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Here, we used the ideas of the theory of excitons to hypothesize about the mechanism of synchronous opening and closing of two membrane channels formed by laterally linked gramicidin A subunits.

Pyrrolomycins C (Pyr_C) and D (Pyr_D) are antibiotics produced by Actinosporangium and Streptomyces. The mechanism of their antimicrobial activity consists in depolarization of bacterial membrane, leading to the suppression of bacterial bioenergetics through the uncoupling of oxidative phosphorylation, which is based on the protonophore action of these antibiotics [Valderrama et al., Antimicrob. Agents Chemother. (2019) 63, e01450]. Here, we studied the effect of pyrrolomycins on the isolated rat liver mitochondria. Pyr_C was found to be more active than Pyr_D and uncoupled mitochondria in the submicromolar concentration range, which was observed as the mitochondrial membrane depolarization and stimulation of mitochondrial respiration. In the case of mitoplasts (isolated mitochondria with impaired outer membrane integrity), the difference in the action of Pyr_C and Pyr_D was significantly less pronounced. By contrast, in inverted submitochondrial particles (SMPs), Pyr_D was more active as an uncoupler, which caused collapse of the membrane potential even at the nanomolar concentrations. The same ratio of the protonophoric activity of Pyr_D and Pyr_C was obtained by us on liposomes loaded with the pH indicator pyranine. The protonophore activity of Pyr_D in the planar bilayer lipid membranes (BLMs) was maximal at ~pH 9, i.e., at pH values close to pK

Background. Nasopharyngeal cysts are mostly congenital malformations. However, their clinical manifestation can also occur in adolescence, depending on their severity, size and location. Nasopharyngeal cysts are rare in the practice of an otolaryngologist, but can be found in nasal obstruction. The article presents the literature data on the theories of the origin, clinical manifestations, peculiarities of the diagnostics and surgical treatment of the nasopharyngeal cysts. Aim. To increase the efficiency of diagnostics and treatment of nasopharyngeal cysts in children on the basis of a differentiated approach to the manifestation of the disease symptoms. Materials and methods. 29 patients aged from 1 to 8 years (mean age 4.210.39 years) with nasopharyngeal cysts and cyst-like neoplasms were treated at the clinical sites of the Department of Otorhinolaryngology and Pediatric Department of Pirogov Russian National Research Medical University (Moscow) from 2009 to 2022. Results. On admission all 29 (100%) children complained of an increasing nasal obstruction, anterior and posterior purulent rhinorrhea, snoring, decreased hearing, and epiphora. 18 patients (62.1%) had a history of recurrent otitis media and were diagnosed with bilateral exudative otitis media on examination. Transnasal or transoroepipharyngeal endoscopic marsupialization and cyst coagulation with an electrosurgical complex were performed in 28 (96.5%) children. In 19 (65.5%) cases the operation was performed with a single-stage adenotomy and in 8 (27.6%) cases with tubal valvular plasty, partial destruction of the tubal tonsils. Conclusion. Improvement of diagnostics quality due to modern imaging technologies leads to detection of a greater number of accidental findings of nasopharyngeal cysts and requires systematization and detailed elaboration of the accumulated knowledge in the work of the pediatric otorhinolaryngologist.

Fibroblast activation protein (FAP) is an integral membrane serine protease that acts as both dipeptidyl peptidase and collagenase. In recent years, FAP has attracted considerable attention due to its specific upregulation in multiple types of tumor cell populations, including cancer cells in various cancer types, making FAP a potential target for therapy. However, relatively few papers pay attention to the mechanisms driving the cell-specific expression of the FAP gene. We found no correlation between the activities of the two FAP promoter variants (short and long) and the endogenous FAP mRNA expression level in several cell lines with different FAP expression levels. This suggested that other mechanisms may be responsible for specific transcriptional regulation of the FAP gene. We analyzed the distribution of known epigenetic and structural chromatin marks in FAP-positive and FAP-negative cell lines and identified two potential enhancer-like elements (E1 and E2) in the FAP gene locus. We confirmed the specific enrichment of H3K27ac in the putative enhancer regions in FAP-expressing cells. Both the elements exhibited enhancer activity independently of each other in the functional test by increasing the activity of the FAP promoter variants to a greater extent in FAP-expressing cell lines than in FAP-negative cell lines. The transcription factors AP-1, CEBPB, and STAT3 may be involved in FAP activation in the tumors. We hypothesized the existence of a positive feedback loop between FAP and STAT3, which may have implications for developing new approaches in cancer therapy.

