The influence of the thermal diffusivity of the lower boundary on eddy motion in convection

The paper presents new concepts and results for the eddy structure of turbulent convection in a horizontal fluid layer of depth h which lies above a solid base with thickness hb. The fluid parameters are the kinematic viscosity ν, the thermal diffusivity κ, which is taken to be comparable with ν, the density ρ, the specific heat cp and the expansion parameter β. The thermal diffusivity of the solid is κb. The results are an extension of the more commonly studied cases, where a constant heat flux or constant temperature is applied at the interface between the fluid and the base. The buoyancy forces induce eddy motions with a typical velocity w∗∼(gβFθh)1/3 where ρcpFθ is the average heat flux and Fθ the covariance of the fluctuations of the temperature and of the vertical velocity. At moderate Reynolds numbers (Re=w∗h/ν), say less than about 103, an order-of-magnitude analysis shows that for the case of high diffusivity of the base (i.e. κb≫κ) elongated ‘plumes’ form at the surface and extend to the top of the fluid layer. When the base diffusivity is low (i.e. κb≤κ) the surface cools below the developing ‘plume’ and either the plume breaks up into elongated puffs or, if κb≪κ, horizontal pressure gradients form so that only small-scale puffs can form near the surface. At very high Reynolds numbers, approximately greater than 104, the surface boundary layer below each puff/plume is highly turbulent with a local logarithmic velocity and temperature profile. An approximate analysis indicates for this case that there is insufficient buoyancy flux from the base, irrespective of its diffusivity, to maintain plumes, because of the high turbulent heat transfer. So puffs dominate high-Reynolds-number thermal convection as numerical simulations and field experiments demonstrate. However, when the surface heat flux is uniform, for example as a result of radiant heat transfer or by forcing with a constant heat flux below a very thin conducting base, plumes are the dominant form of eddy motion, as is commonly observed. In the numerical solutions presented here, where Re∼3×102 and the slab thickness hb=h, it is shown that the spatial scales of eddy structures in the fluid layer close to the surface become significantly smaller as κb/κ is reduced from 100 to 0.1. At the same time in the core of the convective layer the change in the autocorrelation and spatial correlation function indicates that there is a transition from long-duration plumes into shorter-duration and smaller-length-scale elongated puffs. The simulations show that the largest temperature fluctuations near the surface occur when a constant heat flux is applied at the bottom of the fluid layer. The smallest temperature fluctuations are associated with the constant-temperature boundary condition. The finite base diffusivity cases lie in between these limits, with the largest fluctuations occurring when the thermal diffusivity of the base is small. The hypothesis introduced above has been tested qualitatively in a laboratory set-up when the effective diffusivity of the base was varied. The flow structure was observed as it changed from being characterized by nearly steady plumes, into unsteady plumes and finally into puffs when the thickness of the conducting base was first increased and then the diffusivity was decreased

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability

A multi-zoo investigation of nutrient provision for captive red-crested turacos

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record© 2017 Wiley Periodicals, Inc. structural, copper-based feather pigments, and a specialized dietary strategy. Tauraco inhabit tropical woodlands, foraging for predominantly folivorous and/or frugivorous food items. Using a study population of 16 red-crested turacos (T. erythrolophus) at seven zoos in the United Kingdom, the nutrient composition of diets from diet sheets was calculated, using Zootrition v.2.6, Saint Louis Zoo, USA for analyses of important nutrients within each diet, and compared against an example of currently available literature. For all nutrients analyzed, significant differences were noted between amounts presented in each zoo's diet (as fed). Turacos are presented with a wide range of ingredients in diets fed, and all zoos use domestic fruits to a large extent in captive diets. Similarities exist between zoos when comparing amounts of as-fed fiber. Analysis of the calcium to phosphorous ratio for these diets showed there to be no significant difference from the published ratio available. While this is a small-scale study on only a limited number of zoos, it provides useful information on current feeding practice for a commonly-housed species of bird and highlights potential areas of deviation away from standard practice, as well as identifying ways of reducing wastage of food. Data on wild foraging behavior and food selection, or collaboration with tauraco keepers from institutions in the tropics, is recommended as a way of improving feeding regimes and updating feeding practice for this and other Tauraco species

Azoniaspiro salts: towards bridging the gap between room-temperature ionic liquids and molten salts.

