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To meet the demands of a growing world population while reducing carbon dioxide (CO2) emissions, it is necessary to capture CO2 and convert it into value-added compounds. In recent years, metabolic engineering of microbes has gained strong momentum as a strategy for the production of valuable chemicals. As common microbial feedstocks like glucose directly compete with human consumption, the one carbon (C1) compound formate was suggested as an alternative feedstock. Formate can be easily produced by various means including electrochemical reduction of CO2 and could serve as a feedstock for microbial production, hence presenting a novel entry point for CO2 to the biosphere and a storage option for excess electricity. Compared to the gaseous molecule CO2, formate is a highly soluble compound that can be easily handled and stored. It can serve as a carbon and energy source for natural formatotrophs, but these microbes are difficult to cultivate and engineer. In this work, I present the results of several projects that aim to establish efficient formatotrophic growth of E. coli – which cannot naturally grow on formate – via synthetic formate assimilation pathways. In the first study, I establish a workflow for growth-coupled metabolic engineering of E. coli. I demonstrate this approach by presenting an engineering scheme for the PFL-threonine cycle, a synthetic pathway for anaerobic formate assimilation in E. coli. The described methods are intended to create a standardized toolbox for engineers that aim to establish novel metabolic routes in E. coli and related organisms. The second chapter presents a study on the catalytic efficiency of C1-oxidizing enzymes in vivo. As formatotrophic growth requires generation of both energy and biomass from formate, the engineered E. coli strains need to be equipped with a highly efficient formate dehydrogenase, which provides reduction equivalents and ATP for formate assimilation. I engineered a strain that cannot generate reducing power and energy for cellular growth, when fed on acetate. Under this condition, the strain depends on the introduction of an enzymatic system for NADH regeneration, which could further produce ATP via oxidative phosphorylation. I show that the strain presents a valuable testing platform for C1-oxidizing enzymes by testing different NAD-dependent formate and methanol dehydrogenases in the energy auxotroph strain. Using this platform, several candidate enzymes with high in vivo activity, were identified and characterized as potential energy-generating systems for synthetic formatotrophic or methylotrophic growth in E. coli. In the third chapter, I present the establishment of the serine threonine cycle (STC) – a synthetic formate assimilation pathway – in E. coli. In this pathway, formate is assimilated via formate tetrahydrofolate ligase (FtfL) from Methylobacterium extorquens (M. extorquens). The carbon from formate is attached to glycine to produce serine, which is converted into pyruvate entering central metabolism. Via the natural threonine synthesis and cleavage route, glycine is regenerated and acetyl-CoA is produced as the pathway product. I engineered several selection strains that depend on different STC modules for growth and determined key enzymes that enable high flux through threonine synthesis and cleavage. I could show that expression of an auxiliary formate dehydrogenase was required to achieve growth via threonine synthesis and cleavage on pyruvate. By overexpressing most of the pathway enzymes from the genome, and applying adaptive laboratory evolution, growth on glycine and formate was achieved, indicating the activity of the complete cycle. The fourth chapter shows the establishment of the reductive glycine pathway (rGP) – a short, linear formate assimilation route – in E. coli. As in the STC, formate is assimilated via M. extorquens FtfL. The C1 from formate is condensed with CO2 via the reverse reaction of the glycine cleavage system to produce glycine. Another carbon from formate is attached to glycine to form serine, which is assimilated into central metabolism via pyruvate. The engineered E. coli strain, expressing most of the pathway genes from the genome, can grow via the rGP with formate or methanol as a sole carbon and energy source.
Unter Verschluss
(2020)
Sie senden den Wandel
(2020)
Altbekannt ist, welch wichtige Rolle Medien bei der Konsolidierung oder aber auch bei der Transformation einer Gesellschaft spielen. Was aber geschieht, wenn Medien von unten aus agieren und dies in großer Zahl geschieht, unter Einbindung vieler gesellschaftlicher Akteure sowie gegenüber einem umfassenden Publikum? In Argentinien hat sich eine faszinierende Radiolandschaft gebildet, die kollektiv, partizipativ und progressiv arbeitet: Die Community-Radios. Viviana Uriona nimmt uns mit auf eine ethnografische Reise durch die Geschichte dieser Radios, analysiert ihre Arbeitsweise und sucht nach den Gründen ihres Erfolges. Am Ende der Lektüre bleibt eine Frage nicht mehr offen: Könnte hierzulande in gleicher Weise gelingen, was dort geschah?
This thesis offers new insights on the effects of Start-Up Subsidies (SUS) for unemployed individuals as a special kind of active labor market program (ALMP) that aims to re-integrate individuals into the labor market via the route of self-employment. Moreover, this thesis contributes to the literature on methods for causal inference when the treatment variable is continuous rather than binary. For example, this is the case when individuals differ in their degree of exposure to a common treatment.
The analysis of the effects of SUS focuses on the main current German program called “Gründungszuschuss” (New Start-Up Subsidy, NSUS) after its reform in 2011. Average Effects on participants' labor market outcomes - as measured by employment and earnings - as well as subjective well-being are estimated mainly based on propensity score matching (PSM) techniques. PSM aims to achieve balance in terms of observed characteristics by matching participants with at least one comparable non-participant in terms of their probability to receive the treatment. This estimation strategy is valid as long as all relevant characteristics that explain selection patterns into treatment are observed and included in the estimation of the propensity score. To make our analysis as credible as possible, we control for a large vector of characteristics as observed through the combination of rich administrative data from the Federal Employment Agency as well as through survey data.
