfrage) untersucht, sowie spezifisch auf die Entwicklung von Schüler*innen mit und ohne sonderpädagogischem Förderbedarf (sechste Forschungsfrage) fokussiert. Ein zentrales Ergebnis war hierbei, dass Schüler*innen mit sonderpädagogischem Förderbedarf in der Primar- wie Sekundarstufe in ihrer Leistungsentwicklung am stärksten profitierten, wenn sie an Schulen lernten, an denen sich die Lehr- und Fachkräfte sehr regelmäßig über Lernstände der Schüler*innen austauschten (Austausch), Arbeitspakete für differenzierte Lernangebote erarbeiteten und verteilten (Arbeitsteilung) und darüber hinaus gelegentlich gemeinsam Problemlösungen entwickelten (Kokonstruktion).
Die Ergebnisse werden vor dem Hintergrund der postulierten Relevanz multiprofessioneller Kooperation für inklusive Schul- und Unterrichtsentwicklungsprozesse eingeordnet und diskutiert. Weiterhin werden verschiedene praktische Implikationen für die Unterstützung multiprofessioneller Zusammenarbeit im Primar- und Sekundarstufenbereich abgeleitet.
Die vorliegende Arbeit thematisiert die Synthese und die Polymerisation von Monomeren auf der Basis nachwachsender Rohstoffe wie zum Beispiel in Gewürzen und ätherischen Ölen enthaltenen kommerziell verfügbaren Phenylpropanoiden (Eugenol, Isoeugenol, Zimtalkohol, Anethol und Estragol) und des Terpenoids Myrtenol sowie ausgehend von der Rinde einer Birke (Betula pendula) und der Korkeiche (Quercus suber). Ausgewählte Phenylpropanoide (Eugenol, Isoeugenol und Zimtalkohol) und das Terpenoid Myrtenol wurden zunächst in den jeweiligen Laurylester überführt und anschließend das olefinische Strukturelement epoxidiert, wobei 4 neue (2-Methoxy-4-(oxiran-2-ylmethyl)phenyldodecanoat, 2-Methoxy-4-(3-methyl-oxiran-2-yl)phenyldodecanoat, (3-Phenyloxiran-2-yl)methyldodecanoat, (7,7-Dimethyl-3-oxatricyclo[4.1.1.02,4]octan-2-yl)methyldodecanoat) und 2 bereits bekannte monofunktionelle Epoxide (2-(4-Methoxybenzyl)oxiran und 2-(4-Methoxyphenyl)-3-methyloxiran) erhalten wurden, die mittels 1H-NMR-, 13C-NMR- und FT-IR-Spektroskopie sowie mit DSC untersucht wurden. Die Photo-DSC Untersuchung der Epoxidmonomere in einer kationischen Photopolymerisation bei 40 °C ergab die maximale Polymerisationsgeschwindigkeit (Rpmax: 0,005 s-1 bis 0,038 s-1) sowie die Zeit (tmax: 13 s bis 26 s) bis zum Erreichen des Rpmax-Wertes und führte zu flüssigen Oligomeren, deren zahlenmittlerer Polymerisationsgrad mit 3 bis 6 mittels GPC bestimmt wurde. Die Umsetzung von 2-Methoxy-4-(oxiran-2-ylmethyl)phenyldodecanoat mit Methacrylsäure ergab ein Isomerengemisch (2-Methoxy-4-(2-hydroxy-3-(methacryloyloxy)propyl)phenyldodecanoat und 2-Methoxy-4-(2-(methacryl-oyloxy)-3-hydroxypropyl)phenyldodecanoat), das mittels Photo-DSC in einer freien radikalischen Photopolymerisation untersucht wurde (Rpmax: 0,105 s-1 und tmax: 5 s), die zu festen in Chloroform unlöslichen Polymeren führte.