Gramicidin A (gA) is a hydrophobic pentadecapeptide readily incorporating into a planar bilayer lipid membrane (BLM), thereby inducing a large macroscopic current across the BLM. This current results from ion-channel formation due to head-to-head transbilayer dimerization of gA monomers with rapidly established monomer-dimer equilibrium. Any disturbance of the equilibrium, e.g., by sensitized photoinactivation of a portion of gA monomers, causes relaxation toward a new equilibrium state. According to previous studies, the characteristic relaxation time of the gA-mediated electric current decreases as the current increases upon elevating the gA concentration in the membrane. Here, we report data on the current relaxation kinetics for gA analogs with N-terminal valine replaced by glycine or tyrosine. Surprisingly, the relaxation time increased rather than decreased upon elevation of the total membrane conductance induced by these gA analogs, thus contradicting the classical kinetic scheme. We developed a general theoretical model that accounts for lateral interaction of monomers and dimers mediated by membrane elastic deformations. The modified kinetic scheme of the gramicidin dimerization predicts the reverse dependence of the relaxation time on membrane conductance for gA analogs, with a decreased dimerization constant that is in a good agreement with our experimental data. The equilibration process may be also modulated by incorporation of other peptides (“impurities”) into the lipid membrane.

Human FACT (FACT) is a multifunctional histone chaperone involved in transcription, replication and DNA repair. Curaxins are anticancer compounds that induce FACT- dependent nucleosome unfolding and trapping of FACT in the chromatin of cancer cells (c-trapping) through an unknown molecular mechanism. Here, we analyzed the effects of curaxin CBL0137 on nucleosome unfolding by FACT using spFRET and electron microscopy. By itself, FACT adopted multiple conformations, including a novel, compact, four-domain state in which the previously unresolved NTD of the SPT16 subunit of FACT was localized, apparently stabilizing a compact configuration. Multiple, primarily open conformations of FACT-nucleosome complexes were observed during curaxin-supported nucleosome unfolding. The structures of intermediates suggest “decision points” in the unfolding/folding pathway where FACT can either promote disassembly or assembly of nucleosomes, with the outcome possibly being influenced by additional factors. The data suggest novel mechanisms of nucleosome unfolding by FACT and c-trapping by curaxins.

The chase toward endowing chemical compounds with machine-like functions mimicking those of biological molecular machineries has yielded a variety of artificial molecular motors (AMMs). Pharmaceutical applications of photoexcited monomolecular unidirectionally-rotating AMMs have been envisioned in view of their ability to permeabilize biological membranes. Nonetheless, the mechanical properties of lipid membranes render the proposed drilling activity of AMMs doubtful. Here, we show that singlet oxygen released by a photoexcited "molecular drill" oxidized unsaturated lipids composing giant unilamellar vesicles. In contrast, giant liposomes built of saturated lipids were inert to AMM photoactuation. The AMM did not mechanically destroy gramicidin A ion channels in planar bilayer lipid membranes but instead photoinactivated them. Sodium azide, a singlet oxygen quencher, reduced both AMM-mediated light-induced dye release from unsaturated large unilamellar vesicles and protected gramicidin A from photoinactivation. Upon additional consideration of the underlying bilayer mechanics, we conclude that AMMs' envisioned therapeutic and pharmaceutical applications rely on their photodynamic activity rather than their nanomechanical drilling abilities.

Trialkyl phosphonium derivatives of vinyl-substituted p-chlorophenol were synthesized here by a recently developed method of preparing quaternary phosphonium salts from phosphine oxides using Grignard reagents. All the derivatives with a number (n) of carbon atoms in phosphonium alkyl substituents varying from 4 to 7 showed pronounced uncoupling activity in isolated rat liver mitochondria at micromolar concentrations, with a tripentyl derivative being the most effective both in accelerating respiration and causing membrane potential collapse, as well as in provoking mitochondrial swelling in a potassium-acetate medium. Remarkably, the trialkyl phosphonium derivatives with n from 4 to 7 also proved to be rather potent antibacterial agents. Methylation of the chlorophenol hydroxyl group suppressed the effects of P555 and P444 on the respiration and membrane potential of mitochondria but not those of P666, thereby suggesting a mechanistic difference in the mitochondrial uncoupling by these derivatives, which was predominantly protonophoric (carrier-like) in the case of P555 and P444 but detergent-like with P666. The latter was confirmed by the carboxyfluorescein leakage assay on model liposomal membranes.

