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Synapses are the fundamental structures that regulate the functionality of the neural circuit. The ability of the synapse to modulate its structure and function at a fast rate due to various sensory inputs provides the strength to the nervous system to incorporate new adaptations and behaviors in the animal. The synapses are very dynamic throughout the life of the animal starting from early development. Continuous events of formation and elimination of synapse, activation and inhibition of synaptic function are observed in almost all synapses. These processes occur at a high speed and require controlled cellular mechanisms. Imbalance in these processes results in defective nervous system and has been reported in many neurological disorders. Thus, it is important to understand the mechanisms that regulate process of synapse development maintenance and function.
Kinases and phosphatases are the key regulators of cellular mechanisms. Understanding the function of these molecules in the neuron will shed light on the molecular mechanisms of synaptic plasticity. Using Drosophila melanogaster larval neuromuscular junction as a model, Bulat et al. (2014) performed a large RNAi based screen targeting kinome and phosphatome of Drosophila to identify the essential kinases and phosphatases and found Myeloid leukemia factor-1 adaptor molecule (Madm) and Protein phosphatase 4 (PP4) as novel regulators of synapse development and maintenance. The function of these molecules in the nervous system has not been reported and hence I investigated on the role of Madm and PP4 in the regulation of synapse development, maintenance and function.
Myeloid leukemia factor-1 adaptor molecule (Madm), a ubiquitously expressing psuedokinase essentially functions to regulate synaptic growth, stability and function. Using a combination of genetic and high throughput imaging, I could demonstrate that Madm functions to regulate the synaptic growth and stability from the presynapse and synaptic organization form the postsynapse. Also, I could demonstrate that Madm functions in association with mTOR pathway to regulate synapse growth acting downstream of 4E-BP. In addition, using electrophysiology, we could demonstrate that Madm is essential for the basic synaptic transmission with an additive function of retrograde synaptic potentiation. In summary, I could demonstrate that Madm is a novel regulator of synaptic development, maintenance and function.
Protein phosphatase 4 (PP4), a ubiquitously expressing protein phosphatase is involved in the regulation of multiple aspects of the nervous system. I could demonstrate that PP4 is essential for the development of nervous system and the metamorphosis. Using genetics and imaging analysis, I could demonstrate that loss of PP4 results in the abnormal morphology of cell organelles. In addition, I could show that loss of PP4 results in defective brain development with poorly developed structures.
Altogether, in this study, I could demonstrate the importance of novel molecules, a pesudokinase Madm and protein phosphatases PP4 in the nervous system to regulate distinct aspects of the neuron.
Hardware Contention-Aware Real-Time Scheduling on Multi-Core Platforms in Safety-Critical Systems
(2019)
While the computing industry has shifted from single-core to multi-core processors for performance gain, safety-critical systems (SCSs) still require solutions that enable their transition while guaranteeing safety, requiring no source-code modifications and substantially reducing re-development and re-certification costs, especially for legacy applications that are typically substantial. This dissertation considers the problem of worst-case execution time (WCET) analysis under contentions when deadline-constrained tasks in independent partitioned task set execute on a homogeneous multi-core processor with dynamic time-triggered shared memory bandwidth partitioning in SCSs.
Memory bandwidth in multi-core processors is shared across cores and is a significant cause of performance bottleneck and temporal variability of multiple-orders in task’s execution times due to contentions in memory sub-system. Further, the circular dependency is not only between WCET and CPU scheduling of others cores, but also between WCET and memory bandwidth assignments over time to cores. Thus, there is need of solutions that allow tailoring memory bandwidth assignments to workloads over time and computing safe WCET. It is pragmatically infeasible to obtain WCET estimates from static WCET analysis tools for multi-core processors due to the sheer computational complexity involved.
We use synchronized periodic memory servers on all cores that regulate each core’s maximum memory bandwidth based on allocated bandwidth over time. First, we present a workload schedulability test for known even-memory-bandwidth-assignment-to-active-cores over time, where the number of active cores represents the cores with non-zero memory bandwidth assignment. Its computational complexity is similar to merge-sort. Second, we demonstrate using a real avionics certified safety-critical application how our method’s use can preserve an existing application’s single-core CPU schedule under contentions on a multi-core processor. It enables incremental certification using composability and requires no-source code modification.
