Impact of germline and somatic missense variations on drug binding sites.

Advancements in next-generation sequencing (NGS) technologies are generating a vast amount of data. This exacerbates the current challenge of translating NGS data into actionable clinical interpretations. We have comprehensively combined germline and somatic nonsynonymous single-nucleotide variations (nsSNVs) that affect drug binding sites in order to investigate their prevalence. The integrated data thus generated in conjunction with exome or whole-genome sequencing can be used to identify patients who may not respond to a specific drug because of alterations in drug binding efficacy due to nsSNVs in the target protein's gene. To identify the nsSNVs that may affect drug binding, protein-drug complex structures were retrieved from Protein Data Bank (PDB) followed by identification of amino acids in the protein-drug binding sites using an occluded surface method. Then, the germline and somatic mutations were mapped to these amino acids to identify which of these alter protein-drug binding sites. Using this method we identified 12 993 amino acid-drug binding sites across 253 unique proteins bound to 235 unique drugs. The integration of amino acid-drug binding sites data with both germline and somatic nsSNVs data sets revealed 3133 nsSNVs affecting amino acid-drug binding sites. In addition, a comprehensive drug target discovery was conducted based on protein structure similarity and conservation of amino acid-drug binding sites. Using this method, 81 paralogs were identified that could serve as alternative drug targets. In addition, non-human mammalian proteins bound to drugs were used to identify 142 homologs in humans that can potentially bind to drugs. In the current protein-drug pairs that contain somatic mutations within their binding site, we identified 85 proteins with significant differential gene expression changes associated with specific cancer types. Information on protein-drug binding predicted drug target proteins and prevalence of both somatic and germline nsSNVs that disrupt these binding sites can provide valuable knowledge for personalized medicine treatment. A web portal is available where nsSNVs from individual patient can be checked by scanning against DrugVar to determine whether any of the SNVs affect the binding of any drug in the database.

[Antitoxic influence of taurine].

The investigation of single injection of taurine on Lebetina viper' venom-induced shifts of morpho-functional indices of rats' peripheral blood was carried out. It was revealed that taurine eliminates negative effects of influence of venom. The results of investigation allow us to assume that taurine trigger adaptive and compensatory mechanisms of organism in conditions of toxins influence.

[Two routes for the development of chromosome aberrations]. / Dva puti vozniknoveniia aberratsii khromosom

Data on cytogenetic investigations using the method of influence of DNA and protein syntheses inhibitors on the chromosome are summarized. The formation of chromosome rearrangements and gaps is considered to be due to the appearance of DNA damage. The formation of these changes is proved to be similar under radiation and chemical mutagenesis. Successive stages of the realization of chromosome aberrations are united by crossing over (contact) hypothesis. The other was of the formation of cytogenetic changes is due to DNA structural degradation. These two ways can combine in radiation and chemical mutagenesis (depending on doses and mutagens).

Effect of kinetin on the formation of chromosome aberrations during irradiation of Crepis capillaris L. seeds and its radioprotective effect. / Vliianie kinetina na obrazovanie aberratsii khromosom pri obluchenii semian Crepis capillaris L. i ego radiozashchitnyi éffekt

The object of this investigation was the mutagenic effect of kinetin (6-phurphuryl-aminopurine) on chromosomes of Crepis capillaris L. Dry seeds were soaked in the 0.05% kinetin solution for 4, 6 and 8 hours before the irradiation with X-rays. It is observed that soaking of dry seeds in kinetin solution stimulates the appearance of chromatid aberrations for almost two hours earlier, than in the control (soaking seeds in water). A regular increase of the chromatid-type rearrangements with increasing the duration of soaking in the kinetin solution was observed (3.3%, 16-20% and almost 50% at 4 hours; 6 hours' and 8 hours' soaking respectively). This increase is indicative for the effect of kinetin on the processes taking place in the cell before the irradiation. Apparently kinetin stimulates the onset of the stage S for a certain proportion of cells, and thus at the moment of irradiation the cell population is at the asynchronous state. A considerable radioprotective effect of kinetin was observed in all the variants of the experiment, which is not associated with the capacity of stimulating the initiation of chromatid aberrations inherent in kinetin. Kinetin alone (without irradiation) exerts no mutagenic effect on the cells of Crepis capillaris.

[Participation of the nucleus epibasalis centralis in regulating the function of the skin-feather complex of poultry]. / Uchastie n. epibasalis centralis v reguliatsii funkstional'nogo sostoianiia kozhno-per'evogo kompleksa ptits.

