Choice of reaction progress variable under preferential diffusion effects in turbulent syngas combustion based on detailed chemistry direct numerical simulations.

The combustion of hydrogen and carbon-monoxide mixtures, so-called syngas, plays an increasingly important role in the safety context of non-fossil energy generation, more specifically in the risk management of incidents in process engineering plants for ammonia synthesis and in nuclear power plants. In order to characterize and simulate syngas/air combustion on industrially relevant scales, subgrid modelling is required, which is often based on a reaction progress variable. To understand the influence of different fuel compositions, turbulence intensities and flame topologies on different possible definitions of reaction progress variable, detailed chemistry direct numerical simulations data of premixed, lean hydrogen/air and syngas/air flames has been considered. A reaction progress variable based on normalized molecular oxygen mass fraction has been found not to capture the augmentation of the normalized burning rate per unit flame surface area in comparison to the corresponding 1D unstretched premixed flame due to preferential diffusion effects. By contrast, reaction progress variables based on other individual species, such as hydrogen, can capture the augmentation of the rate of burning well, but exhibit a pronounced sensitivity to preferential diffusion effects, especially in response to flame curvatures. However, a reaction progress variable based on the linear combination of the main products can accurately represent the temperature evolution of the flame for different mixtures, turbulence intensities and varying local flame topology, while effectively capturing the augmentation of burning rate due to preferential diffusion effects. However, its tendency to assume values larger than 1.0 in the regions of super-adiabatic temperatures poses challenges for future modeling approaches, whereas the reaction progress variable based on hydrogen mass fraction remains bound between 0.0 and 1.0 despite showing deviations in comparison to corresponding variations obtained from the unstretched laminar flame depending on flame curvature variations.

Direct numerical simulation of an unsteady wall-bounded turbulent flow configuration for the assessment of large-eddy simulation models.

A new benchmark case for the evaluation of direct numerical simulation (DNS) and large-eddy simulation (LES) models and methods is presented in this study. The known Taylor-Green vortex is modified by replacing the periodic boundary conditions in one direction with a no-slip boundary. A passive scalar is added and transported from the wall into the fluid. The addition of walls allows for the study of transient-instationary flows in a simple geometry with clean boundary and initial conditions, which is a key requirement for the assessment of LES modeling strategies. The added scalar mimics heat transfer through the wall. The case features reasonable computational cost for highly-resolved LES and DNS calculations. Simulations of the wall-bounded Taylor-Green vortex are easy to setup and do not require additional modeling. The proposed modification of the case is compared to the default Taylor-Green vortex and the difference in flow-physics is discussed. A detailed convergence study with four meshes, each of them refined by a factor of 2, has been conducted. The results reveal that converged second-order statistics can be obtained up to a dimensionless time of [Formula: see text]. Beyond that, due to the unsteady chaotic nature of the flow, some uncertainties remain. The results show that the case features challenging (near-wall) flow dynamics, which cannot be covered using the default Taylor-Green vortex and hence, justify the proposed case as a useful benchmark.

Surface topologies and self interactions in reactive and nonreactive Richtmyer-Meshkov instability.

The reactive Richtmyer-Meshkov instability (RMI) exhibits strong wrinkling of a reactive flame front after an interaction with a shock wave. High levels of deformation and wrinkling can cause the flame surface to intersect with itself, leading to the events of flame self interactions (FSI). As FSI can have a significant influence on the development and topology of the flame surface, it should be considered an important factor affecting the burning characteristics of the flame. The topological structure and statistics of FSI are analyzed using data from high-fidelity simulations of a planar shock wave interacting with a statistically planar hydrogen/air flame for stoichiometric, lean and nonreactive gas mixtures. FSI events are detected by searching for critical points in the field of the reaction progress variable c and divided into the following topological categories: burned gas mixture pocket (BP), unburned gas mixture pocket (UP), tunnel formation (TF) and tunnel closure (TC). It is found that reactivity and flame thickness are decisive factors, influencing the frequency and topological distribution of the detected FSI events. While in early RMI-stages the FSI is found to be mainly dependent on the flame thickness, later stages are heavily influenced by the reactivity, as high reactivity quickly burns out emerging wrinkled structures (in the stoichiometric case) leading to massively reduced levels of FSI. The findings are further supported by the results from the nonreactive case, which at later stages of the RMI closely resembles the less reactive lean case. Analysis of the topology distribution over time and conditioned over c, reveals further differences between the lean and stoichiometric case, as the strong wrinkling and mixing encountered with the lean case facilitates the build up of many pocket-type and tunnel-type interactions throughout the wrinkled flame front. For the stoichiometric case, mainly tunnel-type and unburned pocket topologies are found in the narrow flame funnels extending into the burned gas.

