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NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.
Bacterial cell appendix formation supports cell-cell interaction, cell adhesion and cell movement. Additionally, in bioelectrochemical systems (BES), cell appendages have been shown to participate in extracellular electron transfer. In this work, the cell appendix formation of Clostridium acetobutylicum in biofilms of a BES are imaged and compared with conventional biofilms. Under all observed conditions, the cells possess filamentous appendages with a higher number and density in the BES. Differences in the amount of extracellular polymeric substance in the biofilms of the electrodes lead to the conclusion that the cathode can be used as electron donor and the anode as electron acceptor by C. acetobutylicum. When using conductive atomic force microscopy, a current response of about 15 nA is found for the cell appendages from the BES. This is the first report of conductivity for clostridial cell appendices and represents the basis for further studies on their role for biofilm formation and electron transfer.
In this paper we report on CO2 Meter, a do-it-yourself carbon dioxide measuring device for the classroom. Part of the current measures for dealing with the SARS-CoV-2 pandemic is proper ventilation in indoor settings. This is especially important in schools with students coming back to the classroom even with high incidents rates. Static ventilation patterns do not consider the individual situation for a particular class. Influencing factors like the type of activity, the physical structure or the room occupancy are not incorporated. Also, existing devices are rather expensive and often provide only limited information and only locally without any networking. This leaves the potential of analysing the situation across different settings untapped. Carbon dioxide level can be used as an indicator of air quality, in general, and of aerosol load in particular. Since, according to the latest findings, SARS-CoV-2 can be transmitted primarily in the form of aerosols, carbon dioxide may be used as a proxy for the risk of a virus infection. Hence, schools could improve the indoor air quality and potentially reduce the infection risk if they actually had measuring devices available in the classroom. Our device supports schools in ventilation and it allows for collecting data over the Internet to enable a detailed data analysis and model generation. First deployments in schools at different levels were received very positively. A pilot installation with a larger data collection and analysis is underway.
Objective
Hemodialysis patients show an approximately threefold higher prevalence of cognitive impairment compared to the age-matched general population. Impaired microcirculatory function is one of the assumed causes. Dynamic retinal vessel analysis is a quantitative method for measuring neurovascular coupling and microvascular endothelial function. We hypothesize that cognitive impairment is associated with altered microcirculation of retinal vessels.
Methods
152 chronic hemodialysis patients underwent cognitive testing using the Montreal Cognitive Assessment. Retinal microcirculation was assessed by Dynamic Retinal Vessel Analysis, which carries out an examination recording retinal vessels' reaction to a flicker light stimulus under standardized conditions.
Results
In unadjusted as well as in adjusted linear regression analyses a significant association between the visuospatial executive function domain score of the Montreal Cognitive Assessment and the maximum arteriolar dilation as response of retinal arterioles to the flicker light stimulation was obtained.
Conclusion
This is the first study determining retinal microvascular function as surrogate for cerebral microvascular function and cognition in hemodialysis patients. The relationship between impairment in executive function and reduced arteriolar reaction to flicker light stimulation supports the involvement of cerebral small vessel disease as contributing factor for the development of cognitive impairment in this patient population and might be a target for noninvasive disease monitoring and therapeutic intervention.
Coincident events in two scintillator crystals coupled to photomultipliers (PMT) are detected by processing just the digital data of the recorded pulses. For this purpose the signals from both PMTs are continuously sampled by free-running ADCs at a sampling rate of 40 MHz. For each sampled pulse the starting time is determined by processing the pulse data. Even a fairly simple interpolating algorithm results in a FWHM of about 2 ns.
The connective tissues such as tendons contain an extracellular matrix (ECM) comprising collagen fibrils scattered within the ground substance. These fibrils are instrumental in lending mechanical stability to tissues. Unfortunately, our understanding of how collagen fibrils reinforce the ECM remains limited, with no direct experimental evidence substantiating current theories. Earlier theoretical studies on collagen fibril reinforcement in the ECM have relied predominantly on the assumption of uniform cylindrical fibers, which is inadequate for modelling collagen fibrils, which possessed tapered ends. Recently, Topçu and colleagues published a paper in the International Journal of Solids and Structures, presenting a generalized shear-lag theory for the transfer of elastic stress between the matrix and fibers with tapered ends. This paper is a positive step towards comprehending the mechanics of the ECM and makes a valuable contribution to formulating a complete theory of collagen fibril reinforcement in the ECM.
