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Fragestellung: Untersucht wird der Verlauf von Kindern mit Lese-Rechtschreibstörungen (LRS) über gut 5 Jahre unter Berücksichtigung des Einflusses des Geschlechts der Betroffenen. Außerdem werden Auswirkungen der LRS auf das spätere Schriftsprachniveau und den Schulerfolg überprüft. Methodik: Eingangs wurden 995 Schüler zwischen 6 und 16 Jahren untersucht. Ein Teil dieser Kinder ist nach 43 sowie 63 Monaten nachuntersucht worden. Eine LRS wurde diagnostiziert, wenn für das Lesen bzw. Rechtschreiben das doppelte Diskrepanzkriterium von 1.5 Standardabweichungen zur nonverbalen Intelligenz und dem Mittelwert der Klassenstufe erfüllt war und gleichzeitig keine Minderbegabung vorlag. Ergebnisse: Die LRS weist über einen Zeitraum von 63 Monaten eine hohe Störungspersistenz von knapp 70 % auf. Der 5-Jahres-Verlauf der mittleren Lese- und Rechtschreibleistungen wurde nicht vom Geschlecht beeinflusst. Trotz durchschnittlicher Intelligenz blieben die LRS-Schüler in der Schriftsprache mindestens eine Standardabweichung hinter durchschnittlich und etwa 0.5 Standardabweichungseinheiten hinter unterdurchschnittlich intelligenten Kindern zurück. Der Schulerfolg der LRS-Schüler glich dem unterdurchschnittlich intelligenter Kinder und fiel deutlich schlechter aus als bei durchschnittlich intelligenten Kontrollkindern. Schlussfolgerungen: Eine LRS stellt ein erhebliches Entwicklungsrisiko dar, was frühzeitige Diagnostik- und Therapiemaßnahmen erfordert. Dafür sind reliable und im Hinblick auf die resultierenden Prävalenzraten sinnvolle, allgemein anerkannte Diagnosekriterien essenziell. Objective: The study examines the 5-year course of children with dyslexia with regard to their sex. Furthermore, the study investigates the impact of dyslexia on the performance in reading and spelling skills and school-related success. Method: A group of 995 6- to 16-year-olds were examined at the initial assessment. Part of the initial sample was then re-examined after 43 and 63 months. The diagnosis of dyslexia was based on the double discrepancy criterion using a standard deviation of 1.5. Though they had no intellectual deficits, the children showed a considerable discrepancy between their reading or writing abilities and (1) their nonverbal intelligence and (2) the mean of their grade norm. Results: Nearly 70 % of those examined had a persisting diagnosis of dyslexia over a period of 63 months. The 5-year course was not influenced by sex. Despite average intelligence, the performance in writing and spelling of children suffering from dyslexia was one standard deviation below a control group without dyslexia with average intelligence and 0.5 standard deviations below a group of children suffering from intellectual deficits. Furthermore, the school-related success of the dyslexics was significantly lower than those of children with average intelligence. Dyslexics showed similar school-related success rates to children suffering from intellectual deficits. Conclusions: Dyslexia represents a considerable developmental risk. The adverse impact of dyslexia on school-related success supports the importance of early diagnostics and intervention. It also underlines the need for reliable and general accepted diagnostic criteria. It is important to define such criteria in light of the prevalence rates.

The increasing exposure to renewable energy has amplified the need for risk management in electricity markets. Electricity price risk poses a major challenge to market participants. We propose an approach to model and forecast electricity prices taking into account information on renewable energy production. While most literature focuses on point forecasting, our methodology forecasts the whole distribution of electricity prices and incorporates spike risk, which is of great value for risk management. It is based on functional principal component analysis and time-adaptive nonparametric density estimation techniques. The methodology is applied to electricity market data from Germany. We find that renewable infeed effects both, the location and the shape of spot price densities. A comparison with benchmark methods and an application to risk management are provided.

The increasing exposure to renewable energy has amplified the need for risk management in electricity markets. Electricity price risk poses a major challenge to market participants. We propose an approach to model and fore- cast electricity prices taking into account information on renewable energy production. While most literature focuses on point forecasting, our method- ology forecasts the whole distribution of electricity prices and incorporates spike risk, which is of great value for risk management. It is based on func- tional principal component analysis and time-adaptive nonparametric density estimation techniques. The methodology is applied to electricity market data from Germany. We find that renewable infeed effect both, the location and the shape of spot price densities. A comparison with benchmark methods and an application to risk management are provided.

