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For a model of a circadian oscillator presented in the form of a 6-dimensional nonlinear dynamical system, conditions of uniqueness of an equilibrium point and conditions of existence of a periodic trajectory (cycle) are established. A client-server application is developed to perform numerical experiments with this model on a cloud server and to visualize the results of these experiments. [ABSTRACT FROM AUTHOR]

We construct two nonlinear dynamical systems of the functioning simplest circadian oscillator. Some conditions of the uniqueness of the equilibrium point of these systems are described as well as the conditions for the existence of cycles in their phase portraits. [ABSTRACT FROM AUTHOR]

Glaucoma is a chronic progressive disease. It involves more than 60 million people worldwide. Primary open-angle glaucoma (POAG) is one of its commonest forms. About 2.71 million people in the United States suffered from POAG in 2011. Currently, POAG is a major cause of irreversible vision loss. The risk of blindness in patients with treated open-angle glaucoma is 27%. It is known that the death of optic nerve cells can be triggered by mechanical stress caused by ocular hypertension, which induces neuronal apoptosis and occurs in patients with POAG. Many scientific publications are dedicated to proteins and genes involved in the development of POAG, including neuronal apoptosis and the cell response to mechanical stress (CRMS). However, the molecular mechanisms underlying the pathophysiology of POAG are still poorly understood. The reconstruction of associative networks describing the functional interactions between these genes/proteins, including biochemical reactions, regulatory interactions, and transport, requires automated knowledge extraction from scientific publications. This work aims to analyze the associative networks describing molecular interactions between proteins and genes involved in CRMS, neuronal apoptosis, and the development of POAG. It has been shown that genes associated with POAG are statistically significantly overrepresented among the genes involved in the interactions between CRMS and neuronal apoptosis in comparison to what is expected on a random basis. This finding may explain how POAG causes the death of the retinal ganglion cell. [ABSTRACT FROM AUTHOR]

The studies of the last decade allow us to look in a new way at the possible association between the aging processes and the circadian rhythm. One of the promising directions in this area appeared thanks to the new data on the involvement of the NAD+-dependent protein deacetylase SIRT1 in the integration of the pathways of the circadian rhythm and metabolism regulation and the new NAD+ function as a 'metabolic oscillator'. We present the a modification and extension of the most detailed circadian oscillator (CO) model developed in 2012 by J.K. Kim and D.B. Forger. The additional oscillator feedback with the involvement of NAMPT, SIRT1 genes/proteins, as well as NAM and NAD+, is included in it. The involvement of the CLOCK/BMAL1 transcription factor in regulating the NAMPT gene transcription determines the appropriate rhythm of mRNA expression and the NAMPT protein. Since the enzyme (this gene product) is a key in the pathway of NAD+ biosynthesis and recycling, the circadian rhythm is also typical for the fluctuation of this coenzyme level and the activity of NAD+-dependent protein deacetylase SIRT1. The deacetylation of the CO components by this enzyme closes the feedback mediated by this pathway. In particular, an increase in the Per2 protein degradation, an increase in the Bmal1 gene transcription, and the deacetylation of the chromatin of the regulatory regions of the CO genes in the area of E-boxes with subsequent transcription suppression can be revealed among the SIRT1 effects in the CO. All these processes are presented in the extended CO model that we suggested. Based on the experimental data about changes in the SIRT1 activity and NAD+ level with age, an attempt to study the effect of these age-related changes on the functioning of a CO was made. The modeling data indicate a decrease in the expression level of a number of CO genes (particularly the Bmal1 and Per2) in older age groups. An increase in the period of circadian oscillations was also registered. The results obtained indicate that a decrease in the SIRT1 activity associated with the age-related violation of the NAD+ metabolism can be one of the reasons for the violations of the functioning of a CO in the suprachiasmatic nuclei (SCN). Such violations can also entail violations of the organism's circadian rhythms in general. [ABSTRACT FROM AUTHOR]

