Inferring the flow properties of epithelial tissues from their geometry

Amorphous materials exhibit complex material properties with strongly nonlinear behaviors. Below a yield stress they behave as plastic solids, while they start to yield above a critical stress sigma(c). A key quantity controlling plasticity which is, however, hard to measure is the density P(x) of weak spots, where x is the additional stress required for local plastic failure. In the thermodynamic limit P(x) similar to x(theta) is singular at x = 0 in the solid phase below the yield stress sigma(c). This singularity is related to the presence of system spanning avalanches of plastic events. Here we address the question if the density of weak spots and the flow properties of a material can be determined from the geometry of an amorphous structure alone. We show that a vertex model for cell packings in tissues exhibits the phenomenology of plastic amorphous systems. As the yield stress is approached from above, the strain rate vanishes and the avalanches size S and their duration tau diverge. We then show that in general, in materials where the energy functional depends on topology, the value x is proportional to the length L of a bond that vanishes in a plastic event. For this class of models P(x) is therefore readily measurable from geometry alone. Applying this approach to a quantification of the cell packing geometry in the developing wing epithelium of the fruit fly, we find that in this tissue P(L) exhibits a power law with exponents similar to those found numerically for a vertex model in its solid phase. This suggests that this tissue exhibits plasticity and non-linear material properties that emerge from collective cell behaviors and that these material properties govern developmental processes. Our approach based on the relation between topology and energetics suggests a new route to outstanding questions associated with the yielding transition

Attenuation of oxytocin and serotonin 2A receptor signaling through novel heteroreceptor formation

The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2Ain vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases

Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex

The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated G alpha q-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality.This article is part of the special issue on Neuropeptides

Modélisation bidimensionnelle dynamique du transistor à effet de champ MESFET : application à la conception de profils optimisés pour fonctionnement en faible bruit

Un modèle de simulation numérique de transistor à effet de champ basé sur une résolution bidimensionnelle des équations des semiconducteurs est présenté. Il inclut les effets de dynamique non stationnaire et permet l'étude du comportement des composants tant en régime statique que dynamique (petit et grand signal, impulsionnel). Il est montré comment on peut accéder aux paramètres caractéristiques du régime petit signal, grâce à l'utilisation d'une transformation de Fourier rapide. Ce modèle est utilisé pour étudier l'influence du profil de dopage sur les éléments caractéristiques du comportement des composants et sur leurs performances potentielles. Il permet de mettre en évidence l'intérêt des composants à canal enterré tant pour l'amplification de puissance que pour l'amplification faible bruit, ce qui est clairement confirmé par les premiers résultats de l'étude expérimentale

Modélisation bidimensionnelle dynamique du transistor à effet de champ MESFET : application à la conception de profils optimisés pour fonctionnement en faible bruit

A GaAs MESFET model, based on the two dimensional resolution of the semiconductor hydrodynamic equations, is presented. It includes a carrier energy relaxation equation, allowing to account for non stationary electron dynamic effects. It is shown that it is possible to obtain an accurate determination of the main equivalent circuit elements by using transient response and fast Fourier transform. This model is systematically used to study the influence of doping profile on device characteristics and the expected performances. The potential interest of burried channel devices is clearly shown under large signal and low noise conditions respectively. These conclusions are confirmed by experiment.Un modèle de simulation numérique de transistor à effet de champ basé sur une résolution bidimensionnelle des équations des semiconducteurs est présenté. Il inclut les effets de dynamique non stationnaire et permet l'étude du comportement des composants tant en régime statique que dynamique (petit et grand signal, impulsionnel). Il est montré comment on peut accéder aux paramètres caractéristiques du régime petit signal, grâce à l'utilisation d'une transformation de Fourier rapide. Ce modèle est utilisé pour étudier l'influence du profil de dopage sur les éléments caractéristiques du comportement des composants et sur leurs performances potentielles. Il permet de mettre en évidence l'intérêt des composants à canal enterré tant pour l'amplification de puissance que pour l'amplification faible bruit, ce qui est clairement confirmé par les premiers résultats de l'étude expérimentale

Cell-Cell Fusion Induced by Measles Virus Amplifies the Type I Interferon Response▿ †

Measles virus (MeV) infection is characterized by the formation of multinuclear giant cells (MGC). We report that beta interferon (IFN-β) production is amplified in vitro by the formation of virus-induced MGC derived from human epithelial cells or mature conventional dendritic cells. Both fusion and IFN-β response amplification were inhibited in a dose-dependent way by a fusion-inhibitory peptide after MeV infection of epithelial cells. This effect was observed at both low and high multiplicities of infection. While in the absence of virus replication, the cell-cell fusion mediated by MeV H/F glycoproteins did not activate any IFN-α/β production, an amplified IFN-β response was observed when H/F-induced MGC were infected with a nonfusogenic recombinant chimerical virus. Time lapse microscopy studies revealed that MeV-infected MGC from epithelial cells have a highly dynamic behavior and an unexpected long life span. Following cell-cell fusion, both of the RIG-I and IFN-β gene deficiencies were trans complemented to induce IFN-β production. Production of IFN-β and IFN-α was also observed in MeV-infected immature dendritic cells (iDC) and mature dendritic cells (mDC). In contrast to iDC, MeV infection of mDC induced MGC, which produced enhanced amounts of IFN-α/β. The amplification of IFN-β production was associated with a sustained nuclear localization of IFN regulatory factor 3 (IRF-3) in MeV-induced MGC derived from both epithelial cells and mDC, while the IRF-7 up-regulation was poorly sensitive to the fusion process. Therefore, MeV-induced cell-cell fusion amplifies IFN-α/β production in infected cells, and this indicates that MGC contribute to the antiviral immune response