Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Ozone and fine particulate matter association with CVD and COPD emergency room visits in Harris County, Texas: Spatiotemporal analysis

This study represents a secondary analysis of the merging of emergency room visits and daily ozone and PM2.5. Although the adverse health effects of ozone and fine particulate matter have been documented in the literature, evidence regarding the health risks of these two pollutants in Harris County, Texas, is limited. Harris County (Houston) has sufficiently unique characteristics that analysis of these relationships in this setting and with the ozone and industry issues in Houston is informative. The objective of this study was to investigate the association between the joint exposure to ozone and fine particulate matter, and emergency room diagnoses of chronic obstructive pulmonary disease and cardiovascular disease in Harris County, Texas, from 2004 to 2009, with zero and one day lags. ^ The study variables were daily emergency room visits for Harris County, Texas, from 2004 to 2009, temperature, relative humidity, east wind component, north wind component, ozone, and fine particulate matter. Information about each patient's age, race, and gender was also included. The two dichotomous outcomes were emergency room visits diagnoses for chronic obstructive pulmonary disease and cardiovascular disease. Estimates of ozone and PM2.5 were interpolated using kriging, in which estimates of the two pollutants were predicted from monitoring data for every case residence zip code for every day of the six years, over 3 million estimates (one of each pollutant for each case in the database). ^ Logistic regressions were conducted to estimate odds ratios of the two outcomes. Three analyses were conducted: one for all records, another for visits during the four months of April and September of 2005 and 2009, and a third one for visits from zip codes that are close to PM2.5 monitoring stations (east area of Harris County). The last two analyses were designed to investigate special temporal and spatial characteristics of the associations. ^ The dataset included all ER visits surveyed by Safety Net from 2004 to 2009, exceeding 3 million visits for all causes. There were 95,765 COPD and 96,596 CVD cases during this six year period. A 1-μg/m3 increase in PM2.5 on the same day was associated with a 1.0% increase in the odds of chronic obstructive pulmonary disease emergency room diagnoses, a 0.4% increase in the odds of cardiovascular disease emergency room diagnoses, and a 0.2% increase in the odds of cardiovascular disease emergency room diagnoses on the following day. A 1-ppb increase in ozone was associated with a 0.1% increase in the odds of chronic obstructive pulmonary disease emergency room diagnoses on the same day. These four percentages add up to 1.7% of ER visits. That is, over the period of six years, one unit increase for both ozone and PM2.5 (joint increase), resulted in about 55,286 (3,252,102 * 0.017) extra ER visits for CVD or COPD, or 9,214 extra ER visits per year. ^ After adjustment for age, race, gender, day of the week, temperature, relative humidity, east wind component, north wind component, and wind speed, there were statistically significant associations between emergency room chronic obstructive pulmonary disease diagnosis in Harris County, Texas, with joint exposure to ozone and fine particulate matter for the same day; and between emergency room cardiovascular disease diagnosis and exposure to PM2.5 of the same day and the previous day. ^ Despite the small association between the two air pollutants and the health outcomes, this study points to important findings. Namely, the need to identify reasons for the increase of CVD and COPD ER visits over the course of the project, the statistical association between humidity (or whatever other variables for which it may serve as a surrogate) and CVD and COPD cases, and the confirmatory finding that males and blacks have higher odds for the two outcomes, as consistent with other studies. ^ An important finding of this research suggests that the number and distribution of PM2.5 monitors in Harris County - although not evenly spaced geographically—are adequate to detect significant association between exposure and the two outcomes. In addition, this study points to other potential factors that contribute to the rising incidence rates of CVD and COPD ER visits in Harris County such as population increases, patient history, life style, and other pollutants. Finally, results of validation, using a subset of the data demonstrate the robustness of the models.^