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The Russian language, as the state language, is given an honorable and important role, uniting all nationalities together. For its mission to serve the unity, solidarity, and mutual understanding of all the peoples of Russia, a mandatory national educational program has been approved, operating throughout the territory of the Russian Federation. The present article is dealing with the problem of mastering the Russian language. The goal of the research is to study the etiology and specifics of writing disorders in primary school children studying at general education school and to develop differentiated strategies for teaching pupils with various manifestations of dysgraphia. Methods used during the preparation of the article included theoretical research, such as learning, generalization, analysis, synthesis, axiomatics, as well as empirical techniques, namely, observation and comparison. Results and novelty of the research consist of clarifying information about the state of the problem of writing disorders in contemporary schoolchildren, updating scientific ideas about the contingent of primary school children in need of correctional assistance from specialists; applying an interdisciplinary approach to the study of the etiology, mechanisms, causes, and specifics of various manifestations of dysgraphia in primary general school children; supplementing the scientific data on the impact of didactogenia on the quality of learning writing and the formation of dysgraphia in pupils with difficulties in the assimilation of the program learning material on the Russian language; as well developing high-performance speech technologies for the early detection and elimination of violations of written language and difficulties in learning academic courses of the Russian language.

The article presents the attitude of prisoners of the past centuries in Russia to punishment, their fate, which they represented in the form of song creation and various metaphorical images. These images have passed through time and are associated with the perception of the prison as a special space. Therefore the authors use already described examples how a prison could look at the end of the Middle Ages.

Enzymes generally display strict stereospecificity and regioselectivity for their substrates. Here by using FAD-dependent human acetylpolyamine oxidase (APAO), human spermine (Spm) oxidase (SMOX) and yeast polyamine oxidase (Fms1), we demonstrate that these fundamental properties of the enzymes may be regulated using simple guide molecules, being either covalently attached to polyamines or used as a supplement to the substrate mixtures. APAO, which naturally metabolizes achiral N 1 -acetylated polyamines, displays aldehyde-controllable stereospecificity with chiral 1-methylated polyamines, like (R)- and (S)- 1-methylspermidine (1,8-diamino-5-azanonane) (1-MeSpd). Among the novel N 1 -acyl derivatives of MeSpd, isonicotinic acid (P4) or benzoic acid (Bz) with (R) -MeSpd had K m of 3.6 ± 0.6/1.2 ± 0.7 µM and k cat of 5.2 ± 0.6/4.6 ± 0.7 s -1 respectively, while N 1 -AcSpd had K m 8.2 ± 0.4 µM and k cat 2.7 ± 0.0 s -1 On the contrary, corresponding (S) -MeSpd amides were practically inactive ( k cat < 0.03 s -1 ) but they retained micromole level K m for APAO. SMOX did not metabolize any of the tested compounds ( k cat < 0.05 s -1 ) that acted as non-competitive inhibitors having K i ≥ 155 µM for SMOX. In addition, we tested (R , R) -1,12-bis-methylspermine (2,13-diamino-5,10-diazatetradecane) (R , R)- (Me 2 Spm) and (S,S) -Me 2 Spm as substrates for Fms1. Fms1 preferred (S,S) - to (R,R) -diastereoisomer, but with notably lower k cat in comparison with spermine. Interestingly, Fms1 was prone to aldehyde supplementation in its regioselectivity, i.e. the cleavage site of spermidine. Thus, aldehyde supplementation to generate aldimines or N -terminal substituents in polyamines, i.e. attachment of guide molecule, generates novel ligands with altered charge distribution changing the binding and catalytic properties with polyamine oxidases. This provides means for exploiting hidden capabilities of polyamine oxidases for controlling their regioselectivity and stereospecificity., (© 2018 The Author(s).)

Experimental pancreatitis is associated with activation of polyamine catabolism. The polyamine analog bismethylspermine (Me(2)Spm) can ameliorate pancreatic injury. We investigated the roles of polyamine catabolism in remote organs during pancreatitis and explored the mechanism of polyamine catabolism by administering Me(2)Spm. Acute pancreatitis was induced by an infusion of 2 or 6% taurodeoxycholate before Me(2)Spm administration. Blood, urine and tissues were sampled at 24 and 72 h to assess multi-organ injury and polyamine catabolism. The effect of Me(2)Spm on mortality in experimental pancreatitis was tested separately. Liver putrescine levels were elevated following liver injury. Me(2)Spm increased the activity of spermidine/spermine N(1)-acetyltransferase (SSAT) and depleted the spermidine, spermine or putrescine levels. Lung putrescine levels increased, and SSAT and spermine decreased following lung injury. Me(2)Spm enhanced the activity of SSAT and decreased the spermidine and spermine levels. Renal injury was manifested as an increase in creatinine or a decrease in urine output. Decreases in kidney SSAT, spermidine or spermine and an increase in putrescine were found during pancreatitis. In the 2% taurodeoxycholate model, Me(2)Spm decreased urine output and raised plasma creatinine levels. Me(2)Spm increased SSAT and decreased polyamines. Excessive Me(2)Spm accumulated in the kidney, and greater amounts were found in the 6% taurodeoxycholate model in which this mortality was not reduced by Me(2)Spm. In the 2% taurodeoxycholate model, Me(2)Spm dose-dependently induced mortality at 72 h. Like pancreatic injury, remote organ injury in pancreatitis is associated with increased putrescine levels. However, Me(2)Spm could not ameliorate multi-organ injury. Me(2)Spm administration was associated with significant renal toxicity and induced mortality, suggesting that the current dose is too high and needs to be modified.

