The focus of this thesis is an investigation of ways to detect weak dependence between two random variables X and Y. Our approach is to design tests for correlation rather than testing for dependence directly, since X and Y are not independent if they are not uncorrelated. We examined the magnified Pearson correlation after the Box-Cox transformation to determine whether X and Y are dependent. The results indicated that our approach not only has the potential to detect and evaluate the weak dependence cases that have previously been intractable, but also is conceptually simple and easy to implement.

Joint kinematics of upper extremity (UE) impairments in a pediatric population are often difficult to examine using marker-based motion capture. As a result of the cost and availability of tools such as marker-based motion capture in clinical settings, clinicians use functional tasks to examine improvement in movement quality. However, some of these tasks, such as the Box and Block test (BBT), which is examined in this study, rely on scoring to assess motor improvement. This scoring method can be misleading due to the possibility of movement compensation to improve scores. Therefore, finding kinematic correlations that can lead to improved BBT scores could improve the quality of functional assessments by providing discrete measures for clinicians. Understanding human motion using marker-based motion capture has been the accepted standard in biomechanics. However, it is not without its drawbacks, especially in upper extremity examination due to complex anatomical positioning. The introduction of markerless motion capture software could drastically alter how human biomechanics is analyzed in various settings. Additionally, avoiding possible errors due to clothing and skin movement could greatly improve reported results. Therefore, examining similarities in UE joint kinematics between accepted marker-based and markerless software could introduce markerless motion capture as a method for examining complex kinematics. This study aims to examine UE joint kinematics in a typically developing pediatric population while they complete the BBT, as well as validate Theia3D (Theia Markerless Inc., Kingston, ON, Canada). Marker-based motion capture was used to capture UE kinematics during the BBT. This study was performed on typically developing children aged 7, 9, and 11. Average and peak joint angles were determined, as well as hand segment velocity and path length. Significant correlations to BBT scores were found in peak shoulder flexion (FLEX) angle (r = -0.556, p-value = 0.009), peak (r = -0.479, p-value = 0.028), and average (ρ = -0.535, p-value = 0.012) wrist extension (EXT) angle, average mediolateral (ML) hand segment velocity (r = 0.494, p-value = 0.023), and path length (r = -0.522, p-value = 0.015). Additionally, significant differences between BBT scores (p-value = 0.005), peak shoulder FLEX (p-value = 0.024), and peak shoulder abduction (ABD) angle (p-value = 0.022) were found between the 7- and 11-year-old age groups. Peak elbow FLEX angle was significantly different (p-value = 0.049) between 9- and 11-year-old age groups. These results show that the BBT score could be related to the shoulder and wrist angle, as well as hand segment velocity and path length for typically developing children. Furthermore, root mean square deviation (RMSD) values less than 6° existed in all joint angles. Intraclass correlation coefficients (ICCs) greater than 0.75 were found in shoulder ABD (ICC = 0.79), forearm pronation (ICC = 0.81), wrist EXT (ICC = 0.75), and radial deviation (ICC = 0.87). Additionally, validation results between the marker-based and markerless systems show that there are differences in pose estimations and joint calculations based on rotation sequences. Overall, UE joint kinematics are shown to have correlations to BBT scores, so scores alone may not be indicative of movement quality in other patient populations. Markerless motion capture shows many benefits, however, it should be noted that, due to the complexity of upper extremity motion analysis, understanding what joint rotation sequences align the best with task-specific motions is important. / Master of Science / Human motion is commonly analyzed using marker-based motion capture, which consists of fitting participants with retroreflective markers that can be seen by specialized cameras. However, due to equipment costs, difficult implementation, and the occurrence of markers shifting on skin or being concealed by clothing, markerless motion capture is beginning to be introduced into biomechanics research and could be used in hospitals, clinical settings, and for outdoor examination due to its versatility. The software uses machine learning software that can determine skin landmarks in videos from several cameras to develop a 3D skeleton. Markerless motion capture could be beneficial in examining patients with neuromotor disorders or injuries due to being able to capture abnormal or quick movement which often accompanies many neurological disorders that affect motor function. Additionally, observing movement in children is a challenge due to markers being too close together on smaller limbs. Due to cost and obtainability, clinicians tend to use functional tests to examine improvements in motor function by a scoring system relevant to the specific test, such as the Box and Block test (BBT) which will be used in this study. However, there is the possibility of the patient's ability to adapt to the test to improve their score without improving general motor function. Therefore, it is important to find a relationship between upper limb movement and BBT scores. This study aims to find correlations between upper limb movement and Box and Block test scores as well as differences between 7-, 9-, and 11-year-old age groups and compare marker-based motion capture and the Theia3D (Theia Markerless Inc., Kingston, ON, Canada) markerless motion capture software. Joint assessment is completed with motion capture, which uses reflective markers on specific landmarks on the skin surface. Markerless motion capture is collected simultaneously with marker-based motion capture to assess similarities. The entire procedure was also completed 2 times within 1 visit. The results showed meaningful comparisons between the BBT scores and shoulder and wrist angle, and hand velocity. BBT scores and shoulder angles were shown to be different between the 7- and 11-year-old age groups. Elbow angles were shown to be different between the 9- and 11-year-old age groups. Additionally, comparisons between the marker-based and markerless results showed that all resulting joint angle data captured by each system were similar. Markerless measurement comparisons showed similarities between both sessions as well. These results show that there are ways to provide discrete measurements in clinical settings to examine movement quality. Comparisons between both motion analysis systems show the need to determine task-specific analyses to obtain meaningful results concerning the upper limbs, due to the inherent joint complexity and differing methods of completing the same task.