Aus Korkpulver und gemahlener Birkenrinde wurden selektiv 2 kristalline ω-Hydroxyfettsäuren (9,10-Epoxy-18-hydroxyoctadecansäure und 22-Hydroxydocosansäure) isoliert. Die kationische Photopolymerisation der 9,10-Epoxy-18-hydroxyoctadecansäure ergab einen nahezu farblosen transparenten und bei Raumtemperatur elastischen Film, welcher ein Anwendungspotential für Oberflächenbeschichtungen hat. Aus der Reaktion von 9,10-Epoxy-18-hydroxyoctadecansäure mit Methacrylsäure wurde ein bei Raumtemperatur flüssiges Gemisch aus zwei Konstitutionsisomeren (9,18-Dihydroxy-10-(methacryloyloxy)octadecansäure und 9-(Methacryloyloxy)-10,18-dihydroxyoctadecansäure) erhalten (Tg: -60 °C). Die radikalische Photopolymerisation dieser Konstitutionsisomere wurde ebenfalls mittels Photo-DSC untersucht (Rpmax: 0,098 s-1 und tmax: 3,8 s). Die Reaktion von 22-Hydroxydocosansäure mit Methacryloylchlorid ergab die kristalline 22-(Methacryloyloxy)docosansäure, welche ebenfalls in einer radikalischen Photopolymerisation mittels Photo-DSC untersucht wurde (Rpmax: 0,023 s-1 und tmax: 9,6 s).
Die mittels AIBN in Dimethylsulfoxid initiierte Homopolymerisation der 22-(Methacryloyloxy)docosansäure und der Isomerengemische bestehend aus 2-Methoxy-4-(2-hydroxy-3-(methacryloyloxy)propyl)phenyldodecanoat und 2-Methoxy-4-(2-(methacryl-oyloxy)-3-hydroxypropyl)phenyldodecanoat sowie aus 9,18-Dihydroxy-10-(methacryloy-loxy)octadecansäure und 9-(Methacryloyloxy)-10,18-dihydroxyoctadecansäure ergab feste lösliche Polymere, die mittels 1H-NMR- und FT-IR-Spektroskopie, GPC (Poly(2-methoxy-4-(2-hydroxy-3-(methacryloyloxy)propyl)phenyldodecanoat / 2-methoxy-4-(2-(methacryloyloxy)-3-hydroxypropyl)phenyldodecanoat): Pn = 94) und DSC (Poly(2-methoxy-4-(2-hydroxy-3-(methacryloyloxy)propyl)phenyldodecanoat / 2-methoxy-4-(2-(methacryloyloxy)-3-hydroxypropyl)phenyldodecanoat): Tg: 52 °C; Poly(9,18-dihydroxy-10-(methacryloyloxy)-octadecansäure / 9-(methacryloyloxy)-10,18-dihydroxyoctadecansäure): Tg: 10 °C; Poly(22-(methacryloyloxy)docosansäure): Tm: 74,1 °C, wobei der Schmelzpunkt mit dem des Photopolymers (Tm = 76,8 °C) vergleichbar ist) charakterisiert wurden.
Das bereits bekannte Monomer 4-(4-Methacryloyloxyphenyl)butan-2-on wurde ausgehend von 4-(4-Hydroxyphenyl)butan-2-on hergestellt, welches aus Birkenrinde gewonnen werden kann, und unter identischen Bedingungen für einen Vergleich mit den neuen Monomeren polymerisiert. Die freie radikalische Polymerisation führte zu Poly(4-(4-methacryloyloxyphenyl)butan-2-on) (Pn: 214 und Tg: 83 °C). Neben der Homopolymerisation wurde eine statistische Copolymerisation des Isomerengemisches 2-Methoxy-4-(2-hydroxy-3-(methacryl-oyloxy)propyl)phenyldodecanoat / 2-Methoxy-4-(2-(methacryloyloxy)-3-hydroxypropyl)-phenyldodecanoat mit 4-(4-Methacryloyloxyphenyl)butan-2-on untersucht, wobei ein äquimolarer Einsatz der Ausgangsmonomere zu einem Anstieg der Ausbeute, der Molmassenverteilung und der Dispersität des Copolymers (Tg: 44 °C) führte. Die unter Verwendung von Diethylcarbonat als „grünes“ Lösungsmittel mittels AIBN initiierten freien radikalischen Homopolymerisationen von 4-(4-Methacryloyloxyphenyl)butan-2-on und von Laurylmethacrylat ergaben vergleichbare Polymerisationsgrade der Homopolymere (Pn: 150), welche jedoch aufgrund ihrer Strukturunterschiede deutlich unterschiedliche Glasübergangstemperaturen hatten (Poly(4-(4-methacryloyloxyphenyl)butan-2-on): Tg: 70 °C, Poly(laurylmethacrylat) Tg: -49 °C. Eine statistische Copolymerisation äquimolarer Stoffmengen der beiden Monomere in Diethylcarbonat führte bei einer Polymerisationszeit von 60 Minuten zu einem leicht bevorzugten Einbau des 4-(4-Methacryloyloxyphenyl)butan-2-on in das Copolymer (Tg: 17 °C). Copolymerisationsdiagramme für die freien radikalischen Copolymerisationen von 4-(4-Methacryloyloxyphenyl)butan-2-on mit n-Butylmethacrylat beziehungsweise 2-(Dimethylamino)ethylmethacrylat (t: 20 min bis 60 min; Molenbrüche (X) für 4-(4-Methacryloyloxyphenyl)butan-2-on: 0,2; 0,4; 0,6 und 0,8) zeigten ein nahezu ideales