Strukturelle Charakterisierung von Flavin-abhängigen Monooxygenasen aus Zonocerus variegatus und der humanen mitochondrialen Amidoxim-reduzierenden Komponente (mARC): Enzyme, welche an der Biotransformation beteiligt sind

Organisms are permanently exposed to foreign and harmful substances. These xenobiotics have to undergo metabolic processes in order to be eliminated from the organism. This process is called biotransformation. Therefore, it is of significant importance to increase our knowledge about enzymes involved in biotransformation processes and detoxification pathways, especially about their three-dimensional structures. This cumulative thesis focuses on structure determination of two biotransformation enzymes, the flavin-dependent monooxygenase from Zonocerus variegatus (ZvFMO) and the human mitochondrial amidoxime reducing component (mARC). FMOs are able to oxygenate heteroatom-containing substances, whereas the mARC enzyme system is very effectively reducing a broad range of heteroatom-hydroxylated xenobiotics. Different high-resolution ZvFMO structures provided insight into the coordination of cofactors and related conformational rearrangements of the enzyme. Furthermore, a hitherto unknown dimeric arrangement of subunits was observed for ZvFMO isoforms. To further investigate differences in the catalytic activity of ZvFMOs, a variety of ZvFMOa variants were generated. Thereby, significant impacts on enzyme activity were observed even for single exchanges within the substrate entry site. The elucidated mARC crystal structure was the first MOSC protein that clearly showed the coordination of its molybdenum cofactor and exhibited a topology, which contradicts in silico predictions of structural domains currently used for online databases. The large substrate spectrum could be correlated to a surface-exposed active site. Paralogue-specific amino acid residues were identified, which allow for the secure discrimination between mARC1 and mARC2 enzymes. Moreover, structural features indicate that mARC enzymes represent an evolutionary link between the two molybdoenzyme superfamilies of sulfite oxidases and xanthine oxidases.Organismen sind ständig verschiedensten körperfremden und oft auch schädlichen Substanzen ausgesetzt. Solche Xenobiotika müssen metabolische Prozesse durchlaufen, um vom Organismus ausgeschieden werden zu können. Dieser Prozess wird als Biotransformation bezeichnet. Es ist daher wichtig, unser Wissen über Biotransformationsenzyme und Detoxifizierungswege zu vertiefen, insbesondere über deren dreidimensionale Strukturen. Diese kumulative Dissertation fokussiert sich auf die Strukturaufklärung zweier Biotransformationsenzyme, der flavinabhängigen Monooxygenase aus Zonocerus variegatus (ZvFMO) und der menschlichen mitochondrialen Amidoxim-reduzierenden Komponente (mARC). FMOs katalysieren die Hydroxylierung von Heteroatom-haltigen Verbindungen, während mARC-Enzyme die Reduktion Heteroatom-hydroxylierter Xenobiotika ausüben. Verschiedene ZvFMO-Strukturen lieferten Erkenntnisse in die Koordination gebundener Kofaktoren und einhergehender Konformationsänderungen. Weiterhin wurde eine bisher unbekannte Dimerformation dieses Enzyms beobachtet. Um tiefere Einblicke in die katalytische Aktivität von ZvFMOs zu erhalten, wurden verschiedene Enzymvarianten untersucht. Dabei wurde festgestellt, dass vor allem im Substrateingangsbereich schon Einzelaustausche von Aminosäuren einen signifikanten Einfluss auf die Enzymaktivität haben. Die gelöste mARC-Kristallstruktur war die erste MOSC-Proteinstruktur, die Einsicht in die Koordination des Molybdän-Kofaktors gab und eine Topologie aufwies, die bisherigen in silico -Vorhersagen widersprach. Das breite Substratspektrum dieses Enzyms konnte dem oberflächenexponierten aktiven Zentrum zugeschrieben werden. Weiterhin wurden Paralog-spezifische Seitenketten identifiziert, die eine sichere Unterscheidung zwischen mARC1 und mARC2-Proteinen erlauben. Zudem weisen einige strukturelle Merkmale darauf hin, dass mARC-Enzyme ein evolutionäres Bindeglied zwischen zwei Molybdo-Enzymfamilien darstellen, den Sulfitoxidasen und den Xanthinoxidasen

