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The purpose of the study is to summarize our own data and literature data on the significance of poreforming proteins of the outer membrane of Yersinia as factors of their pathogenicity and as diagnostic and protective antigens, and their role in pathological processes considered non-infectious. In the last decades of the last century, the epidemic significance of intestinal yersiniosis caused by the bacteria of Yersinia genus, Yersinia pseudotuberculosis and Yersinia enterocolitica, which are the «doubles» of the plague pathogen (Yersinia pestis) by genetic, cultural, biochemical, and other properties, has significantly increased. It has been established that acute yersiniosis infections without effective treatment can pass into secondary focal forms, leading to the development of systemic diseases that were not previously considered infectious (for example, Grave’s disease). They are characterized by multiple organ lesions, dysfunctions of the cardiovascular and nervous systems, musculoskeletal system, urinary system and gastrointestinal tract, which is a consequence of autoimmune processes based on the ability of Yersinia to molecular mimicry. The paper shows that porins play a significant role in the development of the infectious process and can be considered as pathogenic factors of bacteria. Together with other components of the outer membrane of gram negative bacteria, they provide adhesion, invasion and colonization of the cells of the host organism by bacteria. Porins can affect a number of eukaryotic cell functions, including cytokine expression, receptor activation, apoptosis induction, and regulation of the actin cytoskeleton. It has been established that pore-forming Yersinia proteins are protective antigens. The administration of them to laboratory animals induces the formation of species-specific immunity, which allows us to recommend porin protein as a component of chemical and genetic engineering vaccines. Porins are promising for the development of ELISA test systems for the diagnosis of pseudotuberculosis and intestinal yersiniosis, as well as immunopathologies caused by Yersinia bacteria. Given the high degree of similarity of the primary structures of Yersinia porins, it can be assumed that protective preparations created on their basis will protect against infections caused by intestinal yersiniosis, pseudotuberculosis and plague pathogens.

Objective: to establish clinical and epidemiological patterns of chickenpox in adults in the Primorsky Territory to improve treatment and prevention work. Materials and methods: The study used statistics on the incidence of chicken pox in the Primorsky Territory from 2009 to 2017 and demographic data on the population for the specified period. A clinical characteristic of 102 cases of varicella in patients hospitalized in the infectious disease ward of Primorsky Regional Clinical Hospital No. 2 (Vladivostok) in 2015-2017 is given. Results: From 2009 to 2017, the incidence of chickenpox in the Primorsky Territory was consistently high, with an average of 636.2 per 100,000 population. Analysis of the structure of patients showed that the maximum proportion of cases of chicken pox occur in organized children 3-6 years old (55.9%), schoolchildren (19.1%) and children 1–2 years old (11.6%). The proportion of 15–17 year olds was 3.0%. Adults, from 18 years old – 4.9%. The proportion of unorganized children 3–6 years old (2.9%) and children in the first year of life (2.6%) is not high. High risk of infection was detected in Vladivostok (57.8 per 100.000), Yakovlevsky (52.1% ooo), Olginsky (45.9% ooo), Lazovsky (42.8% ooo) and Shkotovsky (40, 2% ooo) areas. In the annual dynamics, a pronounced spring-summer seasonal rise was formed. The clinical course of varicella in the group of adults was characterized by an average duration of the initial period of the disease of 1.4 ± 0.7 days. For clinical diagnosis, an important time was the appearance of the rash, which varied within four days. The phenomenon of “spillage” was noted in 97% of patients. The rash was polymorphic, with the formation of crusts. The period of height was characterized by the presence of catarrhal manifestations. The granularity of the posterior pharyngeal wall was observed in all patients without exception. In 84.3% of patients there was a bright hyperemia of the pharynx. In 14.7% of cases, enantema was detected on the soft palate, palatine arches, and posterior pharyngeal wall. Dry cough was detected in 28 of 103 patients, which probably increased their epidemiological significance. Findings: The clinical picture of varicella was typical and was represented by a combination of intoxication, exanthema, and catarrhal syndrome. The epidemic process of varicella in adults in Primorsky Krai was characterized by relative autonomy of manifestations in adults, children up to one year old, and unorganized children. When implementing chickenpox epidemiological surveillance, priority should be given to interventions in epidemic foci.

