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Numorous psychotherapeutic approaches have been put forward to better treat patients with chronic psychological problems or severe personality disorders, among them Schema Therapy (Young, Klosko & Weishaar, 2003). Within Schema Therapy, there are two important theoretical constructs: early maladaptive schemas, which are conceptualized as stable and lasting emotional, behavioral and cognitive patterns regarding ourselves, the world and other people that have their origins in childhood or adolescence and schema modes, which are current states that describe the rapid shifts in emotion, cognition and behaviour that can be seen in patients with severe personality disorders. Schema Therapy has growing popularity with clinicians in the last decade, but only a few studies have tested the empirical validity of the schema mode model. Lobbestael, van Vreeswijk, Spinhoven, Schouten & Arntz (2010) developed and evaluated the Schema Mode Inventory to assess schema modes within the framework of a questionnaire. This instrument has been translated to the German language and the psychometric properties of the instrument indicate an adequate fit to the model established in the original Dutch study (paper 1).
In Schema Therapy, on the one hand mode concepts have been proposed without a focus on one specific disorder (Young et al., 2003), but on the other hand disorder-specific concepts have been established that form the basis for manualization and research. The most popular disorder specific mode concept is that of Borderline Personality Disorder (Arntz & van Genderen, 2009). In randomized controlled trials the effectiveness of Schema Therapy for Borderline Personality Disorder in the individual setting (Giesen-Bloo, van Dyck, Spinhoven, van Tilburg, Dirksen et al., 2006) and the group setting (Farrell, Shaw & Webber, 2009) was evaluated. Whereas Schema Therapy for Borderline Personality Disorder in the individual setting has been manualized (Arntz & van Genderen, 2009), a manual for group Schema Therapy is not yet available, Therefore, particularly since this last evaluation study, there has been a need to better describe, how the Schema Therapy mode model for Borderline Personality Disorder has been applied to the group setting (papers 2 & 3) as well as how both modalities of Schema Therapy treatment, individual and group, are combined in intensive psychotherapy settings such as inpatient or day care (papers 4 & 5). Lastly the question has been put forward as to how effective Schema Therapy for Borderline Personality Disorder is in intensive treatment environments, where it is assumed that the severity of the disorders treated is even higher. It is found that a combined program of individual and group Schema Therapy for Borderline Personality Disorder is effective in the inpatient setting. Subtle variations in treatment programs in three pilot studies leave room for the discussion of possible factors influencing treatment effects (paper 6). The results of all studies are discussed on the background of Schema Therapy’s development as a new psychotherapy approach for the treatment of complex disorders.
Design and optimization of the lattice of the superconducting synchrotron SIS300 for slow extraction
(2011)
The superconducting synchrotron SIS300 is planned to be built at the new Facility for Antiproton and Ion Research (FAIR), at GSI-Darmstadt [1]. SIS300 will be a versatile machine, which by means of a low-energy stretcher-mode or a high-energy ramped-mode will provide slowly extracted heavy ion beams towards the experimental areas. To reach the required maximum field of 4.5 T, cos(θ) magnets are necessary. Thus, SIS300 will become the first superconducting synchrotron worldwide with cos(θ) magnets providing resonant slow extraction.
Since SIS300 will be installed in the same tunnel as the SIS100 synchrotron, the dipole layout of SIS300 cannot be freely chosen. Thus, a standard lattice cannot be applied. A redesign of the SIS300 lattice accepting compromises concerning the positions and phase advances between the optical elements has been proposed. Using the analytical model of the slow extraction, firstly proposed by Kobayashi, and the analytical description of the resonance driving modes, a multiobjective optimization algorithm has been developed for the optimization of the lattice under the given boundary conditions. The final goal of the lattice optimization is a higher efficiency of the slow extraction. The results are evaluated by means of tracking simulations performed with the code Elegant.
The field quality in superconducting cos(θ) magnets is determined by the positions of the superconducting cable and the static and time-dependent effects of the current in the cable. Furthermore, the fast ramp rates of 1 T/s in the dipoles, which are fifty times faster than in any other superconducting cos(θ) magnet, together with the fact that the aperture is smaller than in conventional accelerator magnets, makes it extremely difficult to obtain a high-quality magnetic field. The unavoidable field errors affect the beam dynamics and worsen the slow extraction efficiency. Therefore, the field errors in the SIS300 dipoles have been estimated, and their effects have been taken into account in the optimization algorithm. As a result a compensation scheme has been proposed, in which time-dependent gradients in the sextupoles counteract the decay of the sextupole field errors in the dipole magnets during the slow extraction. For the limits where the compensation was no longer possible, tolerances to the magnet field errors have been determined.