An impressive body of evidence has been accumulated now on sound beneficial effects of mitochondrial uncouplers in struggling with the most dangerous pathologies such as cancer, infective diseases, neurodegeneration and obesity. To increase their efficacy while gaining further insight in the mechanism of the uncoupling action has been remaining a challenge. Encouraged by our previous promising results on lipophilic derivatives of 7-hydroxycoumarin-4-acetic acid (UB-4 esters), here, we use a 7-hydroxycoumarin-3-carboxylic acid scaffold to synthesize a new series of 7-hydroxycoumarin (umbelliferone, UB)-derived uncouplers of oxidative phosphorylation - alkyl esters of umbelliferone-3-carboxylic acid (UB-3 esters) with varying carbon chain length. Compared to the UB-4 derivatives, UB-3 esters proved to be stronger uncouplers: the most effective of them caused a pronounced increase in the respiration rate of isolated rat heart mitochondria (RHM) at submicromolar concentrations. Both of these series of UB derivatives exhibited a striking difference between their uncoupling patterns in mitochondria isolated from liver and heart or kidney, namely: a pronounced but transient decrease in membrane potential, followed by its recovery, was observed after the addition of these compounds to isolated rat liver mitochondria (RLM), while the depolarization of RHM and rat kidney mitochondria (RKM) was rather stable under the same conditions. Interestingly, partial reversal of this depolarization in RHM and RKM was caused by carboxyatractyloside, an inhibitor of ATP/ADP translocase, thereby pointing to the involvement of this mitochondrial membrane protein in the uncoupling activity of both UB-3 and UB-4 esters. The fast membrane potential recovery in RLM uncoupled by the addition of the UB esters was apparently associated with hydrolysis of these compounds, catalyzed by mitochondrial aldehyde dehydrogenase (ALDH2), being in high abundance in liver compared to other tissues. Protonophoric properties of the UB derivatives in isolated mitochondria were confirmed by measurements of RHM swelling in the presence of potassium acetate. In model bilayer lipid membranes (liposomes), proton-carrying activity of UB-3 esters was demonstrated by measuring fluorescence response of the pH-dependent dye pyranine. Electrophysiological experiments on identified neurons from Lymnaea stagnalis demonstrated low neurotoxicity of UB-3 esters. Resazurin-based cell viability assay showed low toxicity of UB-3 esters to HEK293 cells and primary human fibroblasts. Thus, the present results enable us to consider UB-3 esters as effective tissue-specific protonophoric mitochondrial uncouplers.

Three new rubidium polychromates, Rb2[(UO2)(Cr2O7)(NO3)2] (1), γ-Rb2Cr3O10 (2) and δ-Rb2Cr3O10 (3) were prepared by combination of hydrothermal treatment at 220 °C and evaporation of aqueous solutions under ambient conditions. Compound 1 is monoclinic, P 2 1 / c $P{2}_{1}/c$ , a = 13.6542(19), b = 19.698(3), c = 11.6984(17) Å, β = 114.326(2)°, V = 2867.0(7) Å3, R 1 = 0.040; 2 is hexagonal, P 6 3 / m $P{6}_{3}/m$ , a = 11.991(2), c = 12.828(3) Å, γ = 120°, V = 1597.3(5) Å3, R 1 = 0.031; 3 is monoclinic, P 2 1 / n $P{2}_{1}/n$ , a = 7.446(3), b = 18.194(6), c = 7.848(3) Å, β = 99.953(9)°, V = 1047.3(7) Å3, R 1 = 0.037. In the crystal structure of 1, UO8 bipyramids and NO3 groups share edges to form [(UO2)(NO3)2] species which share common corners with dichromate Cr2O7 groups producing novel type of uranyl dichromate chains [(UO2)(Cr2O7)(NO3)2]2−. In the structures of new Rb2Cr3O10 polymorphs, CrO4 tetrahedra share vertices to form Cr3O10 2− species. The trichromate groups are aligned along the 63 screw axis forming channels running in the ab plane in the structure of 2. The Rb cations reside between the channels and in their centers completing the structure. The trichromate anions are linked by the Rb+ cations into a 3D framework in the structure of 3. Effect of solution acidity on the crystallization of polychromates in uranyl-bearing systems is discussed.

