Kinematic Analysis of Rapid Eye Movements for Vestibular Disorders

The system under development provides a means to assess the semi-circular canals of the human vestibular system. The Impulse Test is a simple method to detect disorders within the three sets of semi-circular canals, by stimulating each pair of canals in turn. This report describes the work carried out to develop a simple, non-intrusive system whereby the patient can be assessed in a matter of seconds. The system consists of a single high-speed monochrome camera connected to a computer with the developed software. The main area of work so far, has been the implementation of an accurate image processing technique to track both the head and the eyes. Pattern recognition was attempted first, but this was met with limited success. The method of image processing then shifted to thresholding performed upon the eye. Modelling the head and eye in three dimensions were also integral parts of the project. The eye's origin must be accurately represented as eye velocity is measured relative to this point. Therefore, inaccuracies in describing the eye's origin yield misleading results

Nonlinear system identification and control using dynamic multi-time scales neural networks

In this thesis, on-line identification algorithm and adaptive control design are proposed for nonlinear singularly perturbed systems which are represented by dynamic neural network model with multi-time scales. A novel on-line identification law for the Neural Network weights and linear part matrices of the model has been developed to minimize the identification errors. Based on the identification results, an adaptive controller is developed to achieve trajectory tracking. The Lyapunov synthesis method is used to conduct stability analysis for both identification algorithm and control design. To further enhance the stability and performance of the control system, an improved . dynamic neural network model is proposed by replacing all the output signals from the plant with the state variables of the neural network. Accordingly, the updating laws are modified with a dead-zone function to prevent parameter drifting. By combining feedback linearization with one of three classical control methods such as direct compensator, sliding mode controller or energy function compensation scheme, three different adaptive controllers have been proposed for trajectory tracking. New Lyapunov function analysis method is applied for the stability analysis of the improved identification algorithm and three control systems. Extensive simulation results are provided to support the effectiveness of the proposed identification algorithms and control systems for both dynamic NN models

Natural Disasters and Financial Markets

The first essay (chapter 2) examines the impact of major U.S. natural disasters on the stock returns and volatilities of firms based in disaster areas. We find that a small proportion of catastrophes (between six and eight percent) have a significant impact on returns, after controlling for false discoveries. The meaningful shocks are distributed over a relatively long period of time with the uttermost effects being felt in the two or three months following disasters. Furthermore, we observe that the second moments of returns of affected firms more than double when hurricanes, floods, winter storms and episodes of extreme temperature occur. The second essay (chapter 3) studies the effect of major floods on new municipal bond issues marketed by U.S. counties. The results show that bonds sold in the midst of floods exhibit yields about seven percent higher than bonds sold at other times, which is a net loss of almost $100,000 in terms of proceeds on a$10 million debt issue. Consistent with a behavioral explanation based on the availability bias, the abnormal yields rapidly decay over time and are limited to first-time disaster counties. The evidence for an increase in credit risk is mixed and the results do not support lower market liquidity stories. Selection bias, underpricing activities and issuance costs are examined and are unlikely to materially affect the conclusions. The final essay (chapter 4) focuses on the consequences of disasters on investor risk preferences. We infer the impact of major catastrophes on the risk-taking behavior of investors from a database of U.S. municipal bond transactions. As the effect of disasters is mostly regional, we exploit the geographic segmentation of the municipal bond market to estimate a measure of regional risk aversion using a conventional consumption capital asset pricing model. The findings strongly support the assumption that natural disasters cause a statistically and economically significant increase in financial risk aversion at the local level

Über Kalziumsignale und Zytotoxizität menschlicher natürlicher Killerzellen : Calcium signaling and cytotoxicity of human natural killer cells