In a continued effort to improve the suitability of ionic liquids in applications operating at raised temperatures, novel spirocyclic 'azoniaspiro' salts (with cations derived from five-, six-, seven-and eight-membered rings) are prepared and characterised. The structural and thermal properties of these salts are compared against those of established analogues. The stable geometries and ion pairing behaviour of these species are investigated via a combined experimental/computational approach, employing X-ray crystallography and Density Functional Theory (DFT) methods. Subsequently, the thermal stabilities of these organic salts are characterised and compared using a broad range of techniques. Hyphenated Thermogravimetry-Mass Spectrometry investigations enable complex mechanisms underlying thermal decomposition to be elucidated. Lastly, transition state structures are optimised, corresponding to plausible decomposition mechanisms of the azoniaspiro salt, 6-azoniaspiro[6.5]dodecanium chloride, and one prototypical monocyclic species 1-butyl-1-methylpiperidinium chloride, using DFT. The observed improved thermal stabilities of the azoniaspiro salts, and their potential higher-temperature stable-liquid ranges, render them promising candidates for future ionic liquid applications

Genotype-by-sex-by-diet interactions for nutritional preference, dietary consumption, and lipid deposition in a field cricket

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordChanges in feeding behaviour, especially the overconsumption of calories, has led to a rise in the rates of obesity, diabetes, and other associated disorders in humans and a range of animals inhabiting human-influenced environments. However, understanding the relative contribution of genes, the nutritional environment, and their interaction to dietary intake and lipid deposition in the sexes still remains a major challenge. By combining nutritional geometry with quantitative genetics, we determined the effect of genes, the nutritional environment, and their interaction on the total nutritional preference (TP), total diet eaten (TE), and lipid mass (LM) of male and female black field crickets (Teleogryllus commodus) fed one of four diet pairs (DPs) differing in the ratio of protein to carbohydrate and total nutritional content. We found abundant additive genetic variance for TP, TE, and LM in both sexes and across all four DPs, with significant genetic correlations between TE and TP and between TP and LM in males. We also found significant genotype-by-DP and genotype-by-sex-by-DP interactions for each trait and significant genotype-by-sex interactions for TE and LM. Complex interactions between genes, sex, and the nutritional environment, therefore, play an important role in nutrient regulation and lipid deposition in T. commodus. This finding may also help explain the increasing rate of obesity and the maintenance of sex differences in obesity observed across many animal species, including humans.H was funded by a University Royal Society Fellowship and Equipment Grant and by NERC (NE/G00949X/1) and AJW by a BBSRC Fellowship. JR was funded by a NERC studentship (NERC/1200242) awarded to JH

Constrained evolution of the sex comb in Drosophila simulans

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Male fitness is dependent on sexual traits that influence mate acquisition (pre-copulatory sexual selection) and paternity (post-copulatory sexual selection), and while many studies have documented the form of selection in one or the other of these arenas, fewer have done it for both. Nonetheless, it appears that the dominant form of sexual selection is directional, although theoretically, populations should converge on peaks in the fitness surface, where selection is stabilizing. Many factors, however, can prevent populations from reaching adaptive peaks. Genetic constraints can be important if they prevent the development of highest fitness phenotypes, as can the direction of selection if it reverses across episodes of selection. In this study, we examine the evidence that these processes influence the evolution of the multivariate sex comb morphology of male Drosophila simulans. To do this, we conduct a quantitative genetic study together with a multivariate selection analysis to infer how the genetic architecture and selection interact. We find abundant genetic variance and covariance in elements of the sex comb. However, there was little evidence for directional selection in either arena. Significant nonlinear selection was detected prior to copulation when males were mated to non-virgin females, and post-copulation during sperm offence (again with males mated to non-virgins). Thus contrary to our predictions, the evolution of the D. simulans sex comb is limited neither by genetic constraints nor by antagonistic selection between pre- and post-copulatory arenas, but nonlinear selection on the multivariate phenotype may prevent sex combs from evolving to reach some fitness maximising optima. This article is protected by copyright. All rights reserved.This work was supported by a BBSRC fellowship to A.W, Royal Society Fellowship to J.H., a NERC grant and a Leverhulme Research Fellowship to D.J.H. and a Leverhulme Early Career Fellowship to C.M.H. We thank two anonymous reviewers for comments on the manuscript

