Modeling collagen fibril self-assembly from extracellular medium in embryonic tendon.

Collagen is a key structural component of multicellular organisms and is arranged in a highly organized manner. In structural tissues such as tendons, collagen forms bundles of parallel fibers between cells, which appear within a 24-h window between embryonic day 13.5 (E13.5) and E14.5 during mouse embryonic development. Current models assume that the organized structure of collagen requires direct cellular control, whereby cells actively lay down collagen fibrils from cell surfaces. However, such models appear incompatible with the time and length scales of fibril formation. We propose a phase-transition model to account for the rapid development of ordered fibrils in embryonic tendon, reducing reliance on active cellular processes. We develop phase-field crystal simulations of collagen fibrillogenesis in domains derived from electron micrographs of inter-cellular spaces in embryonic tendon and compare results qualitatively and quantitatively to observed patterns of fibril formation. To test the prediction of this phase-transition model that free protomeric collagen should exist in the inter-cellular spaces before the formation of observable fibrils, we use laser-capture microdissection, coupled with mass spectrometry, which demonstrates steadily increasing free collagen in inter-cellular spaces up to E13.5, followed by a rapid reduction of free collagen that coincides with the appearance of less-soluble collagen fibrils. The model and measurements together provide evidence for extracellular self-assembly of collagen fibrils in embryonic mouse tendon, supporting an additional mechanism for rapid collagen fibril formation during embryonic development.

Ribbon curling via stress relaxation in thin polymer films.

The procedure of curling a ribbon by running it over a sharp blade is commonly used when wrapping presents. Despite its ubiquity, a quantitative explanation of this everyday phenomenon is still lacking. We address this using experiment and theory, examining the dependence of ribbon curvature on blade curvature, the longitudinal load imposed on the ribbon, and the speed of pulling. Experiments in which a ribbon is drawn steadily over a blade under a fixed load show that the ribbon curvature is generated over a restricted range of loads, the curvature/load relationship can be nonmonotonic, and faster pulling (under a constant imposed load) results in less tightly curled ribbons. We develop a theoretical model that captures these features, building on the concept that the ribbon under the imposed deformation undergoes differential plastic stretching across its thickness, resulting in a permanently curved shape. The model identifies factors that optimize curling and clarifies the physical mechanisms underlying the ribbon's nonlinear response to an apparently simple deformation.

Human placental oxygenation in late gestation: experimental and theoretical approaches.

The placenta is crucial for life. It is an ephemeral but complex organ acting as the barrier interface between maternal and fetal circulations, providing exchange of gases, nutrients, hormones, waste products and immunoglobulins. Many gaps exist in our understanding of the detailed placental structure and function, particularly in relation to oxygen handling and transfer in healthy and pathological states in utero. Measurements to understand oxygen transfer in vivo in the human are limited, with no general agreement on the most appropriate methods. An invasive method for measuring partial pressure of oxygen in the intervillous space through needle electrode insertion at the time of Caesarean sections has been reported. This allows for direct measurements in vivo whilst maintaining near normal placental conditions; however, there are practical and ethical implications in using this method for determination of placental oxygenation. Furthermore, oxygen levels are likely to be highly heterogeneous within the placenta. Emerging non-invasive techniques, such as MRI, and ex vivo research are capable of enhancing and improving current imaging methodology for placental villous structure and increase the precision of oxygen measurement within placental compartments. These techniques, in combination with mathematical modelling, have stimulated novel cross-disciplinary approaches that could advance our understanding of placental oxygenation and its metabolism in normal and pathological pregnancies, improving clinical treatment options and ultimately outcomes for the patient.

Osmotic and electroosmotic fluid transport across the retinal pigment epithelium: A mathematical model.

The retinal pigment epithelium (RPE) is the outermost cell layer of the retina. It has several important physiological functions, among which is removal of excess fluid from the sub-retinal space by pumping it isotonically towards the choroid. Failure of this pumping leads to fluid accumulation, which is closely associated with several pathological conditions, such as age-related macular degeneration, macular oedema and retinal detachment. In the present work we study mechanisms responsible for fluid transport across the RPE with the aim of understanding how fluid accumulation can be prevented. We focus on two possible mechanisms, osmosis and electroosmosis, and develop a spatially resolved mathematical model that couples fluid and ion transport across the epithelium, accounting for the presence of Na+,K+ and Cl- ions. Our model predicts spatial variability of ion concentrations and the electrical potential along the cleft gap between two adjacent cells, which osmotically drives the flow across the lateral membranes. This flow is directed from the sub-retinal space to the choroid and has a magnitude close to measured values. Electroosmosis is subdominant by three orders of magnitude to osmosis and has an opposite direction, suggesting that local osmosis is the main driving mechanism for water transport across the RPE.