Patterns and drivers of plant functional group dominance across the Western Hemisphere: a macroecological re-assessment based on a massive botanical dataset

Plant functional group dominance has been linked to climate, topography and anthropogenic factors. Here, we assess existing theory linking functional group dominance patterns to their drivers by quantifying the spatial distribution of plant functional groups at a 100-km grid scale. We use a standardized plant species occurrence dataset of unprecedented size covering the entire New World. Functional group distributions were estimated from 3 648 533 standardized occurrence records for a total of 83 854 vascular plant species, extracted from the Botanical Information and Ecology Network (BIEN) database. Seven plant functional groups were considered, describing major differences in structure and function: epiphytes; climbers; ferns; herbs; shrubs; coniferous trees; and angiosperm trees. Two measures of dominance (relative number of occurrences and relative species richness) were analysed against a range of hypothesized predictors. The functional groups showed distinct geographical patterns of dominance across the New World. Temperature seasonality and annual precipitation were most frequently selected, supporting existing hypotheses for the geographical dominance of each functional group. Human influence and topography were secondarily important. Our results support the prediction that future climate change and anthropogenic pressures could shift geographical patterns in dominance of plant functional groups, with probable consequences for ecosystem functioning

Drivers of food and nutrition security during the lean period in southeastern Madagascar

The rural population in southeastern Madagascar faces widespread poverty and weak resilience to frequent climate shocks, both contributing to severe food and nutrition insecurity. For effective policy responses and tailored interventions, development stakeholders need to know which factors determine household food and nutrition security status. In particular, the relative contributions of on-farm production diversity versus cash income are of importance since they would suggest different intervention priorities. We collected survey data on household food security and women's diets during the lean season, where improvements are most needed, as well as on households' agricultural activities, market participation, and sources of cash income from 413 randomly sampled households. Regression results suggest that frequent market participation and cash income from non-farm self-employment improve food security, but on-farm diversity does not. Other determinants of household food security include livestock assets and maternal education. Women's dietary diversity, in contrast, is associated only with market participation. The importance of market participation for food and nutrition security reflects the situation in the lean period, when farm production is low and many households' food supply relies, in part, on market purchases enabled by non-agricultural income. Our findings imply that a focus on developing food markets and enabling opportunities for income generation are likely viable strategies for improving the rural food and nutrition security situation during the lean period in southeastern Madagascar. Relatively food- and nutrition-secure households are characterized by their ability to mobilize cash (e.g., from non-farm self-employment) to purchase food

The Pitfalls of Central Clearing in the Presence of Systematic Risk

Through the lens of market participants' objective to minimize counterparty risk, we provide an explanation for the reluctance to clear derivative trades in the absence of a central clearing obligation. We develop a comprehensive understanding of the benefits and potential pitfalls with respect to a single market participant's counterparty risk exposure when moving from a bilateral to a clearing architecture for derivative markets. Previous studies suggest that central clearing is beneficial for single market participants in the presence of a sufficiently large number of clearing members. We show that three elements can render central clearing harmful for a market participant's counterparty risk exposure regardless of the number of its counterparties: 1) correlation across and within derivative classes (i.e., systematic risk), 2) collateralization of derivative claims, and 3) loss sharing among clearing members. Our results have substantial implications for the design of derivatives markets, and highlight that recent central clearing reforms might not incentivize market participants to clear derivatives

Tackling the volatility paradox: persistence and systemic risk

Macro-finance theory predicts that financial fragility builds up when volatility is low. This “volatility paradox’” challenges traditional systemic risk measures. I explore a new dimension of systemic risk, spillover persistence, which is the average time horizon at which a firm’s losses increase future risk in the financial system. Using firm-level data covering more than 30 years and 50 countries, I document that persistence declines when fragility builds up: before crises, during stock market booms, and when banks take more risks. In contrast, persistence increases with loss amplification: during crises and fire sales. These findings support key predictions of recent macrofinance models

Do consumers benefit from more informed firms?

