Loss of cytoskeletal and polarity regulation as key pathogenic principles in glomerular disease

Injury to glomerular podocytes constitutes the predominant cause of glomerular diseases and therefore loss of kidney function. Podocytes are specialized epithelial cells within glomeruli indispensable for the filtration process. Their cell bodies extrude numerous large primary and smaller foot processes that completely enwrap glomerular capillaries. The only cell-cell contact established between adjacent foot processes of neighbouring cells is the slit diaphragm. In addition to contributing to the filtration barrier and preventing the loss of blood proteins into the urine, the slit diaphragm is a vital signaling platform that integrates external signals with the intracellular signaling machinery. The sophisticated architecture of podocytes and their foot processes requires a dynamic actin cytoskeleton and its tight regulation through pathways such as polarity signalling. Upon injury, podocytes start to retract their foot processes, leading to loss of the slit diaphragm and ultimately disruption of the filter apparatus. A common finding upon this so-called effacement are actin cytoskeleton rearrangements. Understanding pathways and key players of actin regulation in podocytes that could prevent the progression of foot process effacement is therefore desirable. This thesis investigated the loss of actin and polarity regulation as key principles of podocyte injury. A first focus was thereby put on utilizing the fruit fly Drosophila melanogaster and in particular nephrocytes as in vivo model for glomerular diseases and to establish solid and reproducible experimental read-outs. Expression of human transgenes in nephrocytes was then used to characterize a so far unknown patient mutation in alpha-Actinin 4, an actin-crosslinking protein. In addition to demonstrating that the mutation alters actin localization, the Drosophila model was utilized to assess the pathogenic potential of the mutant protein. In light of the fact that expression of the mutant variant resulted in severe morphological and functional phenotypes in nephrocytes, it was determined that the novel variant is indeed a pathogenic ACTN4 variant. By this, the power of Drosophila as in vivo tool to complement clinical and genetic diagnostics was emphasized. Lastly, a possible link between podocyte polarity signaling and actin regulation was further investigated by using both, murine and Drosophila models. Here, single and double knockout of Par3A and Par3B in murine podocytes revealed, that the proteins share redundant functions, as only double knockout of Par3A and -B led to a glomerular phenotype. Further analyses in Drosophila nephrocytes focussed on knockdown of the Drosophila Par3 homologue bazooka. Depletion of Bazooka in nephrocytes led to differential expression of various actin-binding and -regulating proteins, including increased activity of the small GTPase Rho1 (the Drosophila RhoA homologue). Interestingly, Rho1 activation could be reverted upon transgenic expression of murine Par3A but not Par3B, indicating that the two proteins also exhibit distinct but unknown functions. These findings strengthen the link between perturbed polarity signalling and dysregulated actin dynamics, making polarity proteins a strong target to possibly counteract the progression of podocyte disease

Relationship Between the Policy Implementation Process and Officer Acceptance of Body-Worn Camera Programs

There is a need to increase body-worn cameras in Ohio, but implementation obstacles include officer resistance. Agency leaders must understand potential barriers to body-worn camera adoption and implementation to prepare for and navigate them. In this study, the relationship was analyzed between the policy implementation process and officer acceptance of body-worn camera programs through the lens of organizational procedural justice theory, considering the possible covariate relationship with the technology acceptance model. The study was designed to determine if officer acceptance of body-worn cameras was influenced by officers being informed about body-worn camera implementation before it occurred, officers having an opportunity to participate in body-worn camera program design, and how officers were trained on body-worn camera policy and usage. The design of this study was quantitative and non-experimental, using SurveyMonkey with multiple choice and selection questions. Data were analyzed in IBM SPSS, using linear regression, univariate, and multivariate analysis. Results indicated the policy implementation process, particularly how the implementation was conducted and if the officer felt well-informed and trusted throughout the process, were indicators of overall program success. Deliberate policy implementation, including varying training methods, is recommended to help ensure program success. By overcoming these obstacles, body-worn cameras can be more widely implemented and help improve positive social change through police-community relations

A linear photodiode array employed in a short range laser triangulation obstacle avoidance sensor

An opto-electronic receiver incorporating a multi-element linear photodiode array as a component of a laser-triangulation rangefinder was developed as an obstacle avoidance sensor for a Martian roving vehicle. The detector can resolve the angle of laser return in 1.5 deg increments within a field of view of 30 deg and a range of five meters. A second receiver with a 1024 elements over 60 deg and a 3 meter range is also documented. Design criteria, circuit operation, schematics, experimental results and calibration procedures are discussed

Modellierung, Regelung, Simulation und Bewertung der Fahrdynamik

In diesem Artikel wird gezeigt, wie beim DLR entwickelte Methoden und Werkzeuge in der Vorentwicklung bei BMW produktiv zum Einsatz kommen. So wurde bei der Entwicklung des xDrive-Allradsystems mit objektorientierter Modellierung in Modelica die Dynamik einer dort eingesetzten Lamellenkupplung untersucht. Des weiteren konnte mit dem Parameterraumverfahren die Fahrstabilisierungsfunktion der Aktivlenkung unter Berücksichtigung variierender Betriebsbedingungen bereits in einer frühen Phase abgesichert werden

The Thickness of Graphs without K5-Minors

The thickness problem on graphs is NP-hard and only few results concerning this graph invariant are known. Using decomposition theorems of Wagner and Truemper, we show that the thickness of graphs without K5-minors is less than or equal to two. Therefore, the thickness of this class of graphs can be determined with a planarity testing algorithm in linear time

A Polyhedral Approach to the Multi-Layer Crossing Minimization Problem

We study the multi-layer crossing minimization problem from a polyhedral point of view. After the introduction of an integer programming formulation of the multi-layer crossing minimization problem, we examine the 2-layer case and derive several classes of facets of the associated polytope. Preliminary computational results for 2- and 3-layer instances indicate, that the usage of the corresponding facet-defining inequalities in a branch-and-cut approach may only lead to a practically useful algorithm, if deeper polyhedral studies are conducted

Analyse und Demonstration des CellFlux-Speichersystems

Diese Arbeit behandelt die Analyse des CellFlux-Speichersystems, eines neuartigen Speicherkonzeptes für sensible Wärme. Die Analyse umfasst die Identifikation geeigneter Komponenten zur Umsetzung, bis hin zur dynamischen Abbildung des Gesamtsystems in einem Simulationsprogramm. Hierbei steht ein Einsatz des Speichersystems in Kombination mit Kraftwerksprozessen im Vordergrund. Die Funktionsfähigkeit des Konzeptes wird im Pilotmaßstab nachgewiesen und auf Basis der erarbeiteten Entwurfsgrundlagen wird abschließend eine beispielhafte Anwendung des Speichers untersucht