A note on how to develop interdisciplinary collaborations between experimentalists and theoreticians

This special issue is inspired by and based on the six-month research programme held at the Isaac Newton Institute (INI) for Mathematical Sciences, Cambridge, UK between 13 July and 18 December 2015 entitled ‘Coupling geometric partial differential equations with physics for cell morphology, motility and pattern formation’. The research programme was the first of its kind to bring together at the INI world-leading theoreticians, experimentalists, biomedical practitioners and statisticians. This diverse and large group came together to share paired goals: understanding how current mathematical techniques, including mathematical modelling and numerical and statistical analysis, can be used to formulate and analyse topical problems in cell motility and pattern formation, and conversely, how diverse experimental results can be translated into predictive mathematical and computational models across several spatio-temporal scales. Recent advances in cell motility and pattern formation, including high-resolution imaging techniques in three dimensions, necessitate new mathematical and computational theories to help guide, suggest, refine and sharpen further experimental hypotheses. The research programme laid down premises for topical research that mandated coupling molecular, cellular, tissue and fluid dynamics in a multi-scale interdisciplinary environment thereby enabling the generation of new scientific knowledge across several disciplines. The six-month research programme included three workshops and an Open for Business event at the INI, a satellite meeting at the University of Sussex, and a unique hands-on experimental workshop in Germany on cell migration and advanced microscopy, hosted jointly by RWTH Aachen University and Forschungszentrum Jülich. Hence, with the goal of breaking barriers between these disciplines, the programme was tailored in a way that best harnessed expertise and knowledge between experimental and theoretical sciences

Mechanical control of spheroid growth: Distinct morphogenetic regimes

We develop a model of transport and growth in epithelio-mesenchymal interactions. Analysis of the growth of an avascular solid spheroid inside a passive mesenchyme or gel shows that sustained volumetric growth requires four generic mechanisms: (1) growth factor, (2) protease, (3) control of cellularity, and (4) swelling. The model reveals a bifurcation delineating two distinct morphogenetic regimes: (A) steady growth, (B) growth arrested by capsule formation in the mesenchyme. In both morphogenetic regimes, growth velocity is constant unless and until a complete capsule forms. Comprehensive exploration of the large parameter space reveals that the bifurcation is determined by just two ratios representing the relative strengths of growth and proteolytic activity. Growth velocity is determined only by the ratio governing growth, independent of proteolytic activity. There is a continuum of interior versus surface growth, with fastest growth at the surface. The model provides a theoretical basis for explaining observations of growth arrest despite proteolysis of surrounding tissue, and gives a quantitative framework for the design and interpretation of experiments involving spheroids, and tissues which are locally equivalent to spheroids

Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche

Human livers have maturational lineages of cells within liver acini, beginning periportally in stem cell niches, the canals of Hering, and ending in polyploid hepatocytes pericentrally and cholangiocytes in bile ducts. Hepatic stem cells (hHpSCs) in vivo are partnered with mesenchymal precursors to endothelia (angioblasts) and stellate cells, and reside in regulated microenvironments, stem cell niches, containing hyaluronans (HA). The in vivo hHpSC niche is modeled in vitro by growing hHpSC in two-dimensional (2D) cultures on plastic. We investigated effects of 3D microenvironment, mimicking the liver’s stem cell niche, on these hHpSCs by embedding them in HA-based hydrogels prepared with Kubota’s Medium (KM), a serum-free medium tailored for endodermal stem/progenitors. The KM-HA hydrogels mimicked the niches, matched diffusivity of culture medium, exhibited shear thinning and perfect elasticity under mechanical loading, and had predictable stiffness depending on their chemistry. KM-HA hydrogels, which supported cell attachment, survival and expansion of hHpSC colonies, induced transition of hHpSC colonies towards stable heterogeneous populations of hepatic progenitors depending on KM-HA hydrogel stiffness, as shown by both their gene and protein expression profile. These acquired phenotypes did not show morphological evidence of fibrotic responses. In conclusion, this study shows that the mechanical properties of the microenvironment can regulate differentiation in endodermal stem cell populations

Just What is Sprawl, Anyway?

Urban sprawl is a hot-button issue in the U.S. Though the term is widely used to describe the distaste for contemporary American suburban and urban development, a select few group of researchers, academics and practitioners have led the response to the argument against sprawl. This paper seeks to characterize sprawl from the perspective of landscape architecture while focusing on quantitative measurements and definitions of sprawl. At its core it examines the issue of the evolution of urban form through time, and offers options for addressing the debates over the negative or positive ramifications of sprawl

Does viral load alter behavior of the bee parasite Varroa destructor?

The invasive mite Varroa destructor has negatively impacted global apiculture, by being a vector for many viruses of the honey bee (Apis mellifera). Until now, most studies have been limited to varroa-honey bee or virus-honey bee interactions. The aim of this study is to bridge the important research gap of varroa-virus interactions by correlating varroa behavior with viral load. Ten-minute video recordings of 200 varroa mites were analyzed, and average speeds of the mites were compared to individual qPCR viral loads for deformed wing virus (DWV) and sacbrood virus (SBV). Statistically significant models reveal that colony, DWV, and SBV all might play a role in mite behavior, suggesting that the varroa-virus interaction needs to be an integral part of future studies on honey bee pathogens

Energy-Based Dynamic Model for Variable Temperature Batch Fermentation by Lactococcus lactis

We developed a mechanistic mathematical model for predicting the progression of batch fermentation of cucumber juice by Lactococcus lactis under variable environmental conditions. In order to overcome the deficiencies of presently available models, we use a dynamic energy budget approach to model the dependence of growth on present as well as past environmental conditions. When parameter estimates from independent experimental data are used, our model is able to predict the outcomes of three different temperature shift scenarios. Sensitivity analyses elucidate how temperature affects the metabolism and growth of cells through all four stages of fermentation and reveal that there is a qualitative reversal in the factors limiting growth between low and high temperatures. Our model has an applied use as a predictive tool in batch culture growth. It has the added advantage of being able to suggest plausible and testable mechanistic assumptions about the interplay between cellular energetics and the modes of inhibition by temperature and end product accumulation