Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia

Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs’ dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.     

Upregulation of Nrf2 Signalling and the Inhibition of Erastin-Induced Ferroptosis by Ferulic Acid in MIN6 Cells

Ferroptosis is a regulated cell death process characterised by the iron-dependent accumulation of oxidised polyunsaturated fatty acid-containing phospholipids. Its initiation is complicated and involves reactive oxygen species (ROS) and a loss of the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). These play critical roles in the development of ferroptotic cell damage by lipid peroxidation. Antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of ferroptosis. This study was designed to demonstrate the protective effect of ferulic acid (FA) against oxidative stress and erastin-mediated ferroptosis in murine MIN6 cells. Cells were treated with FA or its metabolite ferulic acid 4-O-sulfate disodium salt (FAS) and 20 μM of erastin. Cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay, iron levels were measured by inductively coupled plasma mass spectrometry (ICP-MS), ROS levels were determined by a dihydrodichlorofluorescein (H2DCF) cell-permeant probe, and glutathione and lipid peroxidation were assayed with commercially available kits. The phenolic acids enhanced cell viability in erastin-treated MIN6 cells in a dose-dependent manner. Furthermore, MIN6 cells exposed to erastin alone showed elevated levels of iron and ROS, glutathione (GSH) depletion, and lipid peroxidation (p < 0.05) compared to cells that were protected by co-treatment with FA or FAS. The treatment of MIN6 cells with FA or FAS following exposure to erastin increased the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) protein levels. Consequently, levels of its downstream antioxidant proteins, HO-1, NQO1, GCLC, and GPX4, increased. FA and FAS greatly decreased erastin-induced ferroptosis in the presence of the Nrf2 inhibitor, ML385, through the regulation of Nrf2 response genes. In conclusion, these results show that FA and FAS protect MIN6 cells from erastin-induced ferroptosis by the Nrf2 antioxidant protective mechanism.     

Mannosylated Systems for Targeted Delivery of Antibacterial Drugs to Activated Macrophages

Macrophages are a promising target for drug delivery to influence macrophage-associated processes in the body, namely due to the presence of resistant microorganisms in macrophages. In this work, a series of mannosylated carriers based on mannan, polyethylenimine (PEI) and cyclodextrin (CD) was synthesized. The molecular architecture was studied using FTIR and ¹H NMR spectroscopy. The particle size, from small 10–50 nm to large 500 nm, depending on the type of carrier, is potentially applicable for the creation of various medicinal forms: intravenous, oral and inhalation. Non-specific capture by cells with a simultaneous increase in selectivity to CD206+ macrophages was achieved. ConA was used as a model mannose receptor, binding galactosylated (CD206 non-specific) carriers with constants of the order of 10⁴ M⁻¹ and mannosylated conjugates of 10⁶–10⁷ M⁻¹. The results of such primary “ConA-screening” of ligands are in a good agreement in terms of the comparative effectiveness of the interaction of ligands with the CD206+ macrophages: non-specific (up to 10%) absorption of highly charged and small particles; weakly specific uptake of galactosylated polymers (up to 50%); and high affine capture (more than 70–80%) of the ligands with grafted trimannoside was demonstrated using the cytometry method. Double and multi-complexes of antibacterials (moxifloxacin with its adjuvants from the class of terpenoids) were proposed as enhanced forms against resistant pathogens. In vivo pharmacokinetic experiments have shown that polymeric carriers significantly improve the efficiency of the antibiotic: the half-life of moxifloxacin is increased by 2–3 times in conjugate-loaded forms, bio-distribution to the lungs in the first hours after administration of the drug is noticeably greater, and, after 4 h of observation, free moxifloxacin was practically removed from the lungs of rats. Although, in polymer systems, its content is significant—1.2 µg/g. Moreover, the importance of the covalent crosslinking carrier with mannose label was demonstrated. Thus, this paper describes experimental, scientifically based methods of targeted drug delivery to macrophages to create enhanced medicinal forms.     

Remembering John Bardeen: inventor of transistor

Transistor’s invention revolutionized global society by spawning electronics industry. John Bardeen is among one of the inventors of transistor. He was a genius and one of the most influential semiconductor Physicist of 20^th century who won two Nobel prizes in Physics.     

Comparison of tunneling currents in graphene nanoribbon tunnel field effect transistors calculated using Dirac-like equation and Schrödinger's equation

The tunneling current in a graphene nanoribbon tunnel field effect transistor (GNR-TFET) has been quantum mechanically modeled. The tunneling current in the GNR-TFET was compared based on calculations of the Dirac-like equation and Schrödinger's equation. To calculate the electron transmittance, a numerical approach-namely the transfer matrix method (TMM)-was employed and the Launder formula was used to compute the tunneling current. The results suggest that the tunneling currents that were calculated using both equations have similar characteristics for the same parameters, even though they have different values. The tunneling currents that were calculated by applying the Dirac-like equation were lower than those calculated using Schrödinger's equation.     

Additive-additive and additive-surface interactions in lubrication

Combinations of additives are often found to exhibit antagonistic or synergistic effects compared to the performance of the individual additives. This paper reviews the state of knowledge concerning such effects. Direct interactions, where two additives combine at a molecular level, are distinguished from complementary or exclusary effects where the individual contributions of separate additives enhance or reduce overall performance but with no direct interaction. Additive interactions take place in solution and at surfaces, and both are discussed.     

Evaluating thermal and thermooxidation stability for lubricating oils via microscale methods

Differential thermal analysis (DTA) and thermogravimetry (TG) methods have been developed to evaluate the thermal and thermooxidation stability of different lubricating oils. Measurements are carried out either by heating the oil sample at a constant rate (direct programme) or by keeping it at a fixed high temperature (isothermal programme). Oxygen at a constant flow rate is used for thermooxidation measurements. Tested samples included different viscosity grades: neutral base oils, unadditivated lubricating oil blends, and industrial oils. The mechanism of thermal decomposition for ZDDP and the estimation of its optimum concentration was also considered.     

Fracture of ultrafine calcium carbonate/polypropylene composites

The strength and fracture properties of a polypropylene filled with ultrafine calcium carbonate (0.07 μm) have been studied in the composition range of 0 to 40 percent by volume. Untreated and surface treated (with stearic acid and a titanate coupling agent) grades have been considered. The untreated filler caused a decrease of toughness whereas a maximum, at ∼10 percent, was observed for the treated filler. The fracture energy was analyzed in terms of the crack pinning model. Due to the very small size of particles the pinning contribution proved to be negligible.     

Elastomeric matrix-short fibers adhesion

This paper analyzes the effects of the addition of a three-component dry type adhesive system on the properties of composite SBR (styrene-butadiene rubber) material containing 20 percent short polyamide (5 mm length and 60 μm diameter). The curing times are extended and green strength is doubled. The replacement of the silica component in the system by a natural silicate is not only feasible, but proves to be favorable for certain properties, such as the storage modulus E′, which becomes less sensitive towards temperature changes. Dynamic property measurements provide evidence of an additional dispersion corresponding to the matrix-fiber interface located around 40 to 50°C, which does not occur in the composites without adhesive. The activation energies of the main relaxation process of these materials are determined, amounting to 175 KJ/mol for the matrix and 250 KJ/mol for adhesive-containing composites, as a consequence of the formation of strong bonds between both phases.