Mannoheptulose is a seven-carbon sugar. It is an inhibitor of glucose-induced insulin secretion due to its ability to selectively inhibit the enzyme glucokinase. An improved procedure for mannoheptulose isolation from avocados is described in this study (based upon the original method by La Forge). The study focuses on the combination of biotransformation and downstream processing (preparative chromatography) as an efficient method to produce a pure extract of mannoheptulose. The experiments were divided into two major phases. In the first phase, several methods and parameters were compared to optimize the mannoheptulose extraction with respect to efficiency and purity. In the second phase, a mass balance of mannoheptulose over the whole extraction process was undertaken to estimate the yield and efficiency of the total extraction process. The combination of biotransformation and preparative chromatography allowed the production of a pure mannoheptulose extract. In a biological test, the sugar inhibited the glucokinase enzyme activity efficiently.
Real-time and reliable monitoring of the biogas process is crucial for a stable and efficient operation of biogas production in order to avoid digester breakdowns. The concentration of dissolved hydrogen (H₂) represents one of the key parameters for biogas process control. In this work, a one-chip integrated combined amperometric/field-effect sensor for monitoring the dissolved H₂ concentration has been developed for biogas applications. The combination of two different transducer principles might allow a more accurate and reliable measurement of dissolved H₂ as an early warning indicator of digester failures. The feasibility of the approach has been demonstrated by simultaneous amperometric/field-effect measurements of dissolved H₂ concentrations in electrolyte solutions. Both, the amperometric and the field-effect transducer show a linear response behaviour in the H₂ concentration range from 0.1 to 3% (v/v) with a slope of 198.4 ± 13.7 nA/% (v/v) and 14.9 ± 0.5 mV/% (v/v), respectively.
Kawasaki Heavy Industries, Ltd. (KHI), Aachen University of Applied Sciences, and B&B-AGEMA GmbH have investigated the potential of low NOx micro-mix (MMX) hydrogen combustion and its application to an industrial gas turbine combustor. Engine demonstration tests of a MMX combustor for the M1A-17 gas turbine with a co-generation system were conducted in the hydrogen-fueled power generation plant in Kobe City, Japan.
This paper presents the results of the commissioning test and the combined heat and power (CHP) supply demonstration. In the commissioning test, grid interconnection, loading tests and load cut-off tests were successfully conducted. All measurement results satisfied the Japanese environmental regulation values. Dust and soot as well as SOx were not detected. The NOx emissions were below 84 ppmv at 15 % O2. The noise level at the site boundary was below 60 dB. The vibration at the site boundary was below 45 dB.
During the combined heat and power supply demonstration, heat and power were supplied to neighboring public facilities with the MMX combustion technology and 100 % hydrogen fuel. The electric power output reached 1800 kW at which the NOx emissions were 72 ppmv at 15 % O2, and 60 %RH. Combustion instabilities were not observed. The gas turbine efficiency was improved by about 1 % compared to a non-premixed type combustor with water injection as NOx reduction method. During a total equivalent operation time of 1040 hours, all combustor parts, the M1A-17 gas turbine as such, and the co-generation system were without any issues.