Individualized, discrete event, simulations provide insight into inter- and intra-subject variability of extended-release, drug products

Abstract Objective Develop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms. Methods We constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated. Results We discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects. Conclusion We hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review

Endothelial Cells Potentiate Interferon-γ Production in a Novel Tripartite Culture Model of Human Cerebral Malaria

We have established a novel in vitro co-culture system of human brain endothelial cells (HBEC), Plasmodium falciparum parasitised red blood cells (iRBC) and peripheral blood mononuclear cells (PBMC), in order to simulate the chief pathophysiological lesion in cerebral malaria (CM). This approach has revealed a previously unsuspected pro-inflammatory role of the endothelial cell through potentiating the production of interferon (IFN)-γ by PBMC and concurrent reduction of interleukin (IL)-10. The IFN-γ increased the expression of CXCL10 and intercellular adhesion molecule (ICAM)-1, both of which have been shown to be crucial in the pathogenesis of CM. There was a shift in the ratio of IL-10:IFN-γ protein from >1 to <1 in the presence of HBEC, associated with the pro-inflammatory process in this model. For this to occur, a direct contact between PBMC and HBEC, but not PBMC and iRBC, was necessary. These results support HBEC playing an active role in the pathogenesis of CM. Thus, if these findings reflect the pathogenesis of CM, inhibition of HBEC and PBMC interactions might reduce the occurrence, or improve the prognosis, of the condition. © 2013 Khaw et al

A comparison of liquid and solid culture for determining relapse and durable cure in phase III TB trials for new regimens

BACKGROUND: Tuberculosis kills more people than any other infectious disease, and new regimens are essential. The primary endpoint for confirmatory phase III trials for new regimens is a composite outcome that includes bacteriological treatment failure and relapse. Culture methodology is critical to the primary trial outcome. Patients in clinical trials can have positive cultures after treatment ends that may not necessarily indicate relapse, which was ascribed previously to laboratory cross-contamination or breakdown of old lesions. Löwenstein-Jensen (LJ) medium was the previous standard in clinical trials, but almost all current and future trials will use the Mycobacteria Growth Indicator Tube (MGIT) system due to its simplicity and consistency of use, which will affect phase III trial results. LJ was used for the definition of the primary endpoint in the REMoxTB trial, but every culture was also inoculated in parallel into the MGIT system. The data from this trial, therefore, provide a unique opportunity to investigate and compare the incidence of false 'isolated positives' in liquid and solid media and their potential impact on the primary efficacy results. METHODS: All post-treatment positive cultures were reviewed in the REMoxTB clinical trial. Logistic regression models were used to model the incidence of isolated positive cultures on MGIT and LJ. RESULTS: A total of 12,209 sputum samples were available from 1652 patients; cultures were more often positive on MGIT than LJ. In 1322 patients with a favourable trial outcome, 126 (9.5%) had cultures that were positive in MGIT compared to 34 (2.6%) patients with positive cultures on LJ. Among patients with a favourable outcome, the incidence of isolated positives on MGIT differed by study laboratory (p < 0.0001) with 21.9% of these coming from one laboratory investigating only 4.9% of patients. No other baseline factors predicted isolated positives on MGIT after adjusting for laboratory. There was evidence of clustering of isolated positive cultures in some patients even after adjusting for laboratory, p < 0.0001. The incidence of isolated positives on MGIT did not differ by treatment arm (p = 0.845, unadjusted). Compared to negative MGIT cultures, positive MGIT cultures were more likely to be associated with higher grade TB symptoms reported within 7 days either side of sputum collection in patients with an unfavourable primary outcome (p < 0.0001) but not in patients with a favourable outcome (p = 0.481). CONCLUSIONS: Laboratory cross-contamination was a likely cause of isolated positive MGIT cultures which were clustered in some laboratories. Certain patients had repeated positive MGIT cultures that did not meet the definition of a relapse. This pattern was too common to be explained by cross-contamination only, suggesting that host factors were also responsible. We conclude that MGIT can replace LJ in phase III TB trials, but there are implications for the definition of the primary outcome and patient management in trials in such settings. Most importantly, the methodologies differ in the incidence of isolated positives and in their capacity for capturing non-tuberculosis mycobacteria. It emphasises the importance of effective medical monitoring after treatment ends and consideration of clinical signs and symptoms for determining treatment failure and relapse