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The article discusses the properties of the pandemic strain XBB.1.5 S protein in comparison with the 1918 and 2009 pandemic strains hemagglutinin H1. The S-protein XBB.1.5 already contains more than 40 mutations realized by substituting different amino acids through single and dinucleotide substitutions, deletions and the use of predominantly transversions. The variability of H1N1 influenza virus hemagglutinin is associated with single nucleotide substitutions at a constant length. Conditional extrapolation of influenza virus hemagglutinin variability data on coronavirus S-protein sizes suggests that new pandemic strains will emerge in the next 2-3 years, avoiding the immune defense formed by vaccination against the strains preceding them. The inability to create through the adaptive immune system a long-term immunity to pandemic coronaviruses, as well as to other respiratory viruses with a short incubation cycle, puts on the agenda the need to find new vaccine designs that provide a combination of long-term adaptive and trained immunity. The problem in the search for such vaccines is associated with the regulation of the activity of the innate immune system and ensuring the stability of trained immunity.

The article discusses the residual effects of survivors of COVID-19, referred to as long-term covid, a short list of their manifestations, their possible causes and difficulties of recognition. Changes in the primary structure of emerging coronaviruses from the Wuhan strain to new omicron strains are analyzed. Among the features of their evolution, there is an increase in the content of arginine and lysine, especially in the S1 subunit, and a decrease in the proportion of aspartic and glutamic amino acids. The receptorbinding domain of omicrons is characterized by a tendency to decrease the content of threonine, serine and glutamine. Mutations in the S protein are characterized by asymmetry in relation to both substitutable and substitutive amino acids. Isoleucine and cysteine are not replaced. Certain trends and limitations in the mutations of their S protein and especially the unusual ratio transversion: transitions in them argue for the version of the artificial origin of the SARS-Cov-2 variants. At the level of the S protein genes, there are prohibitions regarding the use of certain codons. To assess the effectiveness of vaccines and the sensitivity of coronaviruses to them during a pandemic, it is useful to divide pandemic coronaviruses into two groups: omicrons and pre-omicrons. This division is justified by the fact that these groups differ sharply in the number of mutations and changes in the composition of immune epitopes, especially in the receptor-binding domain. The specific tendency of changes in its amino acid composition, apparently, is associated with a consistent decrease in pathogenicity in BA.1, BA.2, BA.4 and BA.5 variants. Taking into account these features makes it possible to predict the sensitivity of coronavirus strains to the vaccines used and rationally design vaccines with a wide range of specificity.

Relevance of searching for computer methods with high efficiency of immunoepitopes recognition and predicting the longevity of the immunity they induce is determined primarily by the need to quickly create vaccines against newly emerging infections, especially during pandemic periods. Aim. To develop a new immunoinformation method for recognizing immunoepitopes, to identify in the viral proteins possible potential markers to induce long-term immunity and to evaluate by them the vaccines against Covid-19. Materials and methods. For computer analysis, an Internet-accessible databases of immunoep topes 15 and 9 amino acids long, restricted respectively by MHC I and MHC II, and peptides not binding to MHC, as well as human and virus proteins, were used. The algorithm for discriminating immunoepitopes was based on positional distinction of specific short peptides in their primary structures. Results. The «inventory» in the training samples of di- and tripeptides or pentapeptides of immunoepitopes and nonimmunoepitopes makes it possible to accurately recognize in the control samples up to 93–97% of immunoepitopes restricted by MHC I and MHC II. Comparison of the amino acid composition of proteins of subunit vaccines causing long-term immunity revealed dominance of amino acids (especially proline), which form the basis of internally disorganized regions, and proline-containing dipeptides, that allowed them to be considered as biomarkers of the potential of a viral protein to form a long-term immune memory.In the S-protein of coronavirus SARS-CoV-2 two candidates for immunospressive domains are present and the dominance of proline and dipeptides containing it is absent. Conclusion. The immunoepitope recognition method and the biomarker for inducing longterm immune memory can be used as immunoinformative tools of computational vaccinology. Providing long-term immunity by vaccines based on the coronavirus SARS-CoV-2 protein S is unlikely.

