Multi-scale modelling of the dynamics of cell colonies:insights into cell-adhesion forces and cancer invasion from in silico simulations

Studying the biophysical interactions between cells is crucial to understanding how normal tissue develops, how it is structured and also when malfunctions occur. Traditional experiments try to infer events at the tissue level after observing the behaviour of and interactions between individual cells. This approach assumes that cells behave in the same biophysical manner in isolated experiments as they do within colonies and tissues. In this paper, we develop a multi-scale multi-compartment mathematical model that accounts for the principal biophysical interactions and adhesion pathways not only at a cell-cell level but also at the level of cell colonies (in contrast to the traditional approach). Our results suggest that adhesion/separation forces between cells may be lower in cell colonies than traditional isolated single-cell experiments infer. As a consequence, isolated single-cell experiments may be insufficient to deduce important biological processes such as single-cell invasion after detachment from a solid tumour. The simulations further show that kinetic rates and cell biophysical characteristics such as pressure-related cell-cycle arrest have a major influence on cell colony patterns and can allow for the development of protrusive cellular structures as seen in invasive cancer cell lines independent of expression levels of pro-invasion molecules.Publisher PDFPeer reviewe

Computational modelling and simulation of cancer growth and migration within a 3D heterogeneous tissue: The effects of fibre and vascular structure

The term cancer covers a multitude of bodily diseases, broadly categorised by having cells which do not behave normally. Since cancer cells can arise from any type of cell in the body, cancers can grow in or around any tissue or organ making the disease highly complex. Our research is focused on understanding the specific mechanisms that occur in the tumour microenvironment via mathematical and computational modeling. We present a 3D individual-based model which allows one to simulate the behaviour of, and spatio-temporal interactions between, cells, extracellular matrix fibres and blood vessels. Each agent (a single cell, for example) is fully realised within the model and interactions are primarily governed by mechanical forces between elements. However, as well as the mechanical interactions we also consider chemical interactions, for example, by coupling the code to a finite element solver to model the diffusion of oxygen from blood vessels to cells. The current state of the art of the model allows us to simulate tumour growth around an arbitrary blood-vessel network or along the striations of fibrous tissue

Computational Modeling of Single-Cell Migration::The Leading Role of Extracellular Matrix Fibers

Cell migration is vitally important in a wide variety of biological contexts ranging from embryonic development and wound healing to malignant diseases such as cancer. It is a very complex process that is controlled by intracellular signaling pathways as well as the cell's microenvironment. Due to its importance and complexity, it has been studied for many years in the biomedical sciences, and in the last 30 years it also received an increasing amount of interest from theoretical scientists and mathematical modelers. Here we propose a force-based, individual-based modeling framework that links single-cell migration with matrix fibers and cell-matrix interactions through contact guidance and matrix remodelling. With this approach, we can highlight the effect of the cell's environment on its migration. We investigate the influence of matrix stiffness, matrix architecture, and cell speed on migration using quantitative measures that allow us to compare the results to experiments

A comparison between vertical winds in the lower thermosphere and magnetic field perturbations on the ground

Vertical winds in the lower thermosphere are estimated from OI557.7-nm Doppler shifts obtained with a Fabry-Perot interferometer at the Poker Flat Research Range (65.12N, 147.43W in geographic coordinate), Alaska. The temporal variation of vertical winds was compared with the horizontal component of the magnetic field obtained at Poker Flat and two other sites, Gakona (62.12N, 145.14W) and Fort Yukon (66.36N, 145.22W). Two nights of observations were examined and the results were shown here. The results showed that temporal variations of vertical winds were similar to that of magnetic field variation during each substorm. In some cases the results of cross correlation between these two parameters showed that the magnetic field perturbation leads vertical winds in the earlier period of the substorm. The difference increased gradually and reached a maximum at around the center of the recovery phase. From there, the differences decreased. The mechanism for the relation between the two parameters is still unclear, but this result suggests an intimate relation between ionospheric currents and vertical wind in the thermosphere

Rapid fabrication and screening of tailored functional 3D biomaterials: Validation in bone tissue repair – Part II

