Thriving Glasgow Portrait: A shared vision for a healthy, equitable and sustainable future

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Glucose and Fatty Acids Synergize to Promote B-Cell Apoptosis through Activation of Glycogen Synthase Kinase 3β Independent of JNK Activation

The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined.Increasing glucose (5-25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β.Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target

Rate-induced tipping in heterogeneous reaction-diffusion systems: an invariant manifold framework and geographically shifting ecosystems

We propose a framework to study tipping points in reaction-diffusion equations (RDEs) in one spatial dimension, where the reaction term decays in space (asymptotically homogeneous) and varies linearly with time (nonautonomous) due to an external input. A compactification of the moving-frame coordinate together with Lin’s method to construct heteroclinic orbits along intersections of stable and unstable invariant manifolds allows us to (i) obtain multiple coexisting pulse and front solutions for the RDE by computing heteroclinic orbits connecting equilibria at negative and positive infinity in the compactified moving-frame ordinary differential equation, (ii) detect tipping points as dangerous bifurcations of such heteroclinic orbits, and (iii) obtain tipping diagrams by numerical continuation of such bifurcations. We apply our framework to an illustrative model of a habitat patch that features an Allee effect in population growth and is geographically shrinking or shifting due to human activity or climate change. Thus, we identify two classes of tipping points to extinction: bifurcation-induced tipping (B-tipping) when the shrinking habitat falls below some critical length and rate-induced tipping (R-tipping) when the shifting habitat exceeds some critical speed. We explore two-parameter R-tipping diagrams to understand how the critical speed depends on the size of the habitat patch and the dispersal rate of the population, uncover parameter regions where the shifting population survives, and relate these regions to the invasion speed in an infinite homogeneous habitat. Furthermore, we contrast the tipping instabilities with gradual transitions to extinction found for logistic population growth without the Allee effect

Saddle Slow Manifolds and Canard Orbits in R4 R4\mathbb{R}^{4} and Application to the Full Hodgkin–Huxley Model

Abstract Many physiological phenomena have the property that some variables evolve much faster than others. For example, neuron models typically involve observable differences in time scales. The Hodgkin–Huxley model is well known for explaining the ionic mechanism that generates the action potential in the squid giant axon. Rubin and Wechselberger (Biol. Cybern. 97:5–32, 2007) nondimensionalized this model and obtained a singularly perturbed system with two fast, two slow variables, and an explicit time-scale ratio ε. The dynamics of this system are complex and feature periodic orbits with a series of action potentials separated by small-amplitude oscillations (SAOs); also referred to as mixed-mode oscillations (MMOs). The slow dynamics of this system are organized by two-dimensional locally invariant manifolds called slow manifolds which can be either attracting or of saddle type. In this paper, we introduce a general approach for computing two-dimensional saddle slow manifolds and their stable and unstable fast manifolds. We also develop a technique for detecting and continuing associated canard orbits, which arise from the interaction between attracting and saddle slow manifolds, and provide a mechanism for the organization of SAOs in R4 $\mathbb{R}^{4}$. We first test our approach with an extended four-dimensional normal form of a folded node. Our results demonstrate that our computations give reliable approximations of slow manifolds and canard orbits of this model. Our computational approach is then utilized to investigate the role of saddle slow manifolds and associated canard orbits of the full Hodgkin–Huxley model in organizing MMOs and determining the firing rates of action potentials. For ε sufficiently large, canard orbits are arranged in pairs of twin canard orbits with the same number of SAOs. We illustrate how twin canard orbits partition the attracting slow manifold into a number of ribbons that play the role of sectors of rotations. The upshot is that we are able to unravel the geometry of slow manifolds and associated canard orbits without the need to reduce the model

Glucose and Fatty Acids Synergize to Promote B-Cell Apoptosis through Activation of Glycogen Synthase Kinase 3β Independent of JNK Activation

Background: The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined.Principal Findings: Increasing glucose (5–25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β.Conclusions/Significance: Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.</p