Unravelling the factors determining the allocation of carbon to various plant organs is one of the great challenges of modern plant biology. Studying allocation under close to natural conditions requires non-invasive methods, which are now becoming available for measuring plants on a par with those developed for humans. By combining magnetic resonance imaging (MRI) and positron emission tomography (PET), we investigated three contrasting root/shoot systems growing in sand or soil, with respect to their structures, transport routes and the translocation dynamics of recently fixed photoassimilates labelled with the short-lived radioactive carbon isotope 11C. Storage organs of sugar beet (Beta vulgaris) and radish plants (Raphanus sativus) were assessed using MRI, providing images of the internal structures of the organs with high spatial resolution, and while species-specific transport sectoralities, properties of assimilate allocation and unloading characteristics were measured using PET. Growth and carbon allocation within complex root systems were monitored in maize plants (Zea mays), and the results may be used to identify factors affecting root growth in natural substrates or in competition with roots of other plants. MRI–PET co-registration opens the door for non-invasive analysis of plant structures and transport processes that may change in response to genomic, developmental or environmental challenges. It is our aim to make the methods applicable for quantitative analyses of plant traits in phenotyping as well as in understanding the dynamics of key processes that are essential to plant performance.
A method for the integrated extraction and separation of fatty acids from algae using supercritical CO2 is presented. Desmodesmus obliquus and Chlorella sorokiniana were used as algae. First, a method for chromatographic separation of fatty acids of different degrees of saturation was established and optimized. Then, an integrated method for supercritical extraction was developed for both algal species. It was also verified whether prior cell disruption was beneficial for extraction. In developing the method for chromatographic separation, statistical experimental design was used to determine the optimal parameter settings. The methanol content in the mobile phase proved to be the most important parameter for successful separation of the three unsaturated fatty acids oleic acid, linoleic acid, and linolenic acid. Supercritical extraction with dried algae showed that about four times more fatty acids can be extracted from C. sorokiniana relative to the dry mass used.
Many efforts are made worldwide to establish magnetic fluid hyperthermia (MFH) as a treatment for organ-confined tumors. However, translation to clinical application hardly succeeds as it still lacks of understanding the mechanisms determining MFH cytotoxic effects. Here, we investigate the intracellular MFH efficacy with respect to different parameters and assess the intracellular cytotoxic effects in detail. For this, MiaPaCa-2 human pancreatic tumor cells and L929 murine fibroblasts were loaded with iron-oxide magnetic nanoparticles (MNP) and exposed to MFH for either 30 min or 90 min. The resulting cytotoxic effects were assessed via clonogenic assay. Our results demonstrate that cell damage depends not only on the obvious parameters bulk temperature and duration of treatment, but most importantly on cell type and thermal energy deposited per cell during MFH treatment. Tumor cell death of 95% was achieved by depositing an intracellular total thermal energy with about 50% margin to damage of healthy cells. This is attributed to combined intracellular nanoheating and extracellular bulk heating. Tumor cell damage of up to 86% was observed for MFH treatment without perceptible bulk temperature rise. Effective heating decreased by up to 65% after MNP were internalized inside cells.
Combining physiological relevance and throughput for in vitro cardiac contractility measurement
(2020)
Despite increasing acceptance of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in safety pharmacology, controversy remains about the physiological relevance of existing in vitro models for their mechanical testing. We hypothesize that existing signs of immaturity of the cell models result from an improper mechanical environment. We cultured hiPSC-CMs in a 96-well format on hyperelastic silicone membranes imitating their native mechanical environment, resulting in physiological responses to compound stimuli.We validated cell responses on the FLEXcyte 96, with a set of reference compounds covering a broad range of cellular targets, including ion channel modulators, adrenergic receptor modulators and kinase inhibitors. Acute (10 - 30 min) and chronic (up to 7 days) effects were investigated. Furthermore, the measurements were complemented with electromechanical models based on electrophysiological recordings of the used cell types.hiPSC-CMs were cultured on freely-swinging, ultra-thin and hyperelastic silicone membranes. The weight of the cell culture medium deflects the membranes downwards. Rhythmic contraction of the hiPSC-CMs resulted in dynamic deflection changes which were quantified by capacitive distance sensing. The cells were cultured for 7 days prior to compound addition. Acute measurements were conducted 10-30 minutes after compound addition in standard culture medium. For chronic treatment, compound-containing medium was replaced daily for up to 7 days. Electrophysiological properties of the employed cell types were recorded by automated patch-clamp (Patchliner) and the results were integrated into the electromechanical model of the system.Calcium channel agonist S Bay K8644 and beta-adrenergic stimulator isoproterenol induced significant positive inotropic responses without additional external stimulation. Kinase inhibitors displayed cardiotoxic effects on a functional level at low concentrations. The system-integrated analysis detected alterations in beating shape as well as frequency and arrhythmic events and we provide a quantitative measure of these.
