In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug

Drug dissolution and release characteristics from freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose (CMC) have been investigated to determine the mechanisms of drug release from the two systems. The formulations were prepared by freeze-drying (wafers) or drying in air (films), the hydrated gel of the polymer containing paracetamol as a model soluble drug. Scanning electron microscopy (SEM) was used to examine differences between the physical structure of the wafers and films. Dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 242 nm. The effects of drug loading, polymer content and amount of glycerol (films) on the release characteristics of paracetamol were investigated. The release profiles of paracetamol from the wafers and films were also compared. A digital camera was used to observe the times to complete hydration and dissolution of the wafers containing different amounts of CMC and how that impacts on drug release rates. Both formulations showed sustained type drug release that was modelled by the Korsmeyer–Peppas equation. Changes in the concentration of drug and glycerol (films) did not significantly alter the rate of drug release while increasing polymer content significantly decreased the rate of drug release from both formulations. The results show that the rate of paracetamol release was faster from the wafers than the corresponding films due to differences in their physical structures. The wafers which formed a porous network, hydrated faster than the more dense and continuous, (non-porous) sheet-like structure of the films.

Microbial spatial variability: An example from the Celtic Sea

In July 2004, dominant populations of microbial ultraplankton (<5 μm), in the surface of the Celtic Sea (between UK and Eire), were repeatedly mapped using flow cytometry, at 1.5 km resolution over a region of diameter 100 km. The numerically dominant representatives of all basic functional types were enumerated including one group of phototrophic bacteria (Syn), two groups of phytoplankton (PP, NP), three groups of heterotrophic bacterioplankton (HB) and the regionally dominant group of heterotrophic protists (HP). The distributions of all organisms showed strong spatial variability with little relation to variability in physical fields such as salinity and temperature. Furthermore, there was little agreement between distributions of different organisms. The only linear correlation consistently explaining more than 50% of the variance between any pairing of the organism groups enumerated is between two different groups of HB. Specifically, no linear, or non-linear, relationship is found between any pairings of SYB, PP or HB groups with their protist predators HP. Looking for multiple dependencies, factor analysis reveals three groupings: Syn, PP and low nucleic acid content HB (LNA); high nucleic acid content HB (HNA); HP and NP. Even the manner in which the spatial variability of Syn, PP and HB abundance varies as a function of lengthscale (represented by a semivariogram) differs significantly from that for HP. In summary, although all microbial planktonic groups enumerated are present and numerically dominant throughout the region studied, at face value the relationships between them seem weak. Nevertheless, the behaviour of a simple, illustrative ecological model, with strongly interacting phototrophs and heterotrophs, with stochastic forcing, is shown to be consistent with the observed poor correlations and differences in how spatial variability varies with lengthscale. Thus, our study suggests that a comparison of microbial abundances alone may not discern strong underlying trophic interactions. Specific knowledge of these processes, in particular grazing, will be required to explain the causes of the observed microbial spatial variability and its resulting consequences for the functioning of the ecosystem.

Fundamental shift in vitamin B12 eco-physiology of a model alga demonstrated by experimental evolution.

A widespread and complex distribution of vitamin requirements exists over the entire tree of life, with many species having evolved vitamin dependence, both within and between different lineages. Vitamin availability has been proposed to drive selection for vitamin dependence, in a process that links an organism's metabolism to the environment, but this has never been demonstrated directly. Moreover, understanding the physiological processes and evolutionary dynamics that influence metabolic demand for these important micronutrients has significant implications in terms of nutrient acquisition and, in microbial organisms, can affect community composition and metabolic exchange between coexisting species. Here we investigate the origins of vitamin dependence, using an experimental evolution approach with the vitamin B(12)-independent model green alga Chlamydomonas reinhardtii. In fewer than 500 generations of growth in the presence of vitamin B(12), we observe the evolution of a B(12)-dependent clone that rapidly displaces its ancestor. Genetic characterization of this line reveals a type-II Gulliver-related transposable element integrated into the B(12)-independent methionine synthase gene (METE), knocking out gene function and fundamentally altering the physiology of the alga.