Electricity load forecasts are an integral part of many decision-making pro- cesses in the electricity market. However, most literature on electricity load forecasting concentrates on deterministic forecasts, neglecting possibly impor- tant information about uncertainty. A more complete picture of future demand can be obtained by using distributional forecasts, allowing for a more effcient decision-making. A predictive density can be fully characterized by tail mea- sures such as quantiles and expectiles. Furthermore, interest often lies in the accurate estimation of tail events rather than in the mean or median. We pro- pose a new methodology to obtain probabilistic forecasts of electricity load, that is based on functional data analysis of generalized quantile curves. The core of the methodology is dimension reduction based on functional principal components of tail curves with dependence structure. The approach has sev- eral advantages, such as flexible inclusion of explanatory variables including meteorological forecasts and no distributional assumptions. The methodol- ogy is applied to load data from a transmission system operator (TSO) and a balancing unit in Germany. Our forecast method is evaluated against other models including the TSO forecast model. It outperforms them in terms of mean absolute percentage error (MAPE) and achieves a MAPE of 2:7% for the TSO.

Electricity load forecasts are an integral part of many decision-making processes in the electricity market. However, most literature on electricity load forecasting concentrates on deterministic forecasts, neglecting possibly important information about uncertainty. A more complete picture of future demand can be obtained by using distributional forecasts, allowing for a more efficient decision-making. A predictive density can be fully characterized by tail measures such as quantiles and expectiles. Furthermore, interest often lies in the accurate estimation of tail events rather than in the mean or median. We propose a new methodology to obtain probabilistic forecasts of electricity load, that is based on functional data analysis of generalized quantile curves. The core of the methodology is dimension reduction based on functional principal components of tail curves with dependence structure. The approach has several advantages, such as flexible inclusion of explanatory variables including meteorological forecasts and no distributional assumptions. The methodology is applied to load data from a transmission system operator (TSO) and a balancing unit in Germany. Our forecast method is evaluated against other models including the TSO forecast model. It outperforms them in terms of mean absolute percentage error (MAPE) and achieves a MAPE of 2:7% for the TSO.

In this paper we investigate price and volatility risk originating in linkages between energy and agricultural commodity prices in Germany and study their dynamics over time. We propose an econometric approach to quantify the volatility and correlation risk structure, which has a large impact for in- vestment and hedging strategies of market participants as well as for policy makers. Volatilities and their short and long run linkages (spillovers) are analyzed using a dynamic conditional correlation GARCH model as well as a multivariate multiplicative volatility model. Our approach provides a flexible and accurate fitting procedure for volatility and correlation risk.

Schwangerschaften bei seltenen Erkrankungen stellen für den einzelnen behandelnden Arzt eine Herausforderung dar. Der Informationsgehalt ist gering. Einheitliche Standards in der Versorgung existieren nicht. Für fünf ausgewählte Krankheitsbilder, die Syringomyelie, die Friedreich- Ataxie, das VHL-Syndrom, das Sturge-Weber-Syndrom sowie die Neurofibromatose Typ 1 und 2, wird ein Risikoprofil werdender Mütter mit einer seltenen neurologischen Grunderkrankung erstellt sowie Empfehlungen zur präkonzeptionellen Beratung, zur Schwangerschaftsbetreuung und zum geburtshilflichen Management gegeben.

In this paper we investigate price and volatility risk originating in linkages between energy and agricultural commodity prices in Germany and study their dynamics over time. We propose an econometric approach to quantify the volatility and correlation risk structure, which has a large impact for investment and hedging strategies of market participants as well as for policy makers. Volatilities and their short and long run linkages (spillovers) are analyzed using a dynamic conditional correlation GARCH model as well as a multivariate multiplicative volatility model. Our approach provides a flexible and accurate fitting procedure for volatility and correlation risk.

Derzeit gibt es nur wenige molekulare Werkzeuge, um die Genexpression biotechnologisch relevanter Clostridien gezielt zu modifizieren. Daher wurde in dieser Arbeit für den anaeroben Modellorganismus C. acetobutylicum ein neues Fluoreszenz-basiertes In-vivo-Reportersystem etabliert. Es schlossen sich Optimierungen und Anwendungsbeispiele an (Promotorstudien verschiedener C. acetobutylicum-Stämme, Entwicklung eines induzierbaren Systems und eines Fluoreszenz-basierten Hochdurchsatz-Screenings für Clostridien).