The role of polyamines in carbon tetrachloride (CCl(4))-induced organ injury was studied in syngenic rats and transgenic rats with activated polyamine catabolism. In syngenic rats, administration of CCl(4) resulted in the induction of hepatic spermidine/spermine N(1)-acetyltransferase (SSAT), accumulation of putrescine, reduction in spermine level and appearance of moderate hepatic injury within 24 h. Upon treatment with CCl(4), transgenic rats overexpressing SSAT displayed induction of both hepatic and pancreatic SSAT, with subsequent accumulation of putrescine and decrease of both spermidine and spermine pools. Administration of CCl(4) in SSAT transgenic rats induced not only massive hepatic injury, but also severe acute necrotizing pancreatitis. Pretreatment of the animals with catabolically stable functional polyamine mimetic, alpha-methylspermidine (MeSpd) prevented pancreatic and hepatic injury in SSAT rats and markedly reduced liver damage in syngenic animals. As assessed by immunostaining of proliferating cell nuclear antigen, MeSpd increased the amount of regenerating hepatocytes in both genotypes. These results show that CCl(4) induces hepatic and pancreatic polyamine catabolism, and the extent of organ damage correlates with the degree of polyamine depletion. Furthermore, MeSpd protects against CCl(4)-induced hepatic and pancreatic damage and promotes tissue regeneration.

We have earlier shown that alpha-methylated spermidine and spermine analogues rescue cells from polyamine depletion-induced growth inhibition and maintain pancreatic integrity under severe polyamine deprivation. However, because alpha-methylspermidine can serve as a precursor of hypusine, an integral part of functional eukaryotic translation initiation factor 5A required for cell proliferation, and because alpha, omega-bismethylspermine can be converted to methylspermidine, it is not entirely clear whether the restoration of cell growth is actually attributable to hypusine formed from these polyamine analogues. Here, we have used optically active isomers of methylated spermidine and spermine and show that polyamine depletion-induced acute cytostasis in cultured cells could be reversed by all the isomers of the methylpolyamines irrespective of whether they served or not as precursors of hypusine. In transgenic rats with activated polyamine catabolism, all the isomers similarly restored liver regeneration and reduced plasma alpha-amylase activity associated with induced pancreatitis. Under the above experimental conditions, the (S, S)- but not the (R, R)-isomer of bismethylspermine was converted to methylspermidine apparently through the action of spermine oxidase strongly preferring the (S, S)-isomer. Of the analogues, however, only (S)-methylspermidine sustained cell growth during prolonged (more than 1 week) inhibition of polyamine biosynthesis. It was also the only isomer efficiently converted to hypusine, indicating that deoxyhypusine synthase likewise possesses hidden stereospecificity. Taken together, the results show that growth inhibition in response to polyamine depletion involves two phases, an acute and a late hypusine-dependent phase.

Polyamines are essential for normal cellular growth and function. Activation of polyamine catabolism in transgenic rats overexpressing spermidine/spermine N(1)-acetyltransferase, the key enzyme in polyamine catabolism, results in severe acute pancreatitis. Here, we investigated the role of polyamine catabolism in pancreatitis and studied the effect of polyamine analogues on the outcome of the disease. Polyamine depletion was associated with arginine- and cerulein-induced pancreatitis as well as with human acute necrotizing and chronic secondary pancreatitis. Substitution of depleted polyamine pools with methylspermidine partially prevented arginine-induced necrotizing pancreatitis whereas cerulein-induced edematous pancreatitis remained unaffected. Transgenic rats receiving methylated polyamine analogues after the induction of pancreatitis showed less pancreatic damage than the untreated rats. Most importantly, polyamine analogues dramatically rescued the animals from pancreatitis-associated mortality. Induction of spermidine/spermine N(1)-acetyltransferase in acinar cells isolated from transgenic rats resulted in increased trypsinogen activation. Pretreatment of acini with bismethylspermine prevented trypsinogen activation, indicating that premature proteolytic activation is one of the effects triggered by polyamine depletion. Our data suggest that activation of polyamine catabolism is a general pathway in the pathogenesis of acute pancreatitis and that experimental disease can be ameliorated with stable polyamine analogues.

Metabolically stable polyamine derivatives may serve as useful surrogates for the natural polyamines in studies aimed to elucidate the functions of individual polyamines. Here we studied the metabolic stability of alpha-methylspermidine, alpha-methylspermine, and bis-alpha-methylspermine, which all have been reported to fulfill many of the putative physiological functions of the natural polyamines. In vivo studies were performed with the transgenic rats overexpressing spermidine/spermine N(1)-acetyltransferase. alpha-Methylspermidine effectively accumulated in the liver and did not appear to undergo any further metabolism. On the other hand, alpha-methylspermine was readily converted to alpha-methylspermidine and spermidine; similarly, bis-alpha-methylspermine was converted to alpha-methylspermidine to some extent, both conversions being inhibited by the polyamine oxidase inhibitor N(1), N(2)-bis(2,3-butadienyl)-1,4-butanediamine. Furthermore, we used recombinant polyamine oxidase, spermidine/spermine N(1)-acetyltransferase, and the recently discovered spermine oxidase in the kinetic studies. In vitro studies confirmed that methylation did not protect spermine analogs from degradation, whereas the spermidine analog was stable. Both alpha-methylspermidine and bis-alpha-methylspermine overcame the proliferative block of early liver regeneration in transgenic rats and reversed the cytostasis induced by an inhibition of ornithine decarboxylase in cultured fetal fibroblasts.