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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.
The composition of plant biomass varies depending on the feedstock and pre-treatment conditions and influences its processing in biorefineries. In order to ensure optimal process conditions, the quantitative proportion of the main polymeric components of the pre-treated biomass has to be determined. Current standard procedures for biomass compositional analysis are complex, the measurements are afflicted with errors and therefore often not comparable. Hence, new powerful analytical methods are urgently required to characterize biomass. In this contribution, Differential Scanning Calorimetry (DSC) was applied in combination with multivariate data analysis (MVA) to detect the cellulose content of the plant biomass pretreated by Liquid Hot Water (LHW) and Organosolv processes under various conditions. Unlike conventional techniques, the developed analytic method enables the accurate quantification of monosaccharide content of the plant biomass without any previous sample preparation. It is easy to handle and avoids errors in sample preparation.
In diesem Beitrag geht es um die Integration von Stoffströmen einer Lignocellulose-Bioraffinerie in Verfahren zur Batterieherstellung. Pflanzliche Reststoffe aus der Biokraftstoffherstellung wie Lignin sollen zur Herstellung neuer Batteriematerialien verwendet werden. Hierbei wird das Lignin als Matrix für die vorgraphitischen C-haltigen Einlagerungsverbindungen in den Elektroden genutzt. Die Si-C-Komposite werden durch das Einbetten von Si in eine Ligninmatrix mit anschließender Carbonisierung hergestellt. Das Lignin hierfür wird durch die sequentielle hydrothermale Vorbehandlung von Buchenholz bei variablen Bedingungen gewonnen und mit Si-Nanopartikel sowie als Referenz ohne Si-Nanopartikel gefällt. Die Ergebnisse zeigen, dass die sequenzielle Vorbehandlung höhere Ausbeuten im Vergleich zum LHW- oder Organosolv-Aufschluss liefert. Um eine Anode herzustellen, wurde das resultierende Si–C-Kompositmaterial carbonisiert, auf einen Stromsammler aufgetragen und elektro-chemisch charakterisiert. Der Einfluss der Vorbehandlungsschritte auf den Herstellungsprozess und die ökonomische Bewertung des untersuchten Bioraffinerie-Prozesses wurde mithilfe eines Stoffstrommodells analysiert.
A multi-spot light-addressable potentiometric sensor (LAPS), which belongs to the family of semiconductor field-effect devices, was applied for label-free detection of double-stranded deoxyribonucleic acid (dsDNA) molecules by their intrinsic molecular charge. To reduce the distance between the DNA charge and sensor surface and thus, to enhance the electrostatic coupling between the dsDNA molecules and the LAPS, the negatively charged dsDNA molecules were electrostatically adsorbed onto the gate surface of the LAPS covered with a positively charged weak polyelectrolyte layer of PAH (poly(allylamine hydrochloride)). The surface potential changes in each spot of the LAPS, induced by the layer-by-layer adsorption of a PAH/dsDNA bilayer, were recorded by means of photocurrent-voltage and constant-photocurrent measurements. In addition, the surface morphology of the gate surface before and after consecutive electrostatic adsorption of PAH and dsDNA layers was studied by atomic force microscopy measurements. Moreover, fluorescence microscopy was used to verify the successful adsorption of dsDNA molecules onto the PAH-modified LAPS surface. A high sensor signal of 25 mV was registered after adsorption of 10 nM dsDNA molecules. The lower detection limit is down to 0.1 nM dsDNA. The obtained results demonstrate that the PAH-modified LAPS device provides a convenient and rapid platform for the direct label-free electrical detection of in-solution hybridized dsDNA molecules.
This article discusses the contrast between the information transportation companies provide to travellers and that of their brand messaging. Companies’ brand messaging often portrays the service they provide as pleasant, stress free and perfect. Customers and users of the service, on the other hand, often describe their experience of the service as a negative one. This article suggests that the brand value would be greater if transportation companies paid more attention to the users’ experience when designing their information systems, particularly in worst case scenarios.
