A study on the VEGFR2-ligand multi-physics interactions in Angiogenesis.

Tumorgrowthissustainedbyangiogenesis,i.e. theformationofnewbloodvesselsfrompre-existing ones. Angiogenesis is modulated by the interaction between tyrosine kinase receptors (TKRs), expressed by endothelial cells (ECs), and extracellular ligands, produced by tumor cells. This interaction triggers the activation of intracellular signaling cascades and kinetic processes, including cell deformationandadhesion,whicheventuallycausecelldivisionandproliferation. VascularEndothelial Growth Factor Receptor-2 (VEGFR2) is a pro-angiogenic receptor expressed on ECs. Ligand stimulation induces the polarization of ECs and the relocation of VEGFR2 in cell protrusion or in the basal aspect in cells plated on ligand enriched extracellular matrix (ECM) [1]. EC response to angiogenic growth factors is regulated by distinct sets of inputs conveyed by TRKs and different co-receptors including integrins, membrane proteins that are responsible of stress fibers formation and cell contractility [2]. Although biochemical pathways following VEGFR2 activation are well established, knowledge about the receptor dynamics on the plasma membrane remains limited. A multi-physics model has been developed [3] to describe: i) the diffusion of VEGFR2 on the cellularmembrane;ii)thechemicalkineticsoftheligand-receptorbindingreaction;iii)themechanical adhesion and spreading of the cell onto a ligand-rich extracellular substrate, in finite strain. The identification of the multi-physics interactions that regulate receptor polarization could open new perspectives to develop innovative anti-angiogenic strategies through the modulation of EC activation

Multi-physics interactions drive VEGFR2 relocation on endothelial cells.

Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is a pro-angiogenic receptor, expressed on endothelial cells (ECs). Although biochemical pathways that follow the VEGFR2 activation are well established, knowledge about the dynamics of receptors on the plasma membrane remains limited. Ligand stimulation induces the polarization of ECs and the relocation of VEGFR2, either in cell protrusions or in the basal aspect in cells plated on ligand-enriched extracellular matrix (ECM). We develop a mathematical model in order to simulate the relocation of VEGFR2 on the cell membrane during the mechanical adhesion of cells onto a ligand-enriched substrate. Co-designing the in vitro experiments with the simulations allows identifying three phases of the receptor dynamics, which are controlled respectively by the high chemical reaction rate, by the mechanical deformation rate, and by the diffusion of free receptors on the membrane. The identification of the laws that regulate receptor polarization opens new perspectives toward developing innovative anti-angiogenic strategies through the modulation of EC activatio

Nonreciprocal oscillations of polyelectrolyte gel filaments subject to a steady and uniform electric field

Soft actuators typically require time-varying or spatially modulated control to be operationally effective. The scope of the present paper is to show, theoretically and experimentally, that a natural way to overcome this limitation is to exploit mechanical instabilities. We report experiments on active filaments of polyelectrolyte (PE) gels subject to a steady and uniform electric field. A large enough intensity of the field initiates the motion of the active filaments, leading to periodic oscillations. We develop a mathematical model based on morphoelasticity theory for PE gel filaments beating in a viscous fluid, and carry out the stability analysis of the governing equations to show the emergence of flutter and divergence instabilities for suitable values of the system’s parameters. We confirm the results of the stability analysis with numerical simulations for the nonlinear equations of motion to show that such instabilities may lead to periodic self-sustained oscillations, in agreement with experiments. The key mechanism that underlies such behaviour is the capability of the filament to undergo active shape changes depending on its local orientation relative to the external electric field, in striking similarity with gravitropism, the mechanism that drives shape changes in plants via differential growth induced by gravity. Interestingly, the resulting oscillations are nonreciprocal in nature, and hence able to generate thrust and directed flow at low Reynolds number. The exploitation of mechanical instabilities in soft actuators represents a new avenue for the advancement in engineering design in fields such as micro-robotics and micro-fluidics

