Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.

Digital twin with augmented state extended Kalman filters for forecasting electric power consumption of industrial production systems.

The work aims to develop an effective tool based on Digital Twins (DTs) for forecasting electric power consumption of industrial production systems. DTs integrate dynamic models combined with Augmented State Extended Kalman Filters (ASEKFs) in a learning process. The connection with the real counterpart is realized exclusively through non-intrusive sensors. This architecture enables the model development of industrial systems (components, machinery and processes) on which complete knowledge is not available, by identifying the model's unknown parameters through short online training phases and small amounts of real-time raw data. ASEKFs track the unknowns keeping models updated as physical systems evolve. When a forecast is needed, the current estimates of the uncertain parameters are integrated into the dynamic models. These can then be used without ASEKFs to predict the actual energy use of the system under the desired operating conditions, including scenarios that differ from typical functioning. The approach is validated offline with reference to the electricity consumption of an automatic coffee machine, which represents a real test environment and a blueprint to design DTs for other industrial systems. The appliance is observed by measuring the supply voltage and the absorbed current. The accuracy of the results is analyzed and discussed. This method is developed in the context of energy consumption prediction and optimization in the manufacturing industry through refined energy management and planning.

Exploring Photoswitchable Binding Interactions with Small-Molecule- and Peptide-Based Inhibitors of Trypsin.

The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small-molecule- and peptide-based inhibitors of the same protease-trypsin-to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a more than fivefold difference in inhibitory activity between isomeric states, whereas the best small-molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggest this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation; this is not observed for the small-molecule inhibitor. Hence, we demonstrate that significant structural changes in critical binding motifs upon irradiation are essential for maximising the difference in biological activity between isomeric states. This is an important consideration in the design of future photoswitchable drugs for clinical applications.

Class D amplifier for a power piezoelectric load.

We present a high efficiency inverter (>90%) that can drive an acoustic cavitation reactor with a 2 kW power between 10 and 100 kHz. This reactor is composed of numerous piezoelectric transducers and is particularly used to accelerate various industrial chemical reactions and destroy a variety of organic contaminants in water. The class-D amplifier or inverter is composed of power MOSFETs, type IRFP460, in a full bridge configuration driven by IR2110 circuits in bootstrap mode. The specific nature of the problem comes from the fact that, at frequencies slightly different from a resonant frequency frn, the load is mostly capacitive. The insertion of an appropriate low-pass filter in front of the load allowed an efficient solution to the problem due to the load being capacitive for harmonics. The realized system can provide nearly 2 kW to this type of piezoelectric load, with an efficiency of more than 95%

New transmission line analogy applied to single and multilayered piezoelectric transducers.

It is shown that a piezoelectric element vibrating in an extensional or shear mode can be modeled rigorously by systematic use of the transmission line analogy and the superposition theorem. A schematic representation of such an element which is in a way more intuitive than others representations is introduced. The stresses on the electroded faces are considered as sources of stress applied at the two ends of an acoustic transmission line, since the acoustical perturbations may be considered as originating on these faces. Using transmission line theory, a complete set of expressions is found for electrical impedance, acoustic stresses, and velocities. Computed results are exactly the same as those given by the classical method, even if the computation sequence is almost entirely different. An intuitive graphical model for a piezoelectric element is proposed. It is also shown that the acoustic velocities on opposite faces of an asymmetrical loaded piezoelectric plate are exactly equal at the antiresonance frequency when internal losses are neglected. The programs developed can be used efficiently for practical multilayered transducer design.

Practical ultrasonic spectrometric measurement of solution concentrations by a tracking technique.

A practical technique for solution concentration measurement, based on a resonator with enclosed piezoceramics, which can operate at a resonant frequency mode around 500 kHz is designed and evaluated. The resonance can be tracked automatically by means of a phase-locked loop. Measurements made on water-methanol mixtures showing that concentration can be expressed as a function of temperature and resonance frequency, where a multiple regression technique is used to relate them, are reported. It was possible to evaluate the concentration with a repeatability of about 0.06%, which depends essentially on the temperature measurement. Various milk mixtures have also been tested to check if the evaluation of both butterfat and protein concentrations could be achieved from measurements at two different temperatures. It was found that calculations based on two measurements cannot be used when the composition varies too widely.

Fiber characterization in a stationary ultrasonic field.

An instrument has been developed to characterize the mean dimensions of softwood fiber samples. It is based on the phenomenon that particles of cylindrical shape diluted in water and shorter than one fourth of the acoustic wavelength migrate to nodal planes of acoustic radiation pressure and reorient parallel to these planes when subjected to a stationary ultrasonic field. As the resonator operating frequency is 72 kHz, fibers up to 5 mm in length can be measured. The time evolution of the fiber suspension during ultrasonic excitation is monitored with a collimated beam of light. Scattered light signals collected off-axis in the plane perpendicular to the acoustic nodal planes are shown to be a function of the weighted average fiber length. Results are presented for pulp samples in the average fiber length range of 0.2 to 3 mm. It was found that there is a region where the scattered light is linearly related to concentration. Acoustooptical measurements obtained at initial concentration in this linear region, for all fractions, have shown that the longer the average length from screen classifier is, the faster the layer formation is. Since the fiber length the radius are proportional for a wood species, this observation is in agreement with the theoretical prediction.