Diss. Univ. Bern, 2008. / Ed. commerciale de la thèse de Berne, 2008. Bibliogr.

The thesis deals with quasi-static and fatigue simulations of thick composite lugs subjected to three-dimensional stress states. This includes damage prediction of hybrid laminates made of GRFP and CRFP containing unidirectional and woven fabric plies.Focus lies on the development of a progressive damage model in fatigue which accounts for sti˙ness and strength degra-dations. Two methods based on Puck’s failure criterion are proposed to predict failure of unidirectional plies: one for plane stress analysis and and the other which takes out-of-plane damage into account.Virtual testing in FEM is conducted in quasi-static and fatigue analysis on thick composite lugs subjected to uni-axial loading. Damage, strength and life predictions are then compared with experimental results to validate the numerical models under investigations. / In der vorliegenden Arbeit wird die Berechnung der Festig-keit von dickwandigen Lochleibungslaminaten im Faserver-bundwerksto˙en unter dreidimensionalen Spannungszustän-den untersucht. Nichtlineare Materialverhalten von Hybrid-laminaten in CFK und GFK werden für Unidirektionalfa-serlagen und Gewebelagen berücksichtigt.Der Schwerpunkt liegt auf der Entwicklung von progressi-ven Versagensmodellen unter der Berüsichtigung von Rest-festigkeit und Reststeifigkeit des Materials. Zwei Modelli-erungsmethoden nach Puck-Kriterium zur Vorhersage des Versagens in UD-Lagen werden vorgeschlagen: eine Degra-dierungstechnik für ebene Spannungszustände und ein me-hrachsiges Modell.Numerische Simulationen mit der Finite-Elemente-Methode werden in Statik- und Ermüdungsanalyse an dickwandigen Lochleibungslaminaten unter einachsiger Belastung durch-geführt. Beschädigungen, Festigkeiten und Ermüdungsle-bensdauer werden dann mit experimentiellen Daten ver-glichen, um die numerischen Methoden zu validieren.

Syftet med denna studie har varit att studera psykosociala faktorers påverkan på skaderisken hos ungdomslandslagsspelare i fotboll. Tvångsmässig passion är en central faktor som studerats i relation till skada. Även faktorerna antal träningstimmar per vecka, antal spelade matcher, stress, själförtroende och motivation har studerats i relation till skada. En kvantitativ design har använts där 300 svenska ungdomslandslagsspelare i fotboll ingått som undersökningsdeltagare. Använda mätinstrument i undersökningen har varit PANAS, PSS, Grit-scale, PCLDS, Passion Scale, SCI samt SMS. Resultaten visade att män ådrar sig fler allvarliga skador (minst 4 veckors frånvaro) än kvinnor. Vidare visade resultaten att flergångsskadade spelare har en signifikant högre tvångsmässig passion än andra spelare. Resultaten diskuteras i förhållanden till uppsatsens teoretiska ramverk samt resultat från tidigare forskning. Förslag för framtida forskning inom området ges. / The purpose of this study was to study psychosocial factors influence on injury risk among youth national team soccer players. Obsessive passion has been a key factor that has been studied in relation to injury. Also the factors number of training hours per week, number of matches played, stress, self confidence and motivation has been studied in relation to injury. A quantitative design was used in which 300 Swedish youth national team soccer players have concluded as study participants. Used instruments in this survey has been PANAS, PSS, Grit-scale, PCLDS, Passion Scale, SCI and SMS.. The results showed that men incur more serious injuries then women. Furthermore, results showed that players with more than one injury during the season had higher obsessive passion then other players. The results are discussed in relation to the theoretical framework and the results from previous research. Proposal for future research in the field are provided.