Vermessung
(2016)
While plate fixation of proximal ulna fractures might lead to superior clinical results compared to tension band wiring, regular plates represent an established risk factor for wound complications. The olecranon double plates (Medartis, Basel, CH) might decrease complications related to the osteosynthesis because of their low profile and better anatomical fit. This study aimed to evaluate the biomechanical performance and clinical results of the olecranon double plates.
Manufacturing process simulation enables the evaluation and improvement of autoclave mold concepts early in the design phase. To achieve a high part quality at low cycle times, the thermal behavior of the autoclave mold can be investigated by means of simulations. Most challenging for such a simulation is the generation of necessary boundary conditions. Heat-up and temperature distribution in an autoclave mold are governed by flow phenomena, tooling material and shape, position within the autoclave, and the chosen autoclave cycle. This paper identifies and summarizes the most important factors influencing mold heat-up and how they can be introduced into a thermal simulation. Thermal measurements are used to quantify the impact of the various parameters. Finally, the gained knowledge is applied to develop a semi-empirical approach for boundary condition estimation that enables a simple and fast thermal simulation of the autoclave curing process with reasonably high accuracy for tooling optimization.
The light-addressable potentiometric sensor (LAPS) has the unique feature to address different regions of a sensor surface without the need of complex structures. Measurements at different locations on the sensor surface can be performed in a common analyte solution, which distinctly simplifies the fluidic set-up. However, the measurement in a single analyte chamber prevents the application of different drugs or different concentrations of a drug to each measurement spot at the same time as in the case of multi-reservoir-based set-ups. In this work, the authors designed a LAPS-based set-up for cell culture screening that utilises magnetic beads loaded with the endotoxin (lipopolysaccharides, LPS), to generate a spatially distributed gradient of analyte concentration. Different external magnetic fields can be adjusted to move the magnetic beads loaded with a specific drug within the measurement cell. By recording the metabolic activities of a cell layer cultured on top of the LAPS surface, this work shows the possibility to apply different concentrations of a sample along the LAPS measurement spots within a common analyte solution.
Verfügbarkeit und Nachhaltigkeit sind wichtige Anforderungen bei der Planung langlebiger technischer Systeme. Meist werden bei Lebensdaueroptimierungen lediglich einzelne Komponenten vordefinierter Systeme untersucht. Ob eine optimale Lebensdauer eine gänzlich andere Systemvariante bedingt, wird nur selten hinterfragt. Technical Operations Research (TOR) erlaubt es, aus Obermengen technischer Systeme automatisiert die lebensdaueroptimale Systemstruktur auszuwählen. Der Artikel zeigt dies am Beispiel eines hydrostatischen Getriebes.
Turbulent dispersion in bounded horizontal jets : RANS capabilities and physical modeling comparison
(2016)
Self-aeration is traditionally explained by the water turbulent boundary layer outer edge intersection with the free surface. This paper presents a discussion on the commonly accepted hypothesis behind the computation of the critical point of self-aeration in spillway flows and a new formulation is proposed based on the existence of a developing air flow over the free surface. Upstream of the inception point of self-aeration, some surface roughening has been often reported in previous studies which consequently implies some entrapped air transport and air–water flows coupling. Such air flow is proven in this study by presenting measured air velocities and computing the air boundary layer thickness for a 1V:2H smooth chute flow. Additionally, the growth rate of free surface waves has been analysed by means of Ultrasonic Sensors measurements, obtaining also the entrapped air concentration. High-speed camera imaging has been used for qualitative study of the flow perturbations.
Air-water flows can be found in different engineering applications: from nuclear engineering to huge hydraulic structures. In this paper, a single tip fibre optical probe has been used to record high frequency (over 1 MHz) phase functions at different locations of a stepped spillway. These phase functions have been related to the interfacial velocities by means of Artificial Neural Networks (ANN) and the measurements of a classical double tip conductivity probe. Special attention has been put to the input selection and the ANN dimensions. Finally, ANN have shown to be able to link the signal rising times and plateau shapes to the air-water interfacial velocity.
