Bioinformatics education course on gene networks reconstruction using online tools

Bioinformatics education requires the use of online computer tools for modeling protein-protein interactions, visual presentation of the networks, access to open databases. The usage of online bioinformatics tools makes it possible to reconstruct both protein and genes networks, and develop modeling skills for students. We consider the issues of computer reconstruction of gene networks - complexes of interacting macromolecules - using a list of genes associated with a particular disease, or a complex disorder based on public online bioinformatics tools - STRINGDB, GeneMANIA, Metascape, Cytoscape applications. Examples of computer reconstruction and visualization of gene networks of oncological diseases including glioma, breast cancer, as well as complex mental disorders such as Parkinson’s disease, schizophrenia, were recently published in co-authorship with the students. The use of only online bioinformatics tools is educational in nature, focused on students, both in mathematics and in natural sciences and medical disciplines, who do not have enough skills in computer science, programming, and writing their own code. Automatic construction of lists of genes associated with a disease using open databases (OMIM, GeneCards, MalaCards), computer reconstruction of gene networks, calculations of enrichment statistics for gene ontology categories have been successfully mastered by students. The educational bioinformatics materials designed for the students and with the students were tested at several universities in Russia, including courses in English for foreign students studied in Russia. The tasks of digitalization of medicine, the development of IT technologies are in the priority. The epidemic situation that has existed in recent years and the forced transition to distance learning had accelerated the adoption of measures to change the formats of education, the emergence of new learning platforms. Note a number of qualitatively new tasks of education in the field of digital healthcare, such as the use of blockchain technologies, the use of Artificial Intelligence (AI) methods in support of medical decision-making. Overall, the educational course developed includes a theoretical part (video lessons) and a practical part - performing tasks on the use of computer programs and databases that have found a number of applications for medical problems in the reconstruction and analysis of networks of interactions of macromolecules.Book of abstract: 4th Belgrade Bioinformatics Conference, June 19-23, 202

The use of argon plasma coagulation in mammoplasty as a prevention of postoperative complications

The frequency of reoperations associated with complications after mammoplasty reaches 15 % during the first year. There are many ways and means for processing the soft tissues of the breast during mammoplasty, helping to reduce the risk of postoperative complications. The purpose of this work was to develop an algorithm for the application of the argon plasma technique for tissue treatment in mammoplasty. Material and methods. The study included 30 females aged 23 to 46 who underwent mammoplasty. The patients were divided into 2 groups of 15 people. In group 1, standard methods of processing soft tissues were used, and in group 2, the argon plasma technique was used in conjunction with the use of Aristo glue. Patients were observed in the early, late and distant postoperative period. Results. In the course of the study, in addition to the excellent coagulation and bactericidal action of argon plasma, the effect of “pulling up” the soft tissues of the mammary gland was found, which, in case of ptosis of I and II degrees, made it possible to use a smaller implant to achieve an optimal aesthetic result. Also, when using the argon plasma technology, no inflammatory processes were observed, the amount of exudative fluid in the drains decreased, the pain syndrome was significantly less pronounced in comparison with patients who underwent the standard method of tissue processing. Conclusions. This study confirms the fact that the use of argon plasma coagulation in the processing of breast tissue has a significant number of advantages compared to standard methods

Entropy Analysis of Protein Sequences Reveals a Hierarchical Organization

Background: Analyzing the local sequence content in proteins, earlier we found that amino acid residue frequencies differ on various distances between amino acid positions in the sequence, assuming the existence of structural units. Methods: We used informational entropy of protein sequences to find that the structural unit of proteins is a block of adjacent amino acid residues—“information unit”. The ANIS (ANalysis of Informational Structure) method uses these information units for revealing hierarchically organized Elements of the Information Structure (ELIS) in amino acid sequences. Results: The developed mathematical apparatus gives stable results on the structural unit description even with a significant variation in the parameters. The optimal length of the information unit is five, and the number of allowed substitutions is one. Examples of the application of the method for the design of protein molecules, intermolecular interactions analysis, and the study of the mechanisms of functioning of protein molecular machines are given. Conclusions: ANIS method makes it possible not only to analyze native proteins but also to design artificial polypeptide chains with a given spatial organization and, possibly, function

Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation

Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ42 oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ42 interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ42 monomer, triggering Src kinase activation. The co-localization of Aβ42 with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ42 causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ42 with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ42 on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ42 receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ42 in the nervous system

Cysteine residues 244 and 458-459 within the catalytic subunit of Na,K-ATPase control the enzyme's hydrolytic and signaling function under hypoxic conditions

