A new cognitive clock matching phenotypic and epigenetic ages.

Cognitive abilities decline with age, constituting a major manifestation of aging. The quantitative biomarkers of this process, as well as the correspondence to different biological clocks, remain largely an open problem. In this paper we employ the following cognitive tests: 1. differentiation of shades (campimetry); 2. evaluation of the arithmetic correctness and 3. detection of reversed letters and identify the most significant age-related cognitive indices. Based on their subsets we construct a machine learning-based Cognitive Clock that predicts chronological age with a mean absolute error of 8.62 years. Remarkably, epigenetic and phenotypic ages are predicted by Cognitive Clock with an even better accuracy. We also demonstrate the presence of correlations between cognitive, phenotypic and epigenetic age accelerations that suggests a deep connection between cognitive performance and aging status of an individual.

Quantum Lyapunov exponents and complex spacing ratios: Two measures of dissipative quantum chaos.

The agenda of dissipative quantum chaos is to create a toolbox that would allow us to categorize open quantum systems into "chaotic" and "regular" ones. Two approaches to this categorization have been proposed recently. One of them is based on the spectral properties of generators of open quantum evolution. The other one utilizes the concept of Lyapunov exponents to analyze quantum trajectories obtained by unraveling this evolution. By using two quantum models, we relate the two approaches and try to understand whether there is an agreement between the corresponding categorizations. Our answer is affirmative.

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.

Chaotic spin-photonic quantum states in an open periodically modulated cavity.

When applied to dynamical systems, both classical and quantum, time periodic modulations can produce complex non-equilibrium states which are often termed "chaotic." Being well understood within the unitary Hamiltonian framework, this phenomenon is less explored in open quantum systems. Here, we consider quantum chaotic states emerging in a leaky cavity when the intracavity photonic mode is coherently pumped with the pumping intensity varying periodically in time. We show that a single spin when placed inside the cavity and coupled to the mode can moderate transitions between regular and chaotic regimes-that are identified by using quantum Lyapunov exponents or features of photon emission statistics-and thus can be used to control the degree of chaos.

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 Neimark-Sacker bifurcation.

Recently, it has been demonstrated that asymptotic states of open quantum system can undergo qualitative changes resembling pitchfork, saddle-node, and period doubling classical bifurcations. Here, making use of the periodically modulated open quantum dimer model, we report and investigate a quantum Neimark-Sacker bifurcation. Its classical counterpart is the birth of a torus (an invariant curve in the Poincaré section) due to instability of a limit cycle (fixed point of the Poincaré map). The quantum system exhibits a transition from unimodal to bagel shaped stroboscopic distributions, as for Husimi representation, as for observables. The spectral properties of Floquet map experience changes reminiscent of the classical case, a pair of complex conjugated eigenvalues approaching a unit circle. Quantum Monte-Carlo wave function unraveling of the Lindblad master equation yields dynamics of single trajectories on "quantumtorus" and allows for quantifying it by rotation number. The bifurcation is sensitive to the number of quantum particles that can also be regarded as a control parameter.

Unfolding a quantum master equation into a system of real-valued equations: Computationally effective expansion over the basis of SU(N) generators.

Dynamics of an open N-state quantum system is often modeled with a Markovian master equation describing the evolution of the system density operator. By using generators of SU(N) group as a basis, the density operator can be transformed into a real-valued "coherence-vector." A generator of the dissipative evolution, so-called "Lindbladian," can be expanded over the same basis and recast in the form of a real matrix. Together, these expansions result is a nonhomogeneous system of N^{2}-1 real-valued linear ordinary differential equations. Now one can, e.g., implement standard high-performance algorithms to integrate the system of equations forward in time while being sure in exact preservation of the trace (norm) and Hermiticity of the density operator. However, when performed in a straightforward way, the expansion turns to be an operation of the time complexity O(N^{10}). The complexity can be reduced when the number of dissipative operators is independent of N, which is often the case for physically meaningful models. Here we present an algorithm to transform quantum master equation into a system of real-valued differential equations and propagate it forward in time. By using a specific scalable model, we evaluate computational efficiency of the algorithm and demonstrate that it is possible to handle the model system with N=10^{3} states on a single node of a computer cluster.

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.

