Bundgaard Koenig (cavedesign2)

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools commonly-used to manipulate brain activity. The most widely-used synthetic DREADD ligand, clozapine-N-oxide (CNO), is back-metabolized to clozapine which can itself activate endogenous receptors. Studies in non-DREADD-expressing rodents suggest CNO or a DREADD agonist that lacks active metabolites, such as Compound 21 (C21), change rodent behavior (e.g. decrease locomotion), but chronic injection of CNO does not change locomotion. However, it is unknown if chronic CNO changes behaviors relevant to locomotion, exploration, anxiety, and depression, or if chronic C21 changes any aspect of mouse behavior. Here non-DREADD-expressing mice received i.p. Vehicle (Veh), CNO, or C21 (1 mg/kg) 5 days/week for 16 weeks and behaviors were assessed over time. Veh, CNO, and C21 mice had similar weight gain over the 16-week-experiment. During the 3rd injection week, CNO and C21 mice explored more than Veh mice in a novel context and had more open field center entries; however, groups were similar in other measures of locomotion and anxiety. During the 14th-16th injection weeks, Veh, CNO, and C21 mice had similar locomotion and anxiety-like behaviors. We interpret these data as showing chronic Veh, CNO, and C21 injections given to male non-DREADD-expressing mice largely lack behavioral effects. These data may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists.Waddington's epigenetic landscape is a classic metaphor for describing the cellular dynamics during the development modulated by gene regulation. Quantifying Waddington's epigenetic landscape by mathematical modeling would be useful for understanding the mechanisms of cell fate determination. A few computational methods have been proposed for quantitative modeling of landscape; however, to model and visualize the landscape of a high dimensional gene regulatory system with realistic details is still challenging. Here, we propose a Monte Carlo method for modeling the Waddington's epigenetic landscape of a gene regulatory network (GRN). The method estimates the probability distribution of cellular states by collecting a large number of time-course simulations with random initial conditions. By projecting all the trajectories into a 2-dimensional plane of dimensions i and j, we can approximately calculate the quasi-potential U(xi,xj,∗)=-ln P(xi,xj,∗), where P(xi,xj,∗) is the estimated probability of an equilibrium steady state or a non-equilibrium state. Compared to the state-of-the-art methods, our Monte Carlo method can quantify the global potential landscape (or emergence behavior) of GRN for a high dimensional system. The potential landscapes show that not only attractors represent stability, but the paths between attractors are also part of the stability or robustness of biological systems. We demonstrate the novelty and reliability of our method by plotting the potential landscapes of a few published models of GRN. To prolong tooth life expectancy, tooth wear resulting in dentin exposure should be detected early. However, the most objective methods are clinically limited. We validated fluorescence parameters for distinguishing enamel from dentin-exposed wear in clinical images. Quantitative light-induced fluorescence (QLF) images of 73 adults (age range 22-48 years, mean 33.81 ± 7.71 years), including 1949 teeth with varying tooth wear degrees, without restorations, caries, or cusp area fractures, were used to calculate the ΔF values. Areas-of-interest (AOIs) were selected from QLF images; the ΔF values and the tooth wear index (TWI) were calculated for each tooth. The ΔF values were compared according to the TWI scores. The optimum ΔF values for distinguishing enamel and dentin-exposed wear were determined using the receiver operating characteristic (ROC) curve analysis. Overall,