Metabolomic approach to investigate Dactylis glomerata L. from the VIR collection.

The perennial grass cocksfoot (Dactylis glomerata L.) is a valuable early highly nutritious crop used as green fodder in agricultural production. The species is widespread across the Eurasian continent; it is characterized by plasticity and high ecological and geographical variability. The article considers the metabolic profiles of 15 accessions of the cocksfoot from the collection of the N.I. Vavilov Institute of Plant Genetic Resources (VIR). The material is represented by varieties and wild forms of various origin: the European part of the Russian Federation, Norway and Finland. The study was carried out using gas-liquid chromatography coupled with mass spectrometry. The study and comparison of groups of metabolites of cocksfoot accessions of various ecological and geographical origin was carried out. Statistical processing included the calculation of the main parameters of variability, factor analysis of the correlation system (Q- and R-technique), cluster analysis by Ward's method and discriminant analysis. The variability of the quantitative and qualitative composition of the substances identified was revealed. Based on statistical processing of the results obtained, five groups of cocksfoot accessions were identified, differing in the profile of metabolites. One of the groups with a similar composition of metabolites consisted of accessions from one ecological and geographical region; another, of accessions of different origin. Significant differences were noted in the metabolomic profiles of a late-maturing wild cocksfoot accession from the Republic of Karelia at the booting stage from early- and mid-maturing accessions at the heading stage; it contained the largest number of free amino acids and the smallest number of identified primary and secondary metabolites. Wild-growing accession k-44020 from Norway surpassed other wild-growing accessions in the content of free amino acids, sugars and phosphates at the heading stage. Wild-growing accessions differed from breeding varieties with a high content of proline and threonine, indicators of high resistance to lack of moisture and high air temperature.

Anticholinesterase and Antioxidant Activity of New Binary Conjugates of γ-Carbolines.

The synthesized new binary conjugates of tetrahydro-γ-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of ß-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.

Conjugates of Tacrine and Its Cyclic Homologues with p-Toluenesulfonamide as Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitors.

Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5-8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.

Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants.

Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.

Alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates as new effective and selective inhibitors of carboxylesterase.

A series of alkyl 2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates was synthesized and their inhibitory activity with respect to porcine liver carboxylesterase (CaE, EC 3.1.1.1), human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), and horse serum butyrylcholinesterase (BChE, EC 3.1.1.8) was studied. The molecular docking method was used to study the binding mode of the compounds in the active site of CaE. It was found that compounds containing the trifluoromethyl group in the third position of carbonyl chain are highly effective and selective inhibitors of CaE with nanomolar IC50 values, which agrees well with the results of molecular docking.

[Increased risk of tisomy 21 in offspring of carriers of balanced non-contributing autosomal rearrangements is not explained by interchromosomal effect].

Only relatively recently the suggestion that interchromosomal effect (ICE) may be present in man had stopped to be argued. At once it became evident that this phenomenon is inherent to a proportion of balanced chromosome rearrangement carriers, predominantly to patients with fertility problems. It is important to establish whether ICE operates in genome of fertile rearrangement carriers and to determine what kind of rearrangement and how far increases a risk of aneuploidy offspring. Using own and literature data 1) we have assessed rates of inherited non-contributing balanced rearrangements in patients with trisomy 21 (T21) and rates of both mutant and inherited non-contributing balanced rearrangements in parents of offspring with T21 and 2) we have analyzed a parental origin of T21 in affected offspring of carriers of balanced rearrangement. We have found that carriers of balanced reciprocal translocation or inversion, but not robertsonian translocation, are at increased risk of T21 offspring. However these data do not support the existence of ICE in its common sense, i.e. as an effect of rearrangement on other chromosome's segregation at the carrier's meiosis. Probably the data obtained suggest an effect of paternal rearrangements on maternal chromosomes segregation after fertilization.

[Grandmaternal age in children with Down syndrome in St. Petersburg].

Advanced maternal age is a well-established factor of DS occurrence. However the majority of DS cases are born to young couples. Some studies suggested that the risk for Down syndrome may be related to an aging grandmother. We obtained data on grandmaternal ages in 243 families of DS and 330 families of healthy children born in 1990-1999. The data were analyzed according to two categories of maternal ages, <30 yr and > or =30 yr. We did not find systematic differences in grandparental age distribution between the studied groups. Specifically, in 102 young couples with DS, medians for both maternal and paternal grandmother's age appeared to be equal (26 yr). Similar figures were observed in 284 young controls (27 yr). There was no difference in age distribution between 141 older couples with DS and 104 control couples. Therefore we failed to support the suggestion that advanced age of the DS grandmother is responsible for meiotic disturbance in her daughter. Neither the hypothesis suggesting a significant contribution of parentally transmitted trisomy 21 to DS population rate has been confirmed.

