Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism.     

Why People Drink Shampoo? Food Imitating Products Are Fooling Brains and Endangering Consumers for Marketing Purposes

A Food Imitating Product (FIP) is a household cleaner or a personal care product that exhibits food attributes in order to enrich consumption experience. As revealed by many cases worldwide, such a marketing strategy led to unintentional self-poisonings and deaths. FIPs therefore constitute a very serious health and public policy issue. To understand why FIPs are a threat, we first conducted a qualitative analysis on real-life cases of household cleaners and personal care products-related phone calls at a poison control center followed by a behavioral experiment. Unintentional self-poisoning in the home following the accidental ingestion of a hygiene product by a healthy adult is very likely to result from these products being packaged like foodstuffs. Our hypothesis is that FIPs are non-verbal food metaphors that could fool the brain of consumers. We therefore conducted a subsequent functional neuroimaging (fMRI) experiment that revealed how visual processing of FIPs leads to cortical taste inferences. Considered in the grounded cognition perspective, the results of our studies reveal that healthy adults can unintentionally categorize a personal care product as something edible when a food-like package is employed to market nonedible and/or dangerous products. Our methodology combining field (qualitative) and laboratory (behavioral and functional neuroimaging) findings could be of particular relevance for policy makers, as it can help screening products prior to their market release – e.g. the way they are packaged and how they can potentially confuse the mind of consumers – and therefore save lives.     

A Neuro-Mechanical Model for Interpersonal Coordination

The present study investigates the coordination between two people oscillating handheld pendulums, with a special emphasis on the influence of the mechanical properties of the effector systems involved. The first part of the study is an experiment in which eight pairs of participants are asked to coordinate the oscillation of their pendulum with the other participant’s in an in-phase or antiphase fashion. Two types of pendulums, A and B, having different resonance frequencies (Freq A=0.98 Hz and Freq B=0.64 Hz), were used in different experimental combinations. Results confirm that the preferred frequencies produced by participants while manipulating each pendulum individually were close to the resonance frequencies of the pendulums. In their attempt to synchronize with one another, participants met at common frequencies that were influenced by the mechanical properties of the two pendulums involved. In agreement with previous studies, both the variability of the behavior and the shift in the intended relative phase were found to depend on the task-effector asymmetry, i.e., the difference between the mechanical properties of the effector systems involved. In the second part of the study, we propose a model to account for these results. The model consists of two cross-coupled neuro-mechanical units, each composed of a neural oscillator driving a wrist-pendulum system. Taken individually, each unit reproduced the natural tendency of the participants to freely oscillate a pendulum close to its resonance frequency. When cross-coupled through the vision of the pendulum of the other unit, the two units entrain each other and meet at a common frequency influenced by the mechanical properties of the two pendulums involved. The ability of the proposed model to address the other effects observed as a function of the different conditions of the pendulum and intended mode of coordination is discussed.     

Embodied economics: how bodily information shapes the social coordination dynamics of decision-making

To date, experiments in economics are restricted to situations in which individuals are not influenced by the physical presence of other people. In such contexts, interactions remain at an abstract level, agents guessing what another person is thinking or is about to decide based on money exchange. Physical presence and bodily signals are therefore left out of the picture. However, in real life, social interactions (involving economic decisions or not) are not solely determined by a person''s inference about someone else''s state-of-mind. In this essay, we argue for embodied economics: an approach to neuroeconomics that takes into account how information provided by the entire body and its coordination dynamics influences the way we make economic decisions. Considering the role of embodiment in economics—movements, posture, sensitivity to mimicry and every kind of information the body conveys—makes sense. This is what we claim in this essay which, to some extent, constitutes a plea to consider bodily interactions between agents in social (neuro)economics.     

Food behaviour and obesity: insights from decision neuroscience

Neuroimaging allows to estimate brain activity when individuals are doing something. The location and intensity of this estimated activity provides information on the dynamics and processes that guide choice behaviour and associated actions that should be considered a complement to behavioural studies. Decision neuroscience therefore sheds new light on whether the brain evaluates and compares alternatives when decisions are made, or if other processes are at stake. This work helped to demonstrate that the situations faced by individuals (risky, uncertain, delayed in time) do not all have the same (behavioural) complexity, and are not underlined by activity in the cerebral networks. Taking into account brain dynamics of people (suffering from obesity or not) when making food consumption decisions might allow for improved strategies in public health prevention, far from the rational choice theory promoted by neoclassical economics.     