Next, we provide a general framework to perform WCET analysis under dynamic memory bandwidth partitioning when changes in memory bandwidth to cores assignment are time-triggered and known. It provides a stall maximization algorithm that has a complexity similar to a concave optimization problem and efficiently implements the WCET analysis. Last, we demonstrate dynamic memory assignments and WCET analysis using our method significantly improves schedulability compared to the stateof-the-art using an Integrated Modular Avionics scenario.
Substrate channeling is a widespread mechanism in metabolic pathways to avoid decomposition of unstable intermediates, competing reactions, and to accelerate catalytic turnover. During the biosynthesis of light-harvesting phycobilins in cyanobacteria, two members of the ferredoxin-dependent bilin reductases are involved in the reduction of the open-chain tetrapyrrole biliverdin IXα to the pink pigment phycoerythrobilin. The first reaction is catalyzed by 15,16-dihydrobiliverdin:ferredoxin oxidoreductase and produces the unstable intermediate 15,16-dihydrobiliverdin (DHBV). This intermediate is subsequently converted by phycoerythrobilin:ferredoxin oxidoreductase to the final product phycoerythrobilin. Although substrate channeling has been postulated already a decade ago, detailed experimental evidence was missing. Using a new on-column assay employing immobilized enzyme in combination with UV-Vis and fluorescence spectroscopy revealed that both enzymes transiently interact and that transfer of the intermediate is facilitated by a significantly higher binding affinity of DHBV toward phycoerythrobilin:ferredoxin oxidoreductase. Concluding from the presented data, the intermediate DHBV is transferred via proximity channeling.
Using molecular dynamics simulation, we study nanoindentation in large samples of Cu–Zr glass at various temperatures between zero and the glass transition temperature. We find that besides the elastic modulus, the yielding point also strongly (by around 50%) decreases with increasing temperature; this behavior is in qualitative agreement with predictions of the cooperative shear model. Shear-transformation zones (STZs) show up in increasing sizes at low temperatures, leading to shear-band activity. Cluster analysis of the STZs exhibits a power-law behavior in the statistics of STZ sizes. We find strong plastic activity also during the unloading phase; it shows up both in the deactivation of previous plastic zones and the appearance of new zones, leading to the observation of pop-outs. The statistics of STZs occurring during unloading show that they operate in a similar nature as the STZs found during loading. For both cases, loading and unloading, we find the statistics of STZs to be related to directed percolation. Material hardness shows a weak strain-rate dependence, confirming previously reported experimental findings; the number of pop-ins is reduced at slower indentation rate. Analysis of the dependence of our simulation results on the quench rate applied during preparation of the glass shows only a minor effect on the properties of STZs.
The importance of well trained and stable neck flexors and extensors as well as trunk muscles for intentional headers in soccer is increasingly discussed. The neck flexors and extensors should ensure a coupling of trunk and head at the time of ball contact to increase the physical mass hitting the ball and reduce head acceleration. The aim of the study was to analyze the influence of a 6-week strength training program (neck flexors, neck extensors) on the acceleration of the head during standing, jumping and running headers as well as after fatigue of the trunk muscles on a pendulum header. A total of 33 active male soccer players (20.3 ± 3.6 years, 1.81 ± 0.07 m, 75.5 ± 8.3 kg) participated and formed two training intervention groups (IG1: independent adult team, IG2: independent youth team) and one control group (CG: players from different teams). The training intervention consisted of three exercises for the neck flexors and extensors. The training effects were verified by means of the isometric maximum voluntary contraction (IMVC) measured by a telemetric Noraxon DTS force sensor. The head acceleration during ball contact was determined using a telemetric Noraxon DTS 3D accelerometer. There was no significant change of the IMVC over time between the groups (F=2.265, p=.121). Head acceleration was not reduced significantly for standing (IG1 0.4 ± 2.0, IG2 0.1 ± 1.4, CG -0.4 ± 1.2; F = 0.796, p = 0.460), jumping (IG1-0.7 ± 1.4, IG2-0.2 ± 0.9, CG 0.1 ± 1.2; F = 1.272, p = 0.295) and running (IG1-1.0 ± 1.9, IG2-0.2 ± 1.4, CG -0.1 ± 1.6; F = 1.050, p = 0.362) headers as well as after fatigue of the trunk musculature for post-jumping (IG1-0.2 ± 2.1, IG2-0.6 ± 1.4; CG -0.6 ± 1.3; F = 0.184, p = 0.833) and post-running (IG1-0.3 ± 1.6, IG2-0.7 ± 1.2, CG 0.0 ± 1.4; F = 0.695, p = 0.507) headers over time between IG1, IG2 and CG. A 6-week strength training of the neck flexors and neck extensors could not show the presumed preventive benefit. Both the effects of a training intervention and the consequences of an effective intervention for the acceleration of the head while heading seem to be more complex than previously assumed and presumably only come into effect in case of strong impacts.