Within the present work, photodissociation reactions on 100Mo, 93Mo and 92Mo isotopes were studied by means of the Coulomb dissociation method at the LAND setup at GSI. Experimental data on these isotopes are important to explain the problem of the underproduction of the lighter p-nuclei - 92; 94Mo - within the models of the p-process nucleosynthesis. The reaction rates used in the nucleosynthesis calculations are usually obtained within the framework of the statistical model. In order to verify the model predictions and reduce the uncertainties, experimental measurements of the reaction cross sections are required. In particular, the data on (γ,n) reactions are of interest, since these reactions were shown to dominate the p-process flow in the molybdenum mass region.
As a result of the analysis of the present experiment, integrated Coulomb excitation cross sections of the 100Mo(γ,n), 100Mo(γ,2n), 93Mo(γ,n) and 92Mo(γ,n) reactions were determined. The measurement of the 93Mo isotope is particularly important, since this nucleus is unstable, and the corresponding cross section has not been measured before.
It should be emphasized that Coulomb dissociation is a unique tool to study photoninduced reactions on unstable nuclei, which is especially relevant in the context of nucleosynthesis network calculations. However, because of to the complexity of the data analysis procedure and a number of model assumptions that are required in order to extract the Coulomb excitation cross section from the data, one of the main aspects of this thesis was to verify the method by comparing the results with the previously published data obtained with real photon beams. Integrated cross sections of the 100Mo(γ,n) and 100Mo(γ,2n) reactions were directly compared to the data by Beil et al., obtained at Saclay with photons from positron annihilation, while an indirect comparison could be performed with a recent photoactivation measurement by Erhard and co-workers. A reasonable agreement was observed for the 1n channel: a scaling factor of 0.8 ± 0.1 between our result and Beil et al. data is consistent with the scaling factor of 0.89±0.09 reported by Erhard et al. between their data and Beil et al. data. Both results are in agreement with the scaling factor of 0.85 ± 0.03 recommended by Berman et al. for the data measured at Saclay on nuclei in the respective mass region. A somewhat lower factor of 0.61 ± 0.09 between the present data and Beil et al. data was obtained for the 2n channel. The discrepancy might be explained by both the substantial efficiency correction that has to be applied to the LAND data in the two-neutron case, as well as by an insufficiently accurate assumption that the Saclay neutron detector efficiency is energy- and multiplicity- independent.
A second important topic of the present thesis is the investigation of the efficiency of the CsI gamma detector. The calorimetric information that it delivers is essential to reconstruct the energy-differential cross section from the present measurement. The data taken with the gamma calibration sources shortly after the experiment were used for the investigation. In addition, a test experiment in refined conditions was conducted within the framework of this thesis. Numerous GEANT3 simulations of the detector were performed in order to understand various aspects of its performance. As a result, the efficiency of the detector was determined to be approximately a factor of 2 lower than the efficiency expected from the simulation. This result is consistent with several independent investigations, which were performed using different methods. At the same time, a remarkable agreement between the simulated and experimental data was achieved under assumption that the inefficiency of the detector is explained by the loss of data from a number of crystals, which are randomly chosen in each event according to their averaged performance ratio (the ”on-off” effect). The reasons for the observed malfunction are yet not fully clear. Regardless of the exact reason, in the present conditions a deconvolution of the measured data from the CsI response is not possible. Consequently, within the framework of this thesis, the results are presented in terms of integrated cross sections. A search for alternative methods of data interpretation, allowing to extract energy-differential information out of the available data, in currently ongoing.
In the more recent experiments at the LAND setup, where the Crystal Ball gamma detector was used as a calorimeter, the reconstruction of the energy-differential cross section with a reasonable resolution was already shown to be feasible. It means that, even considering the uncertainties of the present experiment of the order of 10%, the uncertainties of the statistical model predictions, which are on average estimated to be within a factor of 1.5-2, can already be constrained.
The analysis of the present experiment is still in progress. As a next step, Coulomb excitation cross section for 94Mo will be obtained. The 94Mo(γ,n) reaction cannot be studied by photoactivation, since the life time of the daughter nucleus is too long (4000 y). At the same time, this reaction plays a key role in the p-process nucleosynthesis.
The future of the LAND setup - the R3B setup1 at FAIR2 - will take advantage of a three orders of magnitude higher intensity of the radioactive beams [85], as well as of a completely new detector system. High-resolution measurements of the energy-differential cross sections will be possible for exotic nuclei, which were never accessible in the laboratory before. Such measurements will open great opportunities for nuclear astrophysics, allowing to obtain high-quality experimental data even for regions of the nuclear chart where the statistical model calculations are not applicable.
In Nervensystemen werden zahlreiche Informationen wahrgenommen und verarbeitet um ein adäquates Verhalten hervorzurufen. Für die Untersuchung der funktionellen Zusammenhänge hierbei wurden verschiedene Methoden entwickelt, die eine gezielte Manipulation neuronaler Prozesse ermöglichen. Durch Analyse der resultierenden Effekte können dabei synaptische Proteine, einzelne Neuronen oder neuronale Netzwerke funktionell charakterisiert werden. Bisherige Ansätze verfügen jedoch nur über eine geringe zeitliche und räumliche Auflösung oder erlauben lediglich eine eingeschränkte Anwendung im frei beweglichen Tier.
