Genetic and Pharmacological Modifications of Thrombin Formation in Apolipoprotein E-deficient Mice Determine Atherosclerosis Severity and Atherothrombosis Onset in a Neutrophil-Dependent Manner

Background: Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination. Methodology/principal findings: We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin $(FII^{−/WT}:ApoE^{−/−})$ was remarkably effective in limiting disease compared to control $ApoE^{−/−}$ mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in $TM^{Pro/Pro}:ApoE^{−/−}$ mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic $TM^{Pro/Pro}:ApoE^{−/−}$ mice. Conclusions/significance: We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease

Maximum Photosynthetic Yield of Green Microalgae in Photobioreactors

The biomass yield on light energy of Dunaliella tertiolecta and Chlorella sorokiniana was investigated in a 1.25- and 2.15-cm light path panel photobioreactor at constant ingoing photon flux density (930 µmol photons m−2 s−1). At the optimal combination of biomass density and dilution rate, equal biomass yields on light energy were observed for both light paths for both microalgae. The observed biomass yield on light energy appeared to be based on a constant intrinsic biomass yield and a constant maintenance energy requirement per gram biomass. Using the model of Pirt (New Phytol 102:3–37, 1986), a biomass yield on light energy of 0.78 and 0.75 g mol photons−1 and a maintenance requirement of 0.0133 and 0.0068 mol photons g−1 h−1 were found for D. tertiolecta and C. sorokiniana, respectively. The observed yield decreases steeply at low light supply rates, and according to this model, this is related to the increase of the amount of useable light energy diverted to biomass maintenance. With this study, we demonstrated that the observed biomass yield on light in short light path bioreactors at high biomass densities decreases because maintenance requirements are relatively high at these conditions. All our experimental data for the two strains tested could be described by the physiological models of Pirt (New Phytol 102:3–37, 1986). Consequently, for the design of a photobioreactor, we should maintain a relatively high specific light supply rate. A process with high biomass densities and high yields at high light intensities can only be obtained in short light path photobioreactors

Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients

OBJECTIVE: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. METHODS: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. RESULTS: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E 2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. CONCLUSION: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs

Sustained release of locally delivered celecoxib provides pain relief for osteoarthritis: a proof of concept in dog patients

Objective: Drug delivery platforms that allow for gradual drug release after intra-articular administration have become of much interest as a treatment strategy for osteoarthritis (OA). The aim of this study was to investigate the safety and efficacy of an intra-articular sustained release formulation containing celecoxib (CXB), a cyclooxygenase-2 (COX-2) selective inhibitor. Methods: Amino acid-based polyesteramide microspheres (PEAMs), a biodegradable and non-toxic platform, were loaded with CXB and employed in two in vivo models of arthritis: an acute inflammatory arthritis model in rats (n = 12), and a randomized controlled study in chronic OA dog patients (n = 30). In parallel, the bioactivity of sustained release of CXB was evaluated in monolayer cultures of primary dog chondrocytes under inflammatory conditions. Results: Sustained release of CXB did not alleviate acute arthritis signs in the rat arthritis model, based on pain measurements and synovitis severity. However, in OA dog patients, sustained release of CXB improved limb function as objective parameter of pain and quality of life based on gait analysis and owner questionnaires. It also decreased pain medication dependency over a 2-month period and caused no adverse effects. Prostaglandin E2 levels, a marker for inflammation, were lower in the synovial fluid of CXB-treated dog OA patients and in CXB-treated cultured dog chondrocytes. Conclusion: These results show that local sustained release of CXB is less suitable to treat acute inflammation in arthritic joints, while safe and effective in treating pain in chronic OA in dogs

Urban Virtual Test Field for HighlyAutomated Vehicle Systems

Autonomous driving is one of the key technologies for increasing road safetyand reducing traffic volumes. Therefore, science and industry are workingtogether on new innovative solutions in this field of technology. One importantcomponent in this context is the approval and testing of new solution concepts,with special focus on the ones for urban environments. Not only because ofthe high diversity of traffic situations, but also because of the close contactbetween vulnerable road users (VRU) and automated vehicles.In the course of this work, a novel approach for testing automated drivingfunctions and vehicle systems in urban environments is presented. The goal isto create a safe and valid environment in which the automated vehicle and theVRU can meet and interact. The basis is a highly realistic virtual model of acity center. The physical behavior of the vehicle and VRU is recorded usingmeasurement technology and transferred to the virtual city model.Based on representative urban traffic scenarios, the functionality of the urbantest field is investigated from various points of view. Thereby, the focus is onreal-time capability and the quality of interaction between the vehicle and theVRU.The investigations show that both the real-time capability and the interactionpossibilities could be demonstrated. Further, the developed methodologies aresuitable for real time applications.CityInMotio

