Optimal model-based control of non-viral siRNA delivery.

Further quantitative understanding of the biological effects and mechanisms involved in cellular and intracellular delivery of nucleic acid materials is required to produce clinical applications of gene therapy. Several modeling approaches have been used in this field; however, a comprehensive approach that integrates all the key pharmacological issues into a holistic framework that is applicable for in vivo conditions is still lacking. This contribution presents a pharmacokinetic/pharmacodynamic model-based control study of non-viral siRNA delivery describing the dynamics of the delivery process and takes into account the main multi-objective optimization issues such as efficacy and toxicity, as well as the effect of uncertainty in cell doubling time. The methodology developed in this work is used to predict the optimal dosage injection rate and optimal intracellular exposure of siRNAs in order to improve the pharmacological effects before cell division occurs. The present analysis successfully provides quantitative predictions of non-viral siRNA activity paving the path for further experimental work to probe more efficient delivery systems.

Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans-epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na(+) channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy.

Artificial Intelligence Modeling-Based Optimization of an Industrial-Scale Steam Turbine for Moving toward Net-Zero in the Energy Sector.

Augmentation of energy efficiency in the power generation systems can aid in decarbonizing the energy sector, which is also recognized by the International Energy Agency (IEA) as a solution to attain net-zero from the energy sector. With this reference, this article presents a framework incorporating artificial intelligence (AI) for improving the isentropic efficiency of a high-pressure (HP) steam turbine installed at a supercritical power plant. The data of the operating parameters taken from a supercritical 660 MW coal-fired power plant is well-distributed in the input and output spaces of the operating parameters. Based on hyperparameter tuning, two advanced AI modeling algorithms, i.e., artificial neural network (ANN) and support vector machine (SVM), are trained and, subsequently, validated. ANN, as turned out to be a better-performing model, is utilized to conduct the Monte Carlo technique-based sensitivity analysis toward the high-pressure (HP) turbine efficiency. Subsequently, the ANN model is deployed for evaluating the impact of individual or combination of operating parameters on the HP turbine efficiency under three real-power generation capacities of the power plant. The parametric study and nonlinear programming-based optimization techniques are applied to optimize the HP turbine efficiency. It is estimated that the HP turbine efficiency can be improved by 1.43, 5.09, and 3.40% as compared to that of the average values of input parameters for half-load, mid-load, and full-load power generation modes, respectively. The annual reduction in CO2 measuring 58.3, 123.5, and 70.8 kilo ton/year (kt/y) corresponds to half-load, mid-load, and full load, respectively, and noticeable mitigation of SO2, CH4, N2O, and Hg emissions is estimated for the three power generation modes of the power plant. The AI-based modeling and optimization analysis is conducted to enhance the operation excellence of the industrial-scale steam turbine that promotes higher-energy efficiency and contributes to the net-zero target from the energy sector.

Modelling and multi-parametric control for delivery of anaesthetic agents.

This article presents model predictive controllers (MPCs) and multi-parametric model-based controllers for delivery of anaesthetic agents. The MPC can take into account constraints on drug delivery rates and state of the patient but requires solving an optimization problem at regular time intervals. The multi-parametric controller has all the advantages of the MPC and does not require repetitive solution of optimization problem for its implementation. This is achieved by obtaining the optimal drug delivery rates as a set of explicit functions of the state of the patient. The derivation of the controllers relies on using detailed models of the system. A compartmental model for the delivery of three drugs for anaesthesia is developed. The key feature of this model is that mean arterial pressure, cardiac output and unconsciousness of the patient can be simultaneously regulated. This is achieved by using three drugs: dopamine (DP), sodium nitroprusside (SNP) and isoflurane. A number of dynamic simulation experiments are carried out for the validation of the model. The model is then used for the design of model predictive and multi-parametric controllers, and the performance of the controllers is analyzed.