Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy

In mammals, the master circadian clock synchronizes daily rhythms of physiology and behavior with the day-night cycle. Failure of synchrony, which increases the risk for numerous chronic diseases, can be treated by phase adjustment of the circadian clock pharmacologically, for example, with melatonin, or a CK1delta/epsilon inhibitor. Here, using in silico experiments with a systems pharmacology model describing molecular interactions, and pharmacokinetic and behavioral experiments in cynomolgus monkeys, we find that the circadian phase delay caused by CK1delta/epsilon inhibition is more strongly attenuated by light in diurnal monkeys and humans than in nocturnal mice, which are common preclinical models. Furthermore, the effect of CK1delta/epsilon inhibition strongly depends on endogenous PER2 protein levels, which differs depending on both the molecular cause of the circadian disruption and the patient\u27s lighting environment. To circumvent such large interindividual variations, we developed an adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions. Our results reveal the importance of photosensitivity in the clinical efficacy of clock-modulating drugs, and enable precision medicine for circadian disruption

UAV Pirates and SilenTrack Integration

The integration of the UAV pirating system with the SilenTrack video tracking system will allow the combined system to automatically identify and track a suspicious air vehicle visually as well as identify and decode the RF control signal. Once a threat has been identified, the system will execute an algorithm to associate each control channel with the corresponding flight control surface. Once the control channels have been decoded the user can use a hand held radio controller to maneuver the drone which is now under their command

Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations

The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and brain concentrations may be projected from a mixture of in vitro absorption, distribution, metabolism, excretion experimental parameters in combination with computed properties (volume of distribution, fraction unbound in microsomes). Finally, we demonstrate the utility of the underlying equations by showing that the maximum total plasma concentrations can be projected from the experimental parameters for a set of compounds with data collected from clinical research

Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations

The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and brain concentrations may be projected from a mixture of in vitro absorption, distribution, metabolism, excretion experimental parameters in combination with computed properties (volume of distribution, fraction unbound in microsomes). Finally, we demonstrate the utility of the underlying equations by showing that the maximum total plasma concentrations can be projected from the experimental parameters for a set of compounds with data collected from clinical research

Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations

The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and brain concentrations may be projected from a mixture of in vitro absorption, distribution, metabolism, excretion experimental parameters in combination with computed properties (volume of distribution, fraction unbound in microsomes). Finally, we demonstrate the utility of the underlying equations by showing that the maximum total plasma concentrations can be projected from the experimental parameters for a set of compounds with data collected from clinical research