Kawasaki Heavy Industries, LTD. (KHI) has research and development projects for a future hydrogen society. These projects comprise the complete hydrogen cycle, including the production of hydrogen gas, the refinement and liquefaction for transportation and storage, and finally the utilization in a gas turbine for electricity and heat supply. Within the development of the hydrogen gas turbine, the key technology is stable and low NOx hydrogen combustion, namely the Dry Low NOx (DLN) hydrogen combustion.
KHI, Aachen University of Applied Science, and B&B-AGEMA have investigated the possibility of low NOx micro-mix hydrogen combustion and its application to an industrial gas turbine combustor. From 2014 to 2018, KHI developed a DLN hydrogen combustor for a 2MW class industrial gas turbine with the micro-mix technology. Thereby, the ignition performance, the flame stability for equivalent rotational speed, and higher load conditions were investigated. NOx emission values were kept about half of the Air Pollution Control Law in Japan: 84ppm (O2-15%). Hereby, the elementary combustor development was completed.
From May 2020, KHI started the engine demonstration operation by using an M1A-17 gas turbine with a co-generation system located in the hydrogen-fueled power generation plant in Kobe City, Japan. During the first engine demonstration tests, adjustments of engine starting and load control with fuel staging were investigated. On 21st May, the electrical power output reached 1,635 kW, which corresponds to 100% load (ambient temperature 20 °C), and thereby NOx emissions of 65 ppm (O2-15, 60 RH%) were verified. Here, for the first time, a DLN hydrogen-fueled gas turbine successfully generated power and heat.
Comparative assessment of parallel-hybrid-electric propulsion systems for four different aircraft
(2020)
As battery technologies advance, electric propulsion concepts are on the edge of disrupting aviation markets. However, until electric energy storage systems are ready to allow fully electric aircraft, the combination of combustion engine and electric motor as a hybrid-electric propulsion system seems to be a promising intermediate solution. Consequently, the design space for future aircraft is expanded considerably, as serial-hybrid-, parallel-hybrid-, fully-electric, and conventional propulsion systems must all be considered. While the best propulsion system depends on a multitude of requirements and considerations, trends can be observed for certain types of aircraft and certain types of missions. This paper provides insight into some factors that drive a new design towards either conventional or hybrid propulsion systems. General aviation aircraft, VTOL air taxis, transport aircraft, and UAVs are chosen as case studies. Typical missions for each class are considered, and the aircraft are analyzed regarding their take-off mass and primary energy consumption. For these case studies, a high-level approach is chosen, using an initial sizing methodology. Results indicate that hybrid-electric propulsion systems should be considered if the propulsion system is sized by short-duration power constraints (e.g. take-off, climb). However, if the propulsion system is sized by a continuous power requirement (e.g. cruise), hybrid-electric systems offer hardly any benefit.
Comparative assessment of parallel-hybrid-electric propulsion systems for four different aircraft
(2020)
Until electric energy storage systems are ready to allow fully electric aircraft, the combination of combustion engine and electric motor as a hybrid-electric propulsion system seems to be a promising intermediate solution. Consequently, the design space for future aircraft is expanded considerably, as serial hybrid-electric, parallel hybrid-electric, fully electric, and conventional propulsion systems must all be considered. While the best propulsion system depends on a multitude of requirements and considerations, trends can be observed for certain types of aircraft and certain types of missions. This Paper provides insight into some factors that drive a new design toward either conventional or hybrid propulsion systems. General aviation aircraft, regional transport aircraft vertical takeoff and landing air taxis, and unmanned aerial vehicles are chosen as case studies. Typical missions for each class are considered, and the aircraft are analyzed regarding their takeoff mass and primary energy consumption. For these case studies, a high-level approach is chosen, using an initial sizing methodology. Only parallel-hybrid-electric powertrains are taken into account. Aeropropulsive interaction effects are neglected. Results indicate that hybrid-electric propulsion systems should be considered if the propulsion system is sized by short-duration power constraints. However, if the propulsion system is sized by a continuous power requirement, hybrid-electric systems offer hardly any benefit.