6-Ketocholestanol (kCh) is known as a mitochondrial recoupler, i.e. it abolishes uncoupling of mitochondria by such potent agents as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and 3,5-di(tert-butyl)-4-hydroxybenzylidenemalononitril (SF6847) [Starkov et al., 1997]. Here, we report data on the kCh-induced inhibition of both NADH-oxidase and NADH-ubiquinone oxidoreductase activities of the respiratory complex I in bovine heart submitochondrial particles (SMP). Based on the absence of such inhibition with hexaammineruthenium (III) (HAR) as the complex I electron acceptor, the kCh effect could be associated with the ubiquinone-binding centre of this respiratory enzyme. In isolated rat liver mitochondria (RLM), kCh inhibited oxygen consumption with the glutamate/malate, substrates of NAD-linked dehydrogenases, while no inhibition of RLM respiration was observed with succinate, in agreement with the absence of the kCh effect on the succinate oxidase activity in SMP. Three kCh analogs (cholesterol, 6α-hydroxycholesterol, and 5α,6α-epoxycholesterol) exhibited no effect on the NADH oxidase activities in both SMP and RLM. Importantly, the kCh analogs were ineffective in the recoupling of RLM treated with CCCP or SF6847. Therefore, interaction of kCh with the complex I may be involved in the kCh-mediated mitochondrial recoupling.

Here, we studied the interaction of Cys-substituted (G56C) cytochrome c labeled with sulfocyanin-3 fluorescent dye (fCyt) with artificial and natural lipid membranes by using fluorescence correlation spectroscopy (FCS). Compared to mitochondria, mitoplasts were shown to have more fCyt binding sites with a lower affinity for this protein. The fCyt affinity for cardiolipin-containing liposomes depended on the content of cardiolipin in liposomes and decreased upon raising the ionic strength of the solution. A high value of the constant of the fCyt binding with mitochondria could be explained by the presence of specific binding sites for this protein on the mitochondrial outer membrane surface. This explanation is confirmed by observation of more efficient displacement of fluorescent cytochrome c by the unlabeled mutant variant K8T than by the WT protein, whereas in mitoplasts and liposomes the WT protein displaced fCyt more efficiently than K8T.

Purpose Preclinical evaluation of PCA3 and AMACR transcript simultaneous detection in urine to diagnose clinical significant prostate cancer (prostate cancer with Gleason score ≥7) in a Russian cohort. Patients and methods We analyzed urine samples of patients with a total serum PSA ≥2 ng/mL: 31 men with prostate cancer scheduled for radical prostatectomy, 128 men scheduled for first diagnostic biopsy (prebiopsy cohort). PCA3, AMACR, PSA and GPI transcripts were detected by multiplex reverse transcription quantitative polymerase chain reaction, and the results were used for scores for calculation and statistical analysis. Results There was no significant difference between clinically significant and nonsignificant prostate cancer PCA3 scores. However, there was a significant difference in the AMACR score (patients scheduled for radical prostatectomy p=0.0088, prebiopsy cohort p=0.029). We estimated AUCs, optimal cutoffs, sensitivities and specificities for PCa and csPCa detection in the prebiopsy cohort by tPSA, PCA3 score, PCPT Risk Calculator and classification models based on tPSA, PCA3 score and AMACR score. In the clinically significant prostate cancer ROC analysis, the PCA3 score AUC was 0.632 (95%CI: 0.511-0.752), the AMACR score AUC was 0.711 (95%CI: 0.617-0.806) and AUC of classification model based on the PCA3 score, the AMACR score and total PSA was 0.72 (95%CI: 0.58-0.83). In addition, the correlation of the AMACR score with the ratio of total RNA and RNA of prostate cells in urine was shown (tau=0.347, p=6.542e-09). Significant amounts of nonprostate RNA in urine may be a limitation for the AMACR score use. Conclusion The AMACR score is a good predictor of clinically significant prostate cancer. Significant amounts of nonprostate RNA in urine may be a limitation for the AMACR score use. Evaluation of the AMACR score and classification models based on it for clinically significant prostate cancer detection with larger samples and a follow-up analysis is promising.