Three-dimensional plant architecture and sunlit-shaded patterns: a stochastic model of light dynamics in canopies.

Background and Aims: Diurnal changes in solar position and intensity combined with the structural complexity of plant architecture result in highly variable and dynamic light patterns within the plant canopy. This affects productivity through the complex ways that photosynthesis responds to changes in light intensity. Current methods to characterize light dynamics, such as ray-tracing, are able to produce data with excellent spatio-temporal resolution but are computationally intensive and the resulting data are complex and high-dimensional. This necessitates development of more economical models for summarizing the data and for simulating realistic light patterns over the course of a day. Methods: High-resolution reconstructions of field-grown plants are assembled in various configurations to form canopies, and a forward ray-tracing algorithm is applied to the canopies to compute light dynamics at high (1 min) temporal resolution. From the ray-tracer output, the sunlit or shaded state for each patch on the plants is determined, and these data are used to develop a novel stochastic model for the sunlit-shaded patterns. The model is designed to be straightforward to fit to data using maximum likelihood estimation, and fast to simulate from. Key Results: For a wide range of contrasting 3-D canopies, the stochastic model is able to summarize, and replicate in simulations, key features of the light dynamics. When light patterns simulated from the stochastic model are used as input to a model of photoinhibition, the predicted reduction in carbon gain is similar to that from calculations based on the (extremely costly) ray-tracer data. Conclusions: The model provides a way to summarize highly complex data in a small number of parameters, and a cost-effective way to simulate realistic light patterns. Simulations from the model will be particularly useful for feeding into larger-scale photosynthesis models for calculating how light dynamics affects the photosynthetic productivity of canopies.

Curvature-Sensitive Kinesin Binding Can Explain Microtubule Ring Formation and Reveals Chaotic Dynamics in a Mathematical Model.

Microtubules are filamentous tubular protein polymers which are essential for a range of cellular behaviour, and are generally straight over micron length scales. However, in some gliding assays, where microtubules move over a carpet of molecular motors, individual microtubules can also form tight arcs or rings, even in the absence of crosslinking proteins. Understanding this phenomenon may provide important explanations for similar highly curved microtubules which can be found in nerve cells undergoing neurodegeneration. We propose a model for gliding assays where the kinesins moving the microtubules over the surface induce ring formation through differential binding, substantiated by recent findings that a mutant version of the motor protein kinesin applied in solution is able to lock-in microtubule curvature. For certain parameter regimes, our model predicts that both straight and curved microtubules can exist simultaneously as stable steady states, as has been seen experimentally. Additionally, unsteady solutions are found, where a wave of differential binding propagates down the microtubule as it glides across the surface, which can lead to chaotic motion. Whilst this model explains two-dimensional microtubule behaviour in an experimental gliding assay, it has the potential to be adapted to explain pathological curling in nerve cells.

Multiscale models in the biomechanics of plant growth.

Plant growth occurs through the coordinated expansion of tightly adherent cells, driven by regulated softening of cell walls. It is an intrinsically multiscale process, with the integrated properties of multiple cell walls shaping the whole tissue. Multiscale models encode physical relationships to bring new understanding to plant physiology and development.

High-Resolution Three-Dimensional Structural Data Quantify the Impact of Photoinhibition on Long-Term Carbon Gain in Wheat Canopies in the Field.