The computational analysis of millions of unannotated SNPs from the 1000 Genomes Project may speed up the search for biomedical SNP markers. We combined the analysis of SNPs at the binding sites of the TATA-binding protein (TBP) using a previously described Web service (http://beehive.bionet.nsc.ru/cgi-bin/mgs/tatascan/start.pl) with a keyword search for biochemical markers of chronopathologies that correspond to the clinical manifestations of these SNPs. We found 32 known and candidate SNP markers of circadian-rhythm disturbances in the [-70;-20] region of the promoters of 14 human genes (location of proven binding sites of TBP). These SNPs include rs17231520 and rs569033466 (both confer risk of chronopathologies in the liver); rs35036378 (behavioral chronoaberrations); rs549858786 (rheumatoid arthritis with a chronoaberration of IL1B expression); rs563207167, rs11557611, and rs5505 (all three: chronopathologies of the tumor-host balance, blood pressure, and the reproductive system); rs1143627 (bipolar disorder with circadian dependence of diagnosis and treatment); rs16887226 and rs544850971 (both: lowered resistance to endotoxins because of the imbalance between the circadian and immune systems); rs367732974 and rs549591993 (both: circadian dependence of heart attacks); rs563763767 (circadian dependence of myocardial infarction); rs2276109 and rs572527200 (both: circadian dependence of asthma attacks); rs34223104, rs563558831, and rs10168 (circadian optima of treatment with methotrexate and cyclophosphamide); and rs397509430, rs33980857, rs34598529, rs33931746, rs33981098, rs34500389, rs63750953, rs281864525, rs35518301, and rs34166473 (all: neurosensory hearing loss and restless legs syndrome). For these SNPs, we evaluated the α (significance) of changes in the affinity of TBP for promoters, where increased affinity corresponds to overexpression of the genes, and decreased affinity to deficient expression (Z-test). Verification of these 32 SNP markers according to the clinical standards and protocols may advance the field of predictive preventive personalized medicine. [ABSTRACT FROM AUTHOR]

Computer simulation is now becoming a central scientific paradigm of systems biology and a basic tool for the theoretical study and understanding of the complex mechanisms of living systems. The increase in the number and complexity of these models leads to the need for their collaborative development, reuse of models, their verification, and the description of computational experiments and their results. Ontological modeling is used to develop formats for knowledge-oriented mathematical modeling of biological systems. In this sense, ontology associated with the entire set of formats that support research in systems biology, in particular, computer modeling of biological systems and processes, can be regarded as a first approximation to the ontology of systems biology. This review summarizes the features of the subject area (bioinformatics, systems biology, and biomedicine), the main motivation for the development of ontologies and the most important examples of ontological modeling and semantic analysis at different levels of the hierarchy of knowledge: molecular genetic, cellular, tissue, organs, and the body. Bioinformatics and systems biology is an excellent ground for testing the technologies and efficient use of ontological modeling. Several dozens of verified basic reference ontologies now represent a source of knowledge for the integration and development of more complex domain models aimed at addressing specific issues in biomedicine and biotechnology. Further formalization and ontological accumulation of knowledge and the use of formal methods of analysis can take the entire cycle of research in systems biology to a new technological level. [ABSTRACT FROM AUTHOR]

Genetic variability in genes of the circadian clock can manifest itself as a phenotypic variability of physiological functions and behavior, as well as functional disorders not only of the clock but also of other systems leading to the development of pathologies. We analyzed the influence of SNPs localized in the [-70,-20] region from the transcription start site on the promoter affinity of the TATA-binding protein (TBP) in two groups of genes that are components of the human circadian clock system. The first group is comprised of the genes of the core of the circadian oscillator (11 genes); the second comprises the genes of nearest regulatory environment of the circadian oscillator components (21 genes).The control comparison group included genes with other functions (31 genes). The SNP_TATA_Comparator web service was used to predict the effects of the SNPs in the regions of the RNA polymerase II positioning on the TBP/promoter dissociation constant. It was shown that the number of SNP markers reducing the TBP/promoter affinity in the first group of genes is significantly lower than the number of SNP markers increasing affinity (α < 10). The opposite was true for the comparison group. A significantly greater number of SNP markers reduced the TBP/promoter affinity than increased it (α < 10). Thus, this property may represent a characteristic feature of the genes of the circadian oscillator that may ensure its stability during the genetic variability of the analyzed promoter regions. These predictions are important for identifying the candidate SNP markers for various pathologies associated with the dysfunction of the circadian clock genes for further testing in the experimental and clinical studies, as well as for the verification of the mathematical models of the circadian oscillator. [ABSTRACT FROM AUTHOR]