Relevance. Coronaviruses and influenza viruses induce pandemics taking away many human lives and seeding social-economic chaos. Possibility to prognose pandemic features on characteristics of surface proteins of their pathogens is not investigated.Aim is to characterize the common features of the pandemic coronavirus S-protein and the pandemic virus influenza hemagglutinin in connection with the features of a coronavirus pandemic and influenza pandemics.Materials and method. For the bioinformatic analysis the protein sequences of pandemic coronavirus strains and pandemic influenza virus strains, influenza virus strains of 2017–2018 season and also influenza virus type B strains were used. In proteins an amino acid content, the sums of the charged amino acids and the.Results. It was found out that the increase of amount of the amino acids forming intrinsically disordered regions in the coronavirus S-protein S1 subunit and influenza virus H1 hemagglutinin HA1 subunit is characteristic of the pandemics with high morbidity and the increase of arginine and lysine with comparison with aspartic and glutamic acids in those proteins is peculiar to viruses inducing the pandemics with lower lethality.Conclusion. The features (morbidity and lethality) of the coronavirus pandemic and influenza virus pandemic are associated with the quantitative amino acids content of pandemic virus surface proteins.

Relevance. Vaccines are regarded as an effective means for control of the Covid-19 pandemic spreading and their search, analysis, and comparison of their features are important for elucidating the most safe and effective one. Aim. At the end of 2020 two types of vaccines (viral based vaccines and mRNA vaccines) have been licensed to vaccinate. The aim is to compare their features for objective substantiation of their application. Conclusions. As both vaccine types have high effectiveness in inducing antibodies to SARS-Cov-2 (in more 90% recipients) the utility of each vaccine type in blocking the Covid-19 pandemic spreading is beyond doubt. In both vaccine types eventually S protein is the antigen source, and they have limitations for vaccination. In comparison with the vector vaccines mRNA vaccines may induce serious complications, have the least potential to induce trained immunity and can be included into the recipient’s genome. The low frequency of influenza cases in the current epidemic season serves as an of interference between SARS-Cov-2 and influenza viruses. In epidemic seasons after the Covid-19 pandemic coronaviruses may dominate amongst viruses inducing acute respiratory viruses diseases. It is likely that the decline of the Covid-19 case count (in December-January) in Russia is determined by the heterologous collective immunity formed earlier.

Relevance . Of the different subtypes, H3N2 influenza virus subtype has the highest variability and pathogenicity, often dominates in epidemiological seasons and induces high mortality exceeding its rate in pandemic. Aim is to identify some features of H3N2 molecular characteristics which could determine its high variability and domination over other subtypes in epidemiological seasons and discuss possible nature of the future influenza pandemic. Materials and method . For the computer analysis, the database of the hemagglutinin (HA) and nucleoprotein primary structures of the H3N2, H1N1, В \Yamagata and В \Victoria strains isolated in the influenza epidemiological seasons 2009-2019 were used from the Internet. From the primary structure of their genes it were defined their translational codes. To trace the H3N2 subtype evolution in the last decade we compared the H3 dominant sequences of adjacent seasons to establish their changes. Results. It has been indicated that H3, in comparison with H1 and В \Yamagata and В \Victoria hema g glutinins, contains more cysteine and the H3N2 strain very similar to the Hong Kong influenza virus continues to circulate in birds.The H3 gene translation code contains the least number of prohibitions. During last decade the H3 dominant sequence evolves faster than H1 one. The nucleoprotein of H3N2 strains is characterized by more content of lysine and less content of arginine. Conclusion : H3N2, H1N1, В \Yamagata and В \Victoria strains one may conclude that least of all the nature restricts H3N2 to evolve and adapt to new hosts. It is likely that the following influenza pandemic will be generated by H1N1 subtype but H3N2 one and also be more mild than the 2019 pandemic.

Relevance. The genetic recombination between viruses and men is known long ago. It can be divided on relict and ontogenic ones. For the host the recombination may display different consequences the nature of which is not exposed explicitly.Aim is to analyze (on the base of computer comparison of the primary structure of viral and human proteins ) the occurrence of twodirectional recombination by small genome fragments between viruses and men and describe its possible after-effects.Materials and methods. For this computer study human and virus protein sequences were used from data bases available in INTERNET.Results. It was indicated that recombination (cryptical and explicit) by small genome fragments between viruses and men occurred many times in the past and many viruses pathogenic for men were involved in it.Conclusion. The bioinformatics approach allows to look at the past of viruses and men and find the traces of genetic information changes between them that may predetermine the effects of vaccines and diagnostic immune tests.

