Pharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state.
A cancer cell line originating from human epithelial colorectal adenocarcinoma (Caco-2 cells) serves as a high capacity model for a preclinical screening of drugs. Recent need for incorporating barrier tissue into multi-organ chips calls for inclusion of Caco-2 cells into microperfused environment. This article describes a series of systems biology insights obtained from comparing Caco-2 models cells grown as conventional 2D layer and in a microfluidic chip. When basic electrical parameters of Caco-2 monolayers were evaluated using impedance spectrometry and MTT assays, no differences were noted. On the other hand, the microarray profiling of mRNAs and miRNAs revealed that grows on a microfluidic chip leads to the change in the production of specific miRNA, which regulate a set of genes for cell adhesion molecules (CAMs), and provide for more complete differentiation of Caco-2 monolayer. Moreover, the sets of miRNAs secreted at the apical surface of Caco-2 monolayers grown in conventional 2D culture and in microfluidic device differ. When integrated into a multi-tissue platform, Caco-2 cells may aid in generating insights into complex pathophysiological processes, not possible to dissect in conventional cultures.
Most common drug development failures originate from either bioavailability problems, or unexpected toxic effects. The culprit is often the liver, which is responsible for biotransformation of a majority of xenobiotics. Liver may be modeled using "liver on a chip" devices, which may include established cell lines, primary human cells, and stem cell-derived hepatocyte-like cells. The choice of biological material along with its processing and maintenance greatly influence both the device performance and the resultant toxicity predictions. Impediments to the development of "liver on a chip" technology include the problems with standardization of cells, limitations imposed by culturing and the necessity to develop more complicated fluidic contours. Fortunately, recent breakthroughs in the development of cell-based reporters, including ones with fluorescent label, permits monitoring of the behavior of the cells embed into the "liver on a chip" devices. Finally, a set of computational approaches has been developed to model both particular toxic response and the homeostasis of human liver as a whole; these approaches pave a way to enhance the in silico stage of assessment for a potential toxicity.
A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit‐level mechanisms responsible for EtOH‐dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration‐dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U‐shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH‐induced boost in the Ih and AMPA currents in the DA firing‐rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well‐established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.
The article discusses the comparative evaluation of combined treatment results in patients with DTC (differentiated thyroid cancer) at different levels of TSH-stimulated prior to RAI (radioactive iodine) treatment. The study included 197 patients (36 female, 161 male) of the age group 18-75 years with a mean age of 47 years. The data was analyzed using several statistical methods: analysis of variance (ANOVA), linear and logistic regression models. The resulting data from the analysis showed that there was no statistically significant association between serum TSH levels prior to RAI and DTC remission.