The development of in vitro technologies has produced new experimental information on protein binding onto DNA, which is accumulated in databases and used in studies of mechanisms regulating gene expression and in the development of computer-assisted methods of binding site recognition in pro- and eukaryotic genomes. However, it is still questionable to what extent in vitro selected sequences reflect the actual structures of the real transcription factor (TF) binding sites. The Kullback-Leibler divergence has been applied to the comparison of frequency matrices of TF binding sites constructed on sets of artificially selected sequences and real sites. The similarity of core sequences of real and artificial sites has been observed for 80% of all TFs studied. For 20% of TFs, in vitro selected binding site sequences have a broader range of permissible significant nucleotides not found in real sites. The optimal lengths of DNA sequences containing real binding sites, at which the sites are recognized most accurately, are estimated by the weight matrix method. For approximately 80% of the TFs studied, the optimal binding site length notably exceeds the lengths of the core sequences, as well as the lengths of in vitro selected sites. The detected features of in vitro selected TF binding sites impose constraints on their use in the development of computer-assisted methods of the recognition of candidate sites in genomic sequences. [ABSTRACT FROM AUTHOR]

This paper presents the results of the reconstruction and analysis of the gene regulatory network of the circadian clock in mammals. Application of graph theory methods makes it possible to analyze the structure of the gene network and identify the central component of circadian clock regulation, which includes the basic regulatory loops passing through the key element of the circadian clock, the Clock/Bmal1 protein. Cluster analysis has revealed subsystems with obvious biological interpretation which are involved in the functioning of the circadian clock by interacting with the central component. This structural model, which includes the central component and functional subsystems that interact with the central component, can provide grounds for the construction of a mathematical model of the dynamics of the gene network regulating the circadian rhythm. [ABSTRACT FROM AUTHOR]

The review describes combined experimental and computational approaches to the investigation of the mechanisms of transcriptional regulation of eukaryotic genes and organization of transcription regulatory regions. These include (a) an analysis of the factors affecting the affinity of TBP (TATA-binding protein) for the TATA box; (b) research on the patterns of chromatin mark distributions and their role in the regulation of gene expression; (c) a study of 3D chromatin organization; (d) an estimation of the effects of polymorphisms on gene expression via high-resolution ChIP-seq and DNase-seq techniques. It was demonstrated that combined experimental and computational approaches are very important for the current understanding of transcription regulatory mechanisms and the structural and functional organization of the regulatory regions controlling transcription. [ABSTRACT FROM AUTHOR]

An Erratum to this paper has been published: https://doi.org/10.1134/S1995423922040103 [ABSTRACT FROM AUTHOR]

The circadian clock system coordinates all the processes occurring in the body and controls the rhythmic pattern in metabolic system functioning. The reciprocal relationship between molecular and genetic systems of the circadian clock and the systems responsible for carbohydrate and lipid turnover provide fine tuning both of metabolic processes and the circadian clock regulation system, permitting the body to adapt to a variable environment. NAD-dependent enzymes, protein-kinases, and transcription regulators could serve as presumable molecular components, which are responsible for such a type of relationship. Genetic models and epidemiological studies demonstrate an association between mutations in the circadian clock genes with the risk of a disturbance of metabolic processes regulation, obesity development, and other manifestations of metabolic syndrome. [ABSTRACT FROM AUTHOR]

The study systemizes the current state of the mechanisms of the internalization of nanoparticles into living systems at all levels of organization (whole body, organ, tissue, and cell). Based on the data of the biological effects of nanoparticles with different characteristics, i.e., shape, size, composition, etc., it has been revealed that the whole set of physicochemical properties of nanoparticles define their ability to overcome biological barriers, as well as the mechanisms of cellular uptake, biodistribution in the organism, organs and tissues, biocompatibility, and cellular effects. [ABSTRACT FROM AUTHOR]

Reconstruction of an associative network, which represents molecular relationships among proteins, metabolites, and molecular processes associated with myopia and glaucoma was performed with the use of the ANDCell computer system which includes a database of knowledge and facts extracted automatically from PubMed. This network contains over 200 proteins and genes and more than 2000 interactions between them, including proteins and genes associated with both open-angle glaucoma and myopia. Reduction of this network and further analysis of molecular pathways revealed candidate genes for simultaneous genotyping of both myopia and open angle glaucoma. [ABSTRACT FROM AUTHOR]