Mutual interference between memory encoding and motor skills: the influence of motor expertise.

In cognitive-motor dual-task situations, the extent of performance decrements is influenced by the attentional requirements of each task. Well-learned motor skills should be automatized, leading to less interference. This study presents two studies combining an episodic memory encoding task with well-practiced motor tasks in athletes. Study 1 asked 40 rowers (early teenagers to middle adulthood) to row on ergometers at slow or fast speeds. In study 2, Taekwondo athletes (n = 37) of different skill levels performed a well-practiced sequence of martial arts movements. Performing the motor task during encoding led to pronounced performance reductions in memory in both studies, with costs of up to 80%. Cognitive costs were even larger when rowing with the fast compared to the slow speed in study 1. Both studies also revealed decrements in motor performances under dual-task conditions: Rowing became slower and more irregular (study 1), and the quality of the Taekwondo performance was reduced. Although higher-level athletes outperformed others in motor skills under single-task conditions, proportional dual-task costs were similar across skill levels for most domains. This indicates that even well-practiced motor tasks require cognitive resources.

Entropy Generation during Head-On Interaction of Premixed Flames with Inert Walls within Turbulent Boundary Layers.

The statistical behaviours of different entropy generation mechanisms in the head-on interaction of turbulent premixed flames with a chemically inert wall within turbulent boundary layers have been analysed using Direct Numerical Simulation data. The entropy generation characteristics in the case of head-on premixed flame interaction with an isothermal wall is compared to that for an adiabatic wall. It has been found that entropy generation due to chemical reaction, thermal diffusion and molecular mixing remain comparable when the flame is away from the wall for both wall boundary conditions. However, the wall boundary condition affects the entropy generation during flame-wall interaction. In the case of isothermal wall, the entropy generation due to chemical reaction vanishes because of flame quenching and the entropy generation due to thermal diffusion becomes the leading entropy generator at the wall. By contrast, the entropy generation due to thermal diffusion and molecular mixing decrease at the adiabatic wall because of the vanishing wall-normal components of the gradients of temperature and species mass/mole fractions. These differences have significant effects on the overall entropy generation rate during flame-wall interaction, which suggest that combustor wall cooling needs to be optimized from the point of view of structural integrity and thermodynamic irreversibility.

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (ß5i).

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (ß1, ß2, and ß5). LMP7 (ß5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (ß5i) Delivering Efficacy in Multiple Myeloma Models.

Large multifunctional peptidase 7 (LMP7/ß5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells both in vitro and in vivo Furthermore, M3258 showed superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in patients with multiple myeloma (NCT04075721).

Near wall Prandtl number effects on velocity gradient invariants and flow topologies in turbulent Rayleigh-Bénard convection.

The statistical behaviours of the invariants of the velocity gradient tensor and flow topologies for Rayleigh-Bénard convection of Newtonian fluids in cubic enclosures have been analysed using Direct Numerical Simulations (DNS) for a range of different values of Rayleigh (i.e. [Formula: see text]) and Prandtl (i.e. [Formula: see text] and 320) numbers. The behaviours of second and third invariants of the velocity gradient tensor suggest that the bulk region of the flow at the core of the domain is vorticity-dominated whereas the regions in the vicinity of cold and hot walls, in particular in the boundary layers, are found to be strain rate-dominated and this behaviour has been found to be independent of the choice of Ra and Pr values within the range considered here. Accordingly, it has been found that the focal topologies S1 and S4 remain predominant in the bulk region of the flow and the volume fraction of nodal topologies increases in the vicinity of the active hot and cold walls for all cases considered here. However, remarkable differences in the behaviours of the joint probability density functions (PDFs) between second and third invariants of the velocity gradient tensor (i.e. Q and R) have been found in response to the variations of Pr. The classical teardrop shape of the joint PDF between Q and R has been observed away from active walls for all values of Pr, but this behavior changes close to the heated and cooled walls for high values of Pr (e.g. [Formula: see text]) where the joint PDF exhibits a shape mirrored at the vertical Q-axis. It has been demonstrated that the junctions at the edges of convection cells are responsible for this behaviour for [Formula: see text], which also increases the probability of finding S3 topologies with large negative magnitudes of Q and R. By contrast, this behaviour is not observed in the [Formula: see text] case and these differences between flow topology distributions in Rayleigh-Bénard convection in response to Pr suggest that the modelling strategy for turbulent natural convection of gaseous fluids may not be equally well suited for simulations of turbulent natural convection of liquids with high values of Pr.

Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects.

Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.

Parental education, television exposure, and children's early cognitive, language and behavioral development.

The association between television exposure and children's development is subject to controversial debates. Heavy television exposure may be detrimental to children by overstimulating their developing brains. It may also infringe on time that children would otherwise spend on more developmentally beneficial activities or parental interactions. In the present analysis, we use data from the 2004/5 birth cohort of the Growing Up in Scotland study to investigate relations between hours of weekly television measured around the ages of two to four and as average over this period with children's linguistic, cognitive, and behavioral outcomes around the age of five. Our analysis shows differences in the level and growth of television exposure by parental education. However, we did not find any substantive associations between television exposure and children's cognitive or language ability. We found small associations of television exposure with conduct problems and prosocial behavior, particularly for children of less-educated parents. Overall, the results suggest that the impact of television on children's development is less pronounced than often assumed.

Social origin, field of study and graduates' career progression: does social inequality vary across fields?

Research on stratification and mobility has consistently shown that in the UK there is a direct impact of social origin on occupational destination net of educational attainment even for degree-holders. However, only a few studies applied a longitudinal and dynamic perspective on how intergenerational mobility shapes graduates' working careers. Using multilevel growth curve modelling and data from the 1970 British cohort study (BCS70), we contribute to this research by looking at the emergence of social inequalities during the first ten years since labour market entry. We further distinguish between graduates of different fields of study as we expect social disparities to develop differently due to differences in initial occupational placement and upward mobility processes. We find that parental class does not affect occupational prestige over and above prior achievement. Separate analyses by the field of study show that initial differences in occupational prestige and career progression do not differ between graduates from different classes of origin in STEM fields, and arts and humanities. It is only in the social sciences that working-class graduates start with lower occupational prestige but soon catch up with their peers from higher classes. Overall, our results indicate no direct effect of social origin on occupational attainment for degree-holders once we broaden our focus to a dynamic life course perspective.

On the stress-strain alignment in premixed turbulent flames.

The interaction of large and small scale structures is fundamental to the energy cascade in turbulent flows. The correct representation of this interaction becomes important in the context of large eddy simulation (LES), where the response of small-scale structures to the resolved quantities, or large-scale structures, must be parametrised. This challenging task becomes more demanding when LES of premixed flames are considered, as heat release affects the interaction of turbulence and chemistry occurring at the unresolved scales. In this work, the influence of sub-grid scale (SGS) stresses on the kinetic energy budget of the resolved velocity field in turbulent premixed flames is investigated. In this spirit, the alignment between the SGS stresses and the resolved strain rate has been analysed by interrogating a direct numerical simulation (DNS) database of statistically planar premixed flames subjected to forced isotropic turbulence. It has been found that the alignment between the eigenvectors of the SGS stresses and the resolved strain rate changes across the flame brush and this change is dependent on the level of turbulence experienced by the flame. The influence of different turbulence intensities and different filter widths along with the implications of this misalignment on the SGS modelling are discussed in detail in the paper.

Direct Numerical Simulation of Head-On Quenching of Statistically Planar Turbulent Premixed Methane-Air Flames Using a Detailed Chemical Mechanism.