Sensitivity of turbulent Schmidt number and turbulence model to simulations of jets in crossflow
(2016)
Environmental discharges have been traditionally designed by means of cost-intensive and time-consuming experimental studies. Some extensively validated models based on an integral approach have been often employed for water quality problems, as recommended by USEPA (i.e.: CORMIX). In this study, FLOW-3D is employed for a full 3D RANS modelling of two turbulent jet-to-crossflow cases, including free surface jet impingement. Results are compared to both physical modelling and CORMIX to better assess model performance. Turbulence measurements have been collected for a better understanding of turbulent diffusion's parameter sensitivity. Although both studied models are generally able to reproduce jet trajectory, jet separation downstream of the impingement has been reproduced only by RANS modelling. Additionally, concentrations are better reproduced by FLOW-3D when the proper turbulent Schmidt number is used. This study provides a recommendation on the selection of the turbulence model and the turbulent Schmidt number for future outfall structures design studies.
Boden, Baugrube, Verbau
(2016)
Die Lösung den Baugrund betreffender Fragestellungen beginnen i. d. R. mit der Durchführung von Baugrunderkundungen, um alle notwendigen Parameter zu erhalten, die für die Planung und Durchführung von Bauvorhaben notwendig sind. Im Folgenden werden die wichtigsten Erkundungen in Abhängigkeit der erforderlichen Güteklasse der Proben beschrieben und vorgestellt.
At the present time, one of the most serious environmental problems of Central Asia and South Kazakhstan is the ongoing large-scale deterioration of principal urban tree populations. Several major centers of massive spread of invasive plant pests have been found in urban dendroflora of this region. The degree of damage of seven most wide-spread aboriginal tree species was found to range from 21.4±1.1 to 85.4±1.8%. In particular, the integrity of the native communities of sycamore (Platanus spp.), willow (Salix spp.), poplar (Populus spp.) and elm (Ulmus spp.) is highly endangered. Our taxonomic analysis of the most dangerous tree pests of the region has revealed them as neobiontic xylophilous insects such as Cossus cossus L. (Order: Lepidoptera L.) Monochamus urussovi Fisch., Monochamus sutor L., Acanthocinus aedelis L. and Ñetonia aureate L. (Order: Coleoptera L.). We relate the origin of this threatening trend with the import of industrial wood in the mid 90s of the last century that was associated with high degree of the constructional work in the region. Because of the absence of efficient natural predators of the pest species, the application of microbiological methods of the pest control and limitation is suggested.
Genussrechte als Instrument der Unternehmensfinanzierung von kommunalen Wohnungs- baugesellschaften
(2016)
Die kommunalen Wohnungsbaugesellschaften und ihr Geschäftszweck bzw. Versorgungsauftrag erfahren aus gesamtgesellschaftlichen Gründen aktuell einen erheblichen Bedeutungszuwachs. Der kommunale Wohnungsbau soll und muss intensiviert werden, da z.B. zunehmend Wohnungsbindungen auslaufen. Bezahlbare Neubauten fehlen speziell Familien, Senioren, Studenten und Flüchtlingen. Um das Investitionsvolumen zu bewältigen, bedarf es nicht nur der Förderkredite, sondern auch der Zuführung „frischen Kapitals“. Der Beitrag stellt dar, dass Genussrechte ein interessantes und oft unbekanntes Finanzierungsinstrument für kommunale Wohnungsbaugesellschaften mit passgenauen Ausgestaltungsmöglichkeiten sind. Mit Hilfe von Genussrechten können die notwendigen Neubau-Investitionen solide mit Quasi-Eigenkapital unterlegt werden und den sozialen Wohnungsbau wiederbeleben. Genussrechte als Hybridkapital lassen sich mangels gesetzlicher Eingrenzung exakt und individuell ebenso an die Bedürfnisse der kommunalen Wohnungsbaugesellschaft anpassen wie an die der Gesellschafter und des jeweiligen Neubauvorhabens.