Photoinhibition reduces photosynthetic productivity; however, it is difficult to quantify accurately in complex canopies partly because of a lack of high-resolution structural data on plant canopy architecture, which determines complex fluctuations of light in space and time. Here, we evaluate the effects of photoinhibition on long-term carbon gain (over 1 d) in three different wheat (Triticum aestivum) lines, which are architecturally diverse. We use a unique method for accurate digital three-dimensional reconstruction of canopies growing in the field. The reconstruction method captures unique architectural differences between lines, such as leaf angle, curvature, and leaf density, thus providing a sensitive method of evaluating the productivity of actual canopy structures that previously were difficult or impossible to obtain. We show that complex data on light distribution can be automatically obtained without conventional manual measurements. We use a mathematical model of photosynthesis parameterized by field data consisting of chlorophyll fluorescence, light response curves of carbon dioxide assimilation, and manual confirmation of canopy architecture and light attenuation. Model simulations show that photoinhibition alone can result in substantial reduction in carbon gain, but this is highly dependent on exact canopy architecture and the diurnal dynamics of photoinhibition. The use of such highly realistic canopy reconstructions also allows us to conclude that even a moderate change in leaf angle in upper layers of the wheat canopy led to a large increase in the number of leaves in a severely light-limited state.

Exploiting heterogeneous environments: does photosynthetic acclimation optimize carbon gain in fluctuating light?

Plants have evolved complex mechanisms to balance the efficient use of absorbed light energy in photosynthesis with the capacity to use that energy in assimilation, so avoiding potential damage from excess light. This is particularly important under natural light, which can vary according to weather, solar movement and canopy movement. Photosynthetic acclimation is the means by which plants alter their leaf composition and structure over time to enhance photosynthetic efficiency and productivity. However there is no empirical or theoretical basis for understanding how leaves track historic light levels to determine acclimation status, or whether they do this accurately. We hypothesized that in fluctuating light (varying in both intensity and frequency), the light-response characteristics of a leaf should adjust (dynamically acclimate) to maximize daily carbon gain. Using a framework of mathematical modelling based on light-response curves, we have analysed carbon-gain dynamics under various light patterns. The objective was to develop new tools to quantify the precision with which photosynthesis acclimates according to the environment in which plants exist and to test this tool on existing data. We found an inverse relationship between the optimal maximum photosynthetic capacity and the frequency of low to high light transitions. Using experimental data from the literature we were able to show that the observed patterns for acclimation were consistent with a strategy towards maximizing daily carbon gain. Refinement of the model will further determine the precision of acclimation.

Multiscale systems analysis of root growth and development: modeling beyond the network and cellular scales.

Over recent decades, we have gained detailed knowledge of many processes involved in root growth and development. However, with this knowledge come increasing complexity and an increasing need for mechanistic modeling to understand how those individual processes interact. One major challenge is in relating genotypes to phenotypes, requiring us to move beyond the network and cellular scales, to use multiscale modeling to predict emergent dynamics at the tissue and organ levels. In this review, we highlight recent developments in multiscale modeling, illustrating how these are generating new mechanistic insights into the regulation of root growth and development. We consider how these models are motivating new biological data analysis and explore directions for future research. This modeling progress will be crucial as we move from a qualitative to an increasingly quantitative understanding of root biology, generating predictive tools that accelerate the development of improved crop varieties.

Growth-induced hormone dilution can explain the dynamics of plant root cell elongation.

In the elongation zone of the Arabidopsis thaliana plant root, cells undergo rapid elongation, increasing their length by ∼10-fold over 5 h while maintaining a constant radius. Although progress is being made in understanding how this growth is regulated, little consideration has been given as to how cell elongation affects the distribution of the key regulating hormones. Using a multiscale mathematical model and measurements of growth dynamics, we investigate the distribution of the hormone gibberellin in the root elongation zone. The model quantifies how rapid cell expansion causes gibberellin to dilute, creating a significant gradient in gibberellin levels. By incorporating the gibberellin signaling network, we simulate how gibberellin dilution affects the downstream components, including the growth-repressing DELLA proteins. We predict a gradient in DELLA that provides an explanation of the reduction in growth exhibited as cells move toward the end of the elongation zone. These results are validated at the molecular level by comparing predicted mRNA levels with transcriptomic data. To explore the dynamics further, we simulate perturbed systems in which gibberellin levels are reduced, considering both genetically modified and chemically treated roots. By modeling these cases, we predict how these perturbations affect gibberellin and DELLA levels and thereby provide insight into their altered growth dynamics.

Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PTM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain-stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that PTM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean PTM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and PTM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the PTM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis.