Antibodies (Ab), especially natural, display multiple specificity not only due to intrinsic conformational dynamics. With computational analysis the distribution of identical and homologous peptides has been studied in surface proteins from RNA and DNA viruses of widely distributed infections. It was established that each virus protein shared the fragments homologous to other virus proteins that allowed to propose the existence of the peptide continuum of the protein relationship (PCPR). Possible manifestations of PCPR are multiple reactivity and autoreactivity in Ab and therefore it is not possible to consider the immune methods of virus identification as high reliable because of crossing interactions. The PCPR excludes the existence of 100% specificity in immune tests for virus identification. Immunodiagnostic collisions may occur either in identification of virus itself or identification of Ab to viruses. Also PCPR may be responsible for heterologous immunity and consequently the infection associated with severe pathology. The comparative analysis of peptide relationship of H1N1 influenza virus nucleoprotein and human proteins found out, beyond early described its common motif with human hypocretin receptor 2, peptides homologous to those in melanotonin and glutamate receptors and three ion channels. It allows to propose that the sleep disorder narcolepsy associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic may be determined not only by Ab to the peptide motif common to influenza nucleoprotein and hypocretin receptor but also Ab to melanotonin and glutamate receptors and ion channels. Decreasing and even avoiding risks of complications from vaccination may be feasible by means of a computer analysis of vaccine proteins for the occurrence of epitopes homologous to the human protein those and particularly by an analysis of Ab profiles induced by vaccine using microarrays with the large number of human protein antigens.

Biological limitations related to the brain regeneration and stem cells transplantation as well as the factors influencing the brain plasticity following the brain injury, including epigenetic regulatory mechanisms, are presented. Non-invasive transcranial microelectrostimulation is considered as a perspective method of polysystemic influence on endogenic mechanisms of brain recovery.Представлен краткий обзор биологических ограничений, связанных с регенерацией мозга и трансплантацией в него стволовых клеток, и факторов, влияющих на пластичность мозга при его повреждении, включая эпигенетические регуляторные механизмы. В качестве перспективного полисистемного воздействия на эндогенные механизмы восстановления мозга рассматривается неинвазивная транскраниальная микроэлектростимуляция.

Molecular aspects of pathogenesis of cardiac failure touching on transmission of pathological signals through the transduction system, involvement of mechanisms of transcriptional reprogramming and metabolic changes in the myocardium, as well as processes of aging and inflammation in the pathogenetic continuum are considered in this paper. Data on markers of early diagnosis, prognosis and progression of heart failure and perspectives of discovery of its pathogenesis within framework of developing system biology integrating analysis of multiple different in their nature biomarkers are also presented.

Abstinent syndrome is a painful condition occurring in drug addicts after cessation of drug intake. It is characterized by a broad spectrum of subjective and objective pathological conditions associated with the brain and other systems of the organism. We attempted to avoid severe complications occurring as a result of treatment of opiate abstinent syndrome (OAS) with medications or by extracorporal detoxification. For this purpose, we proposed to relieve OAS with the use of transcranial brain electrostimulation with weak unipolar impulse current, which makes it possible to change the pathological homeostasis of the brain of drug addicts [1]. This approach has a pronounced positive psychotropic effect. However, it has not always been successful in removal of the somatovegetative disorders and discomfort characteristic of OAS. A possible reason for insufficient therapeutic effect of electrostimulation in OAS treatment may be the use of unipolar impulse current. The latter predominantly exerts a hyperpolarizing effect and does not ensure disturbance of the extracellular matrix components in the brain, the corresponding change in the functional state of nerve cells, and the therapeutic effect that weak bipolar impulse current exerts in stroke, prosopalgia, and infantile cerebral paralysis [2‐4]. Another possible reason is that central mechanisms do not underlie all pathologic OAS manifestations, and it is necessary to affect not only the brain, but also other systems of the organism, whose disorders in OAS are the most pronounced and most frequent. In OAS, these are cardiovascular disorders and pain in the muscles, bones, and joints. We showed that the treatment of acute heart lesion with the use of transcranial electrostimulation [5] and algias of different genesis [4] (prosopalgia, in particular) using targeted electrostimulation was successful. For this reason, we attempted to use this method for changing and increasing the areas affected by electrostimulation in drug addicts so as to rapidly eliminate OAS without or with minimum medications, because they exert undesirable effects on psychological processes, thereby hampering the evaluation of cognitive deficit in drug addicts after the OAS elimination. The new combination of areas subjected to electrostimulation and the change in the characteristics of the current used in electrostimulation were more effective in OAS treatment and allowed us to perform preliminary examination of the cognitive abilities of drug addicts (when not in the drug addiction state). The results of these studies are described below.