We present an effective and simple multiscale method for equilibrating Kremer Grest model polymer melts of varying stiffness. In our approach, we progressively equilibrate the melt structure above the tube scale, inside the tube and finally at the monomeric scale. We make use of models designed to be computationally effective at each scale. Density fluctuations in the melt structure above the tube scale are minimized through a Monte Carlo simulated annealing of a lattice polymer model. Subsequently the melt structure below the tube scale is equilibrated via the Rouse dynamics of a force-capped Kremer-Grest model that allows chains to partially interpenetrate. Finally the Kremer-Grest force field is introduced to freeze the topological state and enforce correct monomer packing. We generate 15 melts of 500 chains of 10.000 beads for varying chain stiffness as well as a number of melts with 1.000 chains of 15.000 monomers. To validate the equilibration process we study the time evolution of bulk, collective, and single-chain observables at the monomeric, mesoscopic, and macroscopic length scales. Extension of the present method to longer, branched, or polydisperse chains, and/or larger system sizes is straightforward.
Kalkulation
(2016)
Das Kapitel behandelt die Kosten- und Preisermittlung, die Kostenvorgabe und Kostenkontrolle.
Der Angebotspreis wird aufgeschlüsselt in die Einzelkosten der Teilleistungen, die Baustellengemeinkosten, die Allgemeinen Geschäftskosten und einen Zuschlag für Wagnis und Gewinn. Auf der Basis der Angebotskalkulation werden die Vorgaben für die Kostenkontrolle entwickelt.
Engineers are of particular importance for the societies of tomorrow. The big social challenges society has to cope with in future, can only be mastered, if engineers link the development and innovation process closely with the requirements of people. As a result, in the frame of the innovation process engineers have to design and develop products for diverse users. Therefore, the consideration of diversity in this process is a core competence engineers should have. Implementing the consideration of diverse requirements into product design is also linked to the development of sustainable products and thus leads to social responsible research and development, the core concept formulated by the EU.
For this reason, future engineers should be educated to look at the technical perspectives of a problem embedded in the related questions within societies they are developing their artefacts for. As a result, the aim of teaching engineering should be to prepare engineers for these requirements and to draw attention to the diverse needs in a globalized world.
To match the competence profiles of future engineers to the global challenges and the resulting social responsibility, RWTH Aachen University, one of the leading technical universities in Germany, has established the bridging professorship “Gender and Diversity in Engineering” (GDI) which educates engineers with an interdisciplinary approach to expand engineering limits. The interdisciplinary teaching concept of the research group pursues an approach which imparts an application oriented Gender and Diversity expertise to future engineers. In the frame of an established teaching concept, which is a result of experiences and expertise of the research group, students gain theoretical knowledge about Gender and Diversity and learn how to transfer their knowledge into their later field of action.
In the frame of the conference the institutional approach will be presented as well as the teaching concept which will be introduced by concrete course examples.
20 Years of RoboCup
(2016)
The research group focuses on the characteristics in the land-and cityscapes of the Drielanden-zone, which contribute to generate common identities, as well as on those features that trigger differences and specificities of the adjacent countries that enrich the perception of the zone. In this research, the instruments of cartography and land survey system serve to detect and localize the fragmented appearance of relevant historic elements. These analytic procedures help to develop strategies for infrastructures and processes that gradually initiate local forms of cross-border tourism. The architectural research displays how top-down and bottom-up interventions can be combined in order to guarantee a sustainable use and development of the considered area.
Concept - this is a key term in architectural discourse. However, all too often it is used imprecisely or merely for marketing purposes. What is a concept actually? This publication moves between design theory and design practice and follows the history of the definition of concept in architecture, leading to the formulation of a specifically instrumental and operative definition. It bases concept in architecture on its strategic potential in design decision-making processes. In the changing profession of the designing architect, decisions are increasingly made in multidisciplinary groups. Concept can serve as a dialogic instrument in the process, making it possible to process heterogeneous information from a range of spheres of knowledge. The effective presentation of selected information becomes a relevant interface in the design process, which has a significant influence on the quality of the design.