We study the impact of estimation errors of firms on social welfare. For this purpose, we present a model of the insurance market in which insurers face parameter uncertainty about expected loss sizes. As consumers react to under- and overestimation by increasing and decreasing demand, respectively, insurers require a safety loading for parameter uncertainty. If the safety loading is too small, less risk averse consumers benefit from less informed insurers by speculating on them underestimating expected losses. Otherwise, social welfare increases with insurers’ information. We empirically estimate safety loadings in the US property and casualty insurance market, and show that these are likely to be sufficiently large for consumers to benefit from more informed insurers

Investor-driven corporate finance: Evidence from insurance markets

This paper documents that the bond investments of insurance companies transmit shocks from insurance markets to the real economy. Liquidity windfalls from household insurance purchases increase insurers’ demand for corporate bonds. Exploiting the fact that insurers persistently invest in a small subset of firms for identification, I show that these increases in bond demand raise bond prices and lower firms’ funding costs. In response, firms issue more bonds, especially when their bond underwriters are well connected with investors. Firms use the proceeds to raise investment rather than equity payouts. The results emphasize the significant impact of investor demand on firms’ financing and investment activities.In diesem Papier wird dokumentiert, dass die Anleiheninvestitionen von Versicherungsunternehmen Schocks von den Versicherungsmärkten auf die Realwirtschaft übertragen. Liquiditätszuwächse durch den Kauf von Haushaltsversicherungen erhöhen die Nachfrage der Versicherer nach Unternehmensanleihen. Ich nutze die Tatsache aus, dass Versicherer zur Identifizierung beharrlich in eine kleine Untergruppe von Unternehmen investieren, und zeige, dass dieser Anstieg der Anleihenachfrage die Anleihepreise erhöht und die Finanzierungskosten der Unternehmen senkt. Als Reaktion darauf geben Unternehmen mehr Anleihen aus, insbesondere wenn ihre Anleiheemittenten gute Kontakte zu den Anlegern haben. Unternehmen verwenden die Erlöse eher für Investitionen als für Eigenkapitalausschüttungen. Die Ergebnisse unterstreichen den erheblichen Einfluss der Investorennachfrage auf die Finanzierungs- und Investitionsaktivitäten von Unternehmen

Investor-driven corporate finance: Evidence from insurance markets

This paper documents that the bond investments of insurance companies transmit shocks from insurance markets to the real economy. Liquidity windfalls from household insurance purchases increase insurers' demand for corporate bonds. Exploiting the fact that insurers persistently invest in a small subset of firms for identification, I show that these increases in bond demand raise bond prices and lower firms' funding costs. In response, firms issue more bonds, especially when their bond underwriters are well connected with investors. Firms use the proceeds to raise investment rather than equity payouts. The results emphasize the significant impact of investor demand on firms' financing and investment activities.In diesem Papier wird dokumentiert, dass die Anleiheninvestitionen von Versicherungsunternehmen Schocks von den Versicherungsmärkten auf die Realwirtschaft übertragen. Liquiditätszuwächse durch den Kauf von Haushaltsversicherungen erhöhen die Nachfrage der Versicherer nach Unternehmensanleihen. Ich nutze die Tatsache aus, dass Versicherer zur Identifizierung beharrlich in eine kleine Untergruppe von Unternehmen investieren, und zeige, dass dieser Anstieg der Anleihenachfrage die Anleihepreise erhöht und die Finanzierungskosten der Unternehmen senkt. Als Reaktion darauf geben Unternehmen mehr Anleihen aus, insbesondere wenn ihre Anleiheemittenten gute Kontakte zu den Anlegern haben. Unternehmen verwenden die Erlöse eher für Investitionen als für Eigenkapitalausschüttungen. Die Ergebnisse unterstreichen den erheblichen Einfluss der Investorennachfrage auf die Finanzierungs- und Investitionsaktivitäten von Unternehmen

Catastrophe modeling with a doubly stochastic process : Bayesian inference and applications

This work proposes to employ the (bursty) GLO model from Bingmer et. al (2011) to model the occurrence of tropical cyclones. We develop a Bayesian framework to estimate the parameters of the model and, particularly, employ a Markov chain Monte Carlo algorithm. This also allows us to develop a forecasting framework for future events. Moreover, we assess the default probability of an insurance company that is exposed to claims that occur according to a GLO process and show that the model is able to substantially improve actuarial risk management if events occur in oscillatory bursts