Key words: Heading, kinetics, head-neck-torso-alignment, neck musculature, repetitive head impacts, concussion
Adjustment Effects of Maximum Intensity Tolerance During Whole-Body Electromyostimulation Training
(2019)
Intensity regulation during whole-body electromyostimulation (WB-EMS) training is mostly controlled by subjective scales such as CR-10 Borg scale. To determine objective training intensities derived from a maximum as it is used in conventional strength training using the one-repetition-maximum (1-RM), a comparable maximum in WB-EMS is necessary. Therefore, the aim of this study was to examine, if there is an individual maximum intensity tolerance plateau after multiple consecutive EMS application sessions. A total of 52 subjects (24.1 ± 3.2 years; 76.8 ± 11.1 kg; 1.77 ± 0.09 m) participated in the longitudinal, observational study (38 males, 14 females). Each participant carried out four consecutive maximal EMS applications (T1–T4) separated by 1 week. All muscle groups were stimulated successively until their individual maximum and combined to a whole-body stimulation index to carry out a possible statement for the development of the maximum intensity tolerance of the whole body. There was a significant main effect between the measurement times for all participants (p < 0.001; ????2 = 0.39) as well as gender specific for males (p = 0.001; ????2 = 0.18) and females (p < 0.001; ????2 = 0.57). There were no interaction effects of gender × measurement time (p = 0.394). The maximum intensity tolerance increased significantly from T1 to T2 (p = 0.001) and T2 to T3 (p < 0.001). There was no significant difference between T3 and T4 (p = 1.0). These results indicate that there is an adjustment of the individual maximum intensity tolerance to a WB-EMS training after three consecutive tests. Therefore, there is a need of several habituation units comparable to the identification of the individual 1-RM in conventional strength training. Further research should focus on an objective intensity-specific regulation of the WB-EMS based on the individual maximum intensity tolerance to characterize different training areas and therefore generate specific adaptations to a WB-EMS training compared to conventional strength training methods.
Visualization is vital to the scientific discovery process.
An interactive high-fidelity rendering provides accelerated insight into complex structures, models and relationships.
However, the efficient mapping of visualization tasks to high performance architectures is often difficult, being subject to a challenging mixture of hardware and software architectural complexities in combination with domain-specific hurdles.
These difficulties are often exacerbated on heterogeneous architectures.
In this thesis, a variety of ray casting-based techniques are developed and investigated with respect to a more efficient usage of heterogeneous HPC systems for distributed visualization, addressing challenges in mesh-free rendering, in-situ compression, task-based workload formulation, and remote visualization at large scale.
A novel direct raytracing scheme for on-the-fly free surface reconstruction of particle-based simulations using an extended anisoptropic kernel model is investigated on different state-of-the-art cluster setups.
The versatile system renders up to 170 million particles on 32 distributed compute nodes at close to interactive frame rates at 4K resolution with ambient occlusion.
To address the widening gap between high computational throughput and prohibitively slow I/O subsystems, in situ topological contour tree analysis is combined with a compact image-based data representation to provide an effective and easy-to-control trade-off between storage overhead and visualization fidelity.
Experiments show significant reductions in storage requirements, while preserving flexibility for exploration and analysis.