Neuroimaging coordination dynamics in the sport sciences

Key methodological issues for designing, analyzing, and interpreting neuroimaging experiments are presented from the perspective of the framework of Coordination Dynamics. To this end, a brief overview of Coordination Dynamics is introduced, including the main concepts of control parameters and collective variables, theoretical modeling, novel experimental paradigms, and cardinal empirical findings. Basic conceptual and methodological issues for the design and implementation of coordination experiments in the context of neuroimaging are discussed. The paper concludes with a presentation of neuroimaging findings central to understanding the neural basis of coordination and addresses their relevance for the sport sciences. The latter include but are not restricted to learning and practice-related issues, the role of mental imagery, and the recovery of function following brain injury.     

Improved Functionality of the Vasculature during Conventionally Fractionated Radiation Therapy of Prostate Cancer

Although endothelial cell apoptosis participates in the tumor shrinkage after single high-dose radiotherapy, little is known regarding the vascular response after conventionally fractionated radiation therapy. Therefore, we evaluated hypoxia, perfusion and vascular microenvironment changes in an orthotopic prostate cancer model of conventionally fractionated radiation therapy at clinically relevant doses (2 Gy fractions, 5 fractions/week). First, conventionally fractionated radiation therapy decreased tumor cell proliferation and increased cell death with kinetics comparable to human prostate cancer radiotherapy. Secondly, the injection of Hoechst 33342 or fluorescent-dextrans showed an increased tumor perfusion within 14 days in irradiated tumors, which was correlated with a clear reduction of hypoxia. Improved perfusion and decreased hypoxia were not explained by increased blood vessel density, size or network morphology. However, a tumor vascular maturation defined by perivascular desmin+/SMA+ cells coverage was clearly observed along with an increase in endothelial, zonula occludens (ZO)-1 positive, intercellular junctions. Our results show that, in addition to tumor cell killing, vascular maturation plays an uncovered role in tumor reoxygenation during fractionated radiation therapy.     

Coordination dynamics: (in)stability and metastability in the behavioural and neural systems

For more than 20 years, coordination dynamics have provided research on human movement science with new views about the nonlinear relationships between behavioral and neural dynamics. A number of studies across various experimental settings including bimanual, postural or interpersonal coordination, and also coordination between movements of a limb and an external event in the environment revealed the self-organized nature of human coordination. Here we review an extensive body of literature - in the human movement science and the neuroscience fields - that has investigated the coordination dynamics of brain and behavior when individuals are involved in two rhythmic coordination patterns: synchronization (on-the-beat movements) and syncopation (in-between beats movements). When the frequency of movement approaches 2 Hz, the syncopation mode is destabilized and synchronization is spontaneously adopted. The abrupt change between the two patterns illustrates a phenomenon known as non-equilibrium phase transition. Phase transitions offer a novel entry point into the investigation of pattern formation (and dissolution) at both the behavioral and the cerebral levels as they illustrate the loss of stability of the system. Brain imaging methods (MEG, EEG and fMRI) were used to reveal the neural signatures of (in)stability underlying the differences between behavioral coordination patterns, and pointed at the role of self-organization and metastability principles in brain functioning. Relationships between behavioral and brain dynamics can therefore be investigated within a unified empirical and theoretical framework.     

The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons

Highly organized circuits of enteric neurons are required for the regulation of gastrointestinal functions, such as peristaltism or migrating motor complex. However, the factors and molecular mechanisms that regulate the connectivity of enteric neurons and their assembly into functional neuronal networks are largely unknown. A better understanding of the mechanisms by which neurotrophic factors regulate this enteric neuron circuitry is paramount to understanding enteric nervous system (ENS) physiology. EphB2, a receptor tyrosine kinase, is essential for neuronal connectivity and plasticity in the brain, but so far its presence and function in the ENS remain largely unexplored. Here we report that EphB2 is expressed preferentially by enteric neurons relative to glial cells throughout the gut in rats. We show that in primary enteric neurons, activation of EphB2 by its natural ligand ephrinB2 engages ERK signaling pathways. Long-term activation with ephrinB2 decreases EphB2 expression and reduces molecular and functional connectivity in enteric neurons without affecting neuronal density, ganglionic fiber bundles, or overall neuronal morphology. This is highlighted by a loss of neuronal plasticity markers such as synapsin I, PSD95, and synaptophysin, and a decrease of spontaneous miniature synaptic currents. Together, these data identify a critical role for EphB2 in the ENS and reveal a unique EphB2-mediated molecular program of synapse regulation in enteric neurons.