Calcium signaling is an essential component of immune cell function. Immunocompetent cells employ calcium ions as a second messenger to regulate proliferation, migration and maturation. In addition, intracellular calcium signals are necessary for cytotoxic lymphocytes (CLs) such as CD8+ T-cells and natural killer cells (NK cells) to eliminate target cells. For several decades, the doctrine used to be that this elimination is mainly achieved by forcing a target cell into apoptosis. In recent years, several groups reported that there is at least one further way of target cell killing. Given the right circumstances, CLs are also able to kill by a direct lysis of the target cell’s membrane, a process referred to as ’necrosis’. Our research group, the Department of Biophysics at Saarland University, directed by Prof. Dr. Markus Hoth, investigates the Ca2+ dependence of signaling processes in immune cells. We found that calcium ion influx into killer cells is not only necessary for a successful attack on pathogens and tumor cells, but that extracellular calcium supply can influence a killer cell’s global killing efficiency. The aim of this doctoral thesis was to study influx kinetics of Ca2+ ions in active NK cells at a single-cell level using fluorescence microscopy. The conducted experiments led to two main conclusions: I) Not only do NK cells employ both necrosis and apoptosis when killing certain target cells, but the frequency distributions of both killing types depend highly on the extracellular Ca2+ concentration ([Ca2+]ext). Low concentrations favor the occurrence of apoptosis, while an increase in [Ca2+]ext shifts the balance towards necrotic killing. This shift occurs even after raising Ca2+ ion levels beyond the amount necessary for necrosis induction. II) The shape of Ca2+ influx differs, regarding necrotic and apoptotic killing. Necrosis induction depends on high sustained rises in [Ca2+]int, while NK cells causing apoptosis tend to show low and oscillatory Ca2+ signals. Further experiments were conducted in attempt to reveal the responsible molecular mechanisms. Artificially releasing high amounts of Ca2+ ions into the cytosol of killing NK cells, using a photolabile Ca2+ chelator, suggests that high cytosolic Ca2+ concentrations are necessary but not sufficient for necrosis induction by NK cells. The presented results have contributed to shedding light on the Ca2+ dependence of NK cell function. In his doctoral thesis published in 2016, Christian Backes from our research group demonstrated that the balance of necrosis to apoptosis induced by NK cells greatly affects their total killing competence. The observation that global killing efficiency of CD8+ T-lymphocytes and NK cells depends on [Ca2+]ext can now in parts be explained by the likelihood of necrotic and apoptotic killing processes shifting. Although different Ca2+ influx patterns in active NK cells were previously described by other groups, no exact quantification of these signals has yet been provided. In addition to giving such a quantification, this thesis can provide evidence that these different signal types are clearly linked to distinct outcomes regarding NK cell cytotoxicity in vitro. NK cells play a pivotal role in tumor surveillance and - in case of already developed cancer - keeping malignant cell clones in check. Apoptosis and lysis of target cells may both help achieve a shared aim but will differently affect the anti-tumor immune response. Hence, different Ca2+ signals in tumor-killing NK cells as well as their likelihood of inducing apoptosis or necrosis may also affect tumor development, progression as well as the efficacy of immune therapy and adoptive cell transfer. Many recent studies suggest that tumor cells benefit from necrosis by taking advantage of the resulting microenvironment. If we can deepen our understanding of how different calcium signal types in CLs come about, we could try to modulate killing behaviour to shape a more desirable cellular immune response to malignancies.Kalziumsignale spielen eine Schlüsselrolle in der Funktion unserer Immunabwehr. Immunzellen verwenden diese Signale, um komplexe Prozesse wie Proliferation, Migration und Reifung zu regulieren. Darüber hinaus benötigen Killerzellen wie CD8+-T-Zellen und natürliche Killerzellen (NK-Zellen) hohe zytosolische Kalziumspiegel, um Zielzellen abzutöten. Die Doktrin der letzten Jahrzehnte war, dass dieses Abtöten im Wesentlichen auf einem einzigen Mechanismus basiert: der Aktivierung des programmierten Zelltodes, der Apoptose der Zielzelle. Seit einiger Zeit mehren sich jedoch die Hinweise, dass es noch mindestens einen weiteren Mechanismus gibt. Unter gewissen Voraussetzungen können Killerzellen ihre Opfer auch durch eine direkte Lyse der Zellmembran töten. Dieser Prozess wird gemeinhin als "Nekrose" bezeichnet. Unter der Leitung von Prof. Dr. Markus Hoth erforscht unsere biophysikalische Arbeitsgruppe seit Jahren die Bedeutung von Kalziumsignalen für eine Vielzahl von Immunzellen. Wissenschaftler unserer Abteilung fanden heraus, dass ein Kalziumeinstrom in Killerzellen nicht nur notwendig für das Abtöten von Bakterien und Tumorzellen ist, sondern dass das extrazelluläre Kalziumionenangebot auch einen Einfluss auf die absolute Killingeffizienz ausübt. Das Ziel der vorliegenden Doktorarbeit war, die Kinetik dieser Kalziumströme in aktiven NK-Zellen mittels Fluoreszenzmikroskopie auf Einzelzellebene zu erforschen. Die in diesem Rahmen durchgeführten Experimente lieferten zwei wichtige Erkenntnisse: I) Zusätzlich zur Bestätigung, dass NK-Zellen sowohl Apoptose als auch Nekrose in geeigneten Zielzellen induzieren, stellte sich heraus, dass die statistische Verteilung beider Killingtypen stark vom extrazellulären Kalziumangebot abhängt. Niedrige Konzentrationen an Kalziumionen begünstigen das Auftreten von Apoptosen, während steigende Kalziumspiegel zu mehr und mehr Nekrosen führen. Dieser Einfluss zeigt sich auch noch bei extrazellulären Kalziumkonzentrationen, die weit über dem für Nekrose notwendigen Maß liegen. II) NK-Zellen zeigen verschiedene Arten von Kalziumsignalen, je nachdem, welchen Typ Zytotoxizität (i.e. Nekrose oder Apoptose) sie in ihrer Zielzelle induzieren. Die Lyse der Zelle bedurfte dabei stets eines hohen und anhaltenden Einstroms von Kalziumionen, während Killerzellen, die Apoptose hervorriefen, niedrigere und oszillierende Kalziumströme zeigten. Weitere Experimente zielten darauf ab, die molekularen Mechanismen für diese Unterschiede in den Signalen aufzudecken. Indem große Mengen an Kalziumionen mittels eines photolabilen Chelators künstlich in Killerzellen freigesetzt wurden, konnte gezeigt werden, dass hohe Kalziumeinströme zwar notwendig, aber sehr wahrscheinlich nicht hinreichend für das nekrosebasierte Abtöten sind. Die vorliegenden Ergebnisse haben dazu beigetragen, die Kalziumabhängigkeit der Funktion von NK-Zellen besser zu verstehen. In seiner 2016 publizierten Doktorarbeit konnte Christian Backes aus unserer Arbeitsgruppe zeigen, dass die Balance von Nekrose- zu Apoptoseinduktion einen starken Einfluss auf das globale Killingpotential von NK-Zellen ausübt. Mit Hilfe der hier gewonnenen Erkenntnis, dass diese Balance vom extrazellulären Kalziumangebot abhängt, kann die Beeinflussung der Effizienz natürlicher Killerzellen durch die Verfügbarkeit von Kalziumionen nun in Teilen erklärt werden. Verschiedenartige Muster von Kalziumströmen in aktiven NK-Zellen wurden in der Vergangenheit bereits von anderen Arbeitsgruppen postuliert, jedoch nicht exakt quantifiziert. Neben einer solchen Quantifizierung kann die vorliegende Arbeit erstmals beweisen, dass diese Signalmuster deutlich mit den verschiedenen Killingarten assoziiert sind, zu denen NK-Zellen fähig sind. Natürliche Killerzellen zählen zu den wichtigsten Effektoren der Tumorüberwachung. Auch im Falle von bereits entstandenen Tumoren tragen sie essenziell dazu bei, den Tumor in Schach zu halten. Unmittelbar führen Apoptoseinduktion und Lyse zwar zum gleichen Ergebnis - dem Tod der Tumorzelle -, beide Prozesse beinflussen jedoch die gegen den Tumor gerichtete folgende Immunantwort auf stark unterschiedliche Weise. Es ist anzunehmen, dass die Frage, wie NK-Zellen Tumorzellen eliminieren und welche Kalziumsignale sie dabei präsentieren, auch einen Einfluss auf die Wirksamkeit von Chemotherapien, immunmodulierenden Therapien und adoptivem Zelltransfer haben könnte. Viele aktuelle Studien legen nahe, dass Tumorzellen von einem bestimmten immunologischen Mikromilieu profitieren. Ein solches Milieu scheint insbesondere durch nekrotische Zellen begünstigt zu werden. Ein tiefer gehendes Verständnis davon, wie verschiedene Kalziumsignale in NK-Zellen zustande kommen, könnte es erlauben, sie pharmakologisch zu beeinflussen, um das Tötungsverhalten von NK-Zellen zu modifizieren. Auf diese Weise könnte ein immunologisches Mikromilieu im Tumorgewebe erreicht werden, das bösartige Zellen schädigt, ohne gleichzeitig die Vermehrung benachbarter Tumorzellen zu stimuliere