A three-dimensional compressible Direct Numerical Simulation (DNS) analysis has been carried out for head-on quenching of a statistically planar stoichiometric methane-air flame by an isothermal inert wall. A multi-step chemical mechanism for methane-air combustion is used for the purpose of detailed chemistry DNS. For head-on quenching of stoichiometric methane-air flames, the mass fractions of major reactant species such as methane and oxygen tend to vanish at the wall during flame quenching. The absence of OH at the wall gives rise to accumulation of carbon monoxide during flame quenching because CO cannot be oxidised anymore. Furthermore, it has been found that low-temperature reactions give rise to accumulation of HO 2 and H 2 O 2 at the wall during flame quenching. Moreover, these low temperature reactions are responsible for non-zero heat release rate at the wall during flame-wall interaction. In order to perform an in-depth comparison between simple and detailed chemistry DNS results, a corresponding simulation has been carried out for the same turbulence parameters for a representative single-step Arrhenius type irreversible chemical mechanism. In the corresponding simple chemistry simulation, heat release rate vanishes once the flame reaches a threshold distance from the wall. The distributions of reaction progress variable c and non-dimensional temperature T are found to be identical to each other away from the wall for the simple chemistry simulation but this equality does not hold during head-on quenching. The inequality between c (defined based on CH 4 mass fraction) and T holds both away from and close to the wall for the detailed chemistry simulation but it becomes particularly prominent in the near-wall region. The temporal evolutions of wall heat flux and wall Peclet number (i.e. normalised wall-normal distance of T = 0.9 isosurface) for both simple and detailed chemistry laminar and turbulent cases have been found to be qualitatively similar. However, small differences have been observed in the numerical values of the maximum normalised wall heat flux magnitude Φ max L and the minimum Peclet number ( P e min ) L obtained from simple and detailed chemistry based laminar head-on quenching calculations. Detailed explanations have been provided for the observed differences in behaviours of Φ max L and ( P e min ) L . The usual Flame Surface Density (FSD) and scalar dissipation rate (SDR) based reaction rate closures do not adequately predict the mean reaction rate of reaction progress variable in the near-wall region for both simple and detailed chemistry simulations. It has been found that recently proposed FSD and SDR based reaction rate closures based on a-priori DNS analysis of simple chemistry data perform satisfactorily also for the detailed chemistry case both away from and close to the wall without any adjustment to the model parameters.

Early Maternal Employment and Children's Vocabulary and Inductive Reasoning Ability: A Dynamic Approach.

This study investigates the relationship between early maternal employment history and children's vocabulary and inductive reasoning ability at age 5, drawing on longitudinal information on 2,200 children from the Growing Up in Scotland data. Prior research rarely addresses dynamics in maternal employment and the methodological ramifications of time-variant confounding. The present study proposes various measures to capture duration, timing, and stability of early maternal employment and uses inverse probability of treatment weighting to control for time-variant confounders that may partially mediate the effect of maternal employment on cognitive scores. The findings suggest only modest differences in the above ability measures between children who have been exposed to very different patterns of eary maternal employment, but with similar observed covariate history.

Enstrophy transport conditional on local flow topologies in different regimes of premixed turbulent combustion.

Enstrophy is an intrinsic feature of turbulent flows, and its transport properties are essential for the understanding of premixed flame-turbulence interaction. The interrelation between the enstrophy transport and flow topologies, which can be assigned to eight categories based on the three invariants of the velocity-gradient tensor, has been analysed here. The enstrophy transport conditional on flow topologies in turbulent premixed flames has been analysed using a Direct Numerical Simulation database representing the corrugated flamelets (CF), thin reaction zones (TRZ) and broken reaction zones (BRZ) combustion regimes. The flame in the CF regime exhibits considerable flame-generated enstrophy, and the dilatation rate and baroclinic torque contributions to the enstrophy transport act as leading order sink and source terms, respectively. Consequently, flow topologies associated with positive dilatation rate values, contribute significantly to the enstrophy transport in the CF regime. By contrast, enstrophy decreases from the unburned to the burned gas side for the cases representing the TRZ and BRZ regimes, with diminishing influences of dilatation rate and baroclinic torque. The enstrophy transport in the TRZ and BRZ regimes is governed by the vortex-stretching and viscous dissipation contributions, similar to non-reacting flows, and topologies existing for all values of dilatation rate remain significant contributors.

Self-Concept in Adolescents-Relationship between Sport Participation, Motor Performance and Personality Traits.

