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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.
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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.
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Descubrimiento de Drogas , Ligandos , Estudios Prospectivos , Estudios Retrospectivos , TermodinámicaRESUMEN
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.
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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.
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Movilidad Laboral , Ocupaciones , Movilidad Social , Factores Socioeconómicos , Femenino , Humanos , Estudios Longitudinales , Masculino , Modelos Teóricos , Ocupaciones/estadística & datos numéricos , Clase Social , Movilidad Social/estadística & datos numéricos , Factores de Tiempo , Reino UnidoRESUMEN
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.
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Aptitud/fisiología , Desarrollo Infantil/fisiología , Empleo/estadística & datos numéricos , Madres/estadística & datos numéricos , Pensamiento/fisiología , Vocabulario , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Desarrollo del Lenguaje , Masculino , Escocia/epidemiologíaRESUMEN
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.
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Cadmio/metabolismo , Nicotiana/metabolismo , Proteínas de Plantas/metabolismo , Homología de Secuencia de Aminoácido , Proteínas de Arabidopsis/química , Regulación de la Expresión Génica de las Plantas , Modelos Biológicos , Mutación/genética , Fenotipo , Hojas de la Planta/metabolismo , Plantas Modificadas Genéticamente , Interferencia de ARN , Nicotiana/genética , Zinc/metabolismoRESUMEN
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.
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Escolaridad , Desempleo/estadística & datos numéricos , Adulto , Aglomeración , Recesión Económica/estadística & datos numéricos , Femenino , Alemania Occidental , Humanos , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
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.
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Catepsina D/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Catepsina D/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Relación Estructura-ActividadRESUMEN
Several studies analyzed the effectiveness of cold-water immersion (CWI) to support recovery after strenuous exercise, but the overall results seem to be conflicting. Most of these studies analyzed only short-term recovery effects, whereas the adaptational aspect has been widely neglected. Therefore, we analyzed the effects of repeated cooling after training sessions (CWI) on adaptations to strength training. Seventeen trained male students volunteered the study. After a 2-week familiarization period, a pretest (T1) of 1 repetition maximum (RM) and 12RM was conducted followed by the 5-week strength training period (within-subject design). After the posttest (T2) and a 2-week detraining period, a retention test (T3) was carried out. Directly after each training session, CWI was applied for 1 randomly assigned leg. Cooling consisted of 3 4-minute intervals with a 30-second rest period. The other leg was not cooled. A significant increase in 1RM and 12RM from baseline to T2 and T3 (p < 0.001), respectively, and a further significant increase in 12RM from T2 to T3 (p ≤ 0.05) were observed. In addition, a tendency for a large leg effect with higher values for the "control leg" in both parameters (p = 0.08 each) and a moderate time × leg interaction in favor of the control leg was found (1RM: p = 0.11; 12RM: p = 0.09). The percentage change differences between both conditions were 1.6% for the increase in 1RM from T1 to T2 and 2.0% from T1 to T3 in favor of the control leg. Long-term strength training adaptations in trained subjects can be negatively affected by CWI. However, effects were small, and the practical relevance relative to possible recovery effects needs to be considered in a sports practical setting.
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Adaptación Fisiológica , Frío , Inmersión , Entrenamiento de Fuerza , Adulto , Ejercicio Físico/fisiología , Humanos , Pierna , Masculino , Fuerza Muscular/fisiología , Músculo Esquelético/fisiología , Proyectos Piloto , Descanso , Agua , Adulto JovenRESUMEN
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.
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Prior research has identified that school absences harm children's academic achievement. However, this literature is focused on brief periods or single school years and does not consistently account for the dynamic nature of absences across multiple school years. This study examined dynamic trajectories of children's authorised and unauthorised absences throughout their compulsory school career in England. It investigated the consequences of these absence trajectories for children's achievement at the end of compulsory schooling. We analyse linked administrative data on children's absences and achievement from the National Pupil Database and survey data from the Millennium Cohort Study for a representative sample of children born in 2000/2001 in England (N = 7218). We used k-means clustering for longitudinal data to identify joint authorised-unauthorised absence trajectories throughout compulsory schooling and a regression-with-residuals approach to examine the link between absence trajectories and achievement. We identified five distinct absence trajectories: (1) 'Consistently Low Absences', (2) 'Consistently Moderate Authorised Absences', (3) 'Moderately Increasing Unauthorised Absences', (4) 'Strongly Increasing Unauthorised Absences', and (5) 'Strongly Increasing Authorised Absences'. We found substantial differences between trajectory groups in GCSE achievement, even when accounting for significant risk factors of school absences. Compared to 'Consistently Low Absences', 'Strongly Increasing Unauthorised Absences' reduced achievement by -1.23 to -1.48 standard deviations, while 'Strongly Increasing Authorised Absences' reduced achievement by -0.72 to -1.00 SD for our continuous outcomes. 'Moderately Increasing Unauthorised Absences' (-0.61 to -0.70 SD) and 'Consistently Moderate Authorised Absences' (-0.13 to -0.21 SD) also negatively affected achievement compared to 'Consistently Low Absences'. Our research underscores the critical importance of examining entire trajectories of absenteeism and differentiating between types of absences to fully grasp their associations with academic outcomes and design targeted interventions accordingly.
