[Molecular and genetic aspects of interactions of the circadian clock and the energy-producing substrate metabolism in mammals].

The circadian clock system coordinates al 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 maniifestations of metabolic syndrome.

[Statistical analysis of nucleosome formation sites].

The prediction of the DNA capacity to form nucleosome structure based on sequence statistics is of importance in the analysis of gene expression regulation in eukaryotes. A context analysis of nucleotide sequences of experimentally defined sites of nucleosome formation made it possible to determine the sequence preference for nucleosome formation on the basis of statistical information. An improved version of the Markov model was developed to predict the preference of DNA sequences to be within a nucleosome structure. The developed VMM (Variable Memory Markov model) program computes the nucleosome formation potential for genomic DNA sequences of arbitrary lengths, including the short transcription factor binding sites. Differences in nucleosome potential for exons, introns, and promoters were revealed. A correlation of the nucleosome potential estimate with text complexity was established. The VMM is available at http://wwwmgs. bionet.nsc.ru/programs/VMM/.

[Locus-controlling regions: description in the LCR-TRRD data base]. / Lokuskontroliruiushchie raiony: Opisanie v baze dannykh LCR-TRRD.

The structural and functional organization of locus control regions (LCR) was analyzed using data of the LCR-TRR Database. 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/dbase/LCR/.

[A generalized chemical-kinetic method for modeling gene networks]. / Obobshchennyi khimiko-kineticheskii metod modelirovaniia gennykh setei.

Development of methods for mathematical simulation of biological systems and building specific simulations is an important trend of bioinformatics development. 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 the 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 possible functional conditions of these gene networks, calculate consequences of mutations, and define optimal strategies for their correction including therapeutic ones. Graphical user interface for these simulations is available at http://wwwmgs.bionet.nsc.ru/systems/MGL/GeneNet/.

[Comparative analysis of methods for recognizing potential transcription factor binding sites]. / Sravnitel'ny analiz metodov raspoznavaniia potentsial'nykh saitov sviazyvaniia transkriptsionnykh faktorov.

A complex approach to recognize 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 no method optimal for all kinds of sites occurs among the considered methods, so in each case, the appropriate way of recognition should be chosen. The approach proposed allows one to minimize the errors of 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.

[Regulation of eukaryotic gene transcription: description in the TRRD database]. / Reguliatsiia transkriptsii genov éukariot: opisanie v baze dannykh TRDD.

The structure of the Transcription Regulatory Regions Database (TRRD) and the principles of considering transcription regulation of eukaryotic genes in TRRD are concerned. Formal 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/.

[Deletional polymorphism of the 11th intron of the human c-fms gene: allele frequency in certain Russian populations and possible functional significance]. / Deletsionnyi polimorfizm 11-go introna gena c-fms cheloveka: chastoty allelei v nekotorykh populiatsiiakh Rossii i vozmozhnaia funktsional'naia znachimost'.

Analysis of deletion polymorphism of human c-fms gene intron 11 (approximately 425-bp deletion) is of particular interest because of the increased proportion of the deletion heterozygotes among the infants born from the parents, one of which lacks the deletion allele, and the other is heterozygous for the deletion. In this study, allele and haplotype frequencies of the polymorphism examined 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 context analysis of DNA of the deleted fragment along with the flanking sequences that this region contained a number of transcription factor motifs (Ets, SRF, and Myc), potentially capable of the regulation of the M-CFF-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 allele lacking the fragment of intron 11 could be restricted in its ability to modulate the level of the c-fms transcription in response to the action of M-CSF. The data of molecular epidemiological survey serve as the indirect evidence favoring the suggestion on the possible functional value of this gene fragment. It was demonstrated that in the samples of acute bronchitis and trichomoniasis patients allelic and genotype frequencies were statistically 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.

[Averaging results of site recognition can increase the accuracy of annotating the human genome]. / Usrednenie rezul'tatov raspoznavaniia saitov mozhet uvelichit' tochnost' annotatsii genoma cheloveka.

A systemic approach is proposed, which makes it possible to increase the accuracy of recognition of functional sites in arbitrary DNA sequences. The approach is based on the Central limit theorem and consists in the averaging of a large number of recognitions of a particular site. To obtain a rather large number of recognitions within the framework of conventional methods of recognition, consensus, and frequency matrix, 20 novel oligonucleotide alphabets were used. The approach was used to study the binding sites of GATA-1 and C/EBP transcription factors. It was found that the averaged recognition of these sites is more precise than each of specific recognitions, which just follows from the Central limit theorem.

[Detection and analysis of clinico-pathogenetic variants of the labile stage of hypertension using mathematical methods of image recognition]. / Vyiavlenie i analiz kliniko-patogeneticheskikh variantov labil'noi stadii gipertonicheskoi bolezni s pomoshch'iu matematicheskikh metodov raspoznavaniia obrazov.

The method of cluster analysis was used for automatic classification of patients with the labile stage of hypertensive disease according to 15 parameters reflecting the condition of hemodynamics and its regulation. Two groups differing in the principal factors of high arterial pressure maintenance were distinguished. Clinical and physiological analysis of the distinguished groups was conducted on the basis of the furosemide test.

[Vascular reactivity and catecholamine excretion in hypertension]. / Sosudistaia reaktivnost' i ékskretsiia katekholaminov pri gipertonicheskoi bolezni.

Increased vascular reactivity to noradrenaline was revealed in patients with Stages I and II hypertensive disease; the reaction to the sympathomimetic agent of indirect action ephedrine remained at the control level. A salt load increased the discrepancy between the level of the reactions to these two agents. It is suggested that processes of catecholamine storage and excretion in the tissues are disturbed in hypertensive disease and that sodium ions probably take part in this process. The daily excretion of noradrenaline was in negative relation with the reactivity to noradrenaline and correlated positively with the reactivity to angiotensin.

[Responses of the pressor and depressor regulatory systems to high sodium intake in borderline arterial hypertension]. / Osobennosti reaktsii pressornykh i depressornykh reguliatornykh sistem na povyshennyi priem povarennoi soli pri pogranichnoi arterial'noi gipertenzii.

A total of 25 healthy individuals and 48 borderline hypertensives aged 22-56 years were examined. The healthy subjects having a salt load showed elevated blood histamine concentrations and an unchanged vascular response to histamine, and reduced plasma renin activity. The patients having a salt load displayed high histamine levels, sharply decreased vascular response to histamine, and undepressed plasma renin activity. It is concluded that the pressor mechanisms responsible for controlling vascular tone are more active than the depressor ones during the salt load in patients with borderline hypertension. The humoral response of the patients to a salt load was impaired with elevated plasma cortisol concentrations, which was not followed by sodium retention in the body.