Diese Nachteile können durch die heterologe Expression von lichtgesteuerten, mikrobiellen Rhodopsinen zur gezielten Manipulation des Membranpotentials umgangen werden. So induziert die Photoaktivierung des Kationenkanals Channelrhodopsin 2 (ChR2; (Nagel et al., Curr Biol 2005)) eine Depolarisation, während die Chloridpumpe Halorhodopsin (NpHR; (Zhang et al., Nature 2007)) für die Hyperpolarisation verwendet werden kann. Dabei ermöglichen die schnellen Kinetiken der Rhodopsine eine zeitlich präzise Steuerung des Membranpotentials. Durch Auswahl geeigneter Promotoren ist zudem oftmals eine zell spezifische Expression möglich. Dieser Ansatz wird daher allgemein als Optogenetik bezeichnet.
In der vorliegenden Arbeit wurden zunächst konventionelle Techniken genutzt, um die Funktion von zwei assoziierten Proteinen eines Acetylcholin Rezeptors in C. elegans zu untersuchen. Des Weiteren wurden verschiedene Methoden für den Fadenwurm entwickelt und angewendet, die die Vorteile optogenetischer Techniken für die funktionelle Charakterisierung synaptischer Proteine und neuronaler Netzwerke nutzbar machen. Hierbei erlaubt die Transparenz von C. elegans die optogenetische Stimulation im lebenden Organismus unter nicht invasiven Bedingungen. Weitere Vorteile von C. elegans als neurobiologischem Modellorganismus liegen in seiner einfachen Handhabung (Hope, 1999) und der stereotypen Entwicklung seines Nervensystems mit bekannten anatomischen Ausprägungen (Sulston and Horvitz, Dev Biol 1977; Varshney et al., PLoS Comput Biol 2011; White et al., Philos Trans R Soc Lond B Biol Sci 1986). Durch ihre Häufigkeit und die experimentelle Zugänglichkeit wird hierbei die neuromuskuläre Synapse oftmals zur Erforschung der synaptischen Reizweiterleitung genutzt (Von Stetina et al., Int Rev Neurobiol 2006). Durch pharmakologische (Lewis et al., Neuroscience 1980; McIntire et al., Nature 1993; Miller et al., Proc Natl Acad Sci U S A 1996; Richmond and Jorgensen, Nat Neurosci 1999) und elektrische Stimulation (Richmond and Jorgensen, Nat Neurosci 1999) können dabei Defekte der Transmission hervorgehoben werden, während Verhaltensexperimente oder elektrophysiologische Messungen der post synaptischen Ströme in Muskelzellen eine quantitative Analyse ermöglichen (Richmond and Jorgensen, Nat Neurosci 1999).
Diese Methoden wurden für die funktionelle Charakterisierung von NRA 2 und NRA 4 verwendet, die beide als akzessorische Proteine zusammen mit dem Levamisol sensitiven Acetylcholin Rezeptor der Körperwandmuskelzellen aufgereinigt wurden (Gottschalk et al., EMBO J 2005). Dabei konnte gezeigt werden, dass NRA 2 und NRA 4 im Endoplasmatischen Retikulum (ER) der Muskelzellen einen Komplex bilden, der die Sensitivität von beiden nikotinischen Acetylcholin Rezeptoren gegenüber verschiedenen cholinergen Agonisten verändert. In diesem Zusammenhang wurde auch nachgewiesen, dass die Oberflächenexpression einzelner Untereinheiten der beiden Rezeptoren durch NRA 2/4 beeinflusst wird. Diese Resultate legen die Vermutung nahe, dass beide Proteine die Zusammensetzung der Rezeptoren und somit ihre pharmakologischen Eigenschaften modulieren. Denkbar ist dabei eine regulatorische Funktion bei der Assemblierung verschiedener Untereinheiten zu einem funktionellen Rezeptor oder bei der Kontrolle des ER Austritts von Rezeptoren mit bestimmter Zusammensetzung. In dieser Hinsicht konnte jedoch keine Interaktion von NRA 2/4 mit der Notch Signalkaskade nachgewiesen werden, wie sie für die homologen Proteine nicalin und NOMO in Vertebraten gezeigt wurde (Haffner et al., J Biol Chem 2007; Haffner et al., EMBO J 2004).
