Sex-Specific Age-Related Changes in Methylation of Certain Genes.

The aim of the study was to conduct a functional analysis of sex-specific age-related changes in DNA methylation. MATERIALS AND METHODS: The study used a GSE87571 methylation dataset obtained from the blood DNA of 729 individuals aged 14 to 94 using the Illumina Infinium HumanMethylation450K BeadChip (USA). Gene ontology analysis was performed for 3 groups of genes (females, males, and duplicates) using the PANTHER database. The DAVID platform was used to perform KEGG metabolic pathway analysis. RESULTS: The studies revealed unique for males and females changes in methylation of CpG sites, associated with certain metabolic processes. It was demonstrated that most of the CpG sites, for which methylation changes with age were revealed in both sexes, are associated with the genes responsible for the development and functioning of the nervous system. In males, unique age-related methylation changes affect CpG sites associated with changes in the immune system and lipid metabolism. In females, most CpGs are associated with changes involved in transcription and translation processes. Analysis of biological functions by KEGG revealed that a unique process associated with age-related changes in methylation of the glutamatergic system is typical for males. In females, unique biological processes with age-related changes include genes responsible for the development of diabetes and genes associated with cAMP signaling cascades (KEGG:04024). CONCLUSION: Our studies reveal fundamental features of sex-dependent changes in methylation of CpG sites with variance increasing, which may indicate differences in age-related changes.

Disentangling age-dependent DNA methylation: deterministic, stochastic, and nonlinear.

DNA methylation variability arises due to concurrent genetic and environmental influences. Each of them is a mixture of regular and noisy sources, whose relative contribution has not been satisfactorily understood yet. We conduct a systematic assessment of the age-dependent methylation by the signal-to-noise ratio and identify a wealth of "deterministic" CpG probes (about 90%), whose methylation variability likely originates due to genetic and general environmental factors. The remaining 10% of "stochastic" CpG probes are arguably governed by the biological noise or incidental environmental factors. Investigating the mathematical functional relationship between methylation levels and variability, we find that in about 90% of the age-associated differentially methylated positions, the variability changes as the square of the methylation level, whereas in the most of the remaining cases the dependence is linear. Furthermore, we demonstrate that the methylation level itself in more than 15% cases varies nonlinearly with age (according to the power law), in contrast to the previously assumed linear changes. Our findings present ample evidence of the ubiquity of strong DNA methylation regulation, resulting in the individual age-dependent and nonlinear methylation trajectories, whose divergence explains the cross-sectional variability. It may also serve a basis for constructing novel nonlinear epigenetic clocks.

Photon waiting-time distributions: A keyhole into dissipative quantum chaos.

Open quantum systems can exhibit complex states, for which classification and quantification are still not well resolved. The Kerr-nonlinear cavity, periodically modulated in time by coherent pumping of the intracavity photonic mode, is one of the examples. Unraveling the corresponding Markovian master equation into an ensemble of quantum trajectories and employing the recently proposed calculation of quantum Lyapunov exponents [I. I. Yusipov et al., Chaos 29, 063130 (2019)], we identify "chaotic" and "regular" regimes there. In particular, we show that chaotic regimes manifest an intermediate power-law asymptotics in the distribution of photon waiting times. This distribution can be retrieved by monitoring photon emission with a single-photon detector so that chaotic and regular states can be discriminated without disturbing the intracavity dynamics.

Quantum Lyapunov exponents beyond continuous measurements.

Quantum systems, when interacting with their environments, may exhibit nonequilibrium states that are tempting to be interpreted as quantum analogs of chaotic attractors. However, different from the Hamiltonian case, the toolbox for quantifying dissipative quantum chaos remains limited. In particular, quantum generalizations of Lyapunov exponents, the main quantifiers of classical chaos, are established only within the framework of continuous measurements. We propose an alternative generalization based on the unraveling of quantum master equation into an ensemble of "quantum trajectories," by using the so-called Monte Carlo wave-function method. We illustrate the idea with a periodically modulated open quantum dimer and demonstrate that the transition to quantum chaos matches the period-doubling route to chaos in the corresponding mean-field system.

[Secretion of bacterial ribonuclease].

The investigation of the effect of some components of the medium on the distribution of the secretory guanyl-specific ribonuclease of Bacillus intermedius (EC 3.1.4.23) among various cell fractions and culture liquid showed that the amount of this enzyme in the culture liquid does not depend on the concentration of calcium ions in the medium (within 1-5 mM). The study of the effect of the amino acid substitutions Trp34Asn and Trp70Asn in the ribonuclease molecule showed that the secretion of ribonuclease depends on the formation rate of its secondary structure. The amino acid substitution Trp34Asn completely inhibits ribonuclease secretion.

[The Pho regulons of bacteria]. / Pho regulony bakterii.

Bacterial Pho regulons contain genes whose expression is regulated by a specific two-component signal transduction system. The products of these genes are involved in the transport and assimilation of inorganic phosphate. The paper summarizes data on the organization and function of Pho regulons in gram-negative and gram-positive bacteria, with particular emphasis on the Pho regulons of the best studied bacteria Escherichia coli and Bacillus subtilis.