Contemporary problems of hemorrhagic fever with renal syndrome (HFRS), being one of hantaviral infection nozoforms and wide-spread on Euro Asiatic continent are considered. Annual increase morbidity with of natural foci expansion, often severe course and a high mortality rate determine the importance of HFRS for health of many countries and in particular the Russia. This article presents of long standing results obtained during the study of epidemiologic, clinical and laboratory diagnostic, immunopathogenesis, treatment trials in Primorsky region of Russian Federation, being the endemic area of co-circulation of several pathogenic hantaviruses.

Abstract. In the last years immunological aspects are studying in the pathogenesis of infectious diseases. The influence of immune response to the infectious processes of acute and chronic virus infectious (Hemorrhagic Fever with Renal Syndrome and Chronic Viral Hepatitis C, as an example) has been revealed. Misbalance of system and local cytokine status characterizes the direct influence of immune system to all organs and systems of human organism. It determines the severity of the disease and its outcomes.

The plant cell wall represents the outer compartment of the plant cell, which provides a physical barrier and triggers signaling cascades under the influence of biotic and abiotic stressors. Drought is a factor that negatively affects both plant growth and development. Cell wall proteins (CWP) play an important role in the plant response to water deficit. The adaptation mechanisms of the cell wall to water loss are of interest for identifying important genetic factors determining plant drought resistance and provide valuable information on biomarkers for further selection aimed at increasing the yield of crop plants. Using ANDSystem, a gene network describing the regulation of CWPs under water restriction conditions was reconstructed. The analysis of the gene network and the transcriptome data analysis allowed prioritizing transcription factors (TF) based on their enrichment of differentially expressed genes regulated by them. As a result, scores were calculated, acting as indicators of the association of TFs with water deficit. On the basis of the score values, eight most significant TFs were selected. The highest priority was given to the TF GBF3. CWPs were prioritized according to the criterion of summing up the scores of transcription factors regulating these genes. Among the most prioritized CWPs were the AT5G03350 gene encoding a lectin-like protein, AT4G20860 encoding BBE-like 22 required for the oxidation of cellulose degradation products, and AT4G37800 encoding xyloglucan endotransglucosy lase/hydrolase 7. Overall, the implemented algorithm could be used for prediction of regulatory interactions between transcription factors and target genes encoding cell wall proteins in plants.

The participants of Hepatitis C virus (HCV) replication are both viral and host proteins. Therapeutic approaches based on activity inhibition of viral non-structural proteins NS3, NS5A, and NS5B are undergoing clinical trials. However, rapid mutation processes in the viral genome and acquisition of drug resistance to the existing drugs remain the main obstacles to fighting HCV. Identifying the host factors, exploring their role in HCV RNA replication, and studying viral effects on their expression is essential for understanding the mechanisms of viral replication and developing novel, effective curative approaches. It is known that the host factors PREB (prolactin regulatory element binding) and PLA2G4C (cytosolic phospholipase A2 gamma) are important for the functioning of the viral replicase complex and the formation of the platforms of HCV genome replication. The expression of PREB and PLA2G4C was significantly elevated in the presence of the HCV genome. However, the mechanisms of its regulation by HCV remain unknown. In this paper, using a text-mining technology provided by ANDSystem, we reconstructed and analyzed gene networks describing regulatory effects on the expression of PREB and PLA2G4C by HCV proteins. On the basis of the gene network analysis performed, we put forward hypotheses about the modulation of the host factors functions resulting from protein-protein interaction with HCV proteins. Among the viral proteins, NS3 showed the greatest number of regulatory linkages. We assumed that NS3 could inhibit the function of host transcription factor (TF) NOTCH1 by protein-protein interaction, leading to upregulation of PREB and PLA2G4C. Analysis of the gene networks and data on differential gene expression in HCV-infected cells allowed us to hypothesize further how HCV could regulate the expression of TFs, the binding sites of which are localized within PREB and PLA2G4C gene regions. The results obtained can be used for planning studies of the molecular-genetic mechanisms of viral-host interaction and searching for potential targets for anti-HCV therapy.