Human adaptive mechatronics methods for mobile working machines

Despite the trend of increasing automation degree in control systems, human operators are still needed in applications such as aviation and surgery, or machines used in remote mining, forestry, construction, and agriculture, just to name a few. Although there are research results showing that the performance between the operators of working machines differ significantly, there are currently no means to improve the performance of the human-machine system automatically based on the skill and working differences of the operators. Traditionally the human-machine systems are designed so that the machine is "constant" for every operator. On the contrary, the Human Adaptive Mechatronics (HAM) approach focuses on individual design, taking into account the skill differences and preferences of the operators. This thesis proposes a new type of a HAM system for mobile working machines called Human Adaptive Mechatronics and Coaching (HAMC) system that is designed to account for the challenges regarding to the measurement capability and the work complexity in the real-life machines. Moreover, the related subproblems including intent recognition, skill evaluation, human operator modeling, intelligent coaching and skill adaptivity are described. The intent recognition is solved using a Hidden Markov model (HMM) based work cycle modeling method, which is a basis for the skill evaluation. The methods are implemented in three industrial applications. The human operator modeling problem is studied from the structural models' perspective. The structural models can be used to describe a continuum of human operator models with respect to the operating points of the controlled machine. Several extensions and new approaches which enable more efficient parameter estimation using the experimental data are described for the conventional Modified Optimal Control Model (MOCM) of human operator. The human operator modeling methods are implemented to model a human operator controlling a trolley crane simulator. Finally, the concept of human adaptive Human-Machine Interface (HMI) is described. The analytic and knowledge-based approaches for realizing the HMI adaptation are presented and implemented for trolley crane simulator control

Statistical methodology for the analysis of road safety data

PhD ThesisPTV Grou