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Temporal control, inherent in all biological processes, relies on intrinsic systems to govern periodical behaviors and physiological responses. The circadian clock, a vital timekeeper, enables organisms to anticipate and adjust to daily environmental changes. In mammals, the circadian clock is organized hierarchically, with a central master clock in the hypothalamic suprachiasmatic nucleus regulating peripheral clocks distributed across the body. To maintain coherent circadian rhythms at the tissue level, peripheral oscillators exchange intercellular coupling factors by paracrine signaling pathways to synchronize. At the individual cell scale, the circadian clock interacts with another periodical biological process: the cell cycle. However, the mechanisms governing this interplay remain poorly elucidated. Here, we explore the influence of extracellular circadian synchronization on the intracellular coordination between the circadian clock and the cell cycle. To do so, we combined a mathematical model and long-term live-imaging recordings at the single-cell and population level of a human cell line. We show that the global circadian and cell cycle coordination within individual cells is disrupted when the extracellular circadian synchronization is lost, obstructing collective tissue growth. Populations with coherent circadian rhythms display rhythmic growth oscillations, uncovering a novel global regulator of tissue dynamics. Knocking down core circadian elements abolished these effects, revealing the fundamental role of circadian clock control as a timing mechanism. These findings advance our understanding of how biological systems maintain equilibrium and regulate proliferation in normal and pathological conditions. The circadian clock plays a crucial role in orchestrating cell proliferation, impacting tumor initiation, growth, and treatment responses. Recent research has reported significant changes in drug response for different administration hours throughout the day, highlighting the benefits of aligning treatment strategies to the inherent circadian rhythm. However, chronotherapy is still omitted in clinical practice, primarily due to a lack of understanding of the underlying mechanisms driving time-dependent drug responses. Currrently, no standardized protocols exist for identifying these temporal factors. Therefore, we developed a combined mathematical and experimental approach to identify the factors influencing time-dependent drug sensitivity in human cells. Our results show how circadian and drug properties independently shape time-of-day drug responses, offering novel insights into the time-dependent treatment outcome. This framework holds potential for developing personalized treatment schedules aligned with the internal circadian clock, optimizing cancer therapeutical strategies. On the other hand, tissue growth masks heterogeneous proliferation patterns at the single-cell level, potentially jeopardizing the treatment outcome, which cannot be exclusively attributed to circadian clock regulation. Clustering the cells upon their overall number of divisions, the proliferative patterns remain strikingly constant across different tissues, a phenomenon reported by several recent studies. This consistency implies the existence of a common underlying mechanism that is currently unknown. Proliferation control relies on a set of checkpoint mechanisms that accurately and quickly detect DNA damage. The onset of cellular stress triggers the activation of the p53 protein, orchestrating the expression of hundreds of genes responsible for cell cycle regulation or apoptosis, among other functions. Here, we present evidence that changes in cellular stress levels contribute to the gradual proliferation variability. Specifically, different DNA damage levels are encoded quantitively into signal parameters of p53 and p21 proteins in a gradual manner, shaping proliferation activity proportionally. These results propose a novel function of the p53-p21 signaling network in deciphering and decoding the magnitude of DNA damage to adjust and control proliferation. / This study examines how extracellular circadian synchronization affects the coordination between the circadian clock and the cell cycle. By combining mathematical modeling and long-term live imaging of human cells, we show that loss of synchronization disrupts global circadian and cell cycle coordination in individual cells, hindering tissue growth. When circadian rhythms are coherent, rhythmic growth oscillations occur, indicating a global tissue dynamics regulator. Knocking down key circadian elements abolished these effects, emphasizing the circadian clock's timing role. These findings enhance our understanding of biological balance and proliferation regulation in both normal and pathological states. The circadian clock is also vital in cell proliferation, influencing tumor growth and treatment responses. Drug responses vary depending on the time of day, highlighting the importance of aligning treatments with circadian rhythms. However, chronotherapy is not widely used in clinical practice due to insufficient understanding of the underlying mechanisms. Our approach identifies factors affecting time-dependent drug sensitivity, offering insights into personalized treatment schedules. Tissue growth masks single-cell proliferation patterns, essential for effective treatment. By clustering cells based on division numbers, we found consistent proliferation patterns across tissues, suggesting an unknown underlying mechanism. The p53-p21 signaling network regulates proliferation by quantifying DNA damage and adjusting cell cycle responses. This study reveals how p53-p21 signaling decodes DNA damage levels to control proliferation. / Diese Studie erforscht, wie extrazelluläre zirkadiane Synchronisation die Abstimmung zwischen der zirkadianen Uhr und dem Zellzyklus beeinflusst. Durch mathematische Modellierung und langfristige Live-Bildgebung an menschlichen Zellen zeigt sie, dass der Verlust der Synchronisation die zirkadiane und Zellzykluskoordination stört und Gewebewachstum hemmt. Bei kohärenten zirkadianen Rhythmen entstehen rhythmische Wachstumsoszillationen, die eine globale Steuerung der Gewebedynamik andeuten. Das Ausschalten zirkadianer Elemente beseitigt diese Effekte und verdeutlicht die zeitliche Rolle der zirkadianen Uhr. Diese Ergebnisse liefern Einblicke in die biologische Balance und Regulierung der Proliferation in normalen und pathologischen Zuständen. Die zirkadiane Uhr beeinflusst die Zellproliferation, das Tumorwachstum und die Wirkung von Behandlungen. Arzneimittelreaktionen variieren tageszeitabhängig, was die Relevanz der Chronotherapie unterstreicht – der Anpassung von Therapien an zirkadiane Rhythmen. Allerdings wird Chronotherapie selten klinisch genutzt, da die zugrundeliegenden Mechanismen nicht ausreichend verstanden sind. Diese Studie identifiziert Faktoren, die die zeitabhängige Arzneimittelempfindlichkeit beeinflussen, und bietet Perspektiven für personalisierte Therapien. Gewebewachstum verdeckt Proliferationsmuster einzelner Zellen, die für Behandlungen entscheidend sind. Durch Clusteranalysen der Zellteilungen zeigten sich konsistente Muster in Geweben, was auf unbekannte Mechanismen hindeutet. Das p53-p21-Signalnetzwerk reguliert die Proliferation, indem es DNA-Schäden bewertet und Zellzyklusreaktionen anpasst. Die Studie zeigt, wie dieses Netzwerk DNA-Schäden interpretiert, um Zellwachstum zu steuern.

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Wird DNA mit UV-Licht bestrahlt, kommt es zur Bildung von Photoschäden, die zu Zelltod oder Krebs führen können. In dieser Arbeit wird die primäre Elektronentransferreaktion des lichtaktivierten Reparaturprozesses des (6-4)-Schadens in Drosophila melanogaster charakterisiert. Der katalytische Reparaturzyklus wird durch das Flavoprotein (6-4)-Photolyase (PL) realisiert. Der Elektronentransfer (ET) vom Flavin-Adenin-Dinukleotid (FADH⁻) Kofaktor zum Schaden initiiert die molekularen Umlagerungen. Diese Arbeit charakterisiert die primäre ET Reaktion mithilfe von molekulardynamischen Langzeitsimulationen (µs) in Kombination mit Quantenmechanik/Molekularmechanik-Simulationen. Ab initio lokale Coupled-Cluster- und Dichtefunktionaltheorierechnungen wurden angewendet, um die relative Energetik von lokal angeregten und Ladungstransferzuständen des (6-4)-Reparaturkomplexes zu charakterisieren. Es zeigt sich, dass die Reduktion des (6-4)-Schadens durch einen Ladungstransferzustand ermöglicht wird an dem die Adeninstruktur des FADH⁻ -Kofaktors beteiligt ist. Über die Simulationen wird ein mikroskopisches Bild der Reaktionskoordinate der Elektronentransferreaktion im Marcusbild entwickelt. Diese ist nicht vollständig durch parabolische freie Energiekurven beschrieben sondern wird, durch Wechselwirkungen in der aktiven Tasche, ein Multiminima-Reaktionspfad ausgebildet. Hierbei hat die Rotation der Seitenkette der benachbarten, geladenen Aminosäure Lys246 dominanten Einfluss. Dies legt nahe, dass die primäre ET Reaktion der (6-4) Schadensreparatur, einen vom Adenin unterstützten ET Weg von der PL zur 5’ Seite des Schadens nimmt. Dieser Prozess wird durch benachbarte Aminosäuren und einer Stärkung der Wasserstoffbrücken mit Wassermolekülen stabilisiert. Die Ergebnisse dieser Arbeit zeigen, dass ET-Reaktionen in komplexen enzymatischen Systemen nicht im Kontinuumsbild von ET beschrieben werden können, da lokale Wechselwirkungen drastischen Einfluss auf die ET Reaktionen haben. / UV-light irradiation of DNA leads to the formation of photolesions that can cause cell death and cancer. This thesis aims at the characterization of the primary electron transfer (ET) reaction in the photoactivated repair process of the (6-4) lesion in Drosophila melanogaster. The catalytic repair cycle is realized by a flavoprotein called photolyase (PL). The ET from the fully reduced flavin-adenine-dinucleotide (FADH⁻) cofactor of the PL to the lesion initiates molecular rearrangements. In this thesis fluctuation properties of the enzyme environment on the excited states are considered by conducting long-time (µs) molecular dynamics simulations combined with extensive quantum mechanical/molecular mechanical simulations. Ab initio local coupled cluster simulations and density functional theory are applied to characterize the relative energetics of locally excited and charge transfer (CT) states in the (6-4) lesion repair complex. Reduction of the (6-4) lesion is found to be enabled by a CT state involving the adenine moiety of the FADH⁻ cofactor. Microscopic characterization of a Marcus-type free energy reaction coordinate reveals that it cannot be fully described by parabolic free energy curves. Specifically, rotation of the side chain of nearby charged amino acid Lys246 imposes a double-well character on the potential energy surface along the reaction coordinate of the ET. For the ET reaction triggering the catalytic (6-4) lesion repair, the findings of this thesis suggest an ET pathway to the 5’ side of the (6-4) lesion mediated by the adenine moiety. The process is stabilized by neighboring amino acids and a strengthening of hydrogen bonds with water molecules. The presented results demonstrate that ET reactions in complex enzymatic systems cannot be described within the continuum ET picture, as local interactions drastically tune the ET reaction.