Postoperative delirium (POD) is considered one of the most severe complications, resulting in impaired cognitive function, extended hospitalization, and higher treatment costs. The challenge of early POD diagnosis becomes particularly significant in cardiac surgery cases, as the incidence of this complication exceeds 50 % in certain patient categories. While it is known that neuroinflammation, neurotransmitter imbalances, disruptions in neuroendocrine regulation, and interneuronal connections contribute significantly to the development of POD, the molecular, genetic mechanisms of POD in cardiac surgery patients, along with potential metabolomic diagnostic markers, remain in adequately understood. In this study, blood plasma was collected from a group of patients over 65 years old after cardiac surgery involving artificial circulation. The collected samples were analyzed for sphingomyelin content and quantity using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS) me thods. The analysis revealed four significantly different sphingomyelin contents in patients with POD compared to those who did not develop POD (control group). Employing gene network reconstruction, we perceived a set of 82 regulatory enzymes affiliated with the genetic coordination of the sphingolipid metabolism pathway. Within this set, 47 are assumed to be regulators of gene expression, governing the transcription of enzymes pivotal to the metabolic cascade. Complementing this, an additional assembly of 35 regulators are considered to be regulators of activity, degradation, and translocation dynamics of enzymes integral to the aforementioned pathway. Analysis of the overrepresentation of diseases with which these regulatory proteins are associated showed that the regulators can be categorized into two groups, associated with cardiovascular pathologies (CVP) and neuropsychiatric diseases (NPD), respectively. The regulators associated with CVP are expectedly related to the effects on myocardial tissue during surgery. It is hypothesized that dysfunction of NPD-associated regulators may specifically account for the development of POD after cardiac surgery. Thus, the identified regulatory genes may provide a basis for planning further experiments, in order to study disorders at the level of expression of these genes, as well as impaired function of proteins encoded by them in patients with POD. The identified significant sphingolipids can be considered as potential markers of POD.

Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important strategy for cancer therapy. The computer design of chemical compounds capable of specifically regulating the external signaling pathway of apoptosis induction represents a promising approach for creating new effective ways of therapy for liver cancer and other oncological diseases. However, at present, most of the studies are devoted to pharmacological effects on the internal (mitochondrial) apoptosis pathway. In contrast, the external pathway induced via cell death receptors remains out of focus. Aberrant gene methylation, along with hepatitis C virus (HCV) infection, are important risk factors for the development of hepatocellular carcinoma. The reconstruction of gene networks describing the molecular mechanisms of interaction of aberrantly methylated genes with key participants of the extrinsic apoptosis pathway and their regulation by HCV proteins can provide important information when searching for pharmacological targets. In the present study, 13 criteria were proposed for prioritizing potential pharmacological targets for developing anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway. The criteria are based on indicators of the structural and functional organization of reconstructed gene networks of hepatocarcinoma, the extrinsic apoptosis pathway, and regulatory pathways of virus-extrinsic apoptosis pathway interaction and aberrant gene methylation-extrinsic apoptosis pathway interaction using ANDSystem. The list of the top 100 gene targets ranked according to the prioritization rating was statistically significantly (p-value = 0.0002) enriched for known pharmacological targets approved by the FDA, indicating the correctness of the prioritization method. Among the promising potential pharmacological targets, six highly ranked genes (JUN, IL10, STAT3, MYC, TLR4, and KHDRBS1) are likely to deserve close attention.

Hepatitis C virus (HCV) is a risk factor that leads to hepatocellular carcinoma (HCC) development. Epigenetic changes are known to play an important role in the molecular genetic mechanisms of virus-induced oncogenesis. Aber rant DNA methylation is a mediator of epigenetic changes that are closely associated with the HCC pathogenesis and considered a biomarker for its early diagnosis. The ANDSystem software package was used to reconstruct and evaluate the statistical significance of the pathways HCV could potentially use to regulate 32 hypermethylated genes in HCC, including both oncosuppressor and protumorigenic ones identified by genome-wide analysis of DNA methylation. The reconstructed pathways included those affecting protein-protein interactions (PPI), gene expression, protein activity, stability, and transport regulations, the expression regulation pathways being statistically significant. It has been shown that 8 out of 10 HCV proteins were involved in these pathways, the HCV NS3 protein being implicated in the largest number of regulatory pathways. NS3 was associated with the regulation of 5 tumor-suppressor genes, which may be the evidence of its central role in HCC pathogenesis. Analysis of the reconstructed pathways has demonstrated that following the transcription factor inhibition caused by binding to viral proteins, the expression of a number of oncosuppressors (WT1, MGMT, SOCS1, P53) was suppressed, while the expression of others (RASF1, RUNX3, WIF1, DAPK1) was activated. Thus, the performed gene-network reconstruction has shown that HCV proteins can influence not only the methylation status of oncosuppressor genes, but also their transcriptional regulation. The results obtained can be used in the search for pharmacological targets to develop new drugs against HCV-induced HCC.