In acute experiments on anesthetized mature chickens, the bioelectrical activity of epibasal neurons was influenced upon both by means of intradermal histamine injections and direct histamine application to the medial region of n. epibasalis centralis, as well as by uni- and bilateral lesion of this structure. The processes under study were evaluated with respect to the parameters of focal potentials and neuronal reactions induced in n. epibasalis centralis as well as by the measurement of the feather adhesive force, the latter being a correlate for the skin analyzer sensibility. It is shown that the feather adhesive force increases with growing activity of the central neurons and decreases in case of their activity suppression or lesion of the nucleus.

[A component analysis of far-field somatosensory evoked potentials in cats with temporary spinal cord compression]. / Komponentnyi analiz dal'nepol'nykh somatosensornykh vyzvannykh potentsialov u koshek pri vremennoi kompressii spinnogo mozga.

Temporary compression of spinal cord was modelled in anesthetized cats. The degree of spinal disfunction was estimated by component analysis of far-field somatosensory EPs which were recorded along vertebral column and scalp. Even a weak and short-term compression of spinal cord's dorsal columns changed biopotentials' latencies, amplitudes and interpeak intervals. Usefulness of correlative analysis of interpeak intervals as an additional way of differential evaluation of spinal pathways conductivity, was shown.

[Cytogenetic activity of various organophosphorus insecticides]. / Tsitogeneticheskaia aktivnost' nekotorykh insektitsidov iz gruppy fosfororganicheskikh soedinenii.

The action of certain insecticides belonging to the group of organophosphorous compounds (chlorophos, metaphos, etaphos, phosphamid, phosalone, carbophos, selecron) has been studied by the test of chromosome aberrations in Crepis capillaris cells. It is shown that these insecticides possess mutagenic activity in all phases of the cell cycle and are mutagens of the undelayed action.

[Alternative and non-alternative processes of the origin of chromosome aberrations]. / Al'ternativnye i neal'ternativnye protsessy vozniknoveniia aberratsii khromosom.

Five differences that form the basis for chromosome aberrations division into exchanges and fragmentations are described. A fragmentation is a more variable component of aberrations that sometimes exhibit the properties of incompleteness. The period of exchanges formation is determined. In most objects, it lasts for about 4 h on an average. Osteichthyes have additional long-term patterns of cytogenetic changes occurrence which, in all appearance, favor the evolutionary processes in this group of vertebrates.

[Effects of the bee and various snake venoms on the rat thermoregulation]. / Issledovanie vliianiia iadov pchel i nekotorykh vidov zmei na termoreguliatsiiu u krys.

The most sensitive organ to any kind of venoms is the skin, whereas muscles response of milder, and the intestine response reveals no difference between effects of different venoms. The isobarin desympathetising effect combined with V.lebetina venom shows that the venom affects thermoregulation interacting with the sympathetic nervous system, and exerts a sympathomimetic effect. This action seems to be not adrenergic as there is no compensation of the catecholamine decrease due to isobarin administration.

Automated electrocardiograph ST segment trending monitors: accuracy in detecting myocardial ischemia.

UNLABELLED: Continuous automated ST segment trending devices (ST trending monitors) are included in most new operating room electrocardiography (ECG) monitors to facilitate ischemia detection, but their efficacy is not well validated. Therefore, we compared their accuracy with that of Holter ECG recorders in detecting ST segment changes (both analyzed offline) in 94 patients undergoing coronary artery bypass graft surgery. Holter ECG tapes were analyzed using standard criteria for determining ECG ischemic episodes, which were compared with those measured by the ST trending monitors. Overall, 42 ischemic episodes were detected by using the Holter monitor in 30 patients. Of the 42 episodes, 38 (90%) were also detected by the ST trending monitors. Sixteen episodes of ST segment deviation were detected by the ST trending monitors, but not by the Holter. The sensitivity of the three ST trending monitors in detecting ischemia was 75%, 78%, and 60% for the Marquette (Milwaukee, WI), Hewlett Packard (Andover, MA), and Datex (Helsinki, Finland) monitors, respectively, with a specificity of 89%, 71%, and 69% relative to the Holter. Compared with the HP and Datex monitors, the Marquette monitor has the best agreement with the Holter (K 0.64). Conditions in which ST trending monitors may be inaccurate were identified and included the appearance of small R-wave amplitude, drifting baseline, and during periods of conduction abnormalities and pacing. We conclude that ST trending monitors have only moderate sensitivity and specificity (< 75% overall) in accurately detecting ECG ST segment changes compared with Holter ECG recordings. Therefore, sole reliance on ST trending monitors for the detection of myocardial ischemia may be insufficient. IMPLICATIONS: Using Holter recordings as the reference standard for detection of intraoperative ischemia, ST trending monitors were found to have overall sensitivity and specificity of 74% and 73%, respectively. Several conditions contribute to the inaccuracy of ST trend monitoring, and additional modification of their performance is necessary to achieve better agreement with the Holter analysis.