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The NMDARs are key players in both physiological and pathologic synaptic plasticity because of their involvement in many aspects of neuronal transmission as well as learning and memory. The contribution in these events of different types of GluN2A-interacting proteins is still unclear. The p140Cap scaffold protein acts as a hub for postsynaptic complexes relevant to psychiatric and neurologic disorders and regulates synaptic functions, such as the stabilization of mature dendritic spine, memory consolidation, LTP, and LTD. Here we demonstrate that p140Cap directly binds the GluN2A subunit of NMDAR and modulates GluN2A-associated molecular network. Indeed, in p140Cap KO male mice, GluN2A is less associated with PSD95 both in ex vivo synaptosomes and in cultured hippocampal neurons, and p140Cap expression in KO neurons can rescue GluN2A and PSD95 colocalization. p140Cap is crucial in the recruitment of GluN2A-containing NMDARs and, consequently, in regulating NMDARs’ intrinsic properties. p140Cap is associated to synaptic lipid-raft (LR) and to soluble postsynaptic membranes, and GluN2A and PSD95 are less recruited into synaptic LR of p140Cap KO male mice. Gated-stimulated emission depletion microscopy on hippocampal neurons confirmed that p140Cap is required for embedding GluN2A clusters in LR in an activity-dependent fashion. In the synaptic compartment, p140Cap influences the association between GluN2A and PSD95 and modulates GluN2A enrichment into LR. Overall, such increase in these membrane domains rich in signaling molecules results in improved signal transduction efficiency.

The growth of a well-formed epithelial structure is governed by mechanical constraints, cellular apico-basal polarity, and spatially controlled cell division. Here we compared the predictions of a mathematical model of epithelial growth with the morphological analysis of 3D epithelial structures. In both in vitro cyst models and in developing epithelial structures in vivo, epithelial growth could take place close to or far from mechanical equilibrium, and was determined by the hierarchy of time-scales of cell division, cell-cell rearrangements, and lumen dynamics. Equilibrium properties could be inferred by the analysis of cell-cell contact topologies, and the nonequilibrium phenotype was altered by inhibiting ROCK activity. The occurrence of an aberrant multilumen phenotype was linked to fast nonequilibrium growth, even when geometric control of cell division was correctly enforced. We predicted and verified experimentally that slowing down cell division partially rescued a multilumen phenotype induced by altered polarity. These results improve our understanding of the development of epithelial organs and, ultimately, of carcinogenesis.

Vascular networks form by a self-aggregation process of individual endothelial cells that differentiate at seemingly random sites in the embryo and collectively migrate toward each other forming a preliminary vascular plexus (vasculogenesis), followed by functional remodelling that gives rise to the final hierarchical system (angiogenesis). The study of this phenomenon is performed by biologists using in vitro and in vivo assays, both in two and three dimensional settings. The lack of direct biological evidence of the chemotactic autocrine loop that is thought to be the main responsible for the early aggregation, called for the development of mathematical models of this process, in order to study the possible effects of such a loop. After successful two-dimensional studies, the model was recently extended to a three dimensional setting and a suitably efficient approximation scheme for the numerical simulations has been developed, while three-dimensional images of embryo vascular networks are becoming available through confocal microscopy. This paper is concerned with the comparison of experimental and simulated data on embryo vascular plexi. Critical exponents of percolation, Euler-Poincaré characteristic, fractal dimension, power spectrum decay and maximum distance from a vessel are considered and compared.

Blood vessel networks form by spontaneous aggregation of individual cells migrating toward vascularization sites (vasculogenesis). A successful theoretical model of two-dimensional experimental vasculogenesis has been recently proposed, showing the relevance of percolation concepts and of cell cross-talk (chemotactic autocrine loop) to the understanding of this self-aggregation process. Here we study the natural 3D extension of the computational model proposed earlier, which is relevant for the investigation of the genuinely three-dimensional process of vasculogenesis in vertebrate embryos. The computational model is based on a multidimensional Burgers equation coupled with a reaction diffusion equation for a chemotactic factor and a mass conservation law. The numerical approximation of the computational model is obtained by high order relaxed schemes. Space and time discretization are performed by using TVD schemes and, respectively, IMEX schemes. Due to the computational costs of realistic simulations, we have implemented the numerical algorithm on a cluster for parallel computation. Starting from initial conditions mimicking the experimentally observed ones, numerical simulations produce network-like structures qualitatively similar to those observed in the early stages of in vivo vasculogenesis. We develop the computation of critical percolative indices as a robust measure of the network geometry as a first step towards the comparison of computational and experimental data.

Many eukaryotic cell types share the ability to migrate directionally in response to external chemoattractant gradients. This ability is central in the development of complex organisms, and is the result of billion years of evolution. Cells exposed to shallow gradients in chemoattractant concentration respond with strongly asymmetric accumulation of several signaling factors, such as phosphoinositides and enzymes. This early symmetry-breaking stage is believed to trigger effector pathways leading to cell movement. Although many factors implied in directional sensing have been recently discovered, the physical mechanism of signal amplification is not yet well understood. We have proposed that directional sensing is the consequence of a phase ordering process mediated by phosphoinositide diffusion and driven by the distribution of chemotactic signal. By studying a realistic computational model that describes enzymatic activity, recruitment to the plasmamembrane, and diffusion of phosphoinositide products we have shown that the effective enzyme-enzyme interaction induced by catalysis and diffusion introduces an instability of the system towards phase separation for realistic values of physical parameters. In this framework, large reversible amplification of shallow chemotactic gradients, selective localization of chemical factors, macroscopic response timescales, and spontaneous polarization arise.

A method for assessing the risk for honeybees from pesticide exposure via pollen is proposed. Four pesticides, selected as markers, were monitored in pollen samples collected in two sampling areas, one located in an intensive agricultural area and the other far from direct pesticide impact. Analytical results were consistent with use patterns of the chemicals and their physico-chemical and persistence properties. For a preliminary estimate of bee exposure via pollen, both by ingestion and by contact, an exposure index was developed, based on physico-chemical properties, persistence and application rates. On the basis of the exposure estimates and acute toxicological data (ingestion and contact LD50), Toxicity Exposure Ratios (TERs) were calculated as indicators of the risk for honeybees due to this particular exposure route. TER values were compared to Hazard Quotient (HQ), calculated as the ratio between application rate and the LC50 value, according to European guidelines, showing a satisfactory agreement. The advantage of the above described procedures is that the environmental fate of the chemicals, and not only application rates, are taken into account. This approach may represent a preliminary tool for a comparative screening of the risk for pollinator insects due to this particular exposure route.