New automated vehicles have the chance of high improvements to road safety. Nevertheless, from today's perspective, accidents will always be a part of future mobility. Following the “Vision Zero”, this thesis proposes the quantification of the driving situation's criticality as the basis to intervene by newly integrated safety systems. In the example application of trajectory planning, a continuous, real-time, risk-based criticality measure is used to consider uncertainties by collision probabilities as well as technical accident severities. As result, a smooth transition between preventative driving, collision avoidance, and collision mitigation including impact point localization is enabled and shown in fleet data analyses, simulations, and real test drives. The feasibility in automated driving is shown with currently available test equipment on the testing ground. Systematic analyses show an improvement of 20-30 % technical accident severity with respect to the underlying scenarios. That means up to one-third less injury probability for the vehicle occupants. In conclusion, predicting the risk preventively has a high chance to increase the road safety and thus to take the “Vision Zero” one step further.:Abstract Acknowledgements Contents Nomenclature 1.1 Background 1.2 Problem statement and research question 1.3 Contribution 2 Fundamentals and relatedWork 2.1 Integral safety 2.1.1 Integral applications 2.1.2 Accident Severity 2.1.2.1 Severity measures 2.1.2.2 Severity data bases 2.1.2.3 Severity estimation 2.1.3 Risk assessment in the driving process 2.1.3.1 Uncertainty consideration 2.1.3.2 Risk as a measure 2.1.3.3 Criticality measures in automated driving functions 2.2 Operational motion planning 2.2.1 Performance of a driving function 2.2.1.1 Terms related to scenarios 2.2.1.2 Evaluation and approval of an automated driving function 2.2.2 Driving function architecture 2.2.2.1 Architecture 2.2.2.2 Planner 2.2.2.3 Reference planner 2.2.3 Ethical issues 3 Risk assessment 3.1 Environment model 3.2 Risk as expected value 3.3 Collision probability and most probable collision configuration 4 Accident severity prediction 4.1 Mathematical preliminaries 4.1.1 Methodical approach 4.1.2 Output definition for pedestrian collisions 4.1.3 Output definition for vehicle collisions 4.2 Prediction models 4.2.1 Eccentric impact model 4.2.2 Centric impact model 4.2.3 Multi-body system 4.2.4 Feedforward neural network 4.2.5 Random forest regression 4.3 Parameterisation 4.3.1 Reference database 4.3.2 Training strategy 4.3.3 Model evaluation 5 Risk based motion planning 5.1 Ego vehicle dynamic 5.2 Reward function 5.3 Tuning of the driving function 5.3.1 Tuning strategy 5.3.2 Tuning scenarios 5.3.3 Tuning results 6 Evaluation of the risk based driving function 6.1 Evaluation strategy 6.2 Evaluation scenarios 6.3 Test setup and simulation environment 6.4 Subsequent risk assessment of fleet data 6.4.1 GIDAS accident database 6.4.2 Fleet data Hamburg 6.5 Uncertainty-adaptive driving 6.6 Mitigation application 6.6.1 Real test drives on proving ground 6.6.2 Driving performance in simulation 7 Conclusion and Prospects References List of Tables List of Figures A Extension to the tuning process