Für die Untersuchung synaptischer Proteine durch optogenetische Techniken wurde ChR2(H134R) selektiv in cholinergen oder GABAergen Motorneuronen exprimiert, um die akute und lichtgesteuerte Freisetzung des jeweiligen Neurotransmitters zu ermöglichen. Die resultierende Stimulation bzw. Inhibition von Muskelzellen wurde hierbei durch elektrophysiologische Messungen der post synaptischen Ströme und durch Analyse von Kontraktionen respektive Relaxationen untersucht. Dabei wurde gezeigt, dass Störungen der synaptischen Reizweiterleitung die Ausprägung und Dynamik dieser lichtinduzierten Effekte beeinflussen und dadurch charakterisiert werden können. So zeigten beispielsweise Mutanten von Synaptojanin und Endophilin nachlassende Effekte bei anhaltender oder wiederholter Stimulation, was durch die gestörte Regeneration synaptischer Vesikel erklärt werden kann (Harris et al., J Cell Biol 2000; Schuske et al., Neuron 2003; Verstreken et al., Neuron 2003).
Die hohe Sensitivität dieser Methode wurde im Nachfolgenden dazu verwendet, die Inhibition cholinerger Motorneuronen durch den metabotropen GABAB Rezeptor zu untersuchen, der in C. elegans aus den beiden Untereinheiten GBB 1 und GBB 2 gebildet wird (Dittman and Kaplan, J Neurosci 2008; Vashlishan et al., Neuron 2008). Dabei konnte zunächst gezeigt werden, dass diese heterosynaptische Inhibition verschiedene lokomotorische Verhaltensweisen der Tiere beeinflusst. Für die mechanistische Untersuchung wurden anschließend cholinerge Motorneuronen durch ChR2(H134R) photoaktiviert, während resultierende Kontraktionseffekte in Abhängigkeit von GBB 1/2 analysiert wurden. Um hierbei die Funktion von GBB 1/2 durch erhöhte GABA Konzentrationen hervorzuheben, wurden zusätzlich GABAerge Motorneuronen optogenetisch stimuliert oder die Wiederaufnahme von GABA aus dem synaptischen Spalt durch Mutation des Membran ständigen GABA Transporters blockiert. So konnte gezeigt werden, dass GBB 1/2 eine akute Inhibition der cholinergen Motorneuronen bewirken, was vermutlich für die Regulation von Bewegungsabläufen eine wichtige Rolle spielt. Die geringe Dynamik der GBB 1/2 induzierten Effekte deutet allerdings darauf hin, dass die synaptische Aktivität durch den metabotropen Rezeptor kaum nachhaltig moduliert wird.
In nachfolgenden Versuchen wurde die optogenetische Stimulation von Motorneuronen außerdem mit der elektronenmikroskopischen Analyse der präsynaptischen Feinstruktur kombiniert. Dadurch konnte die Dynamik der Exozytose und Endozytose synaptischer Vesikel (SV) in Abhängigkeit von neuronaler Aktivität untersucht werden. So wurde gezeigt, dass synaptische Vesikel nahe der aktiven Zone während einer 30 sekündigen Hyperstimulation nahezu komplett aufgebraucht waren. Die vollständige Regeneration der SV Pools benötigte anschließend etwa 12 Sekunden und erfolgte zunächst in der Peripherie der aktiven Zone, was auf eine laterale Heranführung der Vesikel schließen lässt. Nach etwa 20 Sekunden erholte sich ebenfalls die Wirksamkeit der Stimulation von Muskelzellen durch die Motorneuronen, was durch elektrophysiologische Messungen der photo induzierten post synaptischen Ströme gezeigt wurde. Während der Hyperstimulation bildeten sich außerdem große vesikuläre Strukturen, die sich anschließend nach etwa acht Sekunden wieder aufgelöst hatten. In Analogie zu vergleichbaren Experimenten in anderen Organismen liegt die Vermutung nahe, dass es sich dabei um Zwischenprodukte der so genannten Bulk Phase Endozytose handelt, die das Clathrin abhängige Recycling von synaptischen Vesikeln bei starker neuronaler Aktivität ergänzt (Heuser and Reese, J Cell Biol 1973; Miller and Heuser, J Cell Biol 1984; Richards et al., Neuron 2000). Bemerkenswerterweise war der Abbau der vesikulären Strukturen in Synaptojanin und Endophilin defizienten Tieren stark verzögert. Denkbar ist, dass beide Proteine für die Synthese von synaptischen Vesikeln aus den vesikulären Zwischenprodukten der Bulk Phase Endozytose wichtig sind, analog zur ihrer Funktion bei der Clathrin abhängigen Endozytose an der Plasmamembran.