Virtual Test Field for Highly Automated Vehicle Systems in Urban Environments

Autonomous driving was and is one of the most important research and innovation drivers in the automotive and supplier industry. In addition to the predicted energy savings, a reduction in the number of accidents and their level of damage is also expected. In particular, the functional testing and legislation of highly automated driving functions play a decisive key role here. This results in a justified need for innovation and research and means major challenges for the entire technology sector. Traditional methods such as real-world tests and X-in-the-loop tests for proving functional safety still have their justification, but cannot answer all the questions posed by the diverse requirements in daily use. In particular, urban environments with highly complex traffic scenarios and diverse groups of actors can only be mapped to a limited extent using existing methods. In this work, a novel approach for testing automated vehicle systems in urban environments is presented. The goal is to create a safe and valid environment in which the vehicle under test can interact with real road users under realistic conditions. The basis is a highly realistic virtual model of a German city center. The physical behavior of the vehicle and the pedestrian is measured and transferred to the virtual city model in real time. Sensor models enable the interaction of the vehicle with the virtual environment and the pedestrian. With the help of different studies with different focuses, both individual functionalities as well as the overall functionality are finally evaluated

Urban Virtual Test Field for HighlyAutomated Vehicle Systems

Autonomous driving is one of the key technologies for increasing road safetyand reducing traffic volumes. Therefore, science and industry are workingtogether on new innovative solutions in this field of technology. One importantcomponent in this context is the approval and testing of new solution concepts,with special focus on the ones for urban environments. Not only because ofthe high diversity of traffic situations, but also because of the close contactbetween vulnerable road users (VRU) and automated vehicles.In the course of this work, a novel approach for testing automated drivingfunctions and vehicle systems in urban environments is presented. The goal isto create a safe and valid environment in which the automated vehicle and theVRU can meet and interact. The basis is a highly realistic virtual model of acity center. The physical behavior of the vehicle and VRU is recorded usingmeasurement technology and transferred to the virtual city model.Based on representative urban traffic scenarios, the functionality of the urbantest field is investigated from various points of view. Thereby, the focus is onreal-time capability and the quality of interaction between the vehicle and theVRU.The investigations show that both the real-time capability and the interactionpossibilities could be demonstrated. Further, the developed methodologies aresuitable for real time applications.CityInMotio

Model – Based Approach to investigate the Influences of different Load States to the Vehicle Dynamics of Light Electric Vehicles

The need to find alternative urban mobility solutions for delivery and transporthas led mobility companies to devote enormous resources for researchbasedsolutions to increase vehicle safety. This paper documents a virtual approachto investigate the influences of different load states to the vehicle dynamicof light electric vehicle. A model basing on a three-dimensional multibody system was used, which consists of five bodies. By applying methods of multibody modelling the generalized equations of motion were generated. To include the behavior within the contact point between road and vehicle a simplified tire models was added. The implementation of the equations allowed a first validation of the model via simulations. In a final modeling step the simulation results were interpreted in respect of plausibility. Afterwards,the model was simulated numerically to investigate different load states of the vehicle, by applying constant steering stimuli and variable velocities. In sum,the investigated model approach is useful to identify safety relevant parameters and shows the effects of load states to the vehicle dynamics. Furthermore, it behaves plausibly regarding general vehicle dynamics. These results prove the general usability of the model for the development controllers and estimators in driver assistances systems

Development and Analysis of a Detail Model for Steer-by-Wire Systems

Steer-by-wire systems represent a key technology for highly automated and autonomous driving. In this context, robust steering control is a fundamental precondition for automated vehicle lateral control. However, there is a need for improvement due to degrees of freedom, signal delays, and nonlinear characteristics of the plant which are unconsidered in the design models for the design of current steering controls. To be able to design an extremely robust steering control, suitable optimal models of a steer-by-wire system are required. Therefore, this paper presents an innovative nonlinear detail model of a steer-by-wire system. The detail model represents all characteristics of a real steer-by-wire system. In the context of a dominance analysis of the detail model, all dominant characteristics of a steer-by-wire system, including parameter dependencies, are identified. Through model reduction, a reduced model of the steer-by-wire system is then developed that can be used for a subsequent robust control design. Furthermore, this paper compares the steer-by-wire system with a conventional electromechanical power steering and shows similarities as well as differences

Methodical Approach to the Development of a Radar Sensor Model for the Detection of Urban Traffic Participants Using a Virtual Reality Engine

New approaches for testing of autonomous driving functions are using VirtualReality (VR) to analyze the behavior of automated vehicles in variousscenarios. The real time simulation of the environment sensors is still a challenge.In this paper, the conception, development and validation of an automotiveradar raw data sensor model is shown. For the implementation, theUnreal VR engine developed by Epic Games is used. The model consists of asending antenna, a propagation and a receiving antenna model. The microwavefield propagation is simulated by a raytracing approach. It uses the methodof shooting and bouncing rays to cover the field. A diffused scatteringmodel is implemented to simulate the influence of rough structures on thereflection of rays. To parameterize the model, simple reflectors are used. Thevalidation is done by a comparison of the measured radar patterns of pedestriansand cyclists with simulated values. The outcome is that the developedmodel shows valid results, even if it still has deficits in the context of performance.It shows that the bouncing of diffuse scattered field can only be doneonce. This produces inadequacies in some scenarios. In summary, the papershows a high potential for real time simulation of radar sensors by using raytracing in a virtual reality