A three-scale model of spatio-temporal bursting

© 2016 Society for Industrial and Applied Mathematics. We study spatio-temporal bursting in a three-scale reaction diffusion equation organized by the winged cusp singularity. For large time-scale separation the model exhibits traveling bursts, whereas for large space-scale separation the model exhibits standing bursts. Both behaviors exhibit a common singular skeleton, whose geometry is fully determined by persistent bifurcation diagrams of the winged cusp. The modulation of spatio-temporal bursting in such a model naturally translates into paths in the universal unfolding of the winged cusp.The research leading to these results has received funding from the European Research Council under the Advanced ERC Grant Agreement Switchlet 670645 and from DGAPA-Universidad Nacional Aut onoma de Mexico under the PAPIIT Grant IA105816

Control Across Scales by Positive and Negative Feedback

Feedback is a key element of regulation, as it shapes the sensitivity of a process to its environment. Positive feedback upregulates, and negative feedback downregulates. Many regulatory processes involve a mixture of both, whether in nature or in engineering. This article revisits the mixed-feedback paradigm, with the aim of investigating control across scales. We propose that mixed feedback regulates excitability and that excitability plays a central role in multiscale neuronal signaling. We analyze this role in a multiscale network architecture inspired by neurophysiology. The nodal behavior defines a mesoscale that connects actuation at the microscale to regulation at the macroscale. We show that mixed-feedback nodal control provides regulatory principles at the network scale, with a nodal resolution. In this sense, the mixed-feedback paradigm is a control principle across scales. </jats:p

Cell types, network homeostasis, and pathological compensation from a biologically plausible ion channel expression model.

How do neurons develop, control, and maintain their electrical signaling properties in spite of ongoing protein turnover and perturbations to activity? From generic assumptions about the molecular biology underlying channel expression, we derive a simple model and show how it encodes an "activity set point" in single neurons. The model generates diverse self-regulating cell types and relates correlations in conductance expression observed in vivo to underlying channel expression rates. Synaptic as well as intrinsic conductances can be regulated to make a self-assembling central pattern generator network; thus, network-level homeostasis can emerge from cell-autonomous regulation rules. Finally, we demonstrate that the outcome of homeostatic regulation depends on the complement of ion channels expressed in cells: in some cases, loss of specific ion channels can be compensated; in others, the homeostatic mechanism itself causes pathological loss of function.Charles A. King TrustThis is the final version of the article. It first appeared from Cell Press (Elsevier) via http://dx.doi.org/10.1016/j.neuron.2014.04.002

Evaluating Health Performance and Inequalities in Marche region of Italy

A worldwide selection of models for measuring performance in health services was appraised, with the internationally recognised Health System Performance Assessment tool chosen for testing in a local health authority in the Marche Region of Italy, utilising local, regional, national and international comparisons. A complementary means of measuring health inequality involving the Concentration Index enabled a holistic evaluation of the local health environment. Whilst the approach addressed a comprehensive range of issues, limitations with data availability were found to present genuine constraints that require future action. Nevertheless, valuable lessons were learned for policy makers, with the relationship between socio-economic inequalities and systematic variations in health indicators highlighted. The Health System Performance Assessment tool presents the opportunity for strategic alignment in performance measurement. This article presents an overview of extensive piece of research

Switchable slow cellular conductances determine robustness and tunability of network states.

Neuronal information processing is regulated by fast and localized fluctuations of brain states. Brain states reliably switch between distinct spatiotemporal signatures at a network scale even though they are composed of heterogeneous and variable rhythms at a cellular scale. We investigated the mechanisms of this network control in a conductance-based population model that reliably switches between active and oscillatory mean-fields. Robust control of the mean-field properties relies critically on a switchable negative intrinsic conductance at the cellular level. This conductance endows circuits with a shared cellular positive feedback that can switch population rhythms on and off at a cellular resolution. The switch is largely independent from other intrinsic neuronal properties, network size and synaptic connectivity. It is therefore compatible with the temporal variability and spatial heterogeneity induced by slower regulatory functions such as neuromodulation, synaptic plasticity and homeostasis. Strikingly, the required cellular mechanism is available in all cell types that possess T-type calcium channels but unavailable in computational models that neglect the slow kinetics of their activation

New spatial mechanisms for the kinematic analysis of the tibiotalar joint

In virtually unloaded conditions, the tibiotalar (ankle) joint behaves as a single degree-of-freedom system, and two fibres within the calcaneal-fibular and tibio-calcaneal ligaments remain nearly isometric throughout the flexion arc. A relevant theoretical model also showed that three articular surfaces and two ligaments act together as a mechanism to control the passive kinematics. Two equivalent spatial parallel mechanisms were formulated, with ligament fibres assumed isometric and articulating surfaces assumed rigid, either as three sphere-plane contacts, or as a single spherical pair. Predicted and measured motion in three specimens compared fairly well. Important enhancement of this previous work is here presented, with more accurate experimental data, more anatomical model surfaces, and a more robust mathematical model

Neuronal behaviors: A control perspective

The purpose of this tutorial is to introduce and analyze models of neurons from a control perspective and to show how recently developed analytical tools help to address important biological questions. A first objective is to review the basic modeling principles of neurophysiology in which neurons are modeled as equivalent nonlinear electrical circuits that capture their excitable properties. The specific architecture of the models is key to the tractability of their analysis: in spite of their high-dimensional and nonlinear nature, the model properties can be understood in terms of few canonical positive and negative feedback motifs localized in distinct timescales. We use this insight to shed light on a key problem in experimental neurophysiology, the challenge of understanding the sensitivity of neuronal behaviors to underlying parameters in empirically-derived models. Finally, we show how sensitivity analysis of neuronal excitability relates to robustness and regulation of neuronal behaviors.This paper presents research results of the Belgian Network DYSCO (Dynamical Systems, Control, and Optimization), funded by the Interuniversity Attraction Poles Programme, initiated by the Belgian State, Science Policy Office. G.D. is a Marie-Curie COFUND postdoctoral fellow at the University of Liege. Co-funded by the European Union. J.D. is supported by the F.R.S.-FNRS (Belgian Fund for Scientific Research. The scientific responsibility rests with its authors.This is the author accepted manuscript. The final version is available from IEEE via http://dx.doi.org/10.1109/CDC.2015.740249

FlakiMe: Laboratory-Controlled Test Flakiness Impact Assessment

Much research on software testing makes an implicit assumption that test failures are deterministic such that they always witness the presence of the same defects. However, this assumption is not always true because some test failures are due to so-called flaky tests, i.e., tests with non-deterministic outcomes. To help testing researchers better investigate flakiness, we introduce a test flakiness assessment and experimentation platform, called FlakiMe. FlakiMe supports the seeding of a (controllable) degree of flakiness into the behaviour of a given test suite. Thereby, FlakiMe equips researchers with ways to investigate the impact of test flakiness on their techniques under laboratory-controlled conditions. To demonstrate the application of FlakiMe, we use it to assess the impact of flakiness on mutation testing and program repair (the PRAPR and ARJA methods). These results indicate that a 10% flakiness is sufficient to affect the mutation score, but the effect size is modest (2% - 5%), while it reduces the number of patches produced for repair by 20% up to 100% of repair problems; a devastating impact on this application of testing. Our experiments with FlakiMe demonstrate that flakiness affects different testing applications in very different ways, thereby motivating the need for a laboratory-controllable flakiness impact assessment platform and approach such as FlakiMe