Durch die zielgerichtete Manipulation der Zellaktivität ermöglichen optogenetische Techniken außerdem die funktionelle Charakterisierung von Neuronen und neuronalen Netzwerken. Um die zelluläre Spezifität dieses Ansatzes zu erhöhen, wurde ein Tracking System entwickelt das die Position frei beweglicher Tiere in Echtzeit bestimmt und nachverfolgt. Dadurch konnte die Photoaktivierung optogenetischer Proteine auf definierte Bereiche der Fadenwürmer und somit auf ausgewählte Neuronen innerhalb der Expressionsmuster von verwendeten Promotoren eingeschränkt werden. Des Weiteren ermöglichte hierbei die Auswertung translatorischer Parameter die Analyse verschiedener lokomotorischer Merkmale wie Geschwindigkeit, Bewegungsbahn oder Ausprägung der Körperbiegungen. Dieses System wurde beispielhaft für die konzertierte Photoaktivierung durch ChR2(H134R) bzw. Photoinhibition durch MAC von zwei verschiedenen Gruppen von Neuronen angewendet, um die Integration mechanosensorischer Informationen durch Command Interneuronen zu untersuchen. In diesem Zusammenhang wurde zudem eine Rekombinase basierte Methode für optogenetische Proteine adaptiert, die die Transkription auf die zelluläre Schnittmenge von zwei verschiedenen Promotoren einschränkt und somit die Spezifität der Expression erhöht. Idealerweise kann dieser Ansatz außerdem mit der gezielten Photoaktivierung kombiniert werden, um die zelluläre Selektivität optogenetischer Anwendungen weiter zu verbessern.
Weiterhin ist die Anwendung optogenetischer Techniken bisher durch intrinsische Eigenschaften der verwendeten Rhodopsine auf die relativ kurzzeitige Manipulation des Membranpotentials von Zellen beschränkt. So benötigt ChR2 durch die schnelle Schließung seines offenen Kanals eine kontinuierliche Photoaktivierung, um eine andauernde Depolarisation hervorzurufen. Dies ist jedoch potentiell mit phototoxischen und – besonders bei C. elegans – phototaktischen Nebeneffekten verbunden. Deswegen wurden diverse Mutanten von ChR2 mit stark verlangsamter Inaktivierung (Berndt et al., Nat Neurosci 2009) für ihren Nutzen zur Langzeit Stimulation von erregbaren Zellen im Nematode getestet. Dabei wurde gezeigt, dass ChR2(C128S) durch einen kurzen Photostimulus mit vergleichsweise niedriger Intensität eine anhaltende Depolarisation über mehrere Minuten auslösen kann. Die wiederholte Stimulation in ASJ Neuronen ermöglichte zudem eine langzeitige Depolarisation über mehrere Tage, wodurch die genetisch veranlagte Entwicklung von Tieren manipuliert werden konnte. Durch gezielte Punktmutation konnten außerdem relevante Eigenschaften von ChR2(C128S) für die Langzeit Stimulation weiter verbessert werden.
Als weiteres optogenetisches Werkzeug wurde zudem die Photoaktivierbare Adenylatzyklase alpha (PACa) aus Euglena gracilis (Iseki et al., Nature 2002; Ntefidou et al., Plant Physiol 2003; Schroder-Lang et al., Nat Methods 2007) für die akute und lichtgetriebene Synthese des sekundären Botenstoffs cAMP in C. elegans etabliert. Die Photoaktivierung von PACa in cholinergen Motorneuronen verstärkte dabei die Neurotransmitterfreisetzung und induzierte hyperlokomotorische Phänotypen, vergleichbar zu Mutanten mit erhöhten cAMP Konzentrationen.
Zusammengefasst wurden diverse optogenetische Techniken für C. elegans entwickelt und optimiert, die die zellspezifische und nicht invasive Manipulation des Membranpotentials beziehungsweise die Synthese des sekundären Botenstoffs cAMP durch Licht im frei beweglichen Tier ermöglichen. Diese Methoden können zur gezielten Störung neuronaler Aktivität angewendet werden, um dadurch neurobiologische Fragestellungen im Fadenwurm zu untersuchen. Dies wurde beispielhaft für die Erforschung der synaptischen Reizweiterleitung und die funktionelle Analyse neuronaler Netzwerke demonstriert. Denkbar ist außerdem, diese für C. elegans etablierten Methoden vergleichbar in anderen Modellorganismen anzuwenden. So sind die Fruchtfliege ebenso wie der Zebrafisch Embryo bereits für optogenetische Techniken erprobt (Arrenberg et al., Proc Natl Acad Sci U S A 2009; Schroll et al., Curr Biol 2006). Für Säugetiere wie die Maus, die Ratte und den Makaken wurden zudem bereits Ansätze entwickelt, die die gezielte Photostimulation in lebenden und frei beweglichen Tieren ermöglichen (Han et al., Neuron 2009; Wentz et al., J Neural Eng 2011; Yizhar et al., Nature 2011; Zhang et al., Nat Rev Neurosci 2007).
