[Prospects for the design of new therapeutically significant protease inhibitors based on knottins and sunflower seed trypsin inhibitor (SFTI 1)]. / Perspektivy sozdaniia novykh ingibitorov terapevticheski znachimykh serinovykh proteaz na osnove knottinov i peptidnogo ingibitora tripsina iz semian podsolnechnika (SFTI 1).

Plant seed knottins, mainly from the Cucurbitacea family, and sunflower seed trypsin inhibitor (SFTI 1) are the most low-molecular canonical peptide inhibitors of serine proteases. High efficiency of inhibition of various serine proteases, structure rigidity together with the possibility of limited variations of amino acid sequences, high chemical stability, lack of toxic properties, opportunity of production by either chemical synthesis or use of heterologous expression systems make these inhibitors attractive templates for design of new compounds for regulation of therapeutically significant serine protease activities. Hence the design of such compounds represents a prospective research field. The review considers structural characteristics of these inhibitors, their properties, methods of preparation and design of new analogs. Examples of successful employment of natural serine protease inhibitors belonging to knottin family and SFTI 1 as templates for the design of highly specific inhibitors of certain proteases are given.

Zinc ions as cytochrome C oxidase inhibitors: two sites of action.

Zinc ions are shown to be an efficient inhibitor of mitochondrial cytochrome c oxidase activity, both in the solubilized and the liposome-reconstituted enzyme. The effect of zinc is biphasic. First there occurs rapid interaction of zinc with the enzyme at a site exposed to the aqueous phase corresponding to the mitochondrial matrix. This interaction is fully reversed by EDTA and results in a partial inhibition of the enzyme activity (50-90%, depending on preparation) with an effective K(i) of approximately 10 microM. The rapid effect of zinc is observed with the solubilized enzyme, it vanishes upon incorporation of cytochrome oxidase in liposomes, and it re-appears when proteoliposomes are supplied with alamethicin that makes the membrane permeable to low molecular weight substances. Zinc presumably blocks the entrance of the D-protonic channel opening into the inner aqueous phase. Second, zinc interacts slowly (tens of minutes, hours) with a site of cytochrome oxidase accessible from the outer aqueous phase bringing about complete inhibition of the enzymatic activity. The slow phase is characterized by high affinity of the inhibitor for the enzyme: full inhibition can be achieved upon incubation of the solubilized oxidase for 24 h with zinc concentration as low as 2 microM. The rate of zinc inhibitory action in the slow phase is proportional to Zn(2+) concentration. The slow interaction of zinc with the outer surface of liposome-reconstituted cytochrome oxidase is observed only with the enzyme turning over or in the presence of weak reductants, whereas incubation of zinc with the fully oxidized proteoliposomes does not induce the inhibition. It is shown that zinc ions added to cytochrome oxidase proteoliposomes from the outside inhibit specifically the slow electrogenic phase of proton transfer, coupled to a transition of cytochrome oxidase from the oxo-ferryl to the oxidized state (the F --> O step corresponding to transfer of the 4th electron in the catalytic cycle).

[Quantitative patterns in the clinical manifestations of radiation sickness in large laboratory animals exposed to radiation at superlethal doses. The quantitative patterns in the manifestations of radiation sickness in dogs]. / Kolichestvennye zakonomernosti klinicheskikh proiavlenii luchevoi bolezni u krupnykh laboratornykh zhivotnykh pri vozdeistvii izlucheniia v sverkhletal'nykh dozakh. Kolichestvennye zakonomernosti proiavlenii luchevoi bolezni u sobak.

Radiation sickness manifestations have been studied in dogs exposed to electrons (electron energy 25 MeV) and gamma-neutron radiation (neutron energies of 0.37 and 1.2 MeV) in a wide dose range. Dose-response relationships have been calculated for mortality and some clinical manifestations of the intestinal and cerebral forms of radiation sickness. With regard to mortality, the highest effect has been observed for gamma-neutron radiation with a neutron energy of 1.2 MeV. For equal physical doses and for those equally effective in relation to mortality, clinical manifestations of damage are more prominent following exposure to electrons.

[Prognostication of individual radiation sensitivity of animals, based on the use of a mathematical method of object classification]. / Prognozirovanie individual'noi radiochuvstvitel'nosti zhivotnykh, osnovannoe na primenenii matematicheskogo metoda klassifikatsii ob"iektov.

A statistical method of object classification based on the use of linear discriminant analysis, was employed to solve the problem of prediction of the outcome of acute radiation disease. In experiments on 23 monkeys irradiated at a dose of 5.3 Gy 14 animals had survived and 9 perished. The initial state and early response (in 5 h) to gamma-beam radiation were assessed. The total number of the analyzed parameters was 16. According to the experimental results an integral index--discriminator--was computed for each object. Values for the survivors ranged within 136.1-151.3, and for 9 more radiosensitive animals the values of discriminators turned out to be higher (151.9-168.7). The procedure of prognosis was the following. 23 monkeys were randomly divided into 2 groups (using the table of random numbers). The 1st group (a study sample) included 13 animals, of them 8 survived and 5 perished. The 2nd group (a control predictor sample) included 10 animals, of them 6 survived and 4 perished by the end of the experiment. The authors described 3 variants of a random selection of the animals both for the 1st and 2nd groups. The results of prognosis were compared with the experimental results. Erroneous prognosis for each variant was 10, 0 and 20%, respectively.

[Effect of different levels of protein and cellulose in the diet on the radiosensitivity of guinea pigs]. / Vliianie razlichnykh urovnei belka i kletchatki v ratsione na radiochuvstvitel'nost; morskikh svinok

Investigations included 6 groups of male guinea pigs counting 50 guinea pigs in each of them. Starting from the age of 25 days the animals were kept on standard rations consisting of granulated combined fodder with diverse protein (22.8, 17.5, 13.8 per cent) and cellular tissue (11.8, 13.6, 15.7 per cent) content. The results failed to show any significant dependance of the animals' radiosensitivity on the protein and cellular tissue levels in the diet.