azeotropes Copolymerisationsverhalten, obwohl ein leicht bevorzugter Einbau von 4-(4-Methacryloyloxyphenyl)butan-2-on in das jeweilige Copolymer beobachtet wurde. Dabei korreliert ein Anstieg der Ausbeute und der Glasübergangstemperatur der erhaltenen Copolymere mit einem zunehmenden Gehalt an 4-(4-Methacryloyloxyphenyl)butan-2-on im Reaktionsgemisch. Die unter Einsatz der modifizierten Gibbs-DiMarzio-Gleichung berechneten Glasübergangstemperaturen der Copolymere stimmten mit den gemessenen Werten gut überein. Das ist eine gute Ausgangsbasis für die Bestimmung der Glasübergangstemperatur eines Copolymers mit einer beliebigen Zusammensetzung.
Ecosystems play a pivotal role in addressing climate change but are also highly susceptible to drastic environmental changes. Investigating their historical dynamics can enhance our understanding of how they might respond to unprecedented future environmental shifts. With Arctic lakes currently under substantial pressure from climate change, lessons from the past can guide our understanding of potential disruptions to these lakes. However, individual lake systems are multifaceted and complex. Traditional isolated lake studies often fail to provide a global perspective because localized nuances—like individual lake parameters, catchment areas, and lake histories—can overshadow broader conclusions. In light of these complexities, a more nuanced approach is essential to analyze lake systems in a global context.
A key to addressing this challenge lies in the data-driven analysis of sedimentological records from various northern lake systems. This dissertation emphasizes lake systems in the northern Eurasian region, particularly in Russia (n=59). For this doctoral thesis, we collected sedimentological data from various sources, which required a standardized framework for further analysis. Therefore, we designed a conceptual model for integrating and standardizing heterogeneous multi-proxy data into a relational database management system (PostgreSQL). Creating a database from the collected data enabled comparative numerical analyses between spatially separated lakes as well as between different proxies.
When analyzing numerous lakes, establishing a common frame of reference was crucial. We achieved this by converting proxy values from depth dependency to age dependency. This required consistent age calculations across all lakes and proxies using one age-depth modeling software. Recognizing the broader implications and potential pitfalls of this, we developed the LANDO approach ("Linked Age and Depth Modelling"). LANDO is an innovative integration of multiple age-depth modeling software into a singular, cohesive platform (Jupyter Notebook). Beyond its ability to aggregate data from five renowned age-depth modeling software, LANDO uniquely empowers users to filter out implausible model outcomes using robust geoscientific data. Our method is not only novel but also significantly enhances the accuracy and reliability of lake analyses.
Considering the preceding steps, this doctoral thesis further examines the relationship between carbon in sediments and temperature over the last 21,000 years. Initially, we hypothesized a positive correlation between carbon accumulation in lakes and modelled paleotemperature. Our homogenized dataset from heterogeneous lakes confirmed this association, even if the highest temperatures throughout our observation period do not correlate with the highest carbon values. We assume that rapid warming events contribute more to high accumulation, while sustained warming leads to carbon outgassing. Considering the current high concentration of carbon in the atmosphere and rising temperatures, ongoing climate change could cause northern lake systems to contribute to a further increase in atmospheric carbon (positive feedback loop). While our findings underscore the reliability of both our standardized data and the LANDO method, expanding our dataset might offer even greater assurance in our conclusions.