Abstract Metabolomic analysis of blood plasma samples from COVID-19 patients is a promising approach allowing for the evaluation of disease progression. We performed the metabolomic analysis of plasma samples of 30 COVID-19 patients and the 19 controls using the high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometric detection (LC–MS/MS). In our analysis, we identified 103 metabolites enriched in KEGG metabolic pathways such as amino acid metabolism and the biosynthesis of aminoacyl-tRNAs, which differed significantly between the COVID-19 patients and the controls. Using ANDSystem software, we performed the reconstruction of gene networks describing the potential genetic regulation of metabolic pathways perturbed in COVID-19 patients by SARS-CoV-2 proteins. The nonstructural proteins of SARS-CoV-2 (orf8 and nsp5) and structural protein E were involved in the greater number of regulatory pathways. The reconstructed gene networks suggest the hypotheses on the molecular mechanisms of virus-host interactions in COVID-19 pathology and provide a basis for the further experimental and computer studies of the regulation of metabolic pathways by SARS-CoV-2 proteins. Our metabolomic analysis suggests the need for nonstructural protein-based vaccines and the control strategy to reduce the disease progression of COVID-19.

Coronaviruses (CoVs) belong to the subfamily Orthocoronavirinae of the family Coronaviridae. CoVs are enveloped (+) RNA viruses with unusually long genomes. Severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the novel coronavirus (2019-nCoV, SARS-CoV-2) have been identif ied as causing global pandemics. Clinically tested vaccines are widely used to control rapidly spreading, acute, and often severe infections; however, effective drugs are still not available. The genomes of SARS-CoV-2 and SARS-CoV are approximately 80 % identical, while the genomes of SARS-CoV-2 and MERS-CoV are approximately 50 % identical. This indicates that there may be common mechanisms of coronavirus pathogenesis and, therefore, potential therapeutic targets for each virus may be the same. The enzymes and effector proteins that make up the replicationtranscription complex (RTC) of coronaviruses are encoded by a large replicase gene. These enzymes and effector proteins represent promising targets for potential therapeutic drugs. The enzyme targets include papain- and 3C-like cysteine proteinases that process two large viral polyproteins, RNA-dependent RNA polymerase, RNA helicase, viral genome-modifying enzymes, and enzymes with 3’–5’ exoribonuclease or uridylate-specif ic endonuclease activity. Currently, there are many studies investigating the complex molecular mechanisms involved in the assembly and function of the RTC. This review will encompass current, modern studies on the properties and complexes of individual non-structural subunits of the RTC, the structures of individual coronavirus RTC subunits, domain organization and functions of subunits, protein-protein interactions, properties and architectures of subunit complexes, the effect of mutations, and the identif ication of mutations affecting the viability of the virus in cell culture.

Methods for prioritizing or ranking candidate genes according to their importance based on specific criteria via the analysis of gene networks are widely used in biomedicine to search for genes associated with diseases and to predict biomarkers, pharmacological targets and other clinically relevant molecules. These methods have also been used in other fields, particularly in crop production. This is largely due to the development of technologies to solve problems in marker-oriented and genomic selection, which requires knowledge of the molecular genetic mechanisms underlying the formation of agriculturally valuable traits. A new direction for the study of molecular genetic mechanisms is the prioritization of biological processes based on the analysis of associative gene networks. Associative gene networks are heterogeneous networks whose vertices can depict both molecular genetic objects (genes, proteins, me tabolites, etc.) and the higher-level factors (biological processes, diseases, external environmental factors, etc.) related to regulatory, physicochemical or associative interactions. Using a previously developed method, biological processes involved in plant responses to increased cadmium content, saline stress and drought conditions were prioritized according to their degree of connection with the gene networks in the SOLANUM TUBEROSUM knowledge base. The prioritization results indicate that fundamental processes, such as gene expression, post-translational modifications, protein degradation, programmed cell death, photosynthesis, signal transmission and stress response play important roles in the common molecular genetic mechanisms for plant response to various adverse factors. On the other hand, a group of processes related to the development of seeds (“seeding development”) was revealed to be drought specific, while processes associated with ion transport (“ion transport”) were included in the list of responses specific to salt stress and processes associated with the metabolism of lipids were found to be involved specifically in the response to cadmium.