Transient shape morphing of active gel plates: geometry and physics

The control of shape in active structures is a key problem for the realization of smart sensors and actuators, which often draw inspiration from natural systems. In this context, slender structures, such as thin plates, have been studied as a relevant example of shape morphing systems where curvature is generated by in-plane incompatibilities. In particular, in hydrogel plates these incompatibilities can be programmed at fabrication time, such that a target configuration is attained at equilibrium upon swelling or shrinking. While these aspects have been examined in detail, understanding the transient morphing of such active structures deserves further investigation. In this study, we develop a geometrical model for the transient shaping of thin hydrogel plates by extending the theory of non-Euclidean plates. We validate the proposed model using experiments on gel samples that are programmed to reach axisymmetric equilibrium shapes. Interestingly, our experiments show the emergence of non-axisymmetric shapes for early times, as a consequence of boundary layer effects induced by solvent transport. We rationalize these observations using numerical simulations based on a detailed poroelastic model. Overall, this work highlights the limitations of purely geometrical models and the importance of transient, reduced theories for morphing plates that account for the coupled physics driving the evolution of shape. Computational approaches employing these theories will allow to achieve accurate control on the morphing dynamics and ultimately advance 4D printing technologies

JRC Statistical Audit of the 2019 Global Attractiveness Index

Attractiveness is a crucial factor in the global scramble for prosperity as it implies a nation’s ability to ‘charm’ talented people, investments and know-how – a prerequisite for competitiveness. Attractiveness has become even more important with globalisation as it has eased the movement of capitals and the inclusion of new areas of the world in the international circuits of consumption and production. In this context, it has become all the more relevant to have comparable information available to benchmark national performance across the world with a view to support the identification of areas of intervention for public policies as a means to improve a country’s attractiveness power. In line with this view, the European House - Ambrosetti has developed an international monitoring framework – the Global Attractiveness Index (GAI) – that measures a country’s attractiveness as determining element of its ability to be competitive and grow. The GAI builds on four attributes of attractiveness: Openness, Innovation, Efficiency, and Endowment. These pillars are used to organise and aggregate 21 Key Performance Indicators (KPIs) into a single summary measure for 144 countries that altogether cover approximately 93% of the world’s population and 99% of Gross Domestic Product (in US$) worldwide. This framework inevitably entails both conceptual and practical challenges. The statistical audit discussed in this note was conducted by the European Commission’s Joint Research Centre, and it aims at maximising the reliability and transparency of the Global Attractiveness Index. It should enable policy analysts and researchers alike to draw more relevant, meaningful and useful conclusions on good practices and challenges that countries face in today’s competitive game to business and job creation.JRC.I.1-Monitoring, Indicators & Impact Evaluatio

Simulation of VEGF receptor recruitment on ECs membrane

Angiogenesis, the new blood vessel formation from a pre-existing one, is an essential process of cancer growth. Many proteins play major roles in this phenomenon and we focus to the interactions among receptors, in particular Vascular Endothelial Growth Factors Receptor 2 (VEGFR-2), and their canonical and non canonical ligands, as Vascular Endothelial Growth Factors (VEGF) and Gremlin,ontheendothelialcell(EC)membrane. LigandbindingtoVEGFR-2isassociatedwiththe receptordimerizationandactivation,whichtriggersadownstreamsignalingpathwaysleadingtoEC proliferation. The complex VEGFR-2/ligand interacts with others transmembrane receptors, which includes αvβ3 integrins [1], responsible of cell contractility, and co-receptors, as neuropilin (NRP). Mathematical models and computer simulations, accounting for the many findings that have been provided by biologists, are able to predict conditions for angiogenesis and to identify new strategies in drug delivery. Co-designedexperimentsandsimulationsforVEGFR-2relocalizationdrivenbyVEGForGremlin has been recently proposed by the authors [2]. The model is based on continuity equations (for mass, energy and entropy), standard chemical kinetics, thermodynamics restrictions, and constitutive specifications. The governing equations in a weak form, are approximated by Finite Element andBackwardEulerMethodsandimplementedinain-housecomputercode. Numericalsimulations have been validated against experimental data