In this thesis we study linkages between the volatilities of energy prices and agricultural commodity prices in Germany. We investigate whether linkages exist and how they behave over time. To achieve this, weekly prices of biodiesel, crude oil and rapeseed are analyzed over a period from 2002 to 2012. Crude oil and rapeseed prices are first generic future prices traded at ICE futures Europe and LIFFE-Paris respectively. Biodiesel prices are German consumer prices at the pump. We apply a vector error correction model (VECM) in order to filter the data from long run comovement in the level of prices. Volatility and volatility linkages are analyzed using a dynamic conditional correlation (DCC) GARCH model as well as a multiplicative volatility model. We find that in the long run biodiesel prices adjust to crude oil and rapeseed prices. Furthermore, our analysis reveals that the volatility of biodiesel is only weakly linked to the volatility of crude oil and rapeseed. The linkage between the volatility of rapeseed and crude oil is increasing in recent years.

Das Ziel der vorliegenden Arbeit war es, eine neue Struktur abgeleitet von den potenten Aziridin-2,3-dicarboxylaten zu synthetisieren und diese dann an verschiedenen humanen und parasitären Cystein-Proteasen zu testen. Dafür wurde als Baustein die Aziridin-2-carbonsäure gewählt, die an C3-Position unsubstituiert ist und an C2-Position eine Carboxyl-Funktion trägt. Außerdem sollte der Ringstickstoff im Gegensatz zu den bisher bekannten N-acylierten Aziridin-2,3-dicarboxylaten basische Eigenschaften besitzten. Die Struktur der synthetisierten Azridin-2-carboxylate ist daher wie folgt gewählt worden: Die durch Cromwell-Synthese erhaltenen Verbindungen wurden als Racemate oder als Diastereomerengemische erhalten. Dabei wurden die Diastereomeren-Verhältnisse der einzelnen Verbindungen über die Integrale in den 1H-NMR-Spektren bestimmt. Die an Position R3 mit einer Aminosäure substituierten Aziridin-2-carboxylate wurden durch eine Modifikation der Cromwell-Synthese erhalten. Es wurden insgesamt 27 Azridin-2-carboxylate synthetisiert, die dann an verschiedenen Proteasen getestet wurden. Zu den getesteten Cystein-Proteasen gehören die parasitären Enzyme Falcipain 2, 3 und Rhodesain, die virale SARS-CoV Mpro und die humanen Proteasen Cathepsin B und L. Es wurde jeweils ein Screening der Substanzen an den Proteasen durchgeführt. Bei den wirksamen Verbindungen wurden dann die Ki-, ki-, k2nd- oder IC50-Werte bestimmt. Außerdem wurden die Substanzen auch an der SAP2, einer Aspartat-Protease aus Candida albicans, getestet, an der sie allerdings kaum eine Hemmwirkung zeigten. Bei den nicht-selektiven Inhibitoren stellte sich die Verbindung 9.1a, die auch an Rhodesain eine gute Aktivität besitzt, als ein noch potenterer Inhibitor heraus. Hauptsächlich zeigten an Rhodesain Verbindungen eine gute Hemmwirkung, die Nε- oder Nα-geschütztes Lysin-, Phenylalanin- oder Asparaginsäureester als Substituenten enthalten. Dabei waren die Verbindungen 9.1a/b, 4.9b und 4.8a/b die potentesten Inhibitoren am Rhodesain und 9.1b, 9.2, 4.4b und 4.8b an Falcipain 2 und 3. An der SARS-CoV Mpro hemmte die Verbindung 9.1b am besten. Es wurde weiterhin die Abhängigkeit der Aktivität der parasitären Cystein-Protease Rhodesain vom pH-Wert bestimmt, indem die Fluoreszenzzunahme durch die hydrolytische Spaltung des Substrates durch das Enzym bei pH-Werten zwischen 2.5 und 8.0 über 30 min vermessen wurde. Dabei zeigte sich, dass das Rhodesain in einem sehr weiten pH-Bereich von 3.0 – 8.0 eine sehr hohe Aktivität aufweist (80 – 100 %) und erst im relativ sauren Bereich bei pH 2.5 die Aktivität nachlässt (~ 60 %). Außerdem wurde auch die Hemmung von Rhodesain durch 9.1b in Abhängigkeit vom pH-Wert analysiert, wobei die Hemmstärke im sauren pH-Bereich durch die Protonierung des Stickstoffes des Aziridinringes sehr stark zunahm. Im Rahmen des SFB630 („Erkennung, Gewinnung und funktionale Analyse von Wirkstoffen gegen Infektionskrankheiten“) konnten viele der synthetisierten Verbindungen an verschiedenen Krankheitserregern, wie Trypanosoma brucei brucei, Leishmania major, sowie an sog. Problemkeimen, zu denen die gram-negativen Erreger Pseudomonas aeruginosa und Escheria coli, sowie die gram-positiven Staphylococcus-Arten S. aureus (Linie 325, 8325) und S. epidermidis (Linie RP62) gehören, untersucht werden. Dabei stellten sich die Verbindungen 9.1a/b an Trypanosoma brucei brucei als wirksame Inhibitoren gegen den Erreger heraus. Dies korreliert auch sehr gut mit der hohen Aktivität der beiden Verbindungen gegen Rhodesain (9.1a: Ki: 15.41 µM; 9.1b: Ki: 2.99 µM), wobei die Verbindung 9.1b allerdings an Makrophagen toxisch wirkte (9.1b: IC50: 80 µM). Außerdem war 9.1b auch ein Inhibitor des Wachstumes und der Biofilmbildung von S. aureus. Gegenüber Plasmodium falciparum zeigten die Verbindungen 4.9a/b (4.9a: IC50: 0.5 µM; 4.9b: IC50: 2.2 µM) und 9.4 (9.4: IC50: 1.7 µM) die größte Aktivität, wobei allerdings diese Verbindungen keine Hemmung an den Falcipainen aufwiesen und somit das Target der Inhibition noch ungeklärt ist. Im Rahmen eines Auslandsaufenthaltes in der Arbeitsgruppe von Prof. Dr. Philip Rosenthal, San