We have developed the Transcription Regulatory Regions Database (TRRD, http://www.bionet.nsc.ru/trrd/) designed for storage of data on the structural-functional organization of transcriptional regulatory regions of the eukaryotic genes and their expression patterns. TRRD contains experimentally supported data only. Knowledge extraction from scientific literature, storage and further application of the results are all stepwise, conforming to the Data Mining technology: i) knowledge extraction from scientific publications; ii) preprocessing (data cleaning, syntactic and semantic analysis; iii) data transformation; iv) application for prediction; v) interpretation of the obtained knowledge to resolve the timely issues in bioinformatics. TRRD contains a compilation of data on 2 344 genes, their 14 407 expression patterns, 3 490 regulatory units, and 10 135 transcription factor binding sites. TRRD is filled in by manual annotation of scientific publications. The information incorporated into TRRD is the result of annotations of 7 609 scientific papers. Sequence Retrieval System (SRS) is the main tool for search and navigation in TRRD. A large number of indexed fields in its SRS version allow the user to generate queries both within and between libraries. TRRD has thesauruses and search systems that provide additional options for data access. TRRD is currently linked to 20 worldwide information resources, including EMBL/GeneBank, Ensembl, EPD, SWISS-PROT, TRANSFAC, GDB, GeneCards, MGD, RGD, GO. The links serve as a framework for integration in a distributed network environment. [ABSTRACT FROM AUTHOR]

Computer prediction of nucleosome positioning sites from DNA sequences is of great importance for analyzing eukaryotic gene expression regulation. Investigation of experimentally found nucleosome positioning sites determined statistically significant contexts and revealed symmetry of their distribution about the center of a site. Internet-available software was developed to determine the profile of preference of genomic DNA for nucleosome formation (nucleosome potential) on the basis of Markov models. A correlation of the nucleosome potential with the complexity of the nucleotide sequence text was established. The nucleosome potential was estimated for transcription factor binding sites, promoters, exons, and introns of eukaryotic genes. A difference in nucleosome potential between promoters of tissue-specific and constitutively expressed eukaryotic genes was shown. The software is available at the website of the Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences at th address . [ABSTRACT FROM AUTHOR]

The review describes several modules of the GeneExpress integrated computer system concerning the regulation of gene expression in eukaryotes. Approaches to the presentation of experimental data in databases are considered. The employment of GeneExpress in computer analysis and modeling of the organization and function of genetic systems is illustrated with examples. GeneExpress is available at http://wwwmgs.bionet.nsc.ru/mgs/gnw/. [ABSTRACT FROM AUTHOR]

Analysis of deletion polymorphism of the human c-fms gene intron 11 (∼425-bp deletion) is of particular interest because of the increased proportion of the heterozygotes among the children born from parents, one of which lacks the deletion-carrying allele, and the other is heterozygous for this allele. In this study, allele and haplotype frequencies of the polymorphism were assessed in a number of Caucasoid and Mongoloid populations of Russia. In all populations tested, relatively high prevalence of the deletion-bearing allele, ranging from 9.45% in ethnic Germans to 20.75% in Altaians, was detected. Russians and Kazakhs were characterized by intermediate frequencies of the rare allele, constituting in these populations 12.89 and 14.93%, respectively. Hardy–Weinberg expectations were met in all populations examined, pointing to a stable level of polymorphism at the c-fms intron 11. It was established by the contextual analysis of the deleted DNA fragment along with the flanking sequences that this region contained a number of transcription factor motifs (ets, CArG, and myc), potentially capable of the regulation of the M-CSF-dependant c-fms transcription. The deletion breakpoint was localized within the CArG motif, which, together with the neighboring ets motif, form the potential CArG/ets composite element. It was suggested that the allele lacking the fragment of intron 11 might be restricted in its ability to modulate the level of the c-fms transcription in response to M-CSF. The molecular epidemiological survey provided indirect evidence favoring the suggestion on the possible functional value of this gene fragment. It was demonstrated that in the samples from acute bronchitis and trichomoniasis patients allelic and genotype frequencies were significantly different from those in the population sample. In case of trichmoniasis, the frequency of rare allele was 2.4 times lower, and in case of acute bronchitis it was 2.1 times higher than in the control sample. [ABSTRACT FROM AUTHOR]