Inorganic ions are essential factors stabilizing nucleosome structure; however, many aspects of their effects on DNA transactions in chromatin remain unknown. Here, differential effects of K(+) and Na(+) on the nucleosome structure, stability, and interactions with protein complex FACT (FAcilitates Chromatin Transcription), poly(ADP-ribose) polymerase 1, and RNA polymerase II were studied using primarily single-particle Förster resonance energy transfer microscopy. The maximal stabilizing effect of K(+) on a nucleosome structure was observed at ca. 80–150 mM, and it decreased slightly at 40 mM and considerably at >300 mM. The stabilizing effect of Na(+) is noticeably lower than that of K(+) and progressively decreases at ion concentrations higher than 40 mM. At 150 mM, Na(+) ions support more efficient reorganization of nucleosome structure by poly(ADP-ribose) polymerase 1 and ATP-independent uncoiling of nucleosomal DNA by FACT as compared with K(+) ions. In contrast, transcription through a nucleosome is nearly insensitive to K(+) or Na(+) environment. Taken together, the data indicate that K(+) environment is more preserving for chromatin structure during various nucleosome transactions than Na(+) environment.

Salinomycin (SAL), a polyether antibiotic exerting K

The need to formulate qualifications and prepare students for the digital future is changing the teaching strategies and approaches to university education in the direction of digital design of the learning process. The expandable space of accessible data allows the use of new educational data mining (EDM) methods in order to explore unique data types, understand student actions activity, predict academic results, improve process performance, make management decisions and adapt the learning environment. The objective of this study is to create a personalized educational environment for individual accompaniment support of students on the basis of a model of cognitive potential. The task of supporting the learning process is to obtain information on the dynamics of cognitive growth (“growth” of the knowledge level) of each student based on the data obtained during the learning process. The task of differentiating students, predicting the success of training to improve the adaptation and customization of the learning process is considered. An approach to predicting the success of learning based on a cognitive model is important for understanding the productivity of learning materials by students in an informationrich environment. The task of differentiating students, predicting the success of learning to improve adaptation and tuning the learning process is considered. Organization of feedback in the structure of the learning process based on student differentiation allows you to manage and customize learning scenarios to improve the adaptation of the individual process. An integrated web environment combines traditional learning tools with innovative digital online tools.

The article covers a comparative and cognitive review of English proverbs about friends and enemies including their etymological aspects and the historical viewpoint. The aim was to determine the way a proverb fulfils its function as a country-specific element within historical and cultural context and reflects kinds and stages of cognition. The cognitive analysis of friend- and enemy-related paroemias’ implications as well as the association test based on friend and enemy stimulus words were carried out. Based on the research findings, a proverb is seen as a condensed wise saying having potential to actualize a fragment of worldview in a semantically accurate non-ambiguous way in the given context, but having a wider range of implications and interpretations at its core. The association test with friend and enemy stimulus words demonstrates a more limited list of reactions predominantly based on personal experience and basic associations, thus resulting in positive reactions to a friend stimulus word and negative ones to an enemy counterpart. It can be concluded that the proverbs’ etymological aspect turns out to be an essential ground to understand the roots and dynamics of cognitive processes and the worldview as its fundamental component of a particular nation or society. A comparative analysis of proverbs with the given key notions in different languages helps to find evidence of the universal core elements of cognition as well as country-related variations. A cognitive review of friend- and enemy-related proverbs results in a wide scope of implications tending to embody relatively polar interpretations.

