Molecular Mechanisms of Aberrant Neuroplasticity in Autism Spectrum Disorders (Review).

This review presents the analysis and systematization of modern data on the molecular mechanisms of autism spectrum disorders (ASD) development. Polyetiology and the multifactorial nature of ASD have been proved. The attempt has been made to jointly review and systematize current hypotheses of ASD pathogenesis at the molecular level from the standpoint of aberrant brain plasticity. The mechanism of glutamate excitotoxicity formation, the effect of imbalance of neuroactive amino acids and their derivatives, neurotransmitters, and hormones on the ASD formation have been considered in detail. The strengths and weaknesses of the proposed hypotheses have been analyzed from the standpoint of evidence-based medicine. The conclusion has been drawn on the leading role of glutamate excitotoxicity as a biochemical mechanism of aberrant neuroplasticity accompanied by oxidative stress and mitochondrial dysfunction. The mechanism of aberrant neuroplasticity has also been traced at the critical moments of the nervous system development taking into account the influence of various factors of the internal and external environment. New approaches to searching for ASD molecular markers have been considered.

[Reconstruction of gene network associated with Parkinson disease for gene targets search]. / Rekonstruktsiia gennoi seti bolezni Parkinsona dlia poiska genov-mishenei.

Accumulation of genetic data in the field of Parkinson's disease research culminated in identifying risk factors and confident prediction of the disease occurrence. To find new gene-targets for diagnostics and therapy we have to reconstruct gene network of the disease, to cluster genes in the network, to reveal key (hub) genes with largest number of interactions in the network. Using the on-line bioinformatics tools OMIM, PANTHER, g:Profiler, GeneMANIA, and STRING-DB, we have analyzed the current array of data related to Parkinson's disease, calculated the categories of gene ontologies for a large list of genes, visualized them, and built gene networks containing the identified key objects and their relationships. However, translating the results into biological understanding is still a promising major challenge. The analysis of the genes associated with the disease, the assessment of their place in the gene network (connectivity) allows us to evaluate them as target genes for medicinal effects.

Change of Antigenic Determinants of SARS-CoV-2 Virus S-Protein as a Possible Cause of Antibody-Dependent Enhancement of Virus Infection and Cytokine Storm.

A hypothesis is proposed that the cytokine storm syndrome, which complicates COVID-19 in some patients, is a consequence of antibody-dependent enhancement of virus infection, which is in turn happens due to a change in dominant antigenic determinants of SARS-CoV-2 S-protein. The antibody-dependent enhancement of virus infection is a phenomenon in which virus-specific antibodies that are not neutralizing enhance the entry of infectious virus into immune cells causing their death. Antibody-dependent enhancement has been reported for different coronaviruses. This phenomenon happens due to a decrease in the binding strength of neutralizing antibodies to the virus, which converts these antibodies into suboptimal-not neutralizing ones. According to our hypothesis, such a decrease in affinity may be associated with a change in the conformation of the viral S-protein. We believe that this conformational change is the major factor in the switching of antibodies affinity, which triggers antibody-dependent enhancement. However, other factors that contribute to antigen drift and antigenic determinant changes may also play a role.

[Exposure to toxic dose of adrenaline on the functional state of the liver].

The purpose: The blood biochemical parameters characterizing the functional state of the liver, and the morphological profile of the body after a single exposure to a toxic dose of adrenaline were studied. Methods: Studies were conducted on 60 adult rats (female) weighing 0.15-0.2 kg, were divided into groups: intact animals; experience - animals, injected with epinephrine hydrochloride intraperitoneally in a dose of 0.5 mg/kg. All kinds of Biological material (blood, liver) were collected out through one and ten days after the start of the experiment. The degree of influence of high doses of epinephrine were evaluated in terms of lipid peroxidation (LPO) and protein (PSP) in liver homogenates, the concentration of average weight molecules (MSM), the activity of ALT, AST, alkaline phosphatase, LDH, total protein concentration, glucose and lactate in the blood plasma, as well as the determination of the prothrombin time (PTT) with the counting on the basis thereof of international normalized ration (INR). Histology of the liver was studied by light microscopy. Results: It was found that throughout the experiment, there was an increased in the concentration of lipid peroxidation products and protein in liver homogenates, there was an increase in the concentration of MSM 1.7. Twenty-four hours after the administration of a toxic dose of adrenaline observed hyperenzymemia that manifested an increase in the activity of ALT and AST, was an increase in LDH. After 10-day five after the start of the experiment established the presence hyperenzymemia activity decreased ALT and AST, LDH activity remained elevated, total protein level was higher than in the group of animal in which investigations were conducted one day after the start of the experiment, PTV also continued to decline. In histological sections of the development of a pathological condition characterized by circulatory disturbance - plasmatization, both in central and in small vessels. From the hepatocytes both in the center and the periphery had changes granular dystrophy type, to some extent vacuolar.