[Detection of gonadal mosaicism in parents of children with Down syndrome].

The paper presents results of a revision of data of both conventional chromosome testing and a study of cytogenetic (QFQ) markers in families with Down syndrome. Retrospective analysis of 151 families found eight families with a carrier of gonadal mosaicism. In all cases, the mother was younger than 35 years old. Therefore a prevalence of parental mosaicism in young couples was estimated to be 6.5% (8/123). Conventional diagnostic testing, not followed by analysis of segregation of QHQ markers, would have resulted in a prevalence of only 1%. A comparison of the results ofcytogenetic analysis with those expected using molecular polymorphisms suggests that cytogenetic testing cannot be entirely replaced by molecular testing. A combination of both methods should be applied when gonadal mosaicism is suspected.

[Monozygous female twins discordant for a pattern of X chromosome inactivation as a model for study on X-linked intellectual traits].

Ring the last decades, numerous genes for general cognitive ability were identified on human X-chromosome. They were discovered primarily because of X-linked mutations causing nonspecific mental retardation in males. Evidence for imprinted loci on the X chromosome affecting neurodevelopment was found in studies on 45,X females. Investigation of transmission of X-linked traits in normal individuals might further contribute to problem of shaping human being's mind ability. We suggest monozygous female twins discordant for a parent-of-origin of the X chromosome inactivation to be a proper subject for such explorations.

[Anorexia nervosa variants and their correction]. / Varianty nervnoi anoreksii i ikh korrektsiia.

124 girls with anorexia nervosa were investigated. Two types of anorexia nervosa course were revealed. The disease takes its benign course, without derangement of social adaptation in patients having strain of hysteria; those with schizoid stigmas have food reaction abnormality as a debut of schizophrenia.

[Chromosome 21 mosaicism. A review]. / Problemy mozaitsizma po trisomii 21. Obzor literatury.

Despite the great efforts contributed to studies on the trisomy 21 etiology, basic mechanisms of nondisjunction are still poorly understood. Even less is known about mosaic variant of trisonomy 21. In this paper, some problems of masaicism are considered: (1) estimation of the prevalence of mosaicism in patients affected with Down syndrome, (2) determination of population rate of parental mosaicism, (3) evaluation of the role of ovarian mosaicism in etiology of Down syndrome, (4) origin of the extra chromosome, (5) mechanisms of production of mosaic lines, (6) phenomenon of skewed sex ratio (female predominance, in fetuses particularly), (7) effect of maternal age.

[Variation of bacterioplankton number in the north-western part of the Black Sea depending on hydrological and hydrochemical factors]. / Izmenenie chislennosti bakterioplanktona severo-zapadnoi chasti Chernogo moria v zavisimosti ot gidrologo-gidrokhimicheskikh faktorov.

Quantitative analysis of total bacteria numbers variations under influence of river outflow and development of anaerobic conditions has been carried out on the basis of long-term field research in the north-western part of the Black Sea. The regressive equations describing dependence of the total bacteria number on temperature, salinity and water saturation with oxygen have been calculated. These results allow to characterize more completely the regularities of eutrophication processes on the Black Sea shelf.

[Sex ratio in Down syndrome. Estimation of chromosome 21 non-disjunction during spermatogenesis]. / Sootnoshenie polov pri bolezni dauna. Otsenka vklada neraskhozhdeniia khromosomy 21 v spermatogeneze.

Derivation of a formula for determination of proportion of paternal trisomy 21 is presented. The formula can be applied for the literature data on sex ratio in the cases of paternal and maternal origin of the extra chromosome in the populations where direct studies of its origin can not be performed.

[Reproductive behavior and Down syndrome]. / Reproduktivnoe povedenie i bolezn' Dauna.

Coital rates and contraception practice were investigated in mothers of 160 newborns with Down syndrome (DS) in comparison with the same aged (+/- 1 year) mothers of 160 healthy newborns. A considerable lowering of sexual activity is typical for parents, especially young ones, of children with DS. No relationship between parental sexual behavior and maternal hormonal dysfunction was found. Study on children sex ratio (SR) in relation to parental sexual activity revealed that the prevalence of boys in the DS children was due to the excess of boys (SR = 1.85) in the small group of children from sexually active couples. These data are discussed as evidence of association of a high coital rate with chromosome malsegregation in spermatogenesis.

