Local modulation of chemoattractant concentrations by single cells: dissection using a bulk-surface computational model

Chemoattractant gradients are usually considered in terms of sources and sinks that are independent of the chemotactic cell. However, recent interest has focused on ‘self-generated’ gradients, in which cell populations create their own local gradients as they move. Here, we consider the interplay between chemoattractants and single cells. To achieve this, we extend a recently developed computational model to incorporate breakdown of extracellular attractants by membrane-bound enzymes. Model equations are parametrized, using the published estimates from Dictyostelium cells chemotaxing towards cyclic AMP. We find that individual cells can substantially modulate their local attractant field under physiologically appropriate conditions of attractant and enzymes. This means the attractant concentration perceived by receptors can be a small fraction of the ambient concentration. This allows efficient chemotaxis in chemoattractant concentrations that would be saturating without local breakdown. Similar interactions in which cells locally mould a stimulus could function in many types of directed cell motility, including haptotaxis, durotaxis and even electrotaxis

A computational method for the coupled solution of reaction–diffusion equations on evolving domains and manifolds: application to a model of cell migration and chemotaxis

In this paper, we devise a moving mesh finite element method for the approximate solution of coupled bulk–surface reaction–diffusion equations on an evolving two dimensional domain. Fundamental to the success of the method is the robust generation of bulk and surface meshes. For this purpose, we use a novel moving mesh partial differential equation (MMPDE) approach. The developed method is applied to model problems with known analytical solutions; these experiments indicate second-order spatial and temporal accuracy. Coupled bulk–surface problems occur frequently in many areas; in particular, in the modelling of eukaryotic cell migration and chemotaxis. We apply the method to a model of the two-way interaction of a migrating cell in a chemotactic field, where the bulk region corresponds to the extracellular region and the surface to the cell membrane

Point-Valued Mappings of Sets

Let X be a metric space and let CB(X) denote the closed bounded subsets of X with the Hausdorff metric. Given a complete subspace Y of CB(X), two fixed point theorems, analogues of results in [1], are proved, and examples are given to suggest their applicability in practice

Modelling cell movement and chemotaxis pseudopod based feedback

A computational framework is presented for the simulation of eukaryotic cell migration and chemotaxis. An empirical pattern formation model, based on a system of non-linear reaction-diffusion equations, is approximated on an evolving cell boundary using an Arbitrary Lagrangian Eulerian surface finite element method (ALE-SFEM). The solution state is used to drive a mechanical model of the protrusive and retractive forces exerted on the cell boundary. Movement of the cell is achieved using a level set method. Results are presented for cell migration with and without chemotaxis. The simulated behaviour is compared with experimental results of migrating Dictyostelium discoideum cells

The Dictyostelium genome: the private life of a social model revealed?

The complete genome sequence of Dictyostelium, a widely studied social amoeba, reveals unexpected complexities in genome structure, and cell motility and signaling, most notably the presence of a large number of G-protein-coupled receptors not previously found outside animals and the absence of receptor tyrosine kinases

Inference of the drivers of collective movement in two cell types: Dictyostelium and melanoma

Collective cell movement is a key component of many important biological processes, including wound healing, the immune response and the spread of cancers. To understand and influence these movements, we need to be able to identify and quantify the contribution of their different underlying mechanisms. Here, we define a set of six candidate models—formulated as advection–diffusion–reaction partial differential equations—that incorporate a range of cell movement drivers. We fitted these models to movement assay data from two different cell types: Dictyostelium discoideum and human melanoma. Model comparison using widely applicable information criterion suggested that movement in both of our study systems was driven primarily by a self-generated gradient in the concentration of a depletable chemical in the cells' environment. For melanoma, there was also evidence that overcrowding influenced movement. These applications of model inference to determine the most likely drivers of cell movement indicate that such statistical techniques have potential to support targeted experimental work in increasing our understanding of collective cell movement in a range of systems

Assessment of chronic postsurgical pain after knee replacement : a systematic review

Objective: Approximately 20% of patients experience chronic pain after total knee replacement (TKR), yet there is no consensus about how best to assess such pain. This systematic review aimed to identify measures used to characterise chronic pain after TKR. Methods: MEDLINE, Embase, PsycINFO, Cochrane Library and CINAHL databases were searched for research articles published in all languages from January 2002- November 2011. Articles were eligible for inclusion if they assessed knee pain at a minimum of 3-months after TKR, yielding a total of 1,164 articles. Data extracted included study design, country, timings of assessments, and outcome measures containing pain items. Outcome measures were compared with domains recommended by IMMPACT for inclusion in assessment of chronic pain related outcomes within clinical trials. Temporal trends were also explored. Results: The review found use of a wide variety of composite and single-item measures, with the American Knee Society Score most common. Many measures used in published studies do not capture the multi-dimensional nature of pain recommended by IMMPACT; of those commonly used, the WOMAC and Oxford Knee Score are most comprehensive. Geographical trends were evident, with nation-specific preferences for particular measures. A recent reduction in use of some clinically-administered tools was accompanied by increased use of patient-reported outcome measures. Conclusion: There was wide variation in methods of pain assessment alongside nation-specific preferences and changing temporal trends in pain assessment after TKR. Standardisation and improvements in assessment is needed to enhance the quality of research and facilitate the establishment of a core outcome set

Absolute Differentiation in Metric Spaces

In this article, we introduce a new notion of (strong) absolute derivative, for functions derived between metric spaces, and we investigate various properties and uses of this concept, especially regarding the geometry of abstract metric spaces carrying no other structure

Parasexual genetics of Dictyostelium gene disruptions: identification of a ras pathway using diploids

BACKGROUND: The relative ease of targeted gene disruption in the social amoeba Dictyostelium has stimulated its widespread use as an experimental organism for cell and developmental biology. However, the field has been hamstrung by the lack of techniques to recombine disrupted genes. RESULTS: We describe new techniques for parasexual fusion of strains in liquid medium, selection and maintenance of the resulting stable diploid strains, and segregation to make recombined haploids. We have used these techniques to isolate rasS/gefB double nulls. The phenotypes of these mutants are no more severe than either parent, with movement, phagocytosis and fluid-phase endocytosis affected to the same degree as in rasS or gefB single nulls. In addition, we have produced diploids from one AX2- and one AX3-derived parent, providing an axenic strain with fewer secondary phenotypes than has been previously available. CONCLUSIONS: The phenotype of the rasS/gefB double mutant suggests that the RasS and GefB proteins lie on the same linear pathway. In addition, axenic diploids and the techniques to generate, maintain and segregate them will be productive tools for future work on Dictyostelium. They will particularly facilitate generation of multiple mutants and manuipulation of essential genes

Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour

The five-subunit WASH complex generates actin networks that participate in endocytic trafficking, migration and invasion in various cell types. Loss of one of the two subunits WASH or strumpellin in mice is lethal, but little is known about their role in mammals in vivo. We explored the role of strumpellin, which has previously been linked to hereditary spastic paraplegia, in the mouse melanocytic lineage. Strumpellin knockout in melanocytes revealed abnormal endocytic vesicle morphology but no impairment of migration in vitro or in vivo and no change in coat colour. Unexpectedly, WASH and filamentous actin could still localize to vesicles in the absence of strumpellin, although the shape and size of vesicles was altered. Blue native PAGE revealed the presence of two distinct WASH complexes, even in strumpellin knockout cells, revealing that the WASH complex can assemble and localize to endocytic compartments in cells in the absence of strumpellin