Statistical machine translation (SMT) should benefit from linguistic information to improve performance but current state-of-the-art models rely purely on data-driven models. There are several reasons why prior efforts to build linguistically annotated models have failed or not even been attempted. Firstly, the practical implementation often requires too much work to be cost effective. Where ad-hoc implementations have been created, they impose too strict constraints to be of general use. Lastly, many linguistically-motivated approaches are language dependent, tackling peculiarities in certain languages that do not apply to other languages. This thesis successfully integrates linguistic information about part-of-speech tags, lemmas and phrase structure to improve MT quality. The major contributions of this thesis are: 1. We enhance the phrase-based model to incorporate linguistic information as additional factors in the word representation. The factored phrase-based model allows us to make use of different types of linguistic information in a systematic way within the predefined framework. We show how this model improves translation by as much as 0.9 BLEU for small German-English training corpora, and 0.2 BLEU for larger corpora. 2. We extend the factored model to the factored template model to focus on improving reordering. We show that by generalising translation with part-of-speech tags, we can improve performance by as much as 1.1 BLEU on a small French- English system. 3. Finally, we switch from the phrase-based model to a syntax-based model with the mixed syntax model. This allows us to transition from the word-level approaches using factors to multiword linguistic information such as syntactic labels and shallow tags. The mixed syntax model uses source language syntactic information to inform translation. We show that the model is able to explain translation better, leading to a 0.8 BLEU improvement over the baseline hierarchical phrase-based model for a small German-English task. Also, the model requires only labels on continuous source spans, it is not dependent on a tree structure, therefore, other types of syntactic information can be integrated into the model. We experimented with a shallow parser and see a gain of 0.5 BLEU for the same dataset. Training with more training data, we improve translation by 0.6 BLEU (1.3 BLEU out-of-domain) over the hierarchical baseline. During the development of these three models, we discover that attempting to rigidly model translation as linguistic transfer process results in degraded performance. However, by combining the advantages of standard SMT models with linguistically-motivated models, we are able to achieve better translation performance. Our work shows the importance of balancing the specificity of linguistic information with the robustness of simpler models.
Forty two samples of the Late Eocene Kiliran oil shale, Central Sumatra Basin, Indonesia were collected from a 102 m long drill core. Palynofacies and geochemical analyses have been carried out to reconstruct the paleoenvironmental conditions and paleoecology during deposition of the oil shale. Amorphous organic matter (AOM) is very abundant (>76%). B. braunii palynomorph is present (3-16%) as the only autochtonous structured organic matter and generally more abundant in middle part of the profile. The stable carbon isotopic composition of organic matter (δ13C) varies from -27.0 to -30.5‰ and is generally more depleted in middle part of the profile. The ratio of total organic carbon to sulfur (TOC/S), used as salinity indicator, ranges from 2.5 to 15.8 and shows variations along the profile. Relatively less saline environments are observed in the middle part profile. Fungal remains are generally present only in middle part of the profile with distinct peak of abundances. The presence of fungal remains is regarded as an indication for a relatively warmer climate during deposition of middle part of the profile. The warmer climate is thought to influence the establishment of a thermocline, limiting the supply of recycled nutrients to the epilimnion. Consequently, the primary productivity in the Kiliran lake decreased during deposition of the middle part of the profile as indicated by the relatively depleted δ13C and the blooming of B. braunii. The chemocline was also shoaling during deposition of the middle part of the profile according to the higher abundance of isorenieratene derivatives of green sulfur bacteria origin. The warmer climate affected also to increase of water supply and thus less saline environments.
Tectonic subsidence is also thought to be a significant factor for the development of the Kiliran lake. The Zr/Rb ratio, an indicator for grain size, ranges from 0.4 to 1.3 and generally increases upwards along the profile. Three sudden decreases of the ratio are observed, indicating rapid change to finer grain size. These decreases are interpreted to indicate rapid deepening events of the lake due to mainly periodic subsidence. During deposition of lower part of the profile, the subsidence rates might have been relatively higher than sediment and water supply rates, resulting in a higher autochtonous fraction in the oil shale. During deposition of middle part of the profile, the sediment and water supply rates were relatively higher promoting distinct progradational sedimentation. Subsequently, the lake became more shallow and smaller during deposition of the upper part of the profile, leading to a relatively higher terrigenous input to the oil shale.
Norneohop-13(18)-ene and neohop-13(18)-ene derived from methanotrophic bacteria are the dominant hopanoid hydrocarbons. The sum of their concentrations varies from 40.6 to 360.0 μg/g TOC. The δ13C of these compounds are extremely depleted (-45.2 to -50.2‰). The occurrence of abundant bacteria including methanotrophic bacteria was responsible for the recycling of carbon below the chemocline of the lake. The effect of the recycling of carbon is observed by the presence of a concomitant depletion (about 7-9‰) in 13C of some specific biomarkers derived from organisms dwelling in the whole phototrophic zone.
