Learning from the Past, Looking to the Future: Modeling Social Unrest in Karachi, Pakistan

Social unrest represents a major challenge for policy makers around the globe, as it can quickly escalate from small scale disturbances to highly public protests, riots and even civil war. This research was motivated by a need to understand social instability and to unpack the comments made during a spring 2013 conference hosted by Pacific Northwest National Laboratory’s Center for Global Security and the U.S. Institute for Peace, where policymakers noted that models considering social instability are often not suitable for decision-making. This analysis shows that existing state level models of instability could be improved in spatial scale to the city level, even without significantly improved data access. Better data would make this analysis more complete and likely improve the quality of the model. Another challenge with incorporating modeling into decision-making is the need to understand uncertainty in a model. Policy makers are frequently tasked with making decisions without a clear outcome, so characterization of uncertainty is critical. This report describes the work and findings of the project. It took place in three phases: a literature review of social stability research, a “hindsight scan” that looked at historical data, and a “foresight scan” looking at future scenarios

Effect of Haptic Feedback on Static Standing Sway

Study Goal: To explore the use of proprioceptive input as a means of attenuating postural sway through the development and implementation of a hands-free device, with the ultimate goal of providing sway-reference haptic input located at the upper trunk and shoulders to determine: Does sway-referenced haptic input improve static standing stability

Identification of IKr Kinetics and Drug Binding in Native Myocytes

Determining the effect of a compound on IKr is a standard screen for drug safety. Often the effect is described using a single IC50 value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of IKr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on IKr. IKr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from −70 to −20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published IKr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on IKrI–V relation and IKr inactivation. The method produced models that quantitatively reproduce both the control IKr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC50 method. Although the method was developed for IKr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII–induced (Ox-CaMKII–induced) RyR2 and Na v 1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca 2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Na v 1.5 (CaMKII-p-Na v 1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Na v 1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Na v 1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis. Oxidative stress creates atrial fibrillation substrate in heart failure via CAMKII by increasing propensity for triggered calcium waves and reentry in the posterior left atrium