MODELLING THE INFLUENCE OF NUCLEUS ELASTICITY ON CELL INVASION IN FIBER NETWORKS AND MICROCHANNELS

Cell migration in highly constrained extracellular matrices is exploited in scaffold-based tissue engineering and is fundamental in a wide variety of physiological and pathological phenomena, among others in cancer invasion and development. Research into the critical processes involved in cell migration has mainly focused on cell adhesion and proteolytic degradation of the external environment. However, rising evidence has recently shown that a number of cell-derived biophysical and mechanical parameters, among others nucleus stiffness and cell deformability, plays a major role in cell motility, especially in the ameboid-like migration mode in 3D confined tissue structures. We here present an extended cellular Potts model (CPM) first used to simulate a micro-fabricated migration chip, which tests the active invasive behavior of cancer cells into narrow channels. As distinct features of our approach, cells are modeled as compartmentalized discrete objects, differentiated in the nucleus and in the cytosolic region, while the migration chamber is composed of channels of different widths. We find that cell motile phenotype and velocity in open spaces (i.e., 2D flat surfaces or large channels) are not significantly influenced by cell elastic properties. On the contrary, the migratory behavior of cells within subcellular and subnuclear structures strongly relies on the deformability of the cytosol and of the nuclear cluster, respectively. Further, we characterize two migration dynamics: a stepwise way, characterized by fluctuations in cell length, within channels smaller than nucleus dimensions and a smooth sliding (i.e., maintaining constant cell length) behavior within channels larger than the nuclear cluster. These resulting observations are then extended looking at cell migration in an artificial fiber network, which mimics cell invasion in a 3D extracellular matrix. In particular, in this case, we analyze the effect of variations in elasticity of the nucleus on cell movement. In order to summarize, with our simulated migration assays, we demonstrate that the dimensionality of the environment strongly affects the migration phenotype and we suggest that the cytoskeletal and nuclear elastic characteristics correlate with the tumor cell's invasive potentia

A Review of Mathematical Models for the Formation of\ud Vascular Networks

Mainly two mechanisms are involved in the formation of blood vasculature: vasculogenesis and angiogenesis. The former consists of the formation of a capillary-like network from either a dispersed or a monolayered population of endothelial cells, reproducible also in vitro by specific experimental assays. The latter consists of the sprouting of new vessels from an existing capillary or post-capillary venule. Similar phenomena are also involved in the formation of the lymphatic system through a process generally called lymphangiogenesis.\ud \ud A number of mathematical approaches have analysed these phenomena. This paper reviews the different modelling procedures, with a special emphasis on their ability to reproduce the biological system and to predict measured quantities which describe the overall processes. A comparison between the different methods is also made, highlighting their specific features

Differentiated cell behavior: a multiscale approach using measure theory

This paper deals with the derivation of a collective model of cell populations out of an individual-based description of the underlying physical particle system. By looking at the spatial distribution of cells in terms of time-evolving measures, rather than at individual cell paths, we obtain an ensemble representation stemming from the phenomenological behavior of the single component cells. In particular, as a key advantage of our approach, the scale of representation of the system, i.e., microscopic/discrete vs. macroscopic/continuous, can be chosen a posteriori according only to the spatial structure given to the aforesaid measures. The paper focuses in particular on the use of different scales based on the specific functions performed by cells. A two-population hybrid system is considered, where cells with a specialized/differentiated phenotype are treated as a discrete population of point masses while unspecialized/undifferentiated cell aggregates are represented with a continuous approximation. Numerical simulations and analytical investigations emphasize the role of some biologically relevant parameters in determining the specific evolution of such a hybrid cell system.Comment: 25 pages, 6 figure

The AddACO: A bio-inspired modified version of the ant colony optimization algorithm to solve travel salesman problems

The Travel Salesman Problem (TSP) consists in finding the minimal-length closed tour that connects the entire group of nodes of a given graph. We propose to solve such a combinatorial optimization problem with the AddACO algorithm: it is a version of the Ant Colony Optimization method that is characterized by a modified probabilistic law at the basis of the exploratory movement of the artificial insects. In particular, the ant decisional rule is here set to amount in a linear convex combination of competing behavioral stimuli and has therefore an additive form (hence the name of our algorithm), rather than the canonical multiplicative one. The AddACO intends to address two conceptual shortcomings that characterize classical ACO methods: (i) the population of artificial insects is in principle allowed to simultaneously minimize/maximize all migratory guidance cues (which is in implausible from a biological/ecological point of view) and (ii) a given edge of the graph has a null probability to be explored if at least one of the movement trait is therein equal to zero, i.e., regardless the intensity of the others (this in principle reduces the exploratory potential of the ant colony). Three possible variants of our method are then specified: the AddACO-V1, which includes pheromone trail and visibility as insect decisional variables, and the AddACO-V2 and the AddACO-V3, which in turn add random effects and inertia, respectively, to the two classical migratory stimuli. The three versions of our algorithm are tested on benchmark middle-scale TPS instances, in order to assess their performance and to find their optimal parameter setting. The best performing variant is finally applied to large-scale TSPs, compared to the naive Ant-Cycle Ant System, proposed by Dorigo and colleagues, and evaluated in terms of quality of the solutions, computational time, and convergence speed. The aim is in fact to show that the proposed transition probability, as long as its conceptual advantages, is competitive from a performance perspective, i.e., if it does not reduce the exploratory capacity of the ant population w.r.t. the canonical one (at least in the case of selected TSPs). A theoretical study of the asymptotic behavior of the AddACO is given in the appendix of the work, whose conclusive section contains some hints for further improvements of our algorithm, also in the perspective of its application to other optimization problems