Our previous findings suggested that reversible thiol modifications of cysteine residues within the actuator (AD) and nucleotide binding domain (NBD) of the Na,K-ATPase may represent a powerful regulatory mechanism conveying redox- and oxygen-sensitivity of this multifunctional enzyme. S-glutathionylation of Cys244 in the AD and Cys 454-458-459 in the NBD inhibited the enzyme and protected cysteines' thiol groups from irreversible oxidation under hypoxic conditions. In this study mutagenesis approach was used to assess the role these cysteines play in regulation of the Na,K-ATPase hydrolytic and signaling functions. Several constructs of mouse α1 subunit of the Na,K-ATPase were produced in which Cys244, Cys 454-458-459 or Cys 244-454-458-459 were replaced by alanine. These constructs were expressed in human HEK293 cells. Non-transfected cells and those expressing murine α1 subunit were exposed to hypoxia or treated with oxidized glutathione (GSSG). Both conditions induced inhibition of the wild type Na,K-ATPase. Enzymes containing mutated mouse α1 lacking Cys244 or all four cysteines (Cys 244-454-458-459) were insensitive to hypoxia. Inhibitory effect of GSSG was observed for wild type murine Na,K-ATPase, but was less pronounced in Cys454-458-459Ala mutant and completely absent in the Cys244Ala and Cys 244-454-458-459Ala mutants. In cells, expressing wild type enzyme, ouabain induced activation of Src and Erk kinases under normoxic conditions, whereas under hypoxic conditions this effect was inversed. Cys454-458-459Ala substitution abolished Src kinase activation in response to ouabain treatment, uncoupled Src from Erk signaling, and interfered with O2-sensitivity of Na,K-ATPase signaling function. Moreover, modeling predicted that S-glutathionylation of Cys 458 and 459 should prevent inhibitory binding of Src to NBD. Our data indicate for the first time that cysteine residues within the AD and NBD influence hydrolytic as well as receptor function of the Na,K-ATPase and alter responses of the enzyme to hypoxia or upon treatment with cardiotonic steroids

Hemoglobin is an oxygen-dependent glutathione buffer adapting the intracellular reduced glutathione levels to oxygen availability

Fast changes in environmental oxygen availability translate into shifts in mitochondrial free radical production. An increase in intraerythrocytic reduced glutathione (GSH) during deoxygenation would support the detoxification of exogenous oxidants released into the circulation from hypoxic peripheral tissues. Although reported, the mechanism behind this acute oxygen-dependent regulation of GSH in red blood cells remains unknown. This study explores the role of hemoglobin (Hb) in the oxygen-dependent modulation of GSH levels in red blood cells. We have demonstrated that a decrease in Hb O2 saturation to 50% or less observed in healthy humans while at high altitude, or in red blood cell suspensions results in rising of the intraerythrocytic GSH level that is proportional to the reduction in Hb O2 saturation. This effect was not caused by the stimulation of GSH de novo synthesis or its release during deglutathionylation of Hb's cysteines. Using isothermal titration calorimetry and in silico modeling, we observed the non-covalent binding of four molecules of GSH to oxy-Hb and the release of two of them upon deoxygenation. Localization of the GSH binding sites within the Hb molecule was identified. Oxygen-dependent binding of GSH to oxy-Hb and its release upon deoxygenation occurred reciprocally to the binding and release of 2,3-bisphosphoglycerate. Furthermore, noncovalent binding of GSH to Hb moderately increased Hb oxygen affinity. Taken together, our findings have identified an adaptive mechanism by which red blood cells may provide an advanced antioxidant defense to respond to oxidative challenges immediately upon deoxygenation

Evolutionary Invariant of the Structure of DNA Double Helix in RNAP II Core Promoters

Eukaryotic and archaeal RNA polymerase II (POL II) machinery is highly conserved, regardless of the extreme changes in promoter sequences in different organisms. The goal of our work is to find the cause of this conservatism. The representative sets of aligned promoter sequences of fifteen organisms belonging to different evolutional stages were studied. Their textual profiles, as well as profiles of the indexes that characterize the secondary structure and the mechanical and physicochemical properties, were analyzed. The evolutionarily stable, extremely heterogeneous special secondary structure of POL II core promoters was revealed, which includes two singular regions—hexanucleotide “INR” around TSS and octanucleotide “TATA element” of about −28 bp upstream. Such structures may have developed at some stage of evolution. It turned out to be so well matched for the pre-initiation complex formation and the subsequent initiation of transcription for POL II machinery that in the course of evolution there were selected only those nucleotide sequences that were able to reproduce these structural properties. The individual features of specific sequences representing the singular region of the promoter of each gene can affect the kinetics of DNA-protein complex formation and facilitate strand separation in double-stranded DNA at the TSS position

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