Metabolically active, non-nitrogen fixing,Trichodesmiumin UK coastal waters during winter

Trichodesmium, a colonial cyanobacterium typically associated with tropical waters, was observed between January and April 2014 in the western English Channel. Sequencing of the heterocyst differentiation (hetR) and 16S rRNA genes placed this community within the Clade IV Trichodesmium, an understudied clade previously found only in low numbers in warmer waters. Nitrogen fixation was not detected although measurable rates of nitrate uptake and carbon fixation were observed. Trichodesmium RuBisCO transcript abundance relative to gene abundance suggests the potential for viable and potentially active Trichodesmium carbon fixation. Observations of Trichodesmium when coupled with a numerical advection model indicate that Trichodesmium communities can remain viable for >3.5 months at temperatures lower than previously expected. The results suggest that Clade IV Trichodesmium occupies a different niche to other Trichodesmium species, and is a cold- or low-light-adapted variant.

iMarNet: an ocean biogeochemistry model intercomparison project within a common physical ocean modelling framework

Ocean biogeochemistry (OBGC) models span a wide variety of complexities, including highly simplified nutrient-restoring schemes, nutrient–phytoplankton–zooplankton–detritus (NPZD) models that crudely represent the marine biota, models that represent a broader trophic structure by grouping organisms as plankton functional types (PFTs) based on their biogeochemical role (dynamic green ocean models) and ecosystem models that group organisms by ecological function and trait. OBGC models are now integral components of Earth system models (ESMs), but they compete for computing resources with higher resolution dynamical setups and with other components such as atmospheric chemistry and terrestrial vegetation schemes. As such, the choice of OBGC in ESMs needs to balance model complexity and realism alongside relative computing cost. Here we present an intercomparison of six OBGC models that were candidates for implementation within the next UK Earth system model (UKESM1). The models cover a large range of biological complexity (from 7 to 57 tracers) but all include representations of at least the nitrogen, carbon, alkalinity and oxygen cycles. Each OBGC model was coupled to the ocean general circulation model Nucleus for European Modelling of the Ocean (NEMO) and results from physically identical hindcast simulations were compared. Model skill was evaluated for biogeochemical metrics of global-scale bulk properties using conventional statistical techniques. The computing cost of each model was also measured in standardised tests run at two resource levels. No model is shown to consistently outperform all other models across all metrics. Nonetheless, the simpler models are broadly closer to observations across a number of fields and thus offer a high-efficiency option for ESMs that prioritise high-resolution climate dynamics. However, simpler models provide limited insight into more complex marine biogeochemical processes and ecosystem pathways, and a parallel approach of low-resolution climate dynamics and high-complexity biogeochemistry is desirable in order to provide additional insights into biogeochemistry–climate interactions.

Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial

Abstract There is considerable interest in developing medical devices that provide controlled delivery of biologically active agents, for example, to reduce the incidence of device-related infection. Silicone elastomers are one of the commonest biomaterials used in medical device production. However, they have a relatively high coefficient of friction and the resulting lack of lubricity can cause pain and tissue damage on device insertion and removal. Novel silicone cross-linking agents have recently been reported that produce inherently ‘self-lubricating’ silicone elastomers with very low coefficients of friction. In this study, the model antibacterial drug metronidazole has been incorporated into these self-lubricating silicone elastomers to produce a novel bioactive biomaterial. The in vitro release characteristics of the bioactive component were evaluated as a function of cross-linker composition and drug loading. Although conventional matrix-type release kinetics were observed for metronidazole from the silicone systems, it was also observed that increasing the concentration of the cross-linking agent responsible for the lubricious character (tetra(oleyloxy)silane) relative to that of the standard non-lubricious cross-linking agent (tetrapropoxysilane) produced an increase in the metronidazole flux rate by up to 65% for a specified drug loading. The results highlight the potential for developing lubricious silicone medical devices with enhanced drug release characteristics.

Efficient Non-Linear Idealisations of Aircraft Fuselage Panels in Compression

Aircraft fuselages are complex assemblies of thousands of components and as a result simulation models are highly idealised. In the typical design process, a coarse FE model is used to determine loads within the structure. The size of the model and number of load cases necessitates that only linear static behaviour is considered. This paper reports on the development of a modelling approach to increase the accuracy of the global model, accounting for variations in stiffness due to non-linear structural behaviour. The strategy is based on representing a fuselage sub-section with a single non-linear element. Large portions of fuselage structure are represented by connecting these non-linear elements together to form a framework. The non-linear models are very efficient, reducing computational time significantly

Coupled Temperature-Displacement Modelling of Injection Stretch Blow Moulding of PET bottles using Buckley Model

This study presents a fully coupled temperature–displacement finite element modelling of the injection stretch-blow moulding (ISBM) process of polyethylene terephthalate (PET) bottles using ABAQUS with a view to optimising the process conditions. A physically-based material model (Buckley model) was used to predict the mechanical behaviour of PET at temperatures slightly above its glass transition temperature. A model incorporating heat transfer between the stretch rod, the preform and the mould was built using axisymmetric solid elements. Extensive finite element analyses were carried out to predict the deformation, the distribution and history of strain and temperature during ISBM of a 20 g–330 ml bottle, which was made in an in situ test on a Sidel SB06 machine. Comparisons of numerical results with the measurements demonstrate that the model can satisfactorily model the sidewall thickness and material distributions. It is also shown that significant non-linear differentials exist in temperature and strain in both bottle thickness and length directions during the process. This justifies the employment of a volume approach to accurately predict the final mechanical properties of the bottles governed by the orientation and crystallinity which are highly temperature and strain dependent.

A Phase-field Model for Computer Simulation of Lamellar Structure Formation in y-TiAI

In the present paper, a phase-field model is developed to simulate the formation and evolution of lamellar microstructure in γ-TiAl alloys. The mechanism of formation of TiAl lamellae proposed by Denquin and Naka is incorporated into the model. The model describes the formation and evolution of the face-centered cubic (fcc) stacking lamellar zone followed by the subsequent appearance and growth of the γ-phase, involving both the chemical composition change by atom transfer and the ordering of the fcc lattice. The thermodynamics of the model system and the interaction between the displacive and diffusional transformations are described by a non-equilibrium free energy formulated as a function of concentration and structural order parameter fields. The long-range elastic interactions, arising from the lattice misfit between the α, fcc (A1) and the various orientation variants of the γ-phase are taken into account by incorporating of the elastic strain energy into the total free energy. Simulation studies based on the model successfully predicted some essential features of the lamellar structure. It is found that the formation and evolution of the lamellar structure are predominantly controlled by the minimization of the elastic energy of the interfaces between the different fcc stacking groups, low-symmetry product phase γ and the high-symmetry α-phase, as well as between the various orientation variants of the product phase.

A structural basis for different antifreeze protein roles

Antifreeze proteins (AFPs) are produced by a variety of organisms to either protect them from freezing or help them tolerate being frozen. Recent structural work has shown that AFPs bind to ice using ordered surface waters on a particular surface of the protein called the ice-binding site (IBS). These 'anchored clathrate' waters fuse to particular planes of an ice crystal and hence irreversibly bind the AFP to its ligand. An AFP isolated from the perennial ryegrass, Lolium perenne (LpAFP) was previously modelled as a right-handed beta helix with two proposed IBSs. Steric mutagenesis, where small side chains were replaced with larger ones, determined that only one of the putative IBSs was responsible for binding ice. The mutagenesis work also partly validated the fold of the computer-generated model of this AFP. In order to determine the structure of the protein, LpAFP was crystallized and solved to 1.4 Å resolution. The protein folds as an untwisted left-handed beta-helix, of opposite handedness to the model. The IBS identified by mutagenesis is remarkably flat, but less regular than the IBS of most other AFPs. Furthermore, several of the residues constituting the IBS are in multiple conformations. This irregularity may explain why LpAFP causes less thermal hysteresis than many other AFPs. Its imperfect IBS is also argued to be responsible for LpAFP's heightened ice-recrystallization inhibition activity. The structure of LpAFP is the first for a plant AFP and for a protein responsible for providing freeze tolerance rather than freeze resistance. To help understand what constitutes an IBS, a non-ice-binding homologue of type III AFP, sialic acid synthase (SAS), was engineered for ice binding. Point mutations were made to the germinal IBS of SAS to mimic key features seen in type III AFP. The crystal structures of some of the mutant proteins showed that the potential IBS became less charged and flatter as the mutations progressed, and ice affinity was gained. This proof-of-principle study highlights some of the difficulties in AFP engineering.

Integration of shading and texture cues: testing the linear model

One of the first attempts to develop a formal model of depth cue integration is to be found in Maloney and Landy's (1989) "human depth combination rule". They advocate that the combination of depth cues by the visual sysetem is best described by a weighted linear model. The present experiments tested whether the linear combination rule applies to the integration of texture and shading. As would be predicted by a linear combination rule, the weight assigned to the shading cue did vary as a function of its curvature value. However, the weight assigned to the texture cue varied systematically as a function of the curvature value of both cues. Here we descrive a non-linear model which provides a better fit to the data. Redescribing the stimuli in terms of depth rather than curvature reduced the goodness of fit for all models tested. These results support the hypothesis that the locus of cue integration is a curvature map, rather than a depth map. We conclude that the linear comination rule does not generalize to the integration of shading and texture, and that for these cues it is likely that integration occurs after the recovery of surface curvature.

Identification and bisection of temporal durations and tone frequencies: Common models for temporal and non-temporal stimuli.

Two experiments examined identification and bisection of tones varying in temporal duration (Experiment 1) or frequency (Experiment 2). Absolute identification of both durations and frequencies was influenced by prior stimuli and by stimulus distribution. Stimulus distribution influenced bisection for both stimulus types consistently, with more positively skewed distributions producing lower bisection points. The effect of distribution was greater when the ratio of the largest to smallest stimulus magnitude was greater. A simple mathematical model, temporal range frequency theory, was applied. It is concluded that (a) similar principles describe identification of temporal durations and other stimulus dimensions and (b) temporal bisection point shifts can be understood in terms of psychophysical principles independently developed in nontemporal domains, such as A. Parducci's (1965) range frequency theory.

Contingent screening for down syndrome is an efficient alternative to non-disclosure sequential screening

Objective To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening (the Integrated test), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. Methods Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. Results Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. Conclusion Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

A non-LTE analysis of the spectra of two narrow lined main sequence stars in the SMC

An analysis of high-resolution VLT/UVES spectra of two B-type main sequence stars, NGC 346-11 and AV 304, in the Small Magellanic Cloud (SMC), has been undertaken, using the non-LTE tlusty model atmospheres to derive the stellar parameters and chemical compositions of each star. The chemical compositions of the two stars are in reasonable agreement. Moreover, our stellar analysis agrees well with earlier analyses of H II regions. The results derived here should be representative of the current base-line chemical composition of the SMC interstellar medium as derived from B-type stars.

A decentralized model of information pricing in networks

We propose a recursive method of pricing an information good in a network of holders and demanders of this good. The prices are determined via a unique equilibrium outcome in a sequence of bilateral bargaining games that are played by connected agents. If the information is an homogenous, non-depreciating good without network effects we derive explicit formulae which elucidate the role of the link pattern among the players. Particularly, we find out that the equilibrium price is intimately related to the existence of cycles in the network: It is zero if a cycle covers the trading pair and it is proportional to the direct and indirect utility that the good generates otherwise.