Diagnostics of Microcirculatory Disorders in Children with Infectious Pathology

Laser Doppler flowmetry method (LDF) was used to examine children (43 patients with enteroviral infection, 34 patients with Astrakhan rickettsial fever, and 40 healthy controls). In addition, in view of LDF survey data, carried out was thermal assay and amplitude-frequency analysis of peripheral microcirculation predictors. Detected were incipient changes in microvasculature relative to microangiopathy

GeneNet in 2005

The GeneNet system is designed for collection and analysis of the data on gene and metabolic networks, signal transduction pathways and kinetic characteristics of elementary processes. In the past 2 years, the GeneNet structure was considerably improved: (i) the current version of the database is now implemented using ORACLE9i; (ii) the capacities to describe the structure of the protein complexes and the interactions between the units are increased; (iii) two tables with kinetic constants and more detailed descriptions of certain reactions were added; and (iv) a module for kinetic modeling was supplemented. The current SRS release of the GeneNet database contains 37 graphical maps of gene networks, as well as descriptions of 1766 proteins, 1006 genes, 241 small molecules and 3254 relationships between gene network units, and 552 kinetic constants. Information distributed between 16 interlinked tables was obtained by annotating 1980 journal publications. SRS release of the GeneNet database, the graphical viewer and the modeling section are available at http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/

The effects of SN Ps in the regions of positioning RNA polymerase II on the TBP/promoter affinity in the genes of human circadian clock

Genetic variability in the genes of circadian clock is manifested as the phenotypic variability of physiological functions and behavior as well as disorders of the function of not only the clock but also other systems, leading to the development of a pathologies. We analyzed the influence of SNPs localized in the [–70, –20] region from the transcription start site of the gene on TBP / promoter affinity in two groups of genes that are components of the system of human circadian clock. The first group comprises the genes of the circadian oscillator core (11 genes); the second, the genes of the nearest regulatory environment of the circadian oscillator (21 genes). A group for comparison included genes with another function (31 genes). The SNP_TATA_Comparator web service was used for prediction of the effect of SNPs in the regions of positioning of RNA polymerase II on the dissociation constant for TBP / promoter. It was shown that the number of SNP markers reducing the TBP / promoter affinity in the first group of genes significantly lower than the number of SNP markers increasing affinity (α < 10–3). The reverse was true of the comparison group: SNP markers reduced TBP / promoter affinity to a significantly greater extent than the SNP marker increased affinity (α < 10–6). This property may be a characteristic feature of genes  of the circadian oscillator. These predictions are important for identification of candidate SNP markers of various pathologies associated with the dysfunction of circadian clock genes for further testing them in experimental and clinical studies, as well as for verification of mathematical models of the circadian oscillator

Biomedical and candidate SN P markers of chronopathologies can significantly change affinity of ТАТА -binding protein for human gene promoters

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 in the binding sites of ТАТА - binding protein (ТВР) using a previously described W eb service (http://beehive.bionet.nsc.ru/cgi-bin/mgs/ tatascan/start.pl) with a keyword search for biochemicalmarkers of chronopathologies, which correspond to clinical manifestations of these SNPs. In the [–70; –20] region of promoters of 14 human genes (location of proven binding sites of ТВР), we found 32 known and candidate SNP markers of circadian- rhythm disturbances, including rs17231520 and rs569033466 (both: risk of chronopathologies in 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 α (significance) of changes in the affinity of ТВР 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 clinical standards and protocols may advance the field of predictive preventive personalized medicine

Prediction and verification of the influence of the rs367781716 SN P on the interaction of ТАТА -binding protein with the promoter of the human АВСА9 gene

The high-throughput sequencing project “1 000 Genomes” made it possible to catalog and utilize genetic loci and single nucleotide polymorphisms (SNPs) in medicine. Analysis of SNP markers (significantly frequent differences of individual genomes of patients from the reference human genome) allows physicians to optimize treatment. On the other hand, tens of millions of unannotated SNPs correspond to a gigantic number of false positive (false negative) candidate SNP markers that are selected by computer methods for comparison of their frequency in patients with that in healthy people. This approach contributes to undervaluation of clinically relevant SNPs and to unnecessary computational expenses (on verification of neutral SNPs). Preclinical empirical verification of possible candidate SNP markers may eliminate neutral SNPs from the dataset. In the present study, we found, using the SNP_TATA_Comparator web service, the unannotated SNP rs367781716: the substitution of ancestral T (health) with minor C at position –37 before the transcription initiation site of the АВСА9 gene. This SNP significantly reduces affinity of TATAbinding protein (TBP) for this gene’s promoter and corresponds to a deficiency (low protein level) of the АВСА9 gene product (the transporter ATP-binding cassette A9) in patients with the –37C allele. For preclinical empirical verification of rs367781716, we used an electrophoretic mobility shift assay (EMSA) to measure the rates of formation (ka) and decay (kd) of the complexes of TBP with an oligonucleotide matching either allele –37C or –37T of the АВСА9 gene. We found that the rate of formation (ka) of the TBP/TATA complex for the minor allele is 2.4-fold lower than that for the ancestral allele. We calculated the empirical value of the change in the equilibrium constant of dissociation (KD = kd /ka), which characterizes binding affinity of TBP for a promoter containing the ТАТА box. This empirical value matched the value predicted by SNP_ТАТА _Comparator within the margin of error of the measurements and calculations. We also determined the half-life and Gibbs free energy of the complex of TBP with the АВСА9 promoter. Possible phenotypic manifestations of the candidate SNP marker rs367781716 are discussed

A MODEST review

We present an account of the state of the art in the fields explored by the research community invested in 'Modeling and Observing DEnse STellar systems'. For this purpose, we take as a basis the activities of the MODEST-17 conference, which was held at Charles University, Prague, in September 2017. Reviewed topics include recent advances in fundamental stellar dynamics, numerical methods for the solution of the gravitational N-body problem, formation and evolution of young and old star clusters and galactic nuclei, their elusive stellar populations, planetary systems, and exotic compact objects, with timely attention to black holes of different classes of mass and their role as sources of gravitational waves. Such a breadth of topics reflects the growing role played by collisional stellar dynamics in numerous areas of modern astrophysics. Indeed, in the next decade, many revolutionary instruments will enable the derivation of positions and velocities of individual stars in the Milky Way and its satellites and will detect signals from a range of astrophysical sources in different portions of the electromagnetic and gravitational spectrum, with an unprecedented sensitivity. On the one hand, this wealth of data will allow us to address a number of long-standing open questions in star cluster studies; on the other hand, many unexpected properties of these systems will come to light, stimulating further progress of our understanding of their formation and evolution.Comment: 42 pages; accepted for publication in 'Computational Astrophysics and Cosmology'. We are much grateful to the organisers of the MODEST-17 conference (Charles University, Prague, September 2017). We acknowledge the input provided by all MODEST-17 participants, and, more generally, by the members of the MODEST communit