[Sex ratio in Down syndrome]. / Sootnoshenie polov pri bolezni Dauna.

Data from 55 publications providing the sex ratio (SR), i.e. ratio between male and female cases of Down syndrome (DS), are presented. In general, SR was skewed toward an excess of males in the majority of studied populations, either in populations with a high level of cases ascertainment (epidemiological studies) or in selected groups. No significant correlation involving the age of either patients or mothers was found. Some other factors which might influence the sex ratio in DS at birth are mentioned. Meta-analysis of data from epidemiological studies suggests the phenomenon is not restricted to free trisomy 21 alone but appears in translocation cases, both in mutant and inherited translocation carriers (SR = 1.31 and 1.36, respectively). In contrast to nonmosaic 47, +21 cases, where SR is close to 1.3, an excess of females was observed in mosaics 46/47, +21 (SR = 0.83). No male predominance was found among patients with DS not tested cytogenetically (SR = 0.98), which may be explained by female predominance in false-positive cases. In populations with a fraction of clinically diagnosed cases of 30% and over, SR has intermediate value of 1.1. The ratio showed a tendency to increase since 1940's, reaching a mean value of 1.35 in 1980's varying from 1.3 to 1.62 in different populations), which might be a consequence of the growing use of karyotyping to confirm diagnosis and of a real increase in proportion of males. In the 1990's, the ratio fell to 1.22 varying from 1.03 to 1.27. As SR is assumed to reflect a proportion of paternal contribution, the discrepancy between the proportions of paternal errors in cytogenetic studies on parental origin of the extra chromosome (24% in the 1980's) and in molecular studies (5-10% in the 1990's) discussed in the literature might be explained by temporal changes alone. Genetic mechanisms of male predominance in trisomy 21 are reviewed, among them models for joint segregation of chromosome 21 and Y chromosome in spermatogenesis, and the chromosome 21 nondisjunction during 2nd meiotic division of oogenesis caused by Y chromosome-bearing spermatozoa.

[Results of estimation of mutation rates for translocation trisomy 21]. / K otsenke mutatsionnogo urovnia translokatsionnykh variantov trisomii 21.

Among 1332 cases of trisomy 21 born within 1979-1999 in St. Petersburg, 76(5.7%) were carriers of a translocation between chromosome 21 and other acrocentrics. Among 43 Dq; 21q translocations, 17 were inherited from the mother, and one was inherited from the father, 16 were of sporadic occurrence, and in 9 cases the mode of inheritance was not established. Out of 31 cases displaying Gq;21 translocation, 23 were mutants and 8 of unknown origin. One case of non-Robertsonian translocation 21;22 was maternal in origin. It was assumed that the proportion of sporadic cases among translocations of unknown origin is the same as that among translocations of the known origin. However, it is conceivable that the parents of a child with a sporadic anomaly, previously having an uncomplicated reproductive history and healthy children, tend to avoid cytogenetic examination more often than the carriers of translocation. Hence, the reported proportion of de novo cases (-0.6) might be underestimated. The analysis of pregnancy outcomes in mothers of children with Down syndrome, who inherited translocation (n = 12), sporadic translocation (n = 12) and translocation of unknown origin (n = 8), supports this suggestion. Analysis of the data from 8 reports, where the origin of Dq;21 was specified, revealed that in those samples, where the origin was traced in almost all families, the proportion of de novo cases (0.75-0.82) was higher than in samples where an appreciable part of families was not examined (0.46-0.73). Therefore, with the aim of correct determination of mutation rate for Dq;21 translocation, the true proportions in D;21 cases merit evaluation. Meanwhile, using average estimation from all the above mentioned reports (0.67), the mutation rate for translocations Dq;21 in St. Petersburg was calculated to be 1.2 x 10(-5) and 0.8 x 10(-5) in 1980-1989 and 1990-1999, respectively. For Gq;21 translocations/isochromosomes, the corresponding figures were 1.6 x 10(-5) and 1.5 x 10(-5).

[Sex ratio in Down syndrome. Studies in patients with confirmed trisomy 21]. / Sootnoshenie polov pri bolezni dauna. Issledovanie bol'nykh s kariologicheski podtverzhdennym diagnozom.