4-Methylsterane and 4-methyldiasterene homologues occur in the oil shale as the predominant biomarkers. The sum of the concentrations of all homologues are about 40.3-1,009.2 μg/g TOC with generally higher values in uppermost and lower parts of the profile. Ca accounts as the predominant element in the oil shale, ranging from 5.0 to 16.7%. This element shows generally parallel variation with the 4-methylsterane homologues along the profile. This suggests that the 4-methylsteranes were derived from biological sources favoring more alkaline and more trophic environments. On the other hand, these compounds were less abundant in middle part of the profile which is consistent with less alkaline and less trophic environments promoting B. braunii to bloom.
The 4-methylsterane homologues are considered to originate from Dinoflagellates. Alternation between Dinoflagellates and B. braunii in Paleogene lake systems due to water chemistry changes are known from previous studies. Moreover, freshwater Dinoflagellates have been frequently reported to occur in the basin depocenters. In the present case, distinct alternation between B. braunii abundances and concentrations of 4-methylsterane homologues along the studied oil shale profile suggest that the 4-methylsterane homologues were derived from freshwater Dinoflagellates although dinosterane is not present in the sediment extracts. Water alkalinity and trophic level changes were most likely responsible for the alternation of Dinoflagellates and B. braunii blooming.
We found that the HMTase G9a, that catalyzes H3K9me2 in euchromatin, plays a key modulatory role in type I IFN expression. This finding raises the possibility of targeted intervention with type I IFN expression by using small synthetic inhibitors of G9a. Given the overall minimal negative effect of G9a-deficiency on differentiated cells, the short-term suppression of G9a could be used to potentiate type I IFN expression during chronic viral diseases such as hepatitis C. Accordingly, pharmacological enhancement of methylation, for example by inhibition of the H3K9me2 specific demethylases, could be potentially used to attenuate type I IFN expression and help to control chronic inflammatory and autoimmune conditions. The mechanism responsible for canvassing the epigenetic profile of type I IFN expressing cells are not known. It is plausible, that similar to neurons, where G9a is targeted to specific loci with the help of noncoding RNAs, IFN expressing cells possess similar mechanisms to target H3K9me2 demethylating enzymes to type I IFN loci, thus keeping these loci accessible for IFN-inducing transcription factors. Identification of non-coding RNAs that may contribute to the establishment of the epigenetic state of IFN producing cells will provide a further opportunity for targeted manipulation of IFN expression.
In my thesis, I describe the collaborative experiments that show the ability of synthetic compounds that interfere with the histone readers to suppress inflammation. Our results present a novel concept for the regulation of inflammatory gene expression. The diversity of histone readers and the combinatorial nature of regulation of gene transcription may provide an opportunity for highly selective interference with disease associated transcriptional programs by interfering with specific readers. In the future we plan to address the therapeutic potential of BET antagonists in autoimmune and chronic inflammatory conditions.In summary, the experiments described in my thesis provide an example of how the understanding of the basic mechanisms of chromatin control of gene expression can facilitate novel therapeutic approaches that target chromatin.
Purpose: The aim of this retrospective study is to evaluate the long term implant survival at 5 years, periimplantary conditions and prosthetic maintenance requirements for implant supported mandibular removable dentures retained on only 2 Ankylos® implants placed interforaminally in the mandible and using only conical double crown attachments. Materials and methods: Using the database at the Faculty of Dentistry, University of Frankfurt a selection process was performed to choose patients receiving only 2 Ankylos® implants placed interforaminally in the mandible and using only conical double crown attachments. Implant survival, periimplant condition (periodontal bleeding, plaque index and probing depth), bone loss (from panoramic radiographs) and mobility (using Periotest®) were monitored annually following implant loading. In addition a detailed prosthetic maintenance list was created for each patient based on their yearly checkups and emergency appointments. 37 patients with edentulous mandibles (34 with complete dentures in the upper jaw and 3 with tissue-tooth borne coverdentures) received 2 interforaminal Ankylos® implants (67 in the canine region, 7 in 2nd incisor region). Results: Mean Periotest® values at 5 years (-1.97 ±2.24) were lower than at loading (-1.47 ±2.33). A drop was seen in the Periotest® readings after the first year of loading. The decrease in mean Periotest® values between PTV5 and PTV 1 were not statistically significant (Tukey-Kramer test: p>0.05)