A terrible disease of the cardiovascular system, atherosclerosis, develops in the areas of bends and branches of arteries, where the direction and modulus of the blood flow velocity vector change, and consequently so does the mechanical effect on endothelial cells in contact with the blood flow. The review focuses on topical research studies on the development of atherosclerosis – mechanobiochemical events that transform the proatherogenic mechanical stimulus of blood flow – low and low/oscillatory arterial wall shear stress in the chains of biochemical reactions in endothelial cells, leading to the expression of specific proteins that cause the progression of the pathological process. The stages of atherogenesis, systemic risk factors for atherogenesis and its important hemodynamic factor, low and low/oscillatory wall shear stress exerted by blood flow on the endothelial cells lining the arterial walls, have been described. The interactions of cell adhesion molecules responsible for the development of atherosclerosis under low and low/oscillating shear stress conditions have been demonstrated. The activation of the regulator of the expression of cell adhesion molecules, the transcription factor NF­κB, and the factors regulating its activation under these conditions have been described. Mechanosensitive signaling pathways leading to the expression of NF­κB in endothelial cells have been described. Studies of the mechanobiochemical signaling pathways and interactions involved in the progression of atherosclerosis provide valuable information for the development of approaches that delay or block the development of this disease.

The development of highly efficient technologies in genomics, transcriptomics, proteomics and metabolomics, as well as new technologies in agriculture has led to an “information explosion” in plant biology and crop production, including potato production. Only a small part of the information reaches formalized databases (for example, Uniprot, NCBI Gene, BioGRID, IntAct, etc.). One of the main sources of reliable biological data is the scientific literature. The well-known PubMed database contains more than 18 thousand abstracts of articles on potato. The effective use of knowledge presented in such a number of non-formalized documents in natural language requires the use of modern intellectual methods of analysis. However, in the literature, there is no evidence of a widespread use of intelligent methods for automatically extracting knowledge from scientific publications on cultures such as potatoes. Earlier we developed the SOLANUM TUBEROSUM knowledge base (http://www-bionet.sysbio.cytogen. ru/and/plant/). Integrated into the knowledge base information about the molecular genetic mechanisms underlying the selection of significant traits helps to accelerate the identification of candidate genes for the breeding characteristics of potatoes and the development of diagnostic markers for breeding. The article searches for new potential participants of the molecular genetic mechanisms of resistance to adverse factors in plants. Prioritizing candidate genes has shown that the PHYA, GF14, CNIH1, RCI1A, ABI5, CPK1, RGS1, NHL3, GRF8, and CYP21-4 genes are the most promising for further testing of their relationships with resistance to adverse factors. As a result of the analysis, it was shown that the molecular genetic relationships responsible for the formation of significant agricultural traits are complex and include many direct and indirect interactions. The construction of associative gene networks and their analysis using the SOLANUM TUBEROSUM knowledge base is the basis for searching for target genes for targeted mutagenesis and marker-oriented selection of potato varieties with valuable agricultural characteristics.

The paper describes the approach used in implementing OpenMP offloading to NVIDIA accelerators in GCC. Offloading refers to a new capability in OpenMP 4.0 specification update that allows the programmer to specify regions of code that should be executed on an accelerator device that potentially has its own memory space and has an architecture tuned towards highly parallel execution. NVIDIA provides a specification of the abstract PTX architecture for the purpose of low-level, and yet portable, programming of their GPU accelerators. PTX code usually does not use explicit vector (SIMD) computation; instead, vector parallelism is expressed via SIMT (single instruction - multiple threads) execution, where groups of 32 threads are executed in lockstep fashion, with support on hardware level for divergent branching. However, some control flow constructs such as spinlock acquisition can lead to deadlocks, since reconvergence points after branches are inserted implicitly. Thus, our implementation maps logical OpenMP threads to PTX warps (synchronous groups of 32 threads). Individual PTX execution contexts are therefore mapped to logical OpenMP SIMD lanes (this is similar to the mapping used in OpenACC). To implement execution of one logical OpenMP thread by a group of PTX threads we developed a new code generation model that allows to keep all PTX threads active, have their local state (register contents) mirrored, and have side effects from atomic instructions and system calls such as malloc happen only once per warp. This is achieved by executing the original atomic or call instruction under a predicate, and then propagating the register holding the result using the shuffle exchange (shfl) instruction. Furthermore, it is possible to setup the predicate and the source lane index in the shuffle instruction in a way that this sequence has the same effect as just the original instruction inside of SIMD regions. We also describe our implementation of compiler-defined per-warp stacks, which is required to have per-warp automatic storage outside of SIMD regions that allows cross-warp references (normally automatic storage in PTX is implemented via .local memory space which is visible only in the PTX thread that owns it). This is motivated by our use of unmodified OpenMP lowering in GCC where possible, and thus using libgomp routines for entering parallel regions, distribution of loop iterations, etc. We tested our implementation on a set of micro-benchmarks, and observed that there is a fixed overhead of about 100 microseconds when entering a target region, mostly due to startup procedures in libgomp (and notably due to calls to malloc), but for long-running regions where that overhead is small we achieve performance similar to analogous OpenACC and CUDA code.