Chapters two to four of this thesis puts special emphasis on aspects regarding (the evaluation of) SUS programs that have received no or only limited attention thus far. The first aspect relates to the interplay of institutional details of the program and its effectiveness. So far, relatively little is known about the importance of SUS program features such as the duration of support. Second, there is no experimental benchmark evaluation of SUS available and thus, the reliability of non-experimental estimation techniques such as PSM is of crucial importance as estimates are biased when relevant confounders are omitted from the analysis. Third, there may be potentially detrimental effects of transitioning into (relatively risky) self-employment on subjective well-being among subsidized founders out of unemployment. These were to remain undetected if the analysis would focus exclusively on labor market outcomes of participants. The results indicate positive long-term effects of SUS participation on employment and earnings among participants. These effects are substantially larger than what estimated before the reform, indicating room for improvement in program design via changes in institutional details. Moreover, non-experimental estimates of treatment effects are remarkably robust to hidden confounding. Regarding subjective well-being, this thesis finds a positive long-run impact on job satisfaction and a detrimental effect on satisfaction with social security. The latter appears to be driven by adverse effects on social insurance contributions.
In chapter five, a novel automated covariate balancing technique for the estimation of causal effects in the context of continuous treatments is derived and assessed regarding its performance compared to other (automated) balancing techniques. Although binary research designs that only differentiate between participants and non-participants of some treatment remain the most-common case in empirical practice, many applications can be adapted to include continuous treatments as well. Often, this will allow for more meaningful estimates of causal effects in order to further improve the design of programs. In the context of SUS, one may further investigate the effects of the size of monetary support or its duration on participants' labor market outcomes. Both Monte-Carlo investigations and analysis of two well-known datasets suggests superior performance of the proposed Entropy Balancing for continuous treatments (EBCT) compared to other existing estimation strategies.
Philosophische Tugenden
(2020)
Worin besteht gutes Philosophieren? Und weshalb ist gerade John Stuart Mill ein außergewöhnlich guter Philosoph? Joachim Toenges-Hinn verbindet in diesem Band die metaphilosophische Suche danach, was gute Philosophie ausmacht, mit einer historischen Betrachtung des Philosophen John Stuart Mill. Dabei fungiert Mill zugleich als Urheber von und Verkörperung des Strebens nach zwei philosophischen Tugenden, die Toenges-Hinn aus Mills philosophischem Werk ableitet und anschließend systematisch verteidigt. Diese als „Bentham-Ideal“ und „Coleridge-Ideal“ bezeichneten Tugenden stehen dabei ebenso im Fokus seiner Untersuchung wie die Bedeutung von Lebensexperimenten für philosophische Biografien.
The development of methods such as super-resolution microscopy (Nobel prize in Chemistry, 2014) and multi-scale computer modelling (Nobel prize in Chemistry, 2013) have provided scientists with powerful tools to study microscopic systems. Sub-micron particles or even fluorescently labelled single molecules can now be tracked for long times in a variety of systems such as living cells, biological membranes, colloidal solutions etc. at spatial and temporal resolutions previously inaccessible. Parallel to such single-particle tracking experiments, super-computing techniques enable simulations of large atomistic or coarse-grained systems such as biologically relevant membranes or proteins from picoseconds to seconds, generating large volume of data. These have led to an unprecedented rise in the number of reported cases of anomalous diffusion wherein the characteristic features of Brownian motion—namely linear growth of the mean squared displacement with time and the Gaussian form of the probability density function (PDF) to find a particle at a given position at some fixed time—are routinely violated. This presents a big challenge in identifying the underlying stochastic process and also estimating the corresponding parameters of the process to completely describe the observed behaviour. Finding the correct physical mechanism which leads to the observed dynamics is of paramount importance, for example, to understand the first-arrival time of transcription factors which govern gene regulation, or the survival probability of a pathogen in a biological cell post drug administration. Statistical Physics provides useful methods that can be applied to extract such vital information. This cumulative dissertation, based on five publications, focuses on the development, implementation and application of such tools with special emphasis on Bayesian inference and large deviation theory. Together with the implementation of Bayesian model comparison and parameter estimation methods for models of diffusion, complementary tools are developed based on different observables and large deviation theory to classify stochastic processes and gather pivotal information. Bayesian analysis of the data of micron-sized particles traced in mucin hydrogels at different pH conditions unveiled several interesting features and we gained insights into, for example, how in going from basic to acidic pH, the hydrogel becomes more heterogeneous and phase separation can set in, leading to observed non-ergodicity (non-equivalence of time and ensemble averages) and non-Gaussian PDF. With large deviation theory based analysis we could detect, for instance, non-Gaussianity in seeming Brownian diffusion of beads in aqueous solution, anisotropic motion of the beads in mucin at neutral pH conditions, and short-time correlations in climate data. Thus through the application of the developed methods to biological and meteorological datasets crucial information is garnered about the underlying stochastic processes and significant insights are obtained in understanding the physical nature of these systems.
Die §§ 299a, 299b StGB sind das Ergebnis eines legitimen gesetzgeberischen Anliegens, die Umsetzung erfolgte indes defizitär.
Der Rechtsgüterschutz ist nicht konsistent, was zu dessen Weiterentwicklung zwingt.
Die unkritische Übernahme der Auslegungsergebnisse zu § 299 StGB – obwohl vom Gesetzgeber intendiert – ist darüber hinaus oftmals verfehlt. Die Arbeit hinterfragt diesen Ansatz und zeigt Lösungen auf.
Um existente Strafbarkeitslücken zu schließen ist es ferner unerlässlich eine verfassungskonforme „Pflichtverletzungsvariante“ einzuführen. Ferner böte eine Clearingstelle Rechtssicherheit, insbesondere mit der Möglichkeit zur Genehmigung von Austauschverhältnissen im Gesundheitswesen. Hierzu werden Vorschläge gemacht.