[Classification of amino acids based on a comparative analysis of contacts in DNA-protein complexes and specific DNA-protein interactions].

The classification of amino acid residues based on the events of contact formation between distinct amino acid and selected nucleotides was constructed. Thus, the most integral properties, that characterize interactions in organization of DNA-protein complexes, were used. We applied the Voronoi-Delaunay tessellation to draw statistics of contacts and area of contacts for the set included 1937 DNA-protein complexes. Similarities of amino acid residues have been searched for based on the comparison of corresponded rows and matrixes of contacts and areas of contacts. Nine measures of distance were used for estimation of rows similarity degree. The procedure of clustering amino acids in groups included three hierarchical and two nonhierarchical methods. A total tree was built using nine techniques of estimating distance with three hierarchical clustering methods. It was shown that clustering centers in the main groups are always constant while other relationships between objects vary. Clustering of binary associations was found for the most amino acids. Major classes of up to six amino acids correspond to the certain local structures of the polypeptide chain in the context of amino acid composition. These data should be taken into account when designing DNA-protein ligands.

[Conformationally stable segments in helical structures of polypeptide chains of proteins and their role in high level structures formation].

In the work the arguments are presented in favor of the idea on the role of conformationally stable oligo-peptides in specific long-distance interactions in phenomena of molecular recognition during various biological processes. Original authors' and literature data are taken into account. The examples of conformationally stable short oligopeptides participation in alpha-helix and collagen type structures formation are given simultaneously with theoretical approaches. The conformationally stable oligopeptides obtained in the course of PDB bank analysis are discussed. The role of amino acids sequence in collagen helix formation is shown.

[DNA sequencing using specific long-range interaction between macromolecules].

On the basis of the theory of specific long-range interaction between long molecules the approach has been elaborated for the "fast reading" of nucleotide sequences in sole DNA molecule. Firstly, a stretching force applies to the molecule that causes its unwinding from B-form to so called S-form. Then, a molecule disposes in a stretched state on the background. After this, the electrostatic potential is estimated in the space along the DNA filament. Information obtained is sufficient for the deduction of the nucleotide sequence in DNA. Another approach to the "reading" of information reduces to the measurement of the filament element deformation induced by electrostatic field from the electrode that stretches the filament by alternating current applied.

[Analysis of DNA-ligand binding in solution and on biochips].

Ligand binding to DNA, as well as to microarrays, requires a system approach to description and analysis. This type of approach implies a fixed sequence of operations. Firstly, it is necessary to make a description of a binding scheme that realizes ligand and polymer in common spatial way. Secondly, a physical model of binding is required. Thirdly, a mathematical binding model should be constructed on the basis of the binding scheme and the physical model of binding. Every analysis of experimental data needs this preliminary work. A mathematical apparatus and classification of binding models have to follow on. Classification of different binding isotherms by different binding models is the direct problem. The inverse problem is a reconstruction of parameters of a binding model by experimental binding isotherm curves. The inverse problem can only be solved after solving the direct problem. An example of classification of binding models by oligonucleotides or proteins binding cooperativity and polymer properties like homo- or heteropolymer is presented.

[Geometrical analysis of protein-DNA interactions on the basis of the Voronoi-Delaune tessellation].

A new method for the rigorous analysis of DNA-protein contacts has been developed on the basis of Voronoi tessellation. This method permits one to determine close neighbors on the atomic level and compute the area of contact by edges of Voronoi polyhedra. Based on the results of the study of 1109 protein-DNA complexes from PDB, it was demonstrated that about one third of the contacts are the contacts with positively charged Arg and Lys. There is distinct amino acid prevalence for nucleotides: for A - Pro; for T - His; for G - Asp; for C - Trp, Asp, Glu. Therefore, GC pairs prefer to interact with negatively charged residues, and alanine and methionine, whereas AT pairs prefer to interact with histidine and unpolar residues.