Mechanical modelling quantifies the functional importance of outer tissue layers during root elongation and bending.

Root elongation and bending require the coordinated expansion of multiple cells of different types. These processes are regulated by the action of hormones that can target distinct cell layers. We use a mathematical model to characterise the influence of the biomechanical properties of individual cell walls on the properties of the whole tissue. Taking a simple constitutive model at the cell scale which characterises cell walls via yield and extensibility parameters, we derive the analogous tissue-level model to describe elongation and bending. To accurately parameterise the model, we take detailed measurements of cell turgor, cell geometries and wall thicknesses. The model demonstrates how cell properties and shapes contribute to tissue-level extensibility and yield. Exploiting the highly organised structure of the elongation zone (EZ) of the Arabidopsis root, we quantify the contributions of different cell layers, using the measured parameters. We show how distributions of material and geometric properties across the root cross-section contribute to the generation of curvature, and relate the angle of a gravitropic bend to the magnitude and duration of asymmetric wall softening. We quantify the geometric factors which lead to the predominant contribution of the outer cell files in driving root elongation and bending.

Conservative versus interventional management for primary spontaneous pneumothorax in adults.

BACKGROUND: Primary spontaneous pneumothorax is widely managed according to size with interventional techniques based on practice guidelines. Interventional management is not without complications and observational data suggest conservative management works. The current guidelines are based on expert consensus rather than evidence, and a systematic review may help in identifying evidence for this practice. OBJECTIVES: The objective of the review is to compare conservative and interventional treatments of adult primary spontaneous pneumothorax for outcomes of clinical efficacy, tolerability and safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 6, 2014); MEDLINE via Ovid SP (1920 to 26th June 2014); EMBASE via Ovid SP (1947 to 26th June 2014); CINAHL via EBSCO host (1980 to 26th June 2014); and ISI Web of Science (1945 to 26th June 2014). We searched ongoing trials via the relevant databases and contacted authors. We also searched the 'grey literature'. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and we accepted quasi-RCTs if a systematic method of allocation was used. Participants were limited to adults aged 18 to 50 years, with their first symptomatic primary spontaneous pneumothorax with radiological evidence and no underlying lung disease. DATA COLLECTION AND ANALYSIS: Two of five authors independently reviewed all studies in the search criteria and made inclusions and exclusions according to the selection criteria. No statistical methods were necessary as there were no included trials. MAIN RESULTS: We identified 358 studies with duplicates removed. There were three potentially relevant studies that we excluded as they were not randomized controlled trials. There was one ongoing trial that was relevant and we contacted the authors and confirmed the study is ongoing at June 2014. We will update this review when this ongoing study is completed. AUTHORS' CONCLUSIONS: There are no completed randomized controlled trials comparing conservative and interventional management for primary spontaneous pneumothorax in adults. There is a lack of high-quality evidence for current guidelines in management and a need for randomized controlled trials comparing conservative and interventional management for this condition.

On the role of stress anisotropy in the growth of stems.

We review the role of anisotropic stress in controlling the growth anisotropy of stems. Instead of stress, growth anisotropy is usually considered in terms of compliance. Anisotropic compliance is typical of cell walls, because they contain aligned cellulose microfibrils, and it appears to be sufficient to explain the growth anisotropy of an isolated cell. Nevertheless, a role for anisotropic stress in the growth of stems is indicated by certain growth responses that appear too rapid to be accounted for by changes in cell-wall compliance and because the outer epidermal wall of most growing stems has microfibrils aligned axially, an arrangement that would favour radial expansion based on cell-wall compliance alone. Efforts to quantify stress anisotropy in the stem have found that it is predominantly axial, and large enough in principle to explain the elongation of the epidermis, despite its axial microfibrils. That the epidermis experiences a stress deriving from the inner tissue, the so-called 'tissue stress', has been widely recognized; however, the origin of the dominant axial direction remains obscure. Based on geometry, an isolated cylindrical cell should have an intramural stress anisotropy favouring the transverse direction. Explanations for tissue stress have invoked differential elastic moduli, differential plastic deformation (so-called differential growth), and a phenomenon analogous to the maturation stress generated by secondary cell walls. None of these explanations has been validated. We suggest that understanding the role of stress anisotropy in plant growth requires a deeper understanding of the nature of stress in hierarchical, organic structures.