A great variety of coumarin-related compounds, both natural and synthetic, being often brightly fluorescent, have shown themselves beneficial in medicine for both therapeutic and imaging purposes. Here, in search for effective uncouplers of oxidative phosphorylation, we synthesized a series of 7-hydroxycoumarin (umbelliferone, UB) derivatives combining rather high membrane affinity with the presence of a hydroxyl group deprotonable at physiological pH - alkyl esters of umbelliferone-4-acetic acid (UB-4 esters) differing in alkyl chain length. Addition of UB-4 esters to isolated rat liver mitochondria (RLM) resulted in their rapid depolarization, unexpectedly followed by membrane potential recovery on a minute time scale. According to TLC and HPLC data, incubation of RLM with UB-4 esters caused their hydrolysis, which led to disappearance of the uncoupling activity (recoupling). Both mitochondrial recoupling and hydrolysis of UB-4 esters were suppressed by inhibitors of mitochondrial aldehyde dehydrogenase (ALDH2), disulfiram and daidzin, thus pointing to the involvement of this enzyme in the recoupling of RLM incubated with UB-4 esters. The protonophoric mechanism of mitochondrial uncoupling by UB-4 esters was proved in experiments with artificial bilayer lipid membranes (BLM): these compounds induced proton-selective electrical current across planar BLM and caused dissipation of pH gradient on liposomes. UB-4 esters showed antibacterial activity against Bacillus subtilis, Staphylococcus aureus and Mycobacterium smegmatis.

Usnic acid (UA), a unique lichen metabolite, is a protonophoric uncoupler of oxidative phosphorylation, widely known as a weight-loss dietary supplement. In contrast to conventional proton-shuttling mitochondrial uncouplers, UA was found to carry protons across lipid membranes via the induction of an electrogenic proton exchange for calcium or magnesium cations. Here, we evaluated the ability of various divalent metal cations to stimulate a proton transport through both planar and vesicular bilayer lipid membranes by measuring the transmembrane electrical current and fluorescence-detected pH gradient dissipation in pyranine-loaded liposomes, respectively. Thus, we obtained the following selectivity series of calcium, magnesium, zinc, manganese and copper cations: Zn2+ > Mn2+ > Mg2+ > Ca2+ >> Cu2+. Remarkably, Cu2+ appeared to suppress the UA-mediated proton transport in both lipid membrane systems. The data on the divalent metal cation/proton exchange were supported by circular dichroism spectroscopy of UA in the presence of the corresponding cations.

Protonophores are compounds capable of electrogenic transport of protons across membranes. Protonophores have been intensively studied over the past 50 years owing to their ability to uncouple oxidation and phosphorylation in mitochondria and chloroplasts. The action mechanism of classical uncouplers, such as DNP and CCCP, in mitochondria is believed to be related to their protonophoric activity; i.e., their ability to transfer protons across the lipid part of the mitochondrial membrane. Given the recently revealed deviations in the correlation between the protonophoric activity of some uncouplers and their ability to stimulate mitochondrial respiration, this review addresses the involvement of some proteins of the inner mitochondrial membrane, such as the ATP/ADP antiporter, dicarboxylate carrier, and ATPase, in the uncoupling process. However, these deviations do not contradict the Mitchell theory but point to a more complex nature of the interaction of DNP, CCCP, and other uncouplers with mitochondrial membranes. Therefore, a detailed investigation of the action mechanism of uncouplers is required for a more successful pharmacological use, including their antibacterial, antiviral, anticancer, as well as cardio-, neuro-, and nephroprotective effects.

The Moodle environment provides student performance data based on midterm and control tests. The extension of the interface by means of intelligent agents and software implementation in the VBA Excel environment allows the use of algorithms for statistical data analysis and the formation of grade sheets for the purpose of a more detailed visual presentation of the learning outcomes. Algorithms for the functioning of intelligent agents have been developed to generate reports for a single control test and a set of tests for the course being studied.

Cognitive load regulation and management process in the education is becoming one of the central problems in an information-rich learning environment. Many different factors must be taken into account for the effectively analyze human learning processes. The research examines the differences in cognitive tasks solving with the presence of visual uncertainty in an integrated educational environment. The analysis of individual differences allows predicting the cognitive load distribution in the educational process and managing the individual learning process. This method is based on the information-theoretic approach and the computational complexity theory of A.N. Kolmogorov.