FoxP3+ CXCR5+ CD4+ T cell frequencies are increased in peripheral blood of patients with primary Sjögren's syndrome.

We recently explored the expression of CXCR5 on T and B cells from peripheral blood of patients with primary Sjögren's syndrome (SS). Here we investigated the frequency of CD25+ FoxP3+ CD4+ regulatory T cells (Tregs ) among CXCR5+ CD4+ follicular cells in the same cohort of patients. We confirm that the frequency of Tregs among follicular T cells is increased in SS patients and also provide novel data showing an increased frequency of PD-1 expressing cells among CXCR5+ FoxP3+ CD4+ T cells.

The Sjögren's syndrome-associated autoantigen Ro52/TRIM21 modulates follicular B cell homeostasis and immunoglobulin production.

Systemic rheumatic diseases are characterized by abnormal B cell activation with autoantibody production and hypergammaglobulinaemia. Ro52/SSA, also denoted tripartite motif (TRIM)21, is a major autoantigen in Sjögren's syndrome and systemic lupus erythematosus. Interestingly, TRIM21-deficient mice develop systemic autoimmunity with B cell-driven manifestations such as autoantibodies, hypergammaglobulinaemia and glomerulonephritis following tissue injury. The mechanisms by which TRIM21-deficiency leads to enhanced B cell activation and antibody production are, however, not well understood, and to further elucidate the role of TRIM21 in systemic autoimmunity, we investigated the B cell phenotype and antibody responses of Trim21-/- mice following immunization with thymus-dependent (TD) and thymus-independent (TI) antigens. We found that TRIM21-deficient mice developed significantly higher specific antibody titres than their wild-type counterparts upon B cell receptor (BCR) engagement by TD and TI type II antigens, and this was accompanied by an altered B cell phenotype. Furthermore, BCR cross-linking, but not anti-CD40 stimulation, in vitro resulted in a significantly higher proliferation of Trim21-/- cells. We also observed that splenic follicular B cells were expanded not only in immunized mice but also already in young, unmanipulated Trim21-/- mice, and transcriptomic analysis of these cells revealed an up-regulation of genes associated with B cell differentiation, indicating a role for TRIM21 in their regulation. In conclusion, in this study we describe a link between the rheumatic autoantigen Ro52/TRIM21 and increased antibody production associated with follicular B cell expansion, implicating a potential role for Ro52/TRIM21 in the pathogenesis of systemic autoimmune diseases.

Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing.

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+ CD27+ immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+ CD27+ IgD- memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+ CXCR3- CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.

Localization in Open Quantum Systems.

In an isolated single-particle quantum system, a spatial disorder can induce Anderson localization. Being a result of interference, this phenomenon is expected to be fragile in the face of dissipation. Here we show that a proper dissipation can drive a disordered system into a steady state with tunable localization properties. This can be achieved with a set of identical dissipative operators, each one acting nontrivially on a pair of sites. Operators are parametrized by a uniform phase, which controls the selection of Anderson modes contributing to the state. On the microscopic level, quantum trajectories of a system in the asymptotic regime exhibit intermittent dynamics consisting of long-time sticking events near selected modes interrupted by intermode jumps.

Computation of the asymptotic states of modulated open quantum systems with a numerically exact realization of the quantum trajectory method.

Quantum systems out of equilibrium are presently a subject of active research, both in theoretical and experimental domains. In this work, we consider time-periodically modulated quantum systems that are in contact with a stationary environment. Within the framework of a quantum master equation, the asymptotic states of such systems are described by time-periodic density operators. Resolution of these operators constitutes a nontrivial computational task. Approaches based on spectral and iterative methods are restricted to systems with the dimension of the hosting Hilbert space dimH=N≲300, while the direct long-time numerical integration of the master equation becomes increasingly problematic for N≳400, especially when the coupling to the environment is weak. To go beyond this limit, we use the quantum trajectory method, which unravels the master equation for the density operator into a set of stochastic processes for wave functions. The asymptotic density matrix is calculated by performing a statistical sampling over the ensemble of quantum trajectories, preceded by a long transient propagation. We follow the ideology of event-driven programming and construct a new algorithmic realization of the method. The algorithm is computationally efficient, allowing for long "leaps" forward in time. It is also numerically exact, in the sense that, being given the list of uniformly distributed (on the unit interval) random numbers, {η_{1},η_{2},...,η_{n}}, one could propagate a quantum trajectory (with η_{i}'s as norm thresholds) in a numerically exact way. By using a scalable N-particle quantum model, we demonstrate that the algorithm allows us to resolve the asymptotic density operator of the model system with N=2000 states on a regular-size computer cluster, thus reaching the scale on which numerical studies of modulated Hamiltonian systems are currently performed.

Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease.

OBJECTIVE: TRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. MATERIALS AND METHODS: TRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with (3) H-thymidine incorporation and propidium iodine staining. RESULTS: TRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes in vitro. CONCLUSIONS: We show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

Anderson localization or nonlinear waves: a matter of probability.

In linear disordered systems Anderson localization makes any wave packet stay localized for all times. Its fate in nonlinear disordered systems (localization versus propagation) is under intense theoretical debate and experimental study. We resolve this dispute showing that, unlike in the common hypotheses, the answer is probabilistic rather than exclusive. At any small but finite nonlinearity (energy) value there is a finite probability for Anderson localization to break up and propagating nonlinear waves to take over. It increases with nonlinearity (energy) and reaches unity at a certain threshold, determined by the initial wave packet size. Moreover, the spreading probability stays finite also in the limit of infinite packet size at fixed total energy. These results generalize to higher dimensions as well.

[Influence of climatic and geographic factors on the environmental distribution of heavy metals and children's health].

The authors have studied the environmental distribution of salts of heavy metals (cadmium and nickel) under the influence of climatic and geographic factors and formation of geochemical anomalies. They also examined regularities in the accumulation of heavy metals in children's biosubstrates (hair, urine) and the nature of impact of their levels on the physical development of children in the organized collective bodies (preschool institutions) located in anomalous areas.

q Breathers in finite lattices: nonlinearity and weak disorder.

Nonlinearity and disorder are the recognized ingredients of the lattice vibrational dynamics, the factors that could be diminished, but never excluded. We generalize the concept of q breathers-periodic orbits in nonlinear lattices, exponentially localized in the linear mode space-to the case of weak disorder, taking the Fermi-Pasta-Ulan chain as an example. We show that these nonlinear vibrational modes remain exponentially localized near the central mode and stable, provided the disorder is sufficiently small. The instability threshold depends sensitively on a particular realization of disorder and can be modified by specifically designed impurities. Based on this sensitivity, an approach to controlling the energy flow between the modes is proposed. The relevance to other model lattices and experimental miniature arrays is discussed.

The lateral root initiation index: an integrative measure of primordium formation.

BACKGROUND AND AIMS: Lateral root initiation is an essential and continuous process in the formation of root systems; therefore, its quantitative analysis is indispensable. In this study a new measure of lateral root initiation is proposed and analysed, namely the lateral root initiation index (I(LRI)), which defines how many lateral roots and/or primordia are formed along a parent-root portion corresponding to 100 cortical cells in a file. METHODS: For data collection, a commonly used root clearing procedure was employed, and a new simple root clearing procedure is also proposed. The I(LRI) was determined as 100dl, where d is the density of lateral root initiation events (number mm(-1)) and l is the average fully elongated cortical cell length (mm). KEY RESULTS: Analyses of different Arabidopsis thaliana genotypes and of a crop plant, tomato (Solanum lycopersicum), showed that I(LRI) is a more precise parameter than others commonly used as it normalizes root growth for variations in cell length. Lateral root primordium density varied in the A. thaliana accessions Col, Ler, Ws, and C24; however, in all accessions except Ws, I(LRI) was similar under the same growth conditions. The nitrogen/carbon ratio in the growth medium did not change the lateral root primordium density but did affect I(LRI). The I(LRI) was also modified in a number of auxin-related mutants, revealing new root branching phenotypes in some of these mutants. The rate of lateral root initiation increased with Arabidopsis seedling age; however, I(LRI) was not changed in plants between 8 and 14 d post-germination. CONCLUSIONS: The I(LRI) allows for a more precise comparison of lateral root initiation under different growth conditions, treatments, genotypes and plant species than other comparable methods.