Heavy-duty trucks are one of the main contributors to greenhouse gas emissions in German traffic. Drivetrain electrification is an option to reduce tailpipe emissions by increasing energy conversion efficiency. To evaluate the vehicle’s environmental impacts, it is necessary to consider the entire life cycle. In addition to the daily use, it is also necessary to include the impact of production and disposal. This study presents the comparative life cycle analysis of a parallel hybrid and a conventional heavy-duty truck in long-haul operation. Assuming a uniform vehicle glider, only the differing parts of both drivetrains are taken into account to calculate the environmental burdens of the production. The use phase is modeled by a backward simulation in MATLAB/Simulink considering a characteristic driving cycle. A break-even analysis is conducted to show at what mileage the larger CO2eq emissions due to the production of the electric drivetrain are compensated. The effect of parameter variation on the break-even mileage is investigated by a sensitivity analysis. The results of this analysis show the difference in CO2eq/t km is negative, indicating that the hybrid vehicle releases 4.34 g CO2eq/t km over a lifetime fewer emissions compared to the diesel truck. The break-even analysis also emphasizes the advantages of the electrified drivetrain, compensating the larger emissions generated during production after already a distance of 15,800 km (approx. 1.5 months of operation time). The intersection coordinates, distance, and CO2eq, strongly depend on fuel, emissions for battery production and the driving profile, which lead to nearly all parameter variations showing an increase in break-even distance.
Dual frequency magnetic excitation of magnetic nanoparticles (MNP) enables enhanced biosensing applications. This was studied from an experimental and theoretical perspective: nonlinear sum-frequency components of MNP exposed to dual-frequency magnetic excitation were measured as a function of static magnetic offset field. The Langevin model in thermodynamic equilibrium was fitted to the experimental data to derive parameters of the lognormal core size distribution. These parameters were subsequently used as inputs for micromagnetic Monte-Carlo (MC)-simulations. From the hysteresis loops obtained from MC-simulations, sum-frequency components were numerically demodulated and compared with both experiment and Langevin model predictions. From the latter, we derived that approximately 90% of the frequency mixing magnetic response signal is generated by the largest 10% of MNP. We therefore suggest that small particles do not contribute to the frequency mixing signal, which is supported by MC-simulation results. Both theoretical approaches describe the experimental signal shapes well, but with notable differences between experiment and micromagnetic simulations. These deviations could result from Brownian relaxations which are, albeit experimentally inhibited, included in MC-simulation, or (yet unconsidered) cluster-effects of MNP, or inaccurately derived input for MC-simulations, because the largest particles dominate the experimental signal but concurrently do not fulfill the precondition of thermodynamic equilibrium required by Langevin theory.
Comparison of different training algorithms for the leg extension training with an industrial robot
(2018)
In the past, different training scenarios have been developed and implemented on robotic research platforms, but no systematic analysis and comparison have been done so far. This paper deals with the comparison of an isokinematic (motion with constant velocity) and an isotonic (motion against constant weight) training algorithm. Both algorithms are designed for a robotic research platform consisting of a 3D force plate and a high payload industrial robot, which allows leg extension training with arbitrary six-dimensional motion trajectories. In the isokinematic as well as the isotonic training algorithm, individual paths are defined i n C artesian s pace by sufficient s upport p oses. I n t he i sotonic t raining s cenario, the trajectory is adapted to the measured force as the robot should only move along the trajectory as long as the force applied by the user exceeds a minimum threshold. In the isotonic training scenario however, the robot’s acceleration is a function of the force applied by the user. To validate these findings, a simulative experiment with a simple linear trajectory is performed. For this purpose, the same force path is applied in both training scenarios. The results illustrate that the algorithms differ in the force dependent trajectory adaption.