Bacterial fitness shapes the population dynamics of antibiotic-resistant and -susceptible bacteria in a model of combined antibiotic and anti-virulence treatment

Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body's natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population would be unlikely to emerge. However, much controversy surrounds this approach with many believing it would not be powerful enough to clear existing infections, restricting its potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention.Comment: Pre-review manuscript. Submitted to Journal of Theoretical Biology, July 21st 201

A continuum mechanics model of the plant cell wall reveals interplay between enzyme action and cell wall structure

Plant cell growth is regulated through manipulation of the cell wall network, which consists of oriented cellulose microfibrils embedded within a ground matrix incorporating pectin and hemicellulose components. There remain many unknowns as to how this manipulation occurs. Experiments have shown that cellulose reorients in cell walls as the cell expands, while recent data suggest that growth is controlled by distinct collections of hemicellulose called biomechanical hotspots, which join the cellulose molecule together. The enzymes expansin and Cel12A have both been shown to induce growth of the cell wall; however, while Cel12A’s wall-loosening action leads to a reduction in the cell wall strength, expansin’s has been shown to increase the strength of the cell wall. In contrast, members of the XTH enzyme family hydrolyse hemicellulose but do not appear to cause wall creep. This experimentally observed behaviour still awaits a full explanation. We derive and analyse a mathematical model for the effective mechanical properties of the evolving cell wall network, incorporating cellulose microfibrils, which reorient with cell growth and are linked via biomechanical hotspots made up of regions of crosslinking hemicellulose. Assuming a visco-elastic response for the cell wall and using a continuum approach, we calculate the total stress resultant of the cell wall for a given overall growth rate. By changing appropriate parameters affecting breakage rate and viscous properties, we provide evidence for the biomechanical hotspot hypothesis and develop mechanistic understanding of the growth-inducing enzymes. </p

Linear Taylor–Couette stability of a transversely isotropic fluid

Fibre-laden fluids are found in a variety of situations, while Couette devices are used for flow spectroscopy of long biological molecules, such as DNA and proteins in suspension. The presence of these fibres can significantly alter the rheology of the fluid, and hence must be incorporated in any modelling undertaken. A transversely isotropic fluid treats these suspensions as a continuum with an evolving preferred direction, through a modified stress tensor incorporating four viscosity-like parameters. We consider the axisymmetric linear stability of a transversely isotropic viscous fluid, contained between two rotating co-axial cylinders, and determine the critical wave and Taylor numbers for varying gap width and inner cylinder velocity (assuming the outer cylinder is fixed). Through the inclusion of transversely isotropic effects, the onset of instability is delayed, increasing the range of stable operating regimes. This effect is felt most strongly through incorporation of the anisotropic shear viscosity, although the anisotropic extensional viscosity also contributes. The changes to the rheology induced by the presence of the fibres therefore significantly alter the dynamics of the system, and hence should not be neglected

Repair rather than segregation of damage is the optimal unicellular aging strategy

BACKGROUND: How aging, being unfavourable for the individual, can evolve is one of the fundamental problems of biology. Evidence for aging in unicellular organisms is far from conclusive. Some studies found aging even in symmetrically dividing unicellular species; others did not find aging in the same, or in different, unicellular species, or only under stress. Mathematical models suggested that segregation of non-genetic damage, as an aging strategy, would increase fitness. However, these models failed to consider repair as an alternative strategy or did not properly account for the benefits of repair. We used a new and improved individual-based model to examine rigorously the effect of a range of aging strategies on fitness in various environments. RESULTS: Repair of damage emerges as the best strategy despite its fitness costs, since it immediately increases growth rate. There is an optimal investment in repair that outperforms damage segregation in well-mixed, lasting and benign environments over a wide range of parameter values. Damage segregation becomes beneficial, and only in combination with repair, when three factors are combined: (i) the rate of damage accumulation is high, (ii) damage is toxic and (iii) efficiency of repair is low. In contrast to previous models, our model predicts that unicellular organisms should have active mechanisms to repair damage rather than age by segregating damage. Indeed, as predicted, all organisms have evolved active mechanisms of repair whilst aging in unicellular organisms is absent or minimal under benign conditions, apart from microorganisms with a different ecology, inhabiting short-lived environments strongly favouring early reproduction rather than longevity. CONCLUSIONS: Aging confers no fitness advantage for unicellular organisms in lasting environments under benign conditions, since repair of non-genetic damage is better than damage segregation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-014-0052-x) contains supplementary material, which is available to authorized users

Mathematical modelling of fibre-enhanced perfusion inside\ud a tissue-engineering bioreactor

We develop a simple mathematical model for forced flow of culture medium through a porous scaffold in a tissue- engineering bioreactor. Porous-walled hollow fibres penetrate the scaffold and act as additional sources of culture medium. The model, based on Darcy’s law, is used to examine the nutrient and shear-stress distributions throughout the scaffold. We consider several configurations of fibres and inlet and outlet pipes. Compared with a numerical solution of the full Navier–Stokes equations within the complex scaffold geometry, the modelling approach is cheap, and does not require knowledge of the detailed microstructure of the particular scaffold being used. The potential of this approach is demonstrated through quantification of the effect the additional flow from the fibres has on the nutrient and shear-stress distribution

Cellular entry of nanoparticles via serum sensitive clathrin-mediated endocytosis, and plasma membrane permeabilization

Increasing production and application of nanomaterials raises significant questions regarding the potential for cellular entry and toxicity of nanoparticles. It was observed that the presence of serum reduces the cellular association of 20 nm carboxylate-modified fluorescent polystyrene beads up to 20-fold, relative to cells incubated in serum-free media. Analysis by confocal microscopy demonstrated that the presence of serum greatly reduces the cell surface association of nanoparticles, as well as the potential for internalization. However, both in the presence and absence of serum, nanoparticle entry depends upon clathrin-mediated endocytosis. Finally, experiments performed with cells cooled to 4°C suggest that a proportion of the accumulation of nanoparticles in cells was likely due to direct permeabilization of the plasma membrane