Male to female ratio (sex ratio, SR) for 1,329 liveborns with Down syndrome and for 178,160 newborns from the general population of St. Petersburg, Russia was determined as a function of a mother age. Male prevalence (an overall SR of 1.24) was found in children with all trisomy 21 variants except the cases with mosaicism (the ratio of 0.88). The most expressed male predominance was determined in children of mothers aged 20-24 years, where SR was 1.73 in the total group (p = 0.00003) and 1.61 in the cases with free trisomy (p = 0.0007). Some hypotheses concerning the male accumulation in this group are discussed including a suggestion that the SR deviations from the population value 1.06 might be due to different contribution of paternal chromosomal non-disjunction during spermatogenesis.

[O,O-dialkyl-S-bromomethylthiophosphates--inhibitors of mammalian choline- and carboxyl esterases: structure-activity relationship]. / O,O-dialkil-S-brommetiltiofosfaty--ingibitory kholin- i karboksiésteraz mlekopitaiushchikh: sviaz' "Struktura-aktivnost'".

The interaction kinetics of potential pesticides, O,O-dialkyl S-bromomethylthiophosphates (RO)2P(O) SCH2Br (R = Et, i-Pr, n-Pr, n-Bu, or n-Am) with acetylcholinesterase, butyryl cholinesterase, and carboxyl esterase from warm-blooded animals was studied. All the compounds irreversibly inhibit these esterases, with k1 (M-1 min-1) being 1.8 x 10(4) - 1.9 x 10(6) for acetylcholinesterase, 2.0 x 10(6) - 4.1 x 10(7) for the more sensitive butyryl cholinesterase, and 2.3 x 10(7) - 2.3 x 10(8) and higher for the most sensitive carboxyl esterase. By using the Hansch and Kubinyi technique of multiple regression analysis, we quantitatively analyzed the relationship between the structure and inhibiting activity of these substances toward acetylcholinesterase and butyryl cholinesterase. Hydrophobic interactions were found to be important for the inhibition of both enzymes but are more pronounced in the case of butyryl cholinesterase. On the other hand, steric factors were much more significant in the inhibition of acetylcholinesterase. For both enzymes, the steric hindrances affect the phosphorylation stage of the enzyme.

[Antiesterase activity and toxicity of O,O-dialkyl-S-ethoxycarbonylbromomethylthiophosphates]. / Antiésteraznaia aktivnost' i toksichnost' O,O-dialkil-S-étoksikarbonilbrommetiltiofosfatov.

The interaction of potential pesticides, O,O-dialkyl S-ethoxycarbonylbromomethylthiophosphates (RO)2P(O)SCH(Br)COOC2H5 (R = Et, i-Pr, n-Pr, n-Bu, n-Am, or n-Hx) with the esterases of warm-blooded animals [acetylcholinesterase (ACE), butyryl cholinesterase (BCE), and carboxyl esterase (CE)] was studied. The acute toxicities of these compounds for mice were determined. All the compounds were non-hydrolyzable by CE and capable of irreversible inhibition of all these esterases with ki (M-1 min-1) of 1.2 x 10(5)-6 x 10(6), 2.0 x 10(6)-1.5 x 10(8), and 2.0 x 10(8), respectively. By using multiple regression analysis, we found that the steric factor plays a significant role in the inhibition of ACE, with the steric hindrances manifesting themselves even at the sorption stage. On the other hand, hydrophobic interactions predominate in the case of BCE, while steric properties of its substituents exert a markedly weaker effect and manifest themselves at the phosphorylation stage. We suggested the presence of an electrophilic region in the active site of ACE, which can interact with the ethoxycarbonyl group of the thiophosphates under study. The decrease in toxicities and the affinities to BCE and CE were found to correlate with an increase in the length of n-alkyl substituents of the compounds studied. This suggests that the unspecific esterases play a significant role as a buffer system in the exhibition of toxic effects by the thiophosphates under consideration.

[Karyological characteristics of Down's syndrome: clinical and theoretical aspects]. / Kariologicheskaia kharkteristika bolezni Dauna: klinicheskie i teoreticheskie aspekty.

These data have been collected from St. Petersburg Down Syndrome Register that comprises information on 1778 liveborn children with the Down syndrome, including three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223 cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44 cases (3.6%), including 21 males and 24 females, and among these one familial case of mosaicism in a daughter and in a healthy mother. Of 70 cases of translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1 inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free trisomy 21 was associated with structural or numerical anomalies: 46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21, 47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families parental mosaicism was shown or suspected. In 6 families one parent had chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in mothers and an additional small marker in a father. In cases confirmed cytogenetically an increased sex ratio was shown (679 males and 551 females, SR = 1.23), but it was not shown in patients not tested cytogenetically (264 males and 275 females, SR = 0.96, different from the expected 297 males and 242 females, P < 0.01).