Sexual Dimorphism in Substrate Metabolism During Exercise.

During aerobic exercise, women oxidize significantly more lipids and less carbohydrates than men. This sexual dimorphism in substrate metabolism has been attributed, in part, to the observed differences in epinephrine and glucagon levels between men and women during exercise. To identify the underpinning candidate physiological mechanisms for these sex differences, we developed a sex-specific multi-scale mathematical model that relates cellular metabolism in the organs to whole-body responses during exercise. We conducted simulations to test the hypothesis that sex differences in the exercise-induced changes to epinephrine and glucagon would result in the sexual dimorphism of hepatic metabolic flux rates via the glucagon-to-insulin ratio (GIR). Indeed, model simulations indicate that the shift towards lipid metabolism in the female model is primarily driven by the liver. The female model liver exhibits resistance to GIR-mediated glycogenolysis, which helps maintain hepatic glycogen levels. This decreases arterial glucose levels and promotes the oxidation of free fatty acids. Furthermore, in the female model, skeletal muscle relies on plasma free fatty acids as the primary fuel source, rather than intramyocellular lipids, whereas the opposite holds true for the male model.

Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work.

The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural light-dark cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model in the male and female rats. Shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at circadian time (CT) CT12 versus CT0 due to a dynamic change of Interleukin 10 (IL-10), an anti-inflammatory cytokine. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at CT0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.

Is a COVID-19 Vaccine Likely to Make Things Worse?

In order to limit the disease burden and economic costs associated with the COVID-19 pandemic, it is important to understand how effective and widely distributed a vaccine must be in order to have a beneficial impact on public health. To evaluate the potential effect of a vaccine, we developed risk equations for the daily risk of COVID-19 infection both currently and after a vaccine becomes available. Our risk equations account for the basic transmission probability of COVID-19 (ß) and the lowered risk due to various protection options: physical distancing; face coverings such as masks, goggles, face shields or other medical equipment; handwashing; and vaccination. We found that the outcome depends significantly on the degree of vaccine uptake: if uptake is higher than 80%, then the daily risk can be cut by 50% or more. However, if less than 40% of people get vaccinated and other protection options are abandoned-as may well happen in the wake of a COVID-19 vaccine-then introducing even an excellent vaccine will produce a worse outcome than our current situation. It is thus critical that effective education strategies are employed in tandem with vaccine rollout.

Modelling the daily risk of Ebola in the presence and absence of a potential vaccine.

Ebola virus - one of the deadliest viral diseases, with a mortality rate around 90% - damages the immune system and organs, with symptoms including episodic fever, chills, malaise and myalgia. The Recombinant Vesicular Stomatitis Virus-based candidate vaccine (rVSV-ZEBOV) has demonstrated clinical efficacy against Ebola in ring-vaccination clinical trials. In order to evaluate the potential effect of this candidate vaccine, we developed risk equations for the daily risk of Ebola infection both currently and after vaccination. The risk equations account for the basic transmission probability of Ebola and the lowered risk due to various protection protocols: vaccination, hazmat suits, reduced contact with the infected living and dead bodies. Parameter space was sampled using Latin Hypercube Sampling, a statistical method for generating a near-random sample of parameter values. We found that at a high transmission rate of Ebola (i.e., if the transmission rate is greater than 90%), a large fraction of the population must be vaccinated (>80%) to achieve a 50% decrease in the daily risk of infection. If a vaccine is introduced, it must have at least 50% efficacy, and almost everyone in the affected areas must receive it to effectively control outbreaks of Ebola. These results indicate that a low-efficacy Ebola vaccine runs the risk of having vaccinated people be overconfident in a weak vaccine and hence the possibility that the vaccine could make the situation worse, unless the population can be sufficiently educated about the necessity for high vaccine uptake.