Driven by an increasingly heterogeneous system landscape, a flexible distributed direct volume rendering and hybrid compositing framework is presented.
Based on a task-based dynamic runtime environment, it enables adaptable performance-oriented deployment on various platform configurations.
Comprehensive benchmarks with respect to task granularity and scaling are conducted to verify the characteristics and potential of the novel task-based system design.
A core challenge of HPC visualization is the physical separation of visualization resources and end-users.
Using more tiles than previously thought reasonable, a distributed, low-latency multi-tile streaming system is demonstrated, being able to sustain a stable 80 Hz when streaming up to 256 synchronized 3840x2160 tiles and achieve 365 Hz at 3840x2160 for sort-first compositing over the internet, thereby enabling lightweight visualization clients and leaving all the heavy lifting to the remote supercomputer.
Many loads acting on a vehicle depend on the condition and quality of roads
traveled as well as on the driving style of the motorist. Thus, during vehicle development,
good knowledge on these further operations conditions is advantageous.
For that purpose, usage models for different kinds of vehicles are considered. Based
on these mathematical descriptions, representative routes for multiple user
types can be simulated in a predefined geographical region. The obtained individual
driving schedules consist of coordinates of starting and target points and can
thus be routed on the true road network. Additionally, different factors, like the
topography, can be evaluated along the track.
Available statistics resulting from travel survey are integrated to guarantee reasonable
trip length. Population figures are used to estimate the number of vehicles in
contained administrative units. The creation of thousands of those geo-referenced
trips then allows the determination of realistic measures of the durability loads.
Private as well as commercial use of vehicles is modeled. For the former, commuters
are modeled as the main user group conducting daily drives to work and
additional leisure time a shopping trip during workweek. For the latter, taxis as
example for users of passenger cars are considered. The model of light-duty commercial
vehicles is split into two types of driving patterns, stars and tours, and in
the common traffic classes of long-distance, local and city traffic.
Algorithms to simulate reasonable target points based on geographical and statistical
data are presented in detail. Examples for the evaluation of routes based
on topographical factors and speed profiles comparing the influence of the driving
style are included.
To exploit the whole potential of Additive Manufacturing (AM), a sound knowledge about the mechanical and especially cyclic properties of AM materials as well as their dependency on the process parameters is indispensable. In the presented work, the influence of chemical composition of the used powder on the fatigue behavior of Selectively Laser Melted (SLM) and Laser Deposition Welded (LDW) specimens made of austenitic stainless steel AISI 316L was investigated. Therefore, in each manufacturing process two variations of chemical composition of the used powder were utilized. For qualitative characterization of the materials cyclic deformation behavior, load increase tests (LITs) were performed and further used for the physically based lifetime calculation method (PhyBaLLIT), enabling an efficient determination of stress (S)–number of cycles to failure (Nf) curves (S–Nf), which show excellent correlation to additionally performed constant amplitude tests (CATs). Moreover, instrumented cyclic indentation tests (PhyBaLCHT) were utilized to characterize the materials’ defect tolerance in a comparably short time. All material variants exhibit a high influence of microstructural defects on the fatigue properties. Consequently, for the SLM process a higher fatigue lifetime at lower stress amplitudes could be observed for the batch with a higher defect tolerance, resulting from a more pronounced deformation induced austenite–α’-martensite transformation. In correspondence to that, the batch of LDW material with an increased defect tolerance exhibit a higher fatigue strength. However, the differences in defect tolerance between the LDW batches is only slightly influenced by phase transformation and seems to be mainly governed by differences in hardening potential of the austenitic microstructure. Furthermore, a significantly higher fatigue strength could be observed for SLM material in relation to LDW specimens, because of a refined microstructure and smaller microstructural defects of SLM specimens.
A distributional solution framework is developed for systems consisting of linear hyperbolic partial differential equations (PDEs) and switched differential algebraic equations (DAEs) which are coupled via boundary conditions. The unique solvability is then characterize in terms of a switched delay DAE. The theory is illustrated with an example of electric power lines modeled by the telegraph equations which are coupled via a switching transformer where simulations confirm the predicted impulsive solutions.