The relationship between sport participation, personality development, self-concept and self-esteem has been discussed repeatedly. In this research, a standardized written survey together with tests on motor performance were carried out with 1399 students (707 male; 692 female) in school years 7 (12.9 ± 0.6 years) and 10 (15.8 ± 0.6 years) to measure the extent of a relationship between physical self-concept (self-developed short scale) and sporting activity, measured motor performance (German motor performance test DMT (Deutscher Motorik-Test) 6⁻18) and report mark in physical education. Relationships were also analyzed between physical self-concept and general personality traits (neuroticism, extraversion, openness to experiences, compatibility, and conscientiousness, measured with NEO Five Factor Inventory (NEO-FFI)). The assessment of own physical attractiveness and own athleticism differs by sex (F(1, 962) = 35.21; p < 0.001), whereby girls assess themselves more critically. Weak significant relationships are displayed between motor performance and the assessment of own physical attractiveness (r(395) = 0.31; p < 0.01). Motor performance is given a higher predictive value with regard to a subject's own self-concept, (physical attractiveness ß = 0.37; t(249) = 5.24; p < 0.001; athleticism ß = 0.40; t(248) = 6.81; p < 0.001) than the mark achieved in physical education (physical attractiveness ß = -0.01; n.s.; athleticism ß = -0.30; t(248) = 5.10; p < 0.001). Relationships were found overall between personality traits and physical self-concept. The influence of the 'neuroticism' trait is particularly strong (physical attractiveness ß = -0.44; t(947) = -13.58; p < 0.001; athleticism ß = -0.27; t(948) = -7.84; p < 0.001). The more pronounced this trait, the lower the assessment of own physical attractiveness and own athleticism.

Impairing both HMA4 homeologs is required for cadmium reduction in tobacco.

In tobacco, the heavy metal P1B-ATPases HMA4.1 and HMA4.2 function in root-to-shoot zinc and cadmium transport. We present greenhouse and field data that dissect the possibilities to impact the two homeologous genes in order to define the best strategy for leaf cadmium reduction. In a first step, both genes were silenced using an RNAi approach leading to >90% reduction of leaf cadmium content. To modulate HMA4 function more precisely, mutant HMA4.1 and HMA4.2 alleles of a Targeting Induced Local Lesions IN Genomes (TILLING) population were combined. As observed with RNAi plants, knockout of both homeologs decreased cadmium root-to-shoot transfer by >90%. Analysis of plants with segregating null and wild-type alleles of both homeologs showed that one functional HMA4 allele is sufficient to maintain wild-type cadmium levels. Plant development was affected in HMA4 RNAi and double knockout plants that included retarded growth, necrotic lesions, altered leaf morphology and increased water content. The combination of complete functional loss (nonsense mutation) in one homeologous HMA4 gene and the functional reduction in the other HMA4 gene (missense mutation) is proposed as strategy to limit cadmium leaf accumulation without developmental effects.

Socio-economic status and motor performance of children and adolescents.

The study examines the question to what extent children and adolescents differ in terms of motor performance in dependence of their socio-economic status (SES). A sample of 1389 students in Saarland (Germany) in various grades (1st grade: age 7.26 ± 0.38 years, 4th grade: 10.3 ± 0.4 years, 7th grade: 13.44 ± 0.49 years, 10th grade: 16.36 ± 0.69 years) has been examined. Their motor performance has been measured by means of 20-m sprint, standing long jump and a 6-minute run, and the SES by means of a parent survey. Based on the indicators school education, professional education, job position and household income, the SES was categorised in a three-step approach (low, middle, high). The influence on dependent variables was analysed by using multivariate analysis of variance. Students with a higher SES exhibit a higher motor performance compared with that of lower SES (results of the multivariate: Pillai's Trace = .05, F[6; 2526] = 12.56, p = .001; [Formula: see text]). In addition, the data for students of higher SES differ significantly from the data of a German reference sample (higher motor performance compared with standard values). In contrast, persons of lower SES do not differ from the reference sample, and those of middle SES differ only slightly from the reference sample. The results are relevant when considering specific prevention efforts concerning motor performance of certain groups. Especially those institutions and schools should be focused upon whose catchment area includes a high share of socially disadvantaged population groups.

The increasing unemployment gap between the low and high educated in West Germany. Structural or cyclical crowding-out?

This paper addresses trends in education-specific unemployment risks at labor market entry in West Germany from the mid-1970s to the present. In line with previous research it shows that vocationally qualified school-leavers have relatively lower unemployment risks than school-leavers with general education. Over time, the gap in unemployment risks between the low-educated and medium- and highly educated labor market entrants substantially widened for both sexes. The literature identifies two different mechanisms for this trend: structural or cyclical crowding out. While in the former scenario low-educated become increasingly unemployed due to an oversupply of tertiary graduates and displacement from above, in the latter their relative unemployment risk varies with the business cycle. The results provide evidence for cyclical rather than structural crowding-out in West Germany. Since macroeconomic conditions became generally worse over time, this strongly explains the widening unemployment gap between the low-educated and all other education groups.

Structure-based optimization of non-peptidic Cathepsin D inhibitors.

We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy.