A structural model for the in vivo human cornea including collagen-swelling interaction

A structural model of the in vivo cornea, which accounts for tissue swelling behaviour, for the three-dimensional organization of stromal fibres and for collagen-swelling interaction, is proposed. Modelled as a binary electrolyte gel in thermodynamic equilibrium, the stromal electrostatic free energy is based on the mean-field approximation. To account for active endothelial ionic transport in the in vivo cornea, which modulates osmotic pressure and hydration, stromal mobile ions are shown to satisfy a modified Boltzmann distribution. The elasticity of the stromal collagen network is modelled based on three-dimensional collagen orientation probability distributions for every point in the stroma obtained by synthesizing X-ray diffraction data for azimuthal angle distributions and second harmonic-generated image processing for inclination angle distributions. The model is implemented in a finite-element framework and employed to predict free and confined swelling of stroma in an ionic bath. For the in vivo cornea, the model is used to predict corneal swelling due to increasing intraocular pressure (IOP) and is adapted to model swelling in Fuchs'' corneal dystrophy. The biomechanical response of the in vivo cornea to a typical LASIK surgery for myopia is analysed, including tissue fluid pressure and swelling responses. The model provides a new interpretation of the corneal active hydration control (pump-leak) mechanism based on osmotic pressure modulation. The results also illustrate the structural necessity of fibre inclination in stabilizing the corneal refractive surface with respect to changes in tissue hydration and IOP.     

Characterization of age-related variation in corneal biomechanical properties

An experimental study has been conducted to determine the stress–strain behaviour of human corneal tissue and how the behaviour varies with age. Fifty-seven well-preserved ex vivo donor corneas aged between 30 and 99 years were subjected to cycles of posterior pressure up to 60 mm Hg while monitoring their behaviour. The corneas were mechanically clamped along their ring of scleral tissue and kept in physiological conditions of temperature and hydration. The tissue demonstrated hyper-elastic pressure-deformation and stress–strain behaviour that closely matched an exponential trend. Clear stiffening (increased resistance to deformation) with age was observed in all loading cycles, and the rate of stiffness growth was nonlinear with bias towards older specimens. With a strong statistical association between stiffness and age (p < 0.05), it was possible to develop generic stress–strain equations that were suitable for all ages between 30 and 99 years. These equations, which closely matched the experimental results, depicted corneal stiffening with age in a form suitable for implementation in numerical simulations of ocular biomechanical behaviour.     

Modelling cholera epidemics: the role of waterways,human mobility and sanitation

We investigate the role of human mobility as a driver for long-range spreading of cholera infections, which primarily propagate through hydrologically controlled ecological corridors. Our aim is to build a spatially explicit model of a disease epidemic, which is relevant to both social and scientific issues. We present a two-layer network model that accounts for the interplay between epidemiological dynamics, hydrological transport and long-distance dissemination of the pathogen Vibrio cholerae owing to host movement, described here by means of a gravity-model approach. We test our model against epidemiological data recorded during the extensive cholera outbreak occurred in the KwaZulu-Natal province of South Africa during 2000–2001. We show that long-range human movement is fundamental in quantifying otherwise unexplained inter-catchment transport of V. cholerae, thus playing a key role in the formation of regional patterns of cholera epidemics. We also show quantitatively how heterogeneously distributed drinking water supplies and sanitation conditions may affect large-scale cholera transmission, and analyse the effects of different sanitation policies.     

Analytical model for instantaneous lift and shape deformation of an insect-scale flapping wing in hover

In the analysis of flexible flapping wings of insects, the aerodynamic outcome depends on the combined structural dynamics and unsteady fluid physics. Because the wing shape and hence the resulting effective angle of attack are a priori unknown, predicting aerodynamic performance is challenging. Here, we show that a coupled aerodynamics/structural dynamics model can be established for hovering, based on a linear beam equation with the Morison equation to account for both added mass and aerodynamic damping effects. Lift strongly depends on the instantaneous angle of attack, resulting from passive pitch associated with wing deformation. We show that both instantaneous wing deformation and lift can be predicted in a much simplified framework. Moreover, our analysis suggests that resulting wing kinematics can be explained by the interplay between acceleration-related and aerodynamic damping forces. Interestingly, while both forces combine to create a high angle of attack resulting in high lift around the midstroke, they offset each other for phase control at the end of the stroke.     

Time and dose-dependent risk of pneumococcal pneumonia following influenza: a model for within-host interaction between influenza and Streptococcus pneumoniae

A significant fraction of seasonal and in particular pandemic influenza deaths are attributed to secondary bacterial infections. In animal models, influenza virus predisposes hosts to severe infection with both Streptococcus pneumoniae and Staphylococcus aureus. Despite its importance, the mechanistic nature of the interaction between influenza and pneumococci, its dependence on the timing and sequence of infections as well as the clinical and epidemiological consequences remain unclear. We explore an immune-mediated model of the viral–bacterial interaction that quantifies the timing and the intensity of the interaction. Taking advantage of the wealth of knowledge gained from animal models, and the quantitative understanding of the kinetics of pathogen-specific immunological dynamics, we formulate a mathematical model for immune-mediated interaction between influenza virus and S. pneumoniae in the lungs. We use the model to examine the pathogenic effect of inoculum size and timing of pneumococcal invasion relative to influenza infection, as well as the efficacy of antivirals in preventing severe pneumococcal disease. We find that our model is able to capture the key features of the interaction observed in animal experiments. The model predicts that introduction of pneumococcal bacteria during a 4–6 day window following influenza infection results in invasive pneumonia at significantly lower inoculum size than in hosts not infected with influenza. Furthermore, we find that antiviral treatment administered later than 4 days after influenza infection was not able to prevent invasive pneumococcal disease. This work provides a quantitative framework to study interactions between influenza and pneumococci and has the potential to accurately quantify the interactions. Such quantitative understanding can form a basis for effective clinical care, public health policies and pandemic preparedness.     

On constitutive descriptors of the biaxial mechanical behaviour of human abdominal aorta and aneurysms

The abdominal aorta (AA) in older individuals can develop an aneurysm, which is of increasing concern in our ageing population. The structural integrity of the ageing aortic wall, and hence aneurysm, depends primarily on effective elastin and multiple families of oriented collagen fibres. In this paper, we show that a structurally motivated phenomenological ‘four-fibre family’ constitutive relation captures the biaxial mechanical behaviour of both the human AA, from ages less than 30 to over 60, and abdominal aortic aneurysms. Moreover, combining the statistical technique known as non-parametric bootstrap with a modal clustering method provides improved confidence intervals for estimated best-fit values of the eight associated constitutive parameters. It is suggested that this constitutive relation captures the well-known loss of structural integrity of elastic fibres owing to ageing and the development of abdominal aneurysms, and that it provides important insight needed to construct growth and remodelling models for aneurysms, which in turn promise to improve our ability to predict disease progression.     

Analysis of self-overlap reveals trade-offs in plankton swimming trajectories

Movement is a fundamental behaviour of organisms that not only brings about beneficial encounters with resources and mates, but also at the same time exposes the organism to dangerous encounters with predators. The movement patterns adopted by organisms should reflect a balance between these contrasting processes. This trade-off can be hypothesized as being evident in the behaviour of plankton, which inhabit a dilute three-dimensional environment with few refuges or orienting landmarks. We present an analysis of the swimming path geometries based on a volumetric Monte Carlo sampling approach, which is particularly adept at revealing such trade-offs by measuring the self-overlap of the trajectories. Application of this method to experimentally measured trajectories reveals that swimming patterns in copepods are shaped to efficiently explore volumes at small scales, while achieving a large overlap at larger scales. Regularities in the observed trajectories make the transition between these two regimes always sharper than in randomized trajectories or as predicted by random walk theory. Thus, real trajectories present a stronger separation between exploration for food and exposure to predators. The specific scale and features of this transition depend on species, gender and local environmental conditions, pointing at adaptation to state and stage-dependent evolutionary trade-offs.     

Opposite valence social information provided by bio-robotic demonstrators shapes selection processes in the green bottle fly

Social learning represents a high-level complex process to acquire information about the environment, which is increasingly reported in invertebrates. The animal–robot interaction paradigm turned out to be an encouraging strategy to unveil social learning in vertebrates, but it has not been fully exploited in invertebrates. In this study, Lucilia sericata adults were induced to observe bio-robotic conspecific and predator demonstrators to reproduce different flower foraging choices. Can a fly manage two flows of social information with opposite valence? Herein, we attempt a reply. The selection process of L. sericata was affected by social information provided through different bio-robotic demonstrators, by avoiding coloured discs previously visited by a bio-robotic predator and preferring coloured discs previously visited by a bio-robotic conspecific. When both bio-robotic demonstrators visited the same disc, the latency duration increased and the flies significantly tended to avoid this disc. This indicates the complex risk–benefit evaluation process carried out by L. sericata during the acquisition of such social information. Overall, this article provides a unique perspective on the behavioural ecology of social learning in non-social insects; it also highlights the high potential of the animal–robot interaction approach for unveiling the full spectrum of invertebrates'' abilities in using social information.     

Mechanical regulation of the early stages of angiogenesis

Favouring or thwarting the development of a vascular network is essential in fields as diverse as oncology, cardiovascular disease or tissue engineering. As a result, understanding and controlling angiogenesis has become a major scientific challenge. Mechanical factors play a fundamental role in angiogenesis and can potentially be exploited for optimizing the architecture of the resulting vascular network. Largely focusing on in vitro systems but also supported by some in vivo evidence, the aim of this Highlight Review is dual. First, we describe the current knowledge with particular focus on the effects of fluid and solid mechanical stimuli on the early stages of the angiogenic process, most notably the destabilization of existing vessels and the initiation and elongation of new vessels. Second, we explore inherent difficulties in the field and propose future perspectives on the use of in vitro and physics-based modelling to overcome these difficulties.     

Modelling the emergence of polarity patterns for the intercellular transport of auxin in plants

The hormone auxin is actively transported throughout plants via protein machineries including the dedicated transporter known as PIN. The associated transport is ordered with nearby cells driving auxin flux in similar directions. Here, we provide a model of both the auxin transport and of the dynamics of cellular polarization based on flux sensing. Our main findings are: (i) spontaneous intracellular PIN polarization arises if PIN recycling dynamics are sufficiently nonlinear, (ii) there is no need for an auxin concentration gradient and (iii) ordered multi-cellular patterns of PIN polarization are favoured by molecular noise.     

Modelling the dynamics of viral suppressors of RNA silencing

Virus infection in plants is limited by RNA silencing. In turn, viruses can counter RNA silencing with silencing suppressors. Viral suppressors of RNA silencing have been shown to play a role in symptom development in plants. We here study four different strategies employed by silencing suppressors: small interfering RNA (siRNA) binding, double-strand RNA (dsRNA) binding and degrading or inactivating Argonaute. We study the effect of the suppressors on viral accumulation within the cell as well as its spread on a tissue with mathematical and computational models. We find that suppressors which target Argonaute are very effective in a single cell, but that targeting dsRNA or siRNA is much more effective at the tissue level. Although targeting Argonaute can be beneficial for viral spread, it can also cause hindrance in some cases owing to raised levels of siRNAs that can spread to other cells.     

Alkoxide-based precursors for direct drawing of metal oxide micro- and nanofibres

The invention of electrospinning has solved the problem of producing micro- and nanoscaled metal oxide fibres in bulk quantities. However, until now no methods have been available for preparing a single nanofibre of a metal oxide. In this work, the direct drawing method was successfully applied to produce metal oxide (SnO₂, TiO₂, ZrO₂, HfO₂ and CeO₂) fibres with a high aspect ratio (up to 10 000) and a diameter as small as 200 nm. The sol–gel processing includes consumption of precursors obtained from alkoxides by aqueous or non-aqueous polymerization. Shear thinning of the precursors enables pulling a material into a fibre. This rheological behaviour can be explained by sliding of particles owing to external forces. Transmission (propagation) of light along microscaled fibres and their excellent surface morphology suggest that metal oxide nanofibres can be directly drawn from sol precursors for use in integrated photonic systems.     

Spatial heterogeneity enhances and modulates excitability in a mathematical model of the myometrium

The muscular layer of the uterus (myometrium) undergoes profound changes in global excitability prior to parturition. Here, a mathematical model of the myocyte network is developed to investigate the hypothesis that spatial heterogeneity is essential to the transition from local to global excitation which the myometrium undergoes just prior to birth. Each myometrial smooth muscle cell is represented by an element with FitzHugh–Nagumo dynamics. The cells are coupled through resistors that represent gap junctions. Spatial heterogeneity is introduced by means of stochastic variation in coupling strengths, with parameters derived from physiological data. Numerical simulations indicate that even modest increases in the heterogeneity of the system can amplify the ability of locally applied stimuli to elicit global excitation. Moreover, in networks driven by a pacemaker cell, global oscillations of excitation are impeded in fully connected and strongly coupled networks. The ability of a locally stimulated cell or pacemaker cell to excite the network is shown to be strongly dependent on the local spatial correlation structure of the couplings. In summary, spatial heterogeneity is a key factor in enhancing and modulating global excitability.     

Data-driven modelling of group formation in the fission–fusion dynamics of Bechstein’s bats

Communal roosting in Bechstein’s bat colonies is characterized by the formation of several groups that use different day roosts and that regularly dissolve and re-merge (fission–fusion dynamics). Analysing data from two colonies of different sizes over many years, we find that (i) the number of days that bats stay in the same roost before changing follows an exponential distribution that is independent of the colony size and (ii) the number and size of groups that bats formed for roosting depend on the size of the colony, such that above a critical colony size two to six groups of different sizes are formed. To model these two observations, we propose an agent-based model in which agents make their decisions about roosts based on both random and social influences. For the latter, they copy the roost preference of another agent which models the transfer of the respective information. Our model is able to reproduce both the distribution of stay length in the same roost and the emergence of groups of different sizes dependent on the colony size. Moreover, we are able to predict the critical system size at which the formation of different groups emerges without global coordination. We further comment on dynamics that bridge the roosting decisions on short time scales (less than 1 day) with the social structures observed at long time scales (more than 1 year).     

A novel in vivo method for quantifying the interfacial biochemical bond strength of bone implants

Quantifying the in vivo interfacial biochemical bond strength of bone implants is a biological challenge. We have developed a new and novel in vivo method to identify an interfacial biochemical bond in bone implants and to measure its bonding strength. This method, named biochemical bond measurement (BBM), involves a combination of the implant devices to measure true interfacial bond strength and surface property controls, and thus enables the contributions of mechanical interlocking and biochemical bonding to be distinguished from the measured strength values. We applied the BBM method to a rabbit model, and observed great differences in bone integration between the oxygen (control group) and magnesium (test group) plasma immersion ion-implanted titanium implants (0.046 versus 0.086 MPa, n=10, p=0.005). The biochemical bond in the test implants resulted in superior interfacial behaviour of the implants to bone: (i) close contact to approximately 2 μm thin amorphous interfacial tissue, (ii) pronounced mineralization of the interfacial tissue, (iii) rapid bone healing in contact, and (iv) strong integration to bone. The BBM method can be applied to in vivo experimental models not only to validate the presence of a biochemical bond at the bone–implant interface but also to measure the relative quantity of biochemical bond strength. The present study may provide new avenues for better understanding the role of a biochemical bond involved in the integration of bone implants.     

Design and implementation of an adaptive fuzzy sliding mode controller for drug delivery in treatment of vascular cancer tumours and its optimisation using genetic algorithm tool

In this paper, the side effects of drug therapy in the process of cancer treatment are reduced by designing two optimal non‐linear controllers. The related gains of the designed controllers are optimised using genetic algorithm and simultaneously are adapted by employing the Fuzzy scheduling method. The cancer dynamic model is extracted with five differential equations, including normal cells, endothelial cells, cancer cells, and the amount of two chemotherapy and anti‐angiogenic drugs left in the body as the engaged state variables, while double drug injection is considered as the corresponding controlling signals of the mentioned state space. This treatment aims to reduce the tumour cells by providing a timely schedule for drug dosage. In chemotherapy, not only the cancer cells are killed but also other healthy cells will be destroyed, so the rate of drug injection is highly significant. It is shown that the simultaneous application of chemotherapy and anti‐angiogenic therapy is more efficient than single chemotherapy. Two different non‐linear controllers are employed and their performances are compared. Simulation results and comparison studies show that not only adding the anti‐angiogenic reduce the side effects of chemotherapy but also the proposed robust controller of sliding mode provides a faster and stronger treatment in the presence of patient parametric uncertainties in an optimal way. As a result of the proposed closed‐loop drug treatment, the tumour cells rapidly decrease to zero, while the normal cells remain healthy simultaneously. Also, the injection rate of the chemotherapy drug is very low after a short time and converges to zero.     

Sol–Gel Electrophoretic Deposition for the Growth of Oxide Nanorods

By combining sol–gel processing with electrophoretic deposition, we have developed a new method for the growth of oxide nanorods. Both single metal oxides (TiO₂, SiO₂) and complex oxides—BaTiO₃, Sr₂Nb₂O₇, and Pb(Zr_0.52Ti_0.48)O₃—have been grown by this method. Uniformly sized nanorods 45–200 nm in diameter and 10 μm in length can be grown over large areas with near unidirectional alignment. The nanorods have the desired stoichiometric chemical composition and crystal structure, after firing to 500–700 °C for up to one hour.     

A computational approach for predicting the hydroelasticity of flexible structures based on the pressure Poisson equation

This work is concerned with the modeling of the interaction of fluid flow with flexible solid structures. The flow under consideration is governed by the Navier–Stokes equations for incompressible viscous fluids and modeled with low‐order velocity–pressure finite elements. The motion of the fluid domain is accounted for by the arbitrary Lagrangian–Eulerian formulation. The structure is represented by means of an appropriate standard finite element formulation. The spring smooth analogy is used to mesh control. The time integrating algorithm is based on the predictor–multi‐corrector algorithm. An important aspect of the present work is the introduction of a new monolithic approach based on the fluid pressure Poisson equation (PPE) to solve the hydroelasticity problem of an incompressible viscous fluid with an elastic body that is vibrating due to flow excitation. The PPE is derived to be consistent with the coupled system equation for the fluid–structure interaction (FSI). Based on this approach, an efficient monolithic method is adopted to simulate hydroelasticity between the flexible structure and the flow. The fluid pressure is implicitly derived to satisfy the incompressibility constraint, and the other unknown variables are explicitly derived. The coefficient matrix of the PPE for the FSI becomes symmetric and positive definite. To demonstrate the performance of the proposed approach, two working examples, a beam immersed in incompressible fluid and a guide vane of a Francis turbine passage, were used. The results show the validity of the proposed approach. Copyright © 2007 John Wiley & Sons, Ltd.     

Is there the potential for an epidemic of variant Creutzfeldt–Jakob disease via blood transfusion in the UK?

The discovery of three individuals suspected to have contracted variant Creutzfeldt-Jakob disease (vCJD) through blood transfusions has heightened concerns that a secondary epidemic via human-to-human transmission could occur in the UK. The Department of Health responded immediately to this threat by banning those who had received blood transfusions since 1980 from donating blood. In this paper, we conduct a sensitivity analysis to explore the potential size of a blood-borne vCJD epidemic and investigate the effectiveness of public health interventions. A mathematical model was developed together with an expression for the basic reproduction number (R0). The sensitivity of model predictions to unknown parameters determining the transmission of vCJD via infected blood was assessed under pessimistic modelling assumptions. We found that the size of the epidemic (up until 2080) was bounded above by 900 cases, with self-sustaining epidemics (R0>1) also possible; but the scenarios under which such epidemics could arise were found to be biologically implausible. Under optimistic assumptions, public health interventions reduced the upper bound to 250 and further still when only biologically plausible scenarios were considered. Our results support the belief that scenarios leading to large or self-sustaining epidemics are possible but unlikely, and that public health interventions were effective.