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Absentismo , Éxito Académico , Instituciones Académicas , Humanos , Niño , Instituciones Académicas/estadística & datos numéricos , Femenino , Masculino , Estudios Longitudinales , Adolescente , Inglaterra , Encuestas y Cuestionarios , Estudiantes/estadística & datos numéricosRESUMEN
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.
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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.
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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.
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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.
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Descubrimiento de Drogas , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Relación Estructura-ActividadRESUMEN
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).
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Ácidos Borónicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Furanos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/química , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis , Compuestos de Boro/administración & dosificación , Bortezomib/administración & dosificación , Proliferación Celular , Femenino , Glicina/administración & dosificación , Glicina/análogos & derivados , Humanos , Ratones , Ratones Desnudos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteolisis , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Arabidopsis possesses a superfamily of ATP-binding cassette (ABC) transporters. Among these, the multidrug resistance-associated protein AtMRP5/AtABCC5 regulates stomatal aperture and controls plasma membrane anion channels of guard cells. Remarkably, despite the prominent role of AtMRP5 in conferring partial drought insensitivity upon Arabidopsis, we know little of the biochemical function of AtMRP5. Our phylogenetic analysis showed that AtMRP5 is closely related to maize MRP4, mutation of which confers a low inositol hexakisphosphate kernel phenotype. We now show that insertion mutants of AtMRP5 display a low inositol hexakisphosphate phenotype in seed tissue and that this phenotype is associated with alterations of mineral cation and phosphate status. By heterologous expression in yeast, we demonstrate that AtMRP5 encodes a specific and high affinity ATP-dependent inositol hexakisphosphate transporter that is sensitive to inhibitors of ABC transporters. Moreover, complementation of the mrp5-1 insertion mutants of Arabidopsis with the AtMRP5 cDNA driven from a guard cell-specific promoter restores the sensitivity of the mutant to abscisic acid-mediated inhibition of stomatal opening. Additionally, we show that mutation of residues of the Walker B motif prevents restoring the multiple phenotypes associated with mrp5-1. Our findings highlight a novel function of plant ABC transporters that may be relevant to other kingdoms. They also extend the signaling repertoire of this ubiquitous inositol polyphosphate signaling molecule.
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Proteínas de Arabidopsis/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Ácido Fítico/metabolismo , Transducción de Señal/fisiología , Adenilil Imidodifosfato/farmacología , Proteínas de Arabidopsis/genética , Transporte Biológico/efectos de los fármacos , Prueba de Complementación Genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Fosfatos de Inositol/metabolismo , Microscopía Confocal , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Fósforo/metabolismo , Epidermis de la Planta/citología , Epidermis de la Planta/efectos de los fármacos , Epidermis de la Planta/metabolismo , Estomas de Plantas/fisiología , Plantas Modificadas Genéticamente , Semillas/genética , Semillas/metabolismo , Levaduras/genética , Levaduras/metabolismoRESUMEN
The ABC superfamily comprises both membrane-bound transporters and soluble proteins involved in a broad range of processes, many of which are of considerable agricultural, biotechnological and medical potential. Completion of the Arabidopsis and rice genome sequences has revealed a particularly large and diverse complement of plant ABC proteins in comparison with other organisms. Forward and reverse genetics, together with heterologous expression, have uncovered many novel roles for plant ABC proteins, but this progress has been accompanied by a confusing proliferation of names for plant ABC genes and their products. A consolidated nomenclature will provide much-needed clarity and a framework for future research.
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Transportadoras de Casetes de Unión a ATP/clasificación , Proteínas de Plantas/clasificación , Transportadoras de Casetes de Unión a ATP/genética , Arabidopsis/genética , Genoma de Planta , Oryza/genética , Filogenia , Proteínas de Plantas/genéticaRESUMEN
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.
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To further develop gene therapy for patients with glioblastomas, an experimental gene therapy protocol was established comprising a series of imaging parameters for (i) noninvasive assessment of viable target tissue followed by (ii) targeted application of herpes simplex virus type 1 (HSV-1) amplicon vectors and (iii) quantification of treatment effects by imaging. We show that viable target tissue amenable for application of gene therapy vectors can be identified by multitracer positron emission tomography (PET) using 2-(18)F-fluoro-2-deoxy-D-glucose, methyl-(11)C-L-methionine, or 3'-deoxy-3'-(18)F-fluoro-L-thymidine ([(18)F]FLT). Targeted application of HSV-1 amplicon vectors containing two therapeutic genes with synergistic antitumor activity (Escherichia coli cytosine deaminase, cd, and mutated HSV-1 thymidine kinase, tk39, fused to green fluorescent protein gene, gfp) leads to an overall response rate of 68%, with 18% complete responses and 50% partial responses. Most importantly, we show that the "tissue dose" of HSV-1 amplicon vector-mediated gene expression can be noninvasively assessed by 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) PET. Therapeutic effects could be monitored by PET with significant differences in [(18)F]FLT accumulation in all positive control tumors and 72% in vivo transduced tumors (P = 0.01) as early as 4 days after prodrug therapy. For all stably and in vivo transduced tumors, cdIREStk39gfp gene expression as measured by [(18)F]FHBG-PET correlated with therapeutic efficiency as measured by [(18)F]FLT-PET. These data indicate that imaging-guided vector application with determination of tissue dose of vector-mediated gene expression and correlation to induced therapeutic effect using multimodal imaging is feasible. This strategy will help in the development of safe and efficient gene therapy protocols for clinical application.