Due to the engine’s start/stop system and a sudden increase in speed or load, the development of alloys suitable for engine bearings requires excellent tribological properties and high mechanical properties. Including additional elements in the Al-rich matrix of these anti-friction alloys should strengthen their tribological properties. The novelty of this work is in constructing a suitable artificial neural network (ANN) architecture for highly accurate modeling and prediction of the mechanical properties of the bearing aluminum-based alloys and thus optimizing the chemical composition for high mechanical properties. In addition, the study points out the impact of soft and more solid phases on the mechanical properties of these alloys. For this purpose, a huge number of alloys (198 alloys) with different chemical compositions combined from Sn, Pb, Cu, Mg, Zn, Si, Ni, Bi, Ti, Mn, Fe, and Al) were cast, annealed, and tested for determining their mechanical properties. The annealed sample microstructure analysis revealed the formation of soft structural inclusions (Sn-rich, Sn-Pb, and Pb-Sn phases) and solid phase inclusions (strengthened phase, Al2Cu). The mechanical properties of ultimate tensile strength (σu), Brinell hardness (HB), and elongation to failure (δ) were used as control responses for constructing the ANN network. The constructed network was optimized by attempting different network architecture designs to reach minimal errors. Besides the excellent tribological characteristics of the designed set of alloys, soft inclusions based on Sn and Pb and solid-phase Cu inclusions fulfilled the necessary level of mechanical properties for anti-friction alloys; the maximum mechanical properties reached were: σu = 197 ± 7 MPa, HB = 77 ± 4, and δ = 20.3 ± 1.0%. The optimal ANN architecture with the lowest errors (correlation coefficient (R) = 0.94, root mean square error (RMSE) = 3.5, and average actual relative error (AARE) = 1.0%) had two hidden layers with 20 neurons. The model was validated by additional experiments, and the characteristics of the new alloys were accurately predicted with a low level of errors: R ≥ 0.97, RMSE = 1–2.65, and AARE ˂ 10%.

2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in “diet pills”, despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP’s uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP’s protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1.

2, 4-dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria and directly increases the metabolic rate by increasing the body’s heat generation. It is still used as a “diet pill” despite its high toxicity and lack of antidotes. DNP increases the proton current through the pure lipid membranes similar to other chemical uncouplers. However, the molecular mechanism of its action in mitochondria is far from being understood. Since DNP´s protonophoric function in mitochondria is known to be sensitive to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), we hypothesized that DNP modifies the activity of ANT and other mitochondrial proton-transporting proteins. To test this hypothesis, we investigated the contribution of recombinant ANT1 or uncoupling proteins UCP2 and UCP3 to the DNP-mediated proton leak using the well-defined model of the planar bilayer membranes. All three proteins significantly enhanced the DNP-mediated proton transport, an activity previously known to happen only in the presence of long-chain free fatty acids. Using site-directed mutagenesis and molecular dynamic simulations we have shown that arginine 79 of ANT1 is crucial for the DNP-mediated increase of the membrane conductance, implying that this amino acid participates in DNP binding to ANT1. &nbsp

2, 4-dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria and directly increases the metabolic rate by increasing the body’s heat generation. It is still used as a “diet pill” despite its high toxicity and lack of antidotes. DNP increases the proton current through the pure lipid membranes similar to other chemical uncouplers. However, the molecular mechanism of its action in mitochondria is far from being understood. Since DNP´s protonophoric function in mitochondria is known to be sensitive to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), we hypothesized that DNP modifies the activity of ANT and other mitochondrial proton-transporting proteins. To test this hypothesis, we investigated the contribution of recombinant ANT1 or uncoupling proteins UCP2 and UCP3 to the DNP-mediated proton leak using the well-defined model of the planar bilayer membranes. All three proteins significantly enhanced the DNP-mediated proton transport, an activity previously known to happen only in the presence of long-chain free fatty acids. Using site-directed mutagenesis and molecular dynamic simulations we have shown that arginine 79 of ANT1 is crucial for the DNP-mediated increase of the membrane conductance, implying that this amino acid participates in DNP binding to ANT1. &nbsp

2-(2-Hydroxyaryl)alkenylphosphonium salts (here coined as PPR) representing derivatives of quaternary phosphonium with two phenyl (P) and one alkyl (R) substituents linked through alkenyl bridge to substituted phenol were applied here to planar bilayer lipid membranes (BLM), isolated mitochondria, and cell culture. PPR with six carbon atoms in R (PP6) induced proton-selective currents across BLM and caused mitochondrial uncoupling. In particular, PP6 at submicromolar concentrations accelerated respiration, decreased membrane potential, and reduced ATP synthesis in isolated rat liver mitochondria (RLM). Methylation of a hydroxyl group substantially suppressed the protonophoric activity of PP6 on BLM and its uncoupling potency in RLM. Of note, the methylated derivative PP6-OMe was synthesized here via a new synthetic route including cyclization of PP6 with subsequent ring opening. PPR were considered as protonophoric uncouplers of a zwitterionic type, capable of penetrating membranes both as a zwitterion composed of a deprotonated phenol and a cationic quaternary phosphonium, and as a protonated cation. The protonophoric and uncoupling properties of PPR found here were speculated to account for their strong antibacterial activity described previously.