Regenerative medicine strategies place increasingly sophisticated demands on 3D biomaterials to promote tissue formation at sites where tissue would otherwise not form. Ideally, the discovery/fabrication of the 3D scaffolds needs to be high-throughput and uniform to ensure quick and in-depth analysis in order to pinpoint appropriate chemical and mechanical properties of a biomaterial. Herein we present a versatile technique to screen new potential biocompatible acrylate-based 3D scaffolds with the ultimate aim of application in tissue repair. As part of this process, we identified an acrylate-based 3D porous scaffold that promoted cell proliferation followed by accelerated tissue formation, pre-requisites for tissue repair. Scaffolds were fabricated by a facile freeze-casting and an in-situ photo-polymerization route, embracing a high-throughput synthesis, screening and characterization protocol. The current studies demonstrate the dependence of cellular growth and vascularization on the porosity and intrinsic chemical nature of the scaffolds, with tuneable 3D scaffolds generated with large, interconnected pores suitable for cellular growth applied to skeletal reparation. Our studies showed increased cell proliferation, collagen and ALP expression, while chorioallantoic membrane assays indicated biocompatibility and demonstrated the angiogenic nature of the scaffolds. VEGRF2 expression in vivo observed throughout the 3D scaffolds in the absence of growth factor supplementation demonstrates a potential for angiogenesis. This novel platform provides an innovative approach to 3D scanning of synthetic biomaterials for tissue regeneration

Dark Matter implications of the Fermi-LAT measurement of anisotropies in the diffuse gamma-ray background: status report

For the first time, the Fermi-LAT measured the angular power spectrum (APS) of anisotropies in the diffuse gamma-ray background. The data is found to be broadly compatible with a model with contributions from the point sources in the 1-year catalog, the galactic diffuse background, and the extragalactic isotropic emission; however deviations are present at both large and small angular scales. In this study, we complement the model with a contribution from Dark Matter (DM) whose distribution is modeled exploiting the results of the most recent N-body simulations, considering the contribution of extragalactic halos and subhalos (from Millennium-II) and of galactic substructures (from Aquarius). With the use of the Fermi Science Tools, these simulations serve as templates to produce mock gamma-ray count maps for DM gamma-ray emission, both in the case of an annihilating and a decaying DM candidate. The APS will then be computed and compared with the Fermi-LAT results to derive constraints on the DM particle physics properties. The possible systematic due to an imperfect model of the galactic foreground is also studied and taken into account properly. The present paper reports on the status of the project.Comment: Proceeding for the RICAP2011 conferenc

Seasonal dependence of northern high‐latitude upper thermospheric winds: A quiet time climatological study based on ground‐based and space‐based measurements

This paper investigates the large‐scale seasonal dependence of geomagnetically quiet time, northern high‐latitude F region thermospheric winds by combining extensive observations from eight ground‐based (optical remote sensing) and three space‐based (optical remote sensing and in situ) instruments. To provide a comprehensive picture of the wind morphology, data are assimilated into a seasonal empirical vector wind model as a function of season, latitude, and local time in magnetic coordinates. The model accurately represents the behavior of the constituent data sets. There is good general agreement among the various data sets, but there are some major offsets between GOCE and the other data sets, especially on the duskside. The assimilated wind patterns exhibit a strong and large duskside anticyclonic circulation cell, sharp latitudinal gradients in the duskside auroral zone, strong antisunward winds in the polar cap, and a weaker tendency toward a dawnside cyclonic circulation cell. The high‐latitude wind system shows a progressive intensification of wind patterns from winter to equinox to summer. The latitudinal extent of the duskside circulation cell does not depend strongly on season. Zonal winds show a mainly diurnal variation (two extrema) around polar and middle latitudes and semidiurnal variation (four extrema) at auroral latitudes; meridional winds are primarily diurnal at all high latitudes. The strength of zonal winds channeling through the auroral zone on the duskside is strongest in the summer season. The vorticity of the wind pattern increases from winter to summer, whereas divergence is maximum in equinox. In all three seasons, divergence is weaker than vorticity.Key PointsFirst ever investigation of the large‐scale seasonal dependence of northern high‐latitude upper thermospheric winds in magnetic coordinatesResults show progressive intensification of wind circulation from winter to equinox to summerThe vorticity increases from winter to summer. In all the seasons, the strongest divergences occur primarily in and above auroral latitudesPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136373/1/jgra53329.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136373/2/jgra53329_am.pd

Controlled delivery of gold nanoparticle-coupled miRNA therapeutics via an injectable self-healing hydrogel

Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in vitro in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel in vitro demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears via the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs in vitro and has potential for in vivo applications.publishersversionpublishe