The significance of immunological parameters for the prognosis of prostatic cancer is analyzed using a model of a neuronal net based on combinatorial and geometrical principles. Groups of patients with prostatic cancer with favorable and unfavorable prognosis, with and without metastases, have specific spaces for changes in immunological parameters. By immunological parameters these groups are differentiated from each other and from healthy subjects and patients with prostatitis, prostatic adenoma, and their combinations.

Relations of immune tolerance between mother and fetus are considered in view of a common regulatory continuum which is formed under the influence of a growing fetus. To explain such an immune tolerance, a notion of immune system plasticity is introduced, as an analogue to the nervous system plasticity, which develops in response to a continuum of changes occurring in fetal and maternal organisms during the nine months of pregnancy. The immune system plasticity in females is supposed to be among possible factors causing collisions upon conception and in the course of pregnancy. (Med. Immunol., 2011, vol. 13, N 2-3, pp 121-132 )

A new method of therapy of children with cerebral palsy (CP) has been elaborated. Transitory consequent action of weak bipolar low-frequency current (30-100 mcA, 2-10 Hz) on different levels of motor activity regulation (brain and spinal cord, effectory organs) resulted in a stable correction of both motor and other types of disorders in CP patients. Therapeutic course included 2-8 procedures, 1-2 weekly, their duration 3-5 minutes. Depending on the reaction on the transcraniovertebral microelectrostimulation (MES) the patients were divided into fast and slow reactive groups. Different reaction of the children to MES reflected, probably, a variety of pathogenetic CP mechanisms and a mosaic of cerebral damage. Corrective MES action on the patients' brain was polysystemic and was, probably, based on the changes in integral brain mechanisms, voluminous transmission and homeostasis of brain, in particular.

Screening of more than twenty short synthetic peptides characteristic of different proteins has revealed antimicrobial activity of the KRFAE peptide--from human preproenkephalin A against gram-negative bacteria. Modification of the peptide structure by means of administration of d-amino acids has permitted obtaining dKRFdLE analogue with the expressed and stable antimicrobial activity in vitro when growing bacteria on the minimum glucose-mineral medium. Changes and rearrangements of aminoacids in the dKRFdLE peptide in the second, third and fourth positions sharply decreased anti-microbial activity. The weaker antimicrobial activity as compared with that in dKRFdLE was peculiar to peptides with the other primary structure. Possible participation of peptides as antibiotics in the mechanisms of nonspecific immunity as well as the methods of their rational search are discussed.

A screening of new synthetic opioid-like peptides has been carried out by the radioreceptor assay using selective labeled ligands to mu-, delta- and gamma-opioid receptors of the rat brain membranes. With this aim peptides from sequences of the following proteins were used: kapporphin-Tyr-Ser-Phe-Gly-Gly and its analogues-Tyr-Ser-Phe-Gly-Gly-NH2, Tyr-D-Ser-Phe-Gly-Gly, Tyr-D-Ser-Phe-Gly-Gly-NH2, myelorphin-Phe-Gly-Tyr-Gly-Gly, interenkephalin B-Arg-Arg-Gln-Phe-Lys and chimeric peptide IEPhBin 1-Tyr-Gly-Gly-Phe-Leu-Arg-Pro-Tyr-Ile-Leu consisting of leu-enkephalin and pentaneurotensin. It has been found that myelorphin has a prevalent affinity to mu-receptor, while the kapporphin analogues both to mu- and delta-receptors. The presence of pentaneurotensin in chimeric peptide does not affect the specificity of binding to opioid receptors, but decreases affinity to mu- and delta-receptors approximately by an order as compared to leu-enkephalin. Kapprorphin and interenkephalin B displace neither of the selective labeled opioid ligands under study.