Francisco, California, wurde außerdem ein Screening verschiedener im Arbeitskreis synthetisierter Substanzklassen an Falcipain 2, 3 und an Plasmodium falciparum durchgeführt. Die dabei getesteten Substanzklassen sind in Abb. 6.1 aufgezeigt. Die Aziridin-2,3-dicarboxylate II-c, I-v und I-j zeigten dabei die beste Aktivität, sowohl an den Falcipainen als auch an dem Parasiten. Unter den Epoxiden und an Position C3 substituierten Aziridin-2-carboxylaten ist die Verbindung IV-2 die einzige, die eine Hemmwirkung aufweist. Unter den anderen getesten Verbindungen zeigten nur die Ethacrynsäure-Derivate VII-b und VII-f eine antiplasmodiale Aktivität., The goal of the present work was the syntheses of a new structure derived from the aziridine-2,3-dicarboxylate motif, and the testing against different human and parasitic cysteine proteases. Therefore we chose the aziridine-2-carboxylate motif as building block which is unsubstituted at position C3 of the azridine ring and substituted with a carboxyl function at position C2. In addition to this, the nitrogen of the ring should have basic properties in opposite to the common N-acylated aziridine-2,3-dicarboxylates. The compounds were obtained as racemic or diastereomeric mixtures by the Cromwell synthesis. The diastereomeric excesses were determined by analysis of the integrals of the signals of the ring protons in the 1H-NMR spectra. The aziridine-2-carboxylates substituted with an amino acid ester at position R3 were synthesized by a modification of the Cromwell synthesis. Overall, 27 new aziridine-2-carboxylates were synthesized as new potential irreversible inhibitors of cysteine proteases. The aziridine-2-carboxylates were tested against the parasitic cysteine proteases falcipain 2 and 3 and rhodesain, the viral SARS-CoV Mpro and the human enzymes cathepsin B and L. First, we screened the aziridine-2-carboxylates to identify new potential agents against the proteases. Then we determined the inhibition constants Ki, ki, k2nd or IC50 for the most potent compounds. Against the aspartatic protease SAP2 from Candida albicans the aziridine-2-carboxylates showed no activity. In order to determine the inhibition constants we chose the continuous assay according to Tian and Tsou. The inhibition constants against SARS-CoV Mpro and SAP2 were determined using a FRET assay. Within the non-selective inhibitors the compound 9.1a was identified as a very potent inhibitor of cathepsin L and rhodesain. Compounds showing activity against rhodesain are the Nε- or Nα-protected lysine, phenylalanine or aspartic acid derivatives. Thus, the aziridine-2-carboxylates 9.1a/b, 4.9b and 4.8a/b were the most potent inhibitors against rhodesain and 9.1b, 9.2, 4.4b and 4.8b against falcipain 2 and 3. Against the SARS-CoV Mpro the compound 9.1b showed the highest activity. In order to analyse the pH-dependency of hydrolytic activity of the parasitic cysteine protease rhodesain we determined the activity of the enzyme in dilution assays measuring the increase of the fluorescence at different pH values between 2.5 and 8.0. Rhodesain was active in a wide pH range from 3.0 – 8.0 (80 – 100 %) with decreased activity at pH 2.5 (~ 60 %). In addition to this, we determined the pH-dependence of the inhibition constants of 9.1b against rhodesain. We found that the inhibition potency increased at an acid pH range due to the protonation of the basic nitrogen of the aziridine ring. Within the framework of the Collaborative Research Centre SFB 630 most compounds were examined for the activity against various pathogens: Trypanosoma brucei brucei, Leishmania major, the gramnegative bacteria Pseudomonas aeruginosa and Escheria coli, as well as grampositive Staphylococcus strains S. aureus (Linie 325, 8325) and S. epidermidis (line RP62). Tests against Trypanosoma brucei brucei revealed some active compounds which are not cytotoxic against the host cells, the macrophages (IC50 > 100 µM). The best compounds against this pathogen were 9.1a/b (9.1a: Ki: 15.41 µM; 9.1b: Ki: 2.99 µM). These results correlate well with the inhibition constants of this compounds against rhodesain, but unfortunaly 9.1b showed cytotoxity against the macrophages (9.1b: IC50: 80 µM). Furthermore, 9.1b inhibited the growth and biofilm production of S. aureus. The compounds 4.9a/b (4.9a: IC50: 0.5 µM; 4.9b: IC50: 2.2 µM) and 9.4 (9.4: IC50: 1.7 µM) showed the highest activity against Plasmodium falciparum, but unfortunaly they did not inhibit falcipain 2 or 3 and so the target of the inhibition of the pathogen is uncertain. Within the framework of another collaboration with the working group of Prof. Dr. Philip Rosenthal, San Francisco, California, I determined the inhibition constants of series of different compounds (scheme 6.1) against falcipain 2, falcipain 3 and Plasmodium falciparum. The aziridine-2,3-dicarboxylates II-c, I-v and I-j showed the highest activity both against the falcipains and the pathogen Plasmodium falciparum. Within the series of epoxides and the aziridine-2-carboxylates substituted at position 3 only the compound IV-2 showed activity against the pathogen. Besides this, the ethacrynic acid derivates VII-b and VII-f showed a high antiplasmodial activity.