Aggressive behavior in animals plays an important role in protecting the territory, offspring, establishing social hierarchical relations, etc. Increased aggression is observed in a number of diseases ( schizophrenia, bipolar disorder, brain degenerative disorders). Neuronal apoptosis is crucial in the maintenance of developmental processes during neurogenesis. Alterations in neuronal apoptosis are observed in aging and neuropathologies accompanied by changes in psycho­emo­ tional state (epilepsy, Alzheimer’s disease, neurotrauma). The expression of key neuronal apoptosis genes (Casp3, Bax and Bcl-xl) in the brain of highly aggressive rats is significantly altered. The aim of this work was to analyze associative networks that describe genetic interactions between genes/proteins involved in neuronal apoptosis, differentially expressed genes and genes with polymorphisms in grey rats with aggressive behavior. Analysis revealed 819 differentially expressed genes in the hypothalamus, ventral tegmental region and periaqueductus Sylvii grey matter in grey rats with aggressive and tame behavior. The Stx1a, Mbp and Th genes have the highest index of betweenness centrality in the associative network of differentially expressed genes. Genome analysis revealed 137 polymorphic genes. Three of them (Lig4, Parp1 and Pigt) were involved in neuronal apoptosis. It was shown that polymorphic and differentially expressed genes were statistically significantly overrepresented among ge nes interacting with neuronal apoptosis genes (p value < 0.01). Three molecular­genetic chains describing connections between polymorphic and neuronal apoptosis genes mediated by differentially expressed genes were reconstructed. Chains included the polymorphic genes Tsc1, Adamts4 and Lgals3, differentially expressed genes Ezr, Acan, Th and 19 neuronal apoptosis genes. It was shown that neuronal apoptosis is closely related to aggressive behavior in animals.

The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the signaling and repair of DNA. PARP-1 catalyses covalent binding of poly (ADP-ribose) polymers with itself as well as with other acceptor proteins using NAD+ as a donor of ADP-ribose. Inhibitors of poly (ADP-ribose) polymerase have been shown to be effective in improvement of radiation therapy and chemotherapy of cancer in clinical testing. Development of new poly (ADP-ribose) polymerase-1 inhibitors based on derivatives of natural compounds such as NAD+ represents a novel and promising strategy. The structure of complex of human poly (ADP-ribose) polymerase-1 with NAD+ can be a starting point for rational design of small molecule inhibitors based on NAD+ derivatives. Indeed there is no crystal structure of complex poly (ADP-ribose) polymerase-1 with nicotinamide adenine dinucleotide (NAD+) available yet. In this work using molecular modeling approaches we have predicted NAD+ binding modes with PARP-1 at the donor binding site of the catalytic domain. Using structures of PARP-1 homologs in complex with NAD+ we predicted pharmacophore restraints of NAD+ binding to PARP-1. Based on clustering of PARP-1 conformations in complex with co-crystallized inhibitors and predicted pharmacophore restraints, we proposed several possible models of NAD+ binding to PARP-1 at the donor binding site of the catalytic domain. According to the predicted models, two conformations of pyrophosphate group of NAD+ in complex with PARP-1 at the donor binding site are possible. Validation of the proposed models of NAD+ binding with PARP-1 can be achieved by quantitative structure-activity analysis of NAD+ derivatives. We designed two NAD+ derivatives, which can be used for validation of predicted NAD+ binding models.

