The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Multicomponent model of deformation and detachment of a biofilm under fluid flow

A novel biofilm model is described which systemically couples bacteria, extracellular polymeric substances (EPS) and solvent phases in biofilm. This enables the study of contributions of rheology of individual phases to deformation of biofilm in response to fluid flow as well as interactions between different phases. The model, which is based on first and second laws of thermodynamics, is derived using an energetic variational approach and phase-field method. Phase-field coupling is used to model structural changes of a biofilm. A newly developed unconditionally energy-stable numerical splitting scheme is implemented for computing the numerical solution of the model efficiently. Model simulations predict biofilm cohesive failure for the flow velocity between [Image: see text] and [Image: see text] m s(−1) which is consistent with experiments. Simulations predict biofilm deformation resulting in the formation of streamers for EPS exhibiting a viscous-dominated mechanical response and the viscosity of EPS being less than [Image: see text]. Higher EPS viscosity provides biofilm with greater resistance to deformation and to removal by the flow. Moreover, simulations show that higher EPS elasticity yields the formation of streamers with complex geometries that are more prone to detachment. These model predictions are shown to be in qualitative agreement with experimental observations

Reduced Structural Modeling of Integrally-Strained Slender Wings

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77134/1/AIAA-2004-2038-697.pd