The nuclei of splenic lymphocytes were shown to contain nuclease activity whose action is manifested under optimal conditions for different types of DNases: DNase I, micrococcal nuclease, Ca, Mg-dependent endonuclease, and DNase II. No such variety of nuclease activity was found in liver and kidney nuclei. The presence of high nuclease activity in the lymphocytes is responsible for the more intensive degradation of their chromatin by endonuclease than in liver nuclei. The diversity of nuclease activity and the more advanced degree of chromatin degradation by endonuclease in splenic lymphocyte nuclei may perhaps be connected with the rapid renewal of the lymphocyte pool in lymphoid organs and the need for autolysis of the genome of the dying lymphocytes. They may also lie at the basis of the somatic mutagenic mechanism of the diversity of V-genes and of the union of the V-and C-genes of immunoglobulins.

Digestion of deoxyribonucleoproteins (DNP) of Gram-negative bacteria by micrococcal nuclease and by Ca++- and Mg++-activated bacterial endonuclease followed by electrophoresis revealed a group of DNP-fragments of discrete size in each species, as well as large nuclease-resistant DNP fractions. The approximate molecular weight of the smallest bacterial DNP fragment was estimated to be 120–140 base pairs. At least two cationic proteins, with electrophoretic mobility close to that of eukaryote histone H4 were discovered in the DNP of each species of bacteria. The presence of a universal principle of regular subunitary DNP structure in bacteria is postulated.

Different histone fractions contain sequences homologous to those of several regulatory peptides. All the histone fractions demonstrated dose-dependent positive chronotropic effect in spontaneously contracting rat atrial preparations. The range of their activity was as follows: H4 greater than H1 greater than H2a much greater than H3. Synthetic COOH-terminal histone H4 pentapeptide (historphin) Tyr-Gly-Phe-Gly-Gly demonstrated opioid activity by inhibiting electrostimulated guinea-pig ileal contractions. It is suggested that some biological activities of histones are related to the presence of regulatory peptide sequences in their structure.

The nuclei of spleen lymphocytes showed nuclease activity becoming manifest under conditions optimal for different types of DNA-ase (DNA-ase I, DNA-ase II, micrococcal nuclease and Ca, Mg-dependent endonuclease). No diversity of nuclease activity was found in the liver or kidney nuclei. A high nuclease activity in the lymphocyte nuclei provides for a deeper endonucleolysis of the lymphocyte chromatin as compared to that in the liver nuclei. The variety of nucleic activity and more advanced chromatin endonucleolysis in the spleen lymphocyte nuclei may be associated with rapid cell renewal of the lymphocyte pool in lymphoid organs and with necessity for autolysis of degraded lymphocyte genome. It may also ensure the somatomutagenic mechanism of diverse V-genes and of V- and C-gene combination.

Biochemical assay of the length of the element of the highest level of compactization of deoxyribonucleoprotein fibril, i.e. the loop, in interphasic chromosomes of the liver of some animals (rat, cat, hen, pigeon, tortoise, frog) reveals significant variation of the magnitude of this value. The smallest length of the loop among the organisms investigated was found in tortoise chromosomes--5--6 X 10(3) nucleotide pairs. The length of the loop structures in mammalian chromosomes (rats, cats) is equal to 45-75 X 10(3) nucleotide pairs. In birds and amphibians, chromosomes exhibit an intermediate size of the loop element as compared to chromosomes from mammals and reptiles. Possible connection between the length of the loop structures and chromosomal diameter is discussed together with the "anomalous" size of chromosomal loops in the frog.

The structural models of mitotic chromosome, the role of repeating nucleotide sequences of the eukaryotic gene in the regular structure of chromatin, possible principles of organization of polytenic chromosomes, lamp brush chromosomes and mature animal spermatozoa chromosomes and the relationship between macro- and microtransformations of chromosomes with differentiated cells are discussed.

Different histone fractions contain sequences homologous to those of several regulatory peptides. All the histone fractions demonstrated dose-dependent positive chronotropic effect in spontaneously contracting rat atrial preparations. The range of their activity was as follows: H4 greater than H1 greater than H2a much greater than H3. Synthetic COOH-terminal histone H4 pentapeptide (historphin) Tyr-Gly-Phe-Gly-Gly demonstrated opioid activity by inhibiting electrostimulated guinea-pig ileal contractions. It is suggested that some biological activities of histones are related to the presence of regulatory peptide sequences in their structure.