Multiscale developments of cellular Potts models

Multiscale problems are ubiquitous and fundamental in all biological phenomena that emerge naturally from the complex interaction of processes which occur at various levels. A number of both discrete and continuous mathematical models and methods have been developed to address such an intricate network of organization. One of the most suitable individual cell-based model for this purpose is the well-known cellular Potts model (CPM). The CPM is a discrete, lattice-based, flexible technique that is able to accurately identify and describe the phenomenological mechanisms which are responsible for innumerable biological (and nonbiological) phenomena. In this work, we first give a brief overview of its biophysical basis and discuss its main limitations. We then propose some innovative extensions, focusing on ways of integrating the basic mesoscopic CPM with accurate continuous models of microscopic dynamics of individuals. The aim is to create a multiscale hybrid framework that is able to deal with the typical multilevel organization of biological development, where the behavior of the simulated individuals is realistically driven by their internal state. Our CPM extensions are then tested with sample applications that show a qualitative and quantitative agreement with experimental data. Finally, we conclude by discussing further possible developments of the metho

Arab-norman heritage: state of knowledge and new actions and innovative proposal

This paper wants to offers a perlustrative recognition on the 'state of the studies', concerning to the Arab-Norman architecture of Palermo, admissed by Unesco in 2015 and explain a research in progress which, starting from re-cognition of the peculiarities of the restoration work carried out on it, consisting of the identification of authentic material-constructive values and / or reconstruction, it orients itself to develop a concrete proposal of filing for a more conscious knowledge. She, moreover, want\u2019s contribute to real enhancement through the use of targeted communication strategies that use innovative means capable, on one hand, to attracting the greatest possible number of users, on the other hand, to plan further interventions of conservation coherent with the previous data. The product that you want to achieve is that of a Bank-data that allows the "networking" of monumental emergencies, that become the virtual itineraries waypoint, which can be implemented periodically and whose boards meet the cataloging needs and documentation but with reference at georeferiti-systems, compatibles with the conservation and management of heritage and with need of usability, real and virtual

A node-based version of the cellular Potts model

The cellular Potts model (CPM) is a lattice-based Monte Carlo method that uses an energetic formalism to describe the phenomenological mechanisms underlying the biophysical problem of interest. We here propose a CPM-derived framework that relies on a node-based representation of cell-scale elements. This feature has relevant consequences on the overall simulation environment. First, our model can be implemented on any given domain, provided a proper discretization (which can be regular or irregular, fixed or time evolving). Then, it allowed an explicit representation of cell membranes, whose displacements realistically result in cell movement. Finally, our node-based approach can be easily interfaced with continuous mechanics or fluid dynamics models. The proposed computational environment is here applied to some simple biological phenomena, such as cell sorting and chemotactic migration, also in order to achieve an analysis of the performance of the underlying algorithm. This work is finally equipped with a critical comparison between the advantages and disadvantages of our model with respect to the traditional CPM and to some similar vertex-based approaches

A Cellular Potts Model for Analyzing Cell Migration across Constraining Pillar Arrays

Cell migration in highly constrained environments is fundamental in a wide variety of physiological and pathological phenomena. In particular, it has been experimentally shown that the migratory capacity of most cell lines depends on their ability to transmigrate through narrow constrictions, which in turn relies on their deformation capacity. In this respect, the nucleus, which occupies a large fraction of the cell volume and is substantially stiffer than the surrounding cytoplasm, imposes a major obstacle. This aspect has also been investigated with the use of microfluidic devices formed by dozens of arrays of aligned polymeric pillars that limit the available space for cell movement. Such experimental systems, in particular, in the designs developed by the groups of Denais and of Davidson, were here reproduced with a tailored version of the Cellular Potts model, a grid-based stochastic approach where cell dynamics are established by a Metropolis algorithm for energy minimization. The proposed model allowed quantitatively analyzing selected cell migratory determinants (e.g., the cell and nuclear speed and deformation, and forces acting at the nuclear membrane) in the case of different experimental setups. Most of the numerical results show a remarkable agreement with the corresponding empirical data