14 patients (37.8%) displayed no resorption at all with an average of 0.801 mm mesially and 0.807mm distally after 5 years. The most increase in bone loss was seen after the first year of loading. There was a gradual increase in bone resorption after the first year of loading. The differences between both distal and mesial bone resorption level at five years and at one year after loading are not significant (Tukey-Kramer test: p<0.05) Plaque and bleeding index values were low at a mean of 0.97 ±0.86 and 0.59 ±0.77 respectively after 5 years of loading. The increase from the first year of loading till the 5th year of loading was significantly higher for plaque measurements but not for bleeding measurements (Tukey-Kramer Test: p<0.05 and p>0.05 respectively). Mean probing depth values were higher after 5 years (2.61 ±0.92 mm) in comparison to the values at loading (2.15 ±0.75 mm). The difference between average values at year 5 and year 1 was statistically significant (Tukey-Kramer test: p<0.05). The most occurring form of maintenance was minor adjustments such as pressure point (15 patient or 40,5%) and relining 11 patients or 29.7%). Teeth breaking off the denture were less common (4 patients or 10.8%). 5 decementations of primary crowns occurred in 4 patients (10.8%) within the 5 year observation time. Other major complications were 4 loose abutments in 3 patients (8.1%), 3 decementations of secondary copings in 3 patients (8.1%) and 1 case (2.7%) in which the prosthetic metal framework fractured. No fracture of abutments or primary crowns occurred during the investigation. Implant survival was 100% percent after 5 years ,1 implants did not fulfil Albrektsson’s success criteria and showed more than 0.2 mm of bone loss per year after the first year of loading with the first year giving a success rate of 98.8%. Conclusion: In conclusion this study has demonstrated that patients have a wider variety of options when it comes to choosing a reliable prosthesis in the lower jaw. Patients with financial limitations can be provided with a reliable prosthetic option using removable dentures retained by conical double crown attachments on 2 implants. The requirements for such a construction are a mechanically stable implant system and a mechanically stable framework. When these prerequirments are fulfilled, the patient can be satisfied with a prosthesis of superior quality to other attachment types and the dentist can rely on the fact that frequent maintenance which costs time and money can be eliminated or at least reduced. Through further innovation this type of construction can also reach patients who are lower down on the economic scale such as elderly patients and retirees.
Recent data indicate that reactive oxygen species (ROS) are produced in the nociceptive system during persistent pain and contribute to pain sensitization. Aim of this study was to investigate potential antinociceptive effects of ROS scavengers in different animal models of pain. Intrathecal injection of ROS scavengers 1-Oxyl-2,2,6,6-tetramethyl -4-hydroxypiperidine (TEMPOL) or Phenyl-N-tert-butylnitrone (PBN) significantly inhibited formalin-induced nociceptive behavior in mice, suggesting that ROS released in the spinal cord are involved in nociceptive processing. Formalin-induced nociceptive behavior was also inhibited by intraperitoneal injection of a combination of vitamin C and vitamin E, but not of vitamin C or vitamin E alone. Moreover, the combination of vitamin C and E dose-dependently attenuated mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain. The SNI-induced mechanical allodynia was also reduced after intrathecal injection of the combination of vitamin C and E, and western blot analyses revealed that vitamin C and E treatment can ameliorate the activation of p38 MAPK in the spinal cord and in DRGs. These data suggest that a combination of vitamin C and E can inhibit the nociceptive behavior in animal models of pain, and points to a role of the spinal cord as an important area of ROS production during nociceptive processing.
Working memory (WM) contributes to countless activities during everyday live: reading, holding a conversation, making tea and so on. The core processes of WM comprise the phases of encoding, maintenance and retrieval. Successful recognition of stored objects requires several subprocesses such as stimulus encoding and evaluation, memory search and the organisation of a decision and a response. Much research has focused on encoding and maintenance of information but little interest has been directed to the retrieval of information. This is why the present dissertation investigated the neuronal correlates of retrieval of previously stored information and its modulation by load and probe-item similarity.
Here memory load and probe-item similarity were manipulated in order to investigate the neuronal correlates of the recognition process using electroencephalography (EEG). We tested the hypothesis recognition is influenced differently by probe-item similarity and by memory load and that these factors are re Effected by distinct neuronal correlates. Furthermore we tested whether distinct neuronal responses could be related to a summed similarity model.
The analysis of high-density ERP recordings showed both a load effect (load 1>load 3) and a similarity effect In addition, there was an interaction between load and similarity. The load effect was present during the whole epoch and did not change over time, whereas the similarity effect showed two distinct components between 300-600ms. In contrast to the load effect the similarity effect changed its sign over time. For the rest component, match probes elicited the strongest ERP responses, whereas for the second component dissimilar probes yielded the strongest ERP responses. The timing of the similarity effect corresponded well with the early and late P3b complex. The P3b complex is associated with stimulus categorisation and evaluation (early subcomponent) and memory search and criterion testing (late subcomponent).
The results suggest that the difficulty of a task is not only determined by load but also enhanced by probe-item similarity. Since increasing the number of samples (i.e. memory load) can also increase the probe-item similarity (i.e. the probability that one of the samples is perceptually similar to the probe), an independent manipulation of both factors is indispensable to disentangle their particular impact on short-term recognition. Furthermore, I propose that the two distinct neural correlates of the P3b complex reeffects different stages of task processing connected with probe-item similarity. As suggested by summed similarity VI models, these components might reflect the subprocesses of similarity summation (early P3b) and criterion testing (late P3b).