Glaucoma is a chronic and progressive disease, which affects more than 60 million people worldwide. Primary open-angle glaucoma (POAG) is one of the most common forms of glaucoma. For example, about 2.71 million people in the USA had primary open-angle glaucoma in 2011. Currently POAG is a major cause of irreversible vision loss. In patients with treated open-angle glaucoma the risk of blindness reached to be about 27 %. It is known that the death of optic nerve cells can be triggered by mechanical stress caused by increased intraocular pressure, which induces neuronal apoptosis and is observed in patients with POAG. Currently, there is a large number of scientific publications describing proteins and genes involved in the pathogenesis of POAG, including neuronal apoptosis and the cell response to mechanical stress. However, the molecular- genetic mechanisms underlying the pathophysiology of POAG are still poorly understood. Reconstruction of associative networks describing the functional interactions between these genes/proteins, including biochemical reactions, regulatory interactions, transport, etc., requires the use of methods of automated knowledge extraction from texts of scientific publications. The aim of the work was the analysis of associative networks, describing the molecular-genetic interactions between proteins and genes involved in cell response to mechanical stress (CRMS), neuronal apoptosis and pathogenesis of POAG using ANDSystem, our previous development for automated text analysis. It was shown that genes associated with POAG are statistically significantly more often represented among the genes involved in the interactions between CRMS and neuronal apoptosis than it was expected by random reasons, which can be an explanation for the effect of POAG leading to the retinal ganglion cell death.

CD95 is one of the best studied members of the death receptor family. Activation of CD95 leads to the induction of the cell death programme, apoptosis, via formation of the death-inducing signaling complex (DISC). FA DD is a key adaptor protein for the formation of the C D95 DISC and activation of caspase-8 in the receptor complex. FA DD comprises the death domain and the death effector domain (DED). The death domain is essential for the interactions of FA DD with CD95, while DED is necessary for the recruitment of procaspase-8, -10 and the protein c-FLIP into the DISC. The search for the inhibitors that would block the interactions of FA DD with the other core proteins of the DISC is essential for the studies of the structure and function of this complex, investigation of the apoptosis mechanisms and development of new treatments for neurodegenerative diseases. In the course of this work, the screening for small inhibitors in silico that selectively interact with DED has been performed. For this purpose, the molecular modeling of the protein complexes and virtual screening of the potential inhibitors of FA DD has been performed. In addition, a new technology to test the activity of these inhibitors has been developed. The computational and experimental analysis performed allowed us to characterize the optimal conformation of the FA DD protein for the design of the small molecules that can bind in the region of amino acid residue Y25. We presume that further optimization of the structures of chemical compounds that can bind with the hydrophobic pocket next to the residue Y25 of FA DD will allow for the creation of the new perspective inhibitors of the programmed cell death.

Identification of new effective inhibitors of apoptosis is an important task for drug development for treatment of a number diseases including neurogenerative diseases. Initiation of apoptosis occurs via the formationof macromolecular protein complexes. In these complexes, activation of key enzymes in apoptosis, caspases, takes place. One of those macromolecular complexes is DISC (death- inducing signaling complex) playing a central role in the induction of the extrinsic apoptosis pathway. The adaptor protein FA DD has a major role in the formation of the DISC. Therefore, inhibitors of FA DD, preventing its function in the DISC, can act as potential drugs inhibiting apoptosis. Furthermore, the study of the mechanisms of action of these inhibitors is of great interest for understanding the mechanisms of the signal transduction pathways of apoptosis. It has been reported that a natural protein inhibitor of FA DD is mucin-type 1 glycoprotein (MUC1). In particular, two fragments of the primary structure of the cytoplasmic domain of MUC1 (MUC1- CD) are capable of inhibiting the binding of caspase-8 to FA DD. However, the three-dimensional structure of MUC1 has not been obtained yet. It complicates significantly the rational design of potential drugs on the basis of these peptides. In this context, the aim of the present study was in silico prediction ofthree-dimensional structures of MUC1-CD peptides corresponding to protein fragments (1-20 and 46-72), as well as analysis of their conformational properties. The main focus of the work was given to the peptide MUC1-CD (46-72), which is capable of binding to FA DD. Using the methods of molecular dynamics in the implicit water it was shown that the peptide MUC1-CD (46-72) can take conformations similar to the conformations of a number of fragments of the caspase-8 DED domain. It was found that the structure of the peptide MUC1-CD (46-72) is similar to the spatial structure of at least four fragments of caspase-8. These results indicate that the molecular mechanism of the inhibitory activity of the peptide can be explained by competitive binding with FA DD due to the structural and conformational similarity with the fragments of the caspase-8 DED domain.