Cento Tavole
(2016)
When exploring glacier ice it is often necessary to take samples or implement sensors at a certain depth underneath the glacier surface. One way of doing this is by using heated melting probes. In their common form these devices experience a straight one-dimensional downwards motion and can be modeled by standard close-contact melting theory. A recently developed melting probe however, the IceMole, achieves maneuverability by simultaneously applying a surface temperature gradient to induce a change in melting direction and controlling the effective contact-force by means of an ice screw to stabilize its change in attitude. A modeling framework for forced curvilinear melting does not exist so far and will be the content of this paper. At first, we will extend the existing theory for quasi-stationary close-contact melting to curved trajectories. We do this by introducing a rotational mode. This additional unknown in the system implies yet the need for another model closure. Within this new framework we will focus on the effect of a variable contact-force as well as different surface temperature profiles. In order to solve for melting velocity and curvature of the melting path we present both an inverse solution strategy for the analytical model, and a more general finite element framework implemented into the open source software package ELMER. Model results are discussed and compared to experimental data conducted in laboratory tests.
Rubber materials filled with reinforcing fillers display nonlinear rheological behavior at small strain amplitudes below γ0 < 0.1. Nevertheless, rheological data are analyzed mostly in terms of linear parameters, such as shear moduli (G′, G″), which loose their physical meaning in the nonlinear regime. In this work styrene butadiene rubber filled with carbon black (CB) under large amplitude oscillatory shear (LAOS) is analyzed in terms of the nonlinear parameter I3/1. Three different CB grades are used and the filler load is varied between 0 and 70 phr. It is found that I3/1(φ) is most sensitive to changes of the total accessible filler surface area at low strain amplitudes (γ0 = 0.32). The addition of up to 70 phr CB leads to an increase of I3/1(φ) by a factor of more than ten. The influence of the measurement temperature on I3/1 is pronounced for CB levels above the percolation threshold.
This paper describes the development of a capacitively coupled high-pressure lamp with input power between 20 and 43 W at 2.45 GHz, using a coaxial line network. Compared with other electrodeless lamp systems, no cavity has to be used and a reduction in the input power is achieved. Therefore, this lamp is an alternative to the halogen incandescent lamp for domestic lighting. To serve the demands of domestic lighting, the filling of the lamp is optimized over all other resulting requirements, such as high efficacy at low induced powers and fast startups. A workflow to develop RF-driven plasma applications is presented, which makes use of the hot S-parameter technique. Descriptions of the fitting process inside a circuit and FEM simulator are given. Results of the combined ignition and operation network from simulations and measurements are compared. An initial prototype is built and measurements of the lamp's lighting properties are presented along with an investigation of the efficacy optimizations using large signal amplitude modulation. With this lamp, an efficacy of 135 lmW -1 is achieved.
Compared to peripheral pain, trigeminal pain elicits higher levels of fear, which is assumed to enhance the interruptive effects of pain on concomitant cognitive processes. In this fMRI study we examined the behavioral and neural effects of trigeminal (forehead) and peripheral (hand) pain on visual processing and memory encoding. Cerebral activity was measured in 23 healthy subjects performing a visual categorization task that was immediately followed by a surprise recognition task. During the categorization task subjects received concomitant noxious electrical stimulation on the forehead or hand. Our data show that fear ratings were significantly higher for trigeminal pain. Categorization and recognition performance did not differ between pictures that were presented with trigeminal and peripheral pain. However, object categorization in the presence of trigeminal pain was associated with stronger activity in task-relevant visual areas (lateral occipital complex, LOC), memory encoding areas (hippocampus and parahippocampus) and areas implicated in emotional processing (amygdala) compared to peripheral pain. Further, individual differences in neural activation between the trigeminal and the peripheral condition were positively related to differences in fear ratings between both conditions. Functional connectivity between amygdala and LOC was increased during trigeminal compared to peripheral painful stimulation. Fear-driven compensatory resource activation seems to be enhanced for trigeminal stimuli, presumably due to their exceptional biological relevance.