Usnic acid (UA), an old antibiotic and one of the first described mitochondrial uncouplers, has demonstrated many beneficial activities, such as antimicrobial, antiviral, antitumour and anti-inflammatory properties. Here, we performed a thorough investigation of effects of usnic acid and its analogues on artificial planar bilayer lipid membrane (BLM), rat liver mitochondria and bacteria. Surprisingly enough, all of the three hydroxyl groups of UA appeared to be involved in its proton-shuttling activity on BLM. We ascribed this fact to an ability of UA to form complexes with calcium ions, aiding it in cycling protons across the membrane. Actually, the addition of calcium ions markedly stimulated the UA-induced electrical current across BLM. By using the calcium ionophore A23187, we proved the involvement of calcium ions in the UA uncoupling action on isolated rat liver mitochondria. The calcium-chelating property of UA was demonstrated here by the method of extracting metal ions into a hydrophobic phase. Modification of any of the hydroxyl groups in UA dramatically reduced not only the UA-induced current across BLM and the UA-mediated calcium extraction, but also the uncoupling activity of UA in mitochondria and the inhibiting effect of UA on the growth of Bacillus subtilis. The ability of UA to cause dissipation of membrane potential in isolated liver mitochondria and bacterial cells was shown here for the first time. In view of the data obtained, the protonophoric activity of UA is considered to make a significant contribution to its antibacterial action.

The productivity of intellectual activity in any professional field is characterized by the accuracy of decision-making and reaction time. When analyzing these characteristics, the features of the information-rich electronic environment are taken into account, in particular in educational, scientific activities, in which there is information content characterized by visual uncertainty. The consequence of the presence of visual uncertainty in information stimuli is an increase in cognitive load, which can lead to errors in information perception and decision-making by a person. The paper proposes a method for automated analysis of the accuracy and time of solving cognitive test tasks in conditions of visual uncertainty. The method is based on the application of computational complexity theory, in particular on the estimation of the amount of algorithmic entropy of A.N. Kolmogorov in the visual stimuli. The results of research on the examples of solving cognitive tasks in an automated environment using intelligent agents are presented.

In the process of operation of cyber-physical systems, a sufficiently large and heterogeneous set of data is formed - data on custody transfer, data from sensors, data on the state of equipment, etc. To process such data, it is necessary to develop rules for processing raw information, correlate information from different systems, find patterns and analyze the information received. For this task, you can use systems of the class of analytical platforms, otherwise called Business Intelligence Systems.

Appending lipophilic cations to small molecules has been widely used to produce mitochondria-targeted compounds with specific activities. In this work, we obtained a series of derivatives of the well-known fluorescent dye 7-nitrobenzo-2-oxa-1,3-diazole (NBD). According to the previous data [Denisov et al. (2014) Bioelectrochemistry, 98, 30-38], alkyl derivatives of NBD can uncouple isolated mitochondria at concentration of tens of micromoles despite a high pK(a) value (similar to 11) of the dissociating group. Here, a number of triphenylphosphonium (TPP) derivatives linked to NBD via hydrocarbon spacers of varying length (C5, C8, C10, and C12) were synthesized (mitoNBD analogues), which accumulated in the mitochondria in an energy-dependent manner. NBD-C10-TPP (C10-mitoNBD) acted as a protonophore in artificial lipid membranes (liposomes) and uncoupled isolated mitochondria at micromolar concentrations, while the derivative with a shorter linker (NBD-C5-TPP, or C5-mitoNBD) exhibited no such activities. In accordance with this data, C10-mitoNBD was significantly more efficient than C5-mitoNBD in suppressing the growth of Bacillus subtilis. C10-mitoNBD and C12-mitoNBD demonstrated the highest antibacterial activity among the investigated analogues. C10-mitoNBD also exhibited the neuroprotective effect in the rat model of traumatic brain injury.