Couple stresses and discrete potentials in the vertex model of cellular monolayers.

The vertex model is widely used to simulate the mechanical properties of confluent epithelia and other multicellular tissues. This inherently discrete framework allows a Cauchy stress to be attributed to each cell, and its symmetric component has been widely reported, at least for planar monolayers. Here, we consider the stress attributed to the neighbourhood of each tricellular junction, evaluating in particular its leading-order antisymmetric component and the associated couple stresses, which characterise the degree to which individual cells experience (and resist) in-plane bending deformations. We develop discrete potential theory for localised monolayers having disordered internal structure and use this to derive the analogues of Airy and Mindlin stress functions. These scalar potentials typically have broad-banded spectra, highlighting the contributions of small-scale defects and boundary layers to global stress patterns. An affine approximation attributes couple stresses to pressure differences between cells sharing a trijunction, but simulations indicate an additional role for non-affine deformations.

Investigation of Performance Parameters of Spherical Gold Nanoparticles in Localized Surface Plasmon Resonance Biosensing.

In this paper, we present numerical and experimental results on Localized Surface Plasmon Resonance (LSPR) refractive index (RI) sensitivity, Figure of Merit (FoM), and penetration depth (dp) dependence on spherical gold nanoparticles (AuNPs) size, and the effects of AuNP dimer interparticle distance (ds) studied numerically. These parameters were calculated and observed for d = 20, 40, 60, 80, and 100 nm diameter spherical AuNPs. Our investigation shows d = 60 nm AuNPs give the best FoM. The AuNP dimer interparticle distance can significantly influence the RI sensitivity. Therefore, the effect of distances between pairs of d = 20 nm and 60 nm AuNPs is shown. We discuss the importance of penetration depth information for AuNPs functionalized with aptamers for biosensing in the context of aptamer size.

Surfactant amplifies yield-stress effects in the capillary instability of a film coating a tube.

To assess how the presence of surfactant in lung airways alters the flow of mucus that leads to plug formation and airway closure, we investigate the effect of insoluble surfactant on the instability of a viscoplastic liquid coating the interior of a cylindrical tube. Evolution equations for the layer thickness using thin-film and long-wave approximations are derived that incorporate yield-stress effects and capillary and Marangoni forces. Using numerical simulations and asymptotic analysis of the thin-film system, we quantify how the presence of surfactant slows growth of the Rayleigh-Plateau instability, increases the size of initial perturbation required to trigger instability and decreases the final peak height of the layer. When the surfactant strength is large, the thin-film dynamics coincide with the dynamics of a surfactant-free layer but with time slowed by a factor of four and the capillary Bingham number, a parameter proportional to the yield stress, exactly doubled. By solving the long-wave equations numerically, we quantify how increasing surfactant strength can increase the critical layer thickness for plug formation to occur and delay plugging. The previously established effect of the yield stress in suppressing plug formation [Shemilt et al., J. Fluid Mech., 2022, vol. 944, A22] is shown to be amplified by introducing surfactant. We discuss the implications of these results for understanding the impact of surfactant deficiency and increased mucus yield stress in obstructive lung diseases.

Advection-dominated transport past isolated disordered sinks: stepping beyond homogenization.

We investigate the transport of a solute past isolated sinks in a bounded domain when advection is dominant over diffusion, evaluating the effectiveness of homogenization approximations when sinks are distributed uniformly randomly in space. Corrections to such approximations can be non-local, non-smooth and non-Gaussian, depending on the physical parameters (a Péclet number Pe, assumed large, and a Damköhler number Da) and the compactness of the sinks. In one spatial dimension, solute distributions develop a staircase structure for large Pe , with corrections being better described with credible intervals than with traditional moments. In two and three dimensions, solute distributions are near-singular at each sink (and regularized by sink size), but their moments can be smooth as a result of ensemble averaging over variable sink locations. We approximate corrections to a homogenization approximation using a moment-expansion method, replacing the Green's function by its free-space form, and test predictions against simulation. We show how, in two or three dimensions, the leading-order impact of disorder can be captured in a homogenization approximation for the ensemble mean concentration through a modification to Da that grows with diminishing sink size.