The actin-binding protein Drebrin and its implications for Alzheimer's Disease using the model organism C. elegans

Patients of Alzheimer’s Disease (AD) showed reduced levels of the actin-binding protein Drebrin in their neurons. The here presented work was set out to analyse the interaction between Drebrin and the disease-associated peptide Amyloid-β. To analyse the interaction in vivo two novel models were designed, employing the nematode C. elegans. The Amyloid-β pathology was modelled by overexpressing the disease causing peptide pan-neuronally and employing a genetic sub-stoichiometric labelling method to be able to follow the aggregation in vivo and in situ in a non-invasive manner. A second model, expressing human Drebrin pan-neuronally was generated to analyse Drebrin stability, localization and phosphorylation as well as analysing the effect of Drebrin overexpression on the nematodes’ vitality and fitness. The third project combined both generated models to obtain a genetic cross expressing Aβ(1-42) and Drebrin simultaneously. This model was sought to study the interaction between Aβ(1-42) and Drebrin. I could show, that Aβ(1-42) aggregates with the progression of ageing and exhibits multiple disease phenotypes that can be correlated to observations obtained in murine neurons as well as observations of AD patients’ brain tissues. Furthermore, I observed, that a distinct subset of head neurons of the anterior ganglion, the IL2 neurons, exhibits the first aggregates and that a cell-type specific suppression of Aβ(1-42) in IL2 neurons could delay the disease onset. Drebrin was observed to be regulated by phosphorylation at Serine-647 by Ataxia telangiectasia mutated kinase and render nematodes more resistant towards chronic oxidative stress. The genetic cross of Aβ(1-42) and Drebrin unravelled that overexpression of Drebrin can ameliorate Aβ(1-42) aggregation and toxicity and that this beneficial effect is dependent on phosphorylation of Drebrin-S647

An Enhanced Tire Model for Dynamic Simulation based on Geometrically Exact Shells

In the present work, a tire model is derived based on geometrically exact shells. The discretization is done with the help of isoparametric quadrilateral finite elements. The interpolation is performed with bilinear Lagrangian polynomials for the midsurface as well as for the director field. As time stepping method for the resulting differential algebraic equation a backward differentiation formula is chosen. A multilayer material model for geometrically exact shells is introduced, to describe the anisotropic behavior of the tire material. To handle the interaction with a rigid road surface, a unilateral frictional contact formulation is introduced. Therein a special surface to surface contact element is developed, which rebuilds the shape of the tire

The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation.

While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity

Noise, vibration, harshness model of a rotating tyre

The tyre plays a fundamental role in the generation of acoustically perceptible driving noise and vibrations inside the vehicle. An essential part of these vibrations is induced by the road excitation and transferred via the tyre into the vehicle. There are two basic ways to study noise, vibration, harshness (NVH) behaviour: Simulations in time and frequency domains. Modelling the tyre transfer behaviour in frequency domain requires special attention to the rotation of the tyre. This paper shows the approach taken by the authors to include the transfer behaviour in the frequency range up to 250 Hz from geometric road excitations to resulting spindle forces in frequency domain. This paper validates the derived NVH tyre model by comparison with appropriate transient simulations of the base transient model

Simulation of Dynamic Gas Cavity Effects of a Tire under Operational Conditions

The authors are responsible for the development of a structural 3D shell based bead-to-bead model with sidewalls and belt that separately models all functional layers of a modern tire [4]. In this model, the inflation pressure is modeled as a uniform stress acting normal to the shell’s inner face. The pressure can vary depending on the application: prescribed by the MBS-tool to align to a constant pressure specified for a vehicle or scenario, but it can also be modified dynamically to simulate e.g. a sudden pressure loss in a tire [1]. For many applications, this description of the inflation pressure as a time dependent quantity is sufficient. However, there are applications where it is needed to describe the inflation gas using a dynamic gas equation (Euler or Navier-Stokes). One such example is when the tire model is used in NVH (Noise-Vibration-Harshness) applications where the frequency range extends the 200 Hz range. For passenger car tires, a first mode of the inflation gas is at around 200-250. This mode couples with the tire structure and yields significant peaks in the spindle force spectrum, which have to be considered in the NVH assessment of a car. In this paper, we show the effect of modeling the inflation gas of a tire by an isentropic compressible Euler equation and couple it to the tire dynamics in the nonlinear transient application range. After motivation and validation of the overall model by comparison with respective measurements, we also describe how to derive a linear model from the overall transient tire model, that can then be used in linear FEM based NVH-tools. It can be observed that the tire rotation will yield a split in the cavity mode which increases with rotational velocity, an effect that can also be correctly predicted by the linearized model

Evaluation of different modeling approaches for the tire handling simulations - analysis and results

In the last years the need of more accurate vehicle handling simulation is increased. This is due to the wider possibilities that the new CAE methods offers to the vehicle dynamic engineers. In the past the semi-empirical tire models have been the most used, but today it seems to be not enough. In vehicle handling simulation more component become to be important like 3D road, thermal effect on rubber, asphalt conditions and electronic safety systems interaction with the tire dynamic. The cited semiempirical tire model seems to be not adequate to simulate such complex scenario also if they remain still attractive for a group of simulations scenario due to their simplicity and efficiency

An Enhanced Tire Model for Dynamic Simulation based on Geometrically Exact Shells

In the present work, a tire model is derived based on geometrically exact shells. The discretization is done with the help of isoparametric quadrilateral finite elements. The interpolation is performed with bilinear Lagrangian polynomials for the mid-surface as well as for the director field. As time stepping method for the resulting differential algebraic equation a backward differentiation formula is chosen. A multilayer material model for geometrically exact shells is introduced, to describe the anisotropic behavior of the tire material. To handle the interaction with a rigid road surface, a unilateral frictional contact formulation is introduced. Therein a special surface to surface contact element is developed, which rebuilds the shape of the tire