The structure of the Transcription Regulatory Regions Database (TRRD) and the principles of describing transcription regulation of eukaryotic genes in TRRD are considered. Formalized description of the structural and functional organization of the regulatory gene regions is illustrated with examples. By now, TRRD is based on 3500 original works and contains data on transcription regulation of more than 1100 genes known to possess more than 5000 transcription factor binding sites and about 1600 regulatory elements (promoters, enhancers, silencers). TRRD is available at http://www.bionet.nsc.ru/trrd/ [ABSTRACT FROM AUTHOR]

The structural and functional organization of locus control regions (LCR) was analyzed using data of the LCR-TRRDatabase. The role of several transcription factors in the LCR function was considered. A study was made of the possible nucleosomal packing of enhancer regions in LCR. The structure and the format of LCR-TRRD are described. The database has been constructed for SRS and is available at http://wwwmgs.bionet.nsc.ru/mgs/dbases/LCR/ [ABSTRACT FROM AUTHOR]

A complex approach to recognition of transcription factor binding sites (TFBS) has been developed, based on four methods: (i) weight matrix, (ii) information content, (iii) multidimensional alignment, and (iv) pairwise alignment with the most similar representative of known sites. It has been shown that none of the methods considered is optimal for all kinds of sites, so in each case the appropriate way of recognition should be chosen. The approach proposed allows one to minimize the errors in TFBS recognition. The program available through the Internet (http://www.sgi.sscc.ru/mgs/programs/multalig/) has been created to search for the potential TFBS in nucleotide sequences set by the user. [ABSTRACT FROM AUTHOR]

Development of methods for mathematical simulation of biological systems and building specific simulations is an important trend of bioinformatics. Here we describe the method of generalized chemokinetic simulation generating flexible and adequate simulations of various biological systems. Adequate simulations of complex nonlinear gene networks—control system of cholesterol by synthesis in the cell and erythrocyte differentiation and maturation—are given as examples. The simulations were expressed in terms of unit processes—biochemical reactions. Optimal sets of parameters were determined and the systems were numerically simulated under various conditions. The simulations allow us to study the possible functional conditions of these gene networks, calculate the consequences of mutations, and define optimal strategies for their correction including therapeutic ones. A graphical user interface for these simulations is available at http://wwwmgs.bionet.nsc.ru/systems/MGL/GeneNet/ [ABSTRACT FROM AUTHOR]

Gene network is a group of genes functioning in a coordinated manner to control vital processes in an organism. Each gene network includes several essential components: (1) a group of genes which form a core of a gene network, (2) proteins encoded by these genes, (3) signal transduction pathways, (4) negative and positive feedback which provide for autoregulation, and (5) low-molecular-weight compounds. To accumulate the information on gene networks, a database GeneNet has been developed (http://wwwmgs.bionet.nsc.ru/systems/mgl/genet/). At present, GeneNet contains the data on 16 gene networks which are arranged in six sections according to the subject concerned: lipid metabolism, steroidogenesis, erythropoiesis, antiviral response, plant seed development, and heat shock. Analysis of these data revealed the following principles of the gene network organization: (1) there is a great variety of molecular mechanisms which provide for a feedback regulation; (2) each gene network includes key genes which coordinate the function of the other genes of the gene network; (3) one transcription factor activates many genes via a cassette mechanism; and (4) gene networks are autoregulated via regulatory circuits with positive and negative feedback. [ABSTRACT FROM AUTHOR]

Nucleotide substitutions G→A and G→T at positions 663 and 666, respectively, of intron 6 of the human tryptophan dioxygenase gene ( TDO2) are associated with various mental disorders. The gel retardation assay revealed that oligonucleotides corresponding to the three allelic variants of region 651–680 bound with allele-specific sets of rat liver nuclear proteins, including transcription factors. Computer analysis and binding with specific antibodies showed that both mutations altered a site for transcription factor YY1. [ABSTRACT FROM AUTHOR]