Cooperativity mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites

Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH cooperativity in MEP pathway control and antimalarial sensitivity.

Control, computing and communication in industrial cyberphysical systems with feedback

The cyber-physical production base technologies are control, computing and connection being applied altogether in the industrial object technological processes automatic regulation systems. They use control technologies in multi-loops and multi-channel regulation systems forming a hierarchy structure. Automatics functional elements unite in the intermediary regulation scheme stabilizing hierarchy control objects, which states are detected with sensors. Computing technologies are used in the cyber-physical production imitation virtual environment and provide processes simulation based on control models and cyber-physical systems digital twins structured in hierarchy levels. The regulation accuracy increase is provided with physical and model processes results comparison detecting non-definition factors acting production processes accuracy. The communication technology is used for the cyber-physical systems net information exchange given with the Internet of Things parameters. The cyber-physical systems continuous work in the non-ideal communication net regulation interval is provided with preventive control signals compensating operation and information delay of automatic conveyor lines. There is a scheme given of multi-loop and multi-channel automatic cyber-physical production using control objects hierarchy based on cyber-physical systems hierarchy and item manufacturing technological tasks.

An Enhanced Distributed Voltage Regulation Scheme for Radial Feeder in Islanded Microgrid

Even the simplest version of the distribution networks face challenges such as maintaining load voltage and system frequency stability and at the same time minimizing the circulating reactive power in grid-forming nodes. As the consumers at the far end of the radial distribution network face serious voltage fluctuations and deviations once the load varies. Therefore, this paper presents an enhanced distributed control strategy to restore the load voltage magnitude and to realize power-sharing proportionally in islanded microgrids. This proposed study considers the voltage regulation at the load node as opposed to the inverter terminal. At the same time, a supervisory control layer is put on to observe and correct the load voltage and system frequency deviations. This presented method is aimed at replacing paralleled inverter control methods hitherto used. Stability analysis using system-wide methodical small-signal models, the MATLAB/Simulink, and experimental results obtained with conventional and proposed control schemes verify the effectiveness of the proposed methodology.

On the Reachability of a Feedback Controlled Leontief-Type Singular Model Involving Scheduled Production, Recycling and Non-Renewable Resources

This paper proposes and studies the reachability of a singular regular dynamic discrete Leontief-type economic model which includes production industries, recycling industries, and non-renewable products in an integrated way. The designed prefixed final state to be reached, under discussed reachability conditions, is subject to necessary additional positivity-type constraints which depend on the initial conditions and the final time for the solution to match such a final prescribed state. It is assumed that the model may be driven by both the demand and an additional correcting control in order to achieve the final targeted state in finite time. Formal sufficiency-type conditions are established for the proposed singular Leontief model to be reachable under positive feedback, correcting controls designed for appropriate demand/supply regulation. Basically, the proposed regulation scheme allows fixing a prescribed final state of economic goods stock in finite time if the model is reachable.

Using Unsupervised Learning for Regulating Deposition Speed During Robotic Wire Arc Additive Manufacturing

Robotic Wire Arc Additive Manufacturing (WAAM) is the layer-by-layer deposition of molten metal to build a three-dimensional part. In this process, the fed metal wire is melted using an electric arc as a heat source. The process is sensitive to the arc conditions, such as arc length. While building WAAM parts, the metal beads overlap at corners causing material accumulation. Material accumulation is undesirable as it leads to uneven build height and process failures caused by arc length variation. This paper introduces a deposition speed regulation scheme to avoid the corner accumulation problem and build parts with uniform build height. The regulated speed has a complex relationship with the corner angle, bead geometry, and molten metal dynamics. So we need to train a model that can predict suitable speed regulations for corner angles encountered while building the part. We develop an unsupervised learning technique to characterize the uniformity of the bead profile of a WAAM built layer and check for anomalous bead profiles. We train a model using these results that can predict suitable speed regulation parameters for different corner angles. We test this model by building a WAAM part using our speed regulation scheme and validate if the built part has uniform build height and reduced corner defects.