[Regulation of extracellular phosphohydrolase biosynthesis in bacilli]. / Reguliatsiia biosinteza vnekletochnykh fosfogidrolaz u batsill.

Under phosphate-deficient conditions, B. intermedius, B. pumilus, and B. thuringiensis secrete phosphohydrolases, including phosphomono-, phosphodiesterases, and guanyl-specific ribonucleases which cleave RNA molecules to nucleoside-3'-phosphatases. The enzymes are synthesized by phosphate-starved vegetative cells, which is not associated with sporulation. Using B. subtilis strains with mutation in the regulatory protein genes phoP and phoR, it was shown that these proteins regulate expression of B. intermedius, B. pumilus, and B. thuringiensis ribonuclease genes in B. subtilis cells. Genes of heterologous RNAses were activated in recombinant B. subtilis strains simultaneously with its own PHO regulon genes. Presumably a regulatory system homologous to B. subtilis two-component PhoP-PhoR signal transduction system functions in other representatives of the Bacillus genus.

[Expression of genes for guanyl-specific ribonucleases in Bacillus intermedius and Bacillus pumilus is regulated by the PhoP-PhoR two-component signal transduction system of PHO regulon of Bacillus subtilis]. / Ekspressiia genov guanilspetsifichnykh ribonukleaz Bacillus intermedius i Bacillus pumilus reguliruetsia dvukhkomponentnoi sistemoi transduktsii signala PHO regulona Bacillus subtilis PhoP-PhoR.

Promoters of the genes of guanyl-specific ribonucleases of Bacillus intermedius (binase) and Bacillus pumilus (RNase Bp) were found to contain sequences homologous to those recognizable by the regulatory protein PhoP in the promoters of the PHO regulon of B. subtilis, as well as regions partially homologous to the binding sites of another regulatory protein, PhoB, in the promoters of the PHO regulon of Escherichia coli. The role of the two-component regulatory systems PhoP-PhoR and PhoB-PhoR in the regulation of expression of the genes of binase and RNase Bp in recombinant strains of B. subtilis and E. coli was studied by using mutant strains. It was established that the expression of these genes in recombinant B. subtilis cells is stringently controlled by the PhoP-PhoR two-component regulatory system, whereas the expression of these genes in E. coli cells is not controlled by the regulatory proteins PhoB or PhoR. Presumably, regulatory systems of the response to phosphate starvation, analogous to the PHO regulon of B. subtilis, also function in other representatives of the genus Bacillus.

[Expression of secreted guanyl-specific ribonuclease genes from Bacillus intermedius and Bacillus pumilus in Bacillus subtilis cells]. / Ekspressiia genov sekretiruemykh guanilspetsifichnykh ribonukleaz iz Bacillus intermedius i Bacillus pumilus v kletkakh Bacillus subtilis.

Plasmids with whole genes for ribonucleases from B. intermedius (binase) and B. pumilis (RNase Bp) assembled with the whole gene of barstar, a specific intracellular inhibitor, are constructed. The resultant plasmids pMZ55 and pMZ56 effectively express binase and RNase Bp genes in B. subtilis cells. A medium for maximum expression of RNase genes by recombinant strains is developed. The expression of binase and RNase Bp genes in B. subtilis cells is negatively regulated by exogenic inorganic phosphate.

Expression of the genes for guanyl-specific ribonucleases from Bacillus intermedius and Bacillus pumilus is regulated by the two component signal transduction system PhoP-PhoR in B. subtilis.

Promoters of the genes for guanyl-specific ribonucleases, secreted by B. intermedius (binase) and B. pumilus (Rnase Bp) in phosphate deficient conditions, contain regions similar to appropriate consensus sequences in promoters of the PHO regulated genes of B. subtilis. A number of genes expressed in response to phosphate starvation in B. subtilis are regulated by the two component signal transduction system PhoP-PhoR. Expression of recombinant genes for binase and RNase Bp in B. subtilis strains with mutations in the regulatory protein genes of the PHO regulon was studied. Their expression is strongly regulated by the regulatory proteins of the B. subtilis PHO regulon.

Isolation and properties of extracellular alkaline phosphatase from Bacillus intermedius.

Alkaline phosphatase (APase) was isolated from the culture liquid of the streptomycin-resistant strain of Bacillus intermedius S3-19 and purified as a homogeneous preparation by ion-exchange chromatography and FPLC. Electrophoresis and gel-filtration revealed that the active enzyme is a monomer with molecular weight of 46-47 kD. The enzyme possessed phosphomonoesterase and phosphodiesterase activities with maximal levels at pH 9.5 and 55 degreesC and was stable until 60 degreesC at pH 8.0-10.0. The isolated APase exhibits a broad specificity towards a wide variety of substrates. The effect of divalent metal ions and other reagents on its catalytic activities was studied. It was concluded that alkaline phosphatase of B. intermedius is similar to the secreted alkaline phosphatases from other Bacillus species in its physicochemical and catalytic properties.