Zur Produktion von gewirkten Textilien werden mehrere Nadeln auf eine Legebarre gesetzt, die durch Servoantriebe positioniert werden. Aufgrund der erzwungenen Bewegung kann der Antriebsstrang bei hohen Drehzahlen zur Schwingung angeregt werden. Die richtige Wahl der Steuerkurven ist daher eine sehr wichtige und anspruchsvolle Aufgabe, die durch ein Antriebsstrangmodell unterstützt werden soll. Dafür wird am Beispiel eines Teststands ein Modell des Antriebsstranges in MATLAB/Simulink® entwickelt. Für das Antriebsstrangmodell müssen eine geeignete Modellordnung und Modellparameter gewählt werden. Die unbekannten Modellparameter werden durch eine Parameteridentifikation ermittelt. Mit einer Validierung wird ein geeignetes Anregungsspektrum für die Bestimmung der Modellordnung und die Parameteridentifikation ermittelt.

Forkhead box O transcription factors are a family of proteins involved in cellular processes downstream of the Insulin-PI3K-PKB pathway. In response to extra- or intracellular stresses, for example starvation or oxidative stress, FoxOs are required to direct cell cycle progression and apoptosis. In endothelial cells, they induce apoptosis, and their deregulation is linked to diseases involving the insulin pathway, such as diabetes. FoxOs also exhibit a complex role in tumour transformation: here their main function is to suppress tumorigenesis. In both physiological and cancer contexts, FoxO activation leads to the transcription of some general targets, such as p27kip1 or IGFBP1. The FoxOs can also induce tissue-specific genes, as ANGPT2 and BIM in the endothelium. In endothelial cells, another pathway with a pivotal function is the MEK5/ERK5 MAPK signalling way. Its activation promotes cell survival and proliferation in stressful conditions, e.g., when blood vessels are exposed to the shear forces exerted by the blood stream. Furthermore, recent data described ERK5 as a kinase directing tumour resistance upon therapy-induced stress. Comparing their reported roles in various tumours and in the endothelium, FoxO proteins and the MEK5/ERK5 MAPK cascade appear to exert opposite functions. First non-published data confirmed the hypothesis that FoxO factors are subject to a negative modulation by the MEK5/ERK5 pathway. Hence, one goal of this PhD project was to further characterise this crosstalk at molecular level. The major mechanism of FoxO regulation is the balance among several post translational modifications, such as phosphorylation, acetylation, and ubiquitination. Most importantly, the PKB dependent phosphorylation of FoxOs negatively controls their activity, and it is critical for their subcellular localization. Therefore, the regulation of FoxO localization as mechanism of ERK5 dependent suppression was studied, but the results presented in this thesis argue against this hypothesis. However, additional experiments are required to explore the impact of ERK5 activity on FoxO post-translational modifications. FoxO activity can also be modulated by the interaction with other proteins, which in turn could explain general- and tissue-specific gene expression. Thus, another objective of this work was to investigate FoxO3-interactome in endothelial cells and the impact of MEK5/ERK5 activation on it. As published in (Fusi et al. 2022) and presented here, this analysis unveiled TRRAP as new FoxO bound protein in several cell types. Moreover, the interaction did not rely on the capacity of the FoxOs to bind their consensus DNA sequences at the promoter of target genes. Functional data demonstrated that TRRAP is required for FoxO-dependent gene transcription in endothelial and osteosarcoma cells. In addition, TRRAP expression in the endothelium is important for FoxO induced apoptosis. In summary, the interaction between FoxO factors and TRRAP revealed a new regulatory mechanism of FoxO-dependent gene transcription. It remains to be analysed whether the MEK5/ERK5 cascade may exert its suppressive effect on FoxO activity