Tuberculosis (TB) is a common disease caused by infection of Mycobacterium tuberculosis and influenced by host hereditary and environmental factors. Accumulated genomic data obtained through the use of new methodological approaches, including analysis of associative networks, contribute to the understanding of the hereditary basis of the disease. In the current study, we carried out the reconstruction and analysis of associative network representing molecular genetic links between proteins/genes involved in the development of TB. In the associative network, well studied proteins and genes with a decisive importance in the efficiency of the human immune response against a pathogen predominated. However, this approach identified 12 new genes encoding for the respective proteins in the associative network polymorphismsof which has not been studied regarding the development of TB.

A new strain, Geobacillus stearothermophilus 22 was isolated from the Garga hot spring in the Bargusin Valley, Baikal Region, Russia. The morphology and biochemistry of the strain were analyzed, and the genomewide sequencing was conducted. The sequence was subjected to bioinformatic analysis. Nucleotide sequences (contigs) of the strain were found to be similar to the genome of the thermophilic strain G. kaustophilus Y412MC52. The proteome of the new strain was analyzed. Fragments associated with hemicellulases (endoxylanase, beta xylosidase, and arabinofuranosidase) and the endoxylanase enzyme were detected.

This paper describes the SNP-MED modular computer-based information system for estimation of the influence of single nucleotide polymorphisms (SNPs) on the function of genes associated with the risk of socially significant diseases. The system includes software components Genomics, Proteomics, Gene networks and the Information resource database (BDIR).

Properties of thermostable lipases from Geobacillus bacteria are considered. The enzymes are divided into groups with regard to their thermostability. Coordinated amino acid substitutions are demonstrated in the highly thermostable group (half-inactivation time > 1000 min); V198A, Q203E, V204I, Q217E; and V294I, P306A, T307A, D312S, R313H, E316G, V324I, S334N, A343T. The hydrophilic moment of α helices, correlating with the charge and polarity of amino acid in the region, exerts the most significant influence on enzyme thermostability. Most thermostable lipases are characterized by structural stabilization of the lid domain in the 198А-217Е region.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which affects motor neurons in the brain and spinal cord and leads to patients’ death. One of the causes of motor neuron degeneration and death is the formation of intracellular protein aggregates formed by a mutant SOD1 protein. Recently, it has been shown that the survival time of ALS patients with specific mutation in SOD1 gene inversely correlates with thermodynamic stability of the SOD1 mutant protein. In the present paper, we hypothesize that mutant SOD1 aggregation can be facilitated by not only destabilization due to hydrogen bonds disruption but also by formation of new hydrogen bonds, which can stabilize intermediate “pathogenic” conformations of the mutant SOD1 protein. Molecular dynamics simulations were conducted to estimate frequencies of hydrogen bond occurrence in the protein structure. It was shown that the regression model based on frequencies of hydrogen bond occurrence significantly better correlated with patients’ survival time (R = 0.89, p < 0.00001) than the estimation based on thermodynamic stability analysis of mutant SOD1 proteins.

Hepatitis C virus (HCV) causes a severe liver disease frequentlyassociatedwith cirrhosis andhepatocellular carcinoma. No effective anti-HCVtherapyis available so far. Thus, it is pertinent to applymathematical modelingto prediction ofthe efficiencyofnew candidate pharmaceuticals. Astochastic mathematical model for subgenomic HCVreplicon replication in Huh-7 cells with the presence ofthe HCVNS3 protease inhibitor SCH 503034 is proposed. The model describes the experimental kinetic curves ofviral RNAsuppression at various SCH 503034 concentrations. It is applicable to the development ofapproaches to HCVRNAsuppression in Huh-7 cells.

The prevalence of allergic diseases was rapidly increasing in the 20th century. Currently, many people suffer from allergy in industrial countries. Therefore, analysis of allergenic properties of proteins is an urgent task. The following factors were formerly hypothesized to determine the allergenicity of a protein: size, enzymatic properties, and similarity to human proteins. However, no analysis of the relationship between allergenicity of proteins and the habitat of the organisms producing them has been conducted hitherto. We predict allergenicity of proteins from proteomes of more than 500 species of microorganisms. It is shown that the number of allergenic proteins in the proteomes of microorganisms is significantly associated with their pathogenicity, habitat, temperature conditions of the habitat, and oxygen demand.