The main focus of this work was the theoretical investigation of alkali cation microhydration clusters with sodium, potassium, and caesium as central ion and up to 24 water molecules per cluster. Structures were obtained applying global geometry optimisation, using a specialised version of genetic algorithms and the common TIP4P/OPLS model potential. The global and most important local minimum energy structures have been investigated and the results obtained constitute a first complete and systematic overview on structures of alkali cation microhydration clusters. By analysis of various interactions reasons for structural trends could be provided. A structural pattern all magic number cluster structures do have in common is that only three and/or four-coordinated water molecules can be observed. Molecular dynamics simulations were applied to all global minimum energy cluster structures at different temperatures (canonical ensemble). Entropy effects and free energy surfaces were obtained using constrained dynamics on dissociating magic number clusters. It was found that indeed cluster structures containing only three and/or four-coordinated water molecules are more stable than others thus arriving at a possible explanation for the existence of magic number clusters. General structural trends and building patterns already observed for the static picture obtained by the global geometry optimisation are consistent with the dynamical behaviour in a canonical ensemble. For a better understanding of these systems, and to provide data for direct comparison to the experiment, anharmonic infrared spectra for each global as well as some low-lying local minimum energy structures were calculated in the OH-stretch region within an empirical model. At the beginning of this investigation this model had been calibrated only for pure water clusters and ice, however, it was found to produce qualitatively correct data also for the present system. The spectra obtained with this model show characteristic correlations between cluster structures and certain spectral signatures which should make it possible to discern these cluster structures experimentally. It has been also shown that at temperatures up to 100 K global minimum structures (computed at 0 K) still dominate the spectra. Recently available experimental data, kindly provided by J.M. Lisy (University of Illinois) was used for a manual re-calibration of the empirical model. This provided almost perfect quantitative agreement with the experiment. Hence, it was possible for the first time to assign spectral peaks unambiguously to vibrational modes and deduce which isomers are present in the experiments. J.M. Lisy is currently extending this spectral measurements to larger clusters. In combination with our theoretical analysis, this will provide direct information on magic number cluster structures for the first time.