by interfering with their binding to TRRAP and whether such a mechanism may be relevant for tumorigenesis. / Forkhead-Box-O-Proteine sind eine Familie von Transkriptionsfaktoren, die an verschiedenen zellulären Prozessen stromabwärts des Insulin-PI3K-PKB-Signalwegs beteiligt sind. Als Reaktion auf extra- oder intrazelluläre Stressfaktoren, wie Wachstumsfaktorentzug oder oxidativen Stress, werden die FoxOs benötigt, um Zellzyklusprogression und Apoptose zu regulieren. In Endothelzellen induzieren sie Apoptose und ihre Fehlregulation ist mit Krankheiten, bei denen der Insulinsignalweg involviert ist, wie etwa Diabetes mellitus, verbunden. FoxOs spielen auch eine komplexe Rolle bei der Tumortransformation: Hier besteht ihre Hauptfunktion darin, die Tumorentstehung zu unterdrücken. Sowohl im physiologischen als auch im Kontext von Krebs führt die FoxO-Aktivierung zur Transkription verschiedener allgemeiner Zielgene, wie p27kip1, BIM oder IGFBP1. Die FoxOs können aber auch gewebespezifische Gene, wie zum Beispiel ANGPT2 im Endothel, induzieren. Ein weiterer Signalweg mit wichtiger Funktion in Endothelzellen ist der MEK5/ERK5-MAPK Signalweg. Seine Aktivierung fördert das Überleben und Wachstum von Zellen unter Stressbedingungen, wie z. B. wenn Blutgefäße durch den Blutstrom Schubspannungskräften ausgesetzt sind. Darüber hinaus zeigen neuere Daten, dass ERK5 auch an der Tumorresistenzentwicklung unter therapieinduziertem Stress beteiligt ist. Ein Vergleich der bekannten Rolle beider Signalwege im Endothel und bei der Tumorgenese, impliziert eine mutmaßlich gegensätzliche Funktion von FoxO Proteinen und der MEK5/ERK5-MAPK Kaskade. Erste unveröffentlichte Daten stützen die Hypothese, dass FoxO Faktoren einer Negativregulation durch MEK5/ERK5 unterliegen. Ein Ziel dieses Promotionsprojekts, war es daher diesen Zusammenhang auf molekularer Ebene näher zu charakterisieren. Die FoxO-Regulierung ist primär das Zusammenspiel mehrerer posttranslationaler Modifikationen wie Phosphorylierung, Acetylierung und Ubiquitinierung. Der wichtigste Regulationsmechanismus ist dabei die inhibitorische Phosphorylierung durch die Kinase PKB, welche die transkriptionelle FoxO-Aktivität hemmt und deren subzelluläre Lokalisierung ins Zytoplama fördert. Daher wurde zunächst der Einfluss von ERK5 auf die FoxO-Lokalisierung untersucht. Die Daten dieser Arbeit sprechen gegen einen Einfluss von der ERK5 Aktivität auf FoxO Lokalisation, doch sind zusätzliche Experimente erforderlich, um dessen Wirkung auf das Muster der posttranslationalen Modifikation der FoxOs zu klären. FoxO-Aktivität kann auch durch die Interaktion mit anderen Proteinen moduliert werden, die wiederum auch die allgemeine und gewebespezifische Genexpression steuern könnten. Ein weiteres Ziel dieser Arbeit war es daher, das FoxO3-Interaktom in Endothelzellen und den Einfluss forcierter MEK5/ERK5-Aktivierung darauf zu untersuchen. Wie in (Fusi et al. 2022) gezeigt und hier vorgestellt, führte diese Analyse zur Identifikation von TRRAP als neuem generellen FoxO Bindepartner. Die zelltypunabhängige Interaktion beider Proteine beruhte dabei nicht auf der Fähigkeit der FoxOs direkt an ihre Konsensus-DNA-Sequenzen in den Promotoren ihrer Zielgene zu binden. Funktionelle Daten zeigten nachfolgend, dass TRRAP entscheidend zur FoxO abhängigen Gentranskription in Endothel- und Osteosarkomzellen beiträgt. Darüber hinaus ist TRRAP im Endothel für die effiziente Apoptoseinduktion durch FoxOs wichtig. Zusammenfassend offenbarte die Interaktion zwischen FoxO-Faktoren und TRRAP einen neuen Regulationsmechanismus der FoxO-abhängigen Gentranskription. Es bleibt zu prüfen, ob die MEK5/ERK5 Kaskade FoxOs dadurch hemmt, dass sie die Bindungsfähigkeit von FoxO an TRRAP stört, und ob die beobachtete FoxO-TRRAP Interaktion auch im Kontext der Tumorgenese von Bedeutung ist.

Note:

No description available.

No description available.

No description available.

No description available.

No description available.