Dynamics of Oscillator Populations Globally Coupled with Distributed Phase Shifts.

We consider a population of globally coupled oscillators in which phase shifts in the coupling are random. We show that in the maximally disordered case, where the pairwise shifts are independent identically distributed random variables, the dynamics of a large population reduces to one without randomness in the shifts but with an effective coupling function, which is a convolution of the original coupling function with the distribution of the phase shifts. This result is valid for noisy oscillators and/or in the presence of a distribution of natural frequencies. We argue also, using the property of global asymptotic stability, that this reduction is valid in a partially disordered case, where random phase shifts are attributed to the forced units only. However, the reduction to an effective coupling in the partially disordered noise-free situation may fail if the coupling function is complex enough to ensure the multistability of locked states.

Quantitative intra- and intergeneric taxonomic relationships among Micrococcaceae strains reveal contradictions in the historical assignments of the strains and indicate the need for species reclassification.

This article reports the results of quantitative intra- and intergeneric taxonomic relationships among Micrococcaceae strains and a novel endophytic bacterium (SG) isolated from a suspension culture of Arabidopsis thaliana (L.) Heynh in our laboratory. The known strain Rothia sp. ND6WE1A was used as a reference one for SG. Whole-genome sequencing and phylogenetic analysis were based on the 16S rRNA test. Quantitative analysis for the nucleotide identity (ANI) and calculation of evolutionary distances were based on the identified amino acids (AAI) test indicating the generic assignment of the reference strain within and between the identified monophyletic groups of Micrococcaceae. The amino acid data structure of Rothia sp. ND6WE1A was compared against the UniProt database (250 million records) of close lineage of Micrococcaceae, including other Rothia spp. These data presented unique and evolutionary amino acid alignments, eventually expected in the new SG isolate as well. The metagenomic entries of the respective genome and proteome, characterized at the genus and species levels, could be considered for evolutionary taxonomic reclassification of the isolated and the reference strain (SG + Rothia sp. ND6WE1A). Therefore, our results warrant further investigations on the isolated SG strain.

Dynamics of large oscillator populations with random interactions.

We explore large populations of phase oscillators interacting via random coupling functions. Two types of coupling terms, the Kuramoto-Daido coupling and the Winfree coupling, are considered. Under the assumption of statistical independence of the phases and the couplings, we derive reduced averaged equations with effective non-random coupling terms. As a particular example, we study interactions defined via the coupling functions that have the same shape but possess random coupling strengths and random phase shifts. While randomness in coupling strengths just renormalizes the interaction, a distribution of the phase shifts in coupling reshapes the coupling function.

K-Space Approach in Optical Coherence Tomography: Rigorous Digital Transformation of Arbitrary-Shape Beams, Aberration Elimination and Super-Refocusing beyond Conventional Phase Correction Procedures.

For the most popular method of scan formation in Optical Coherence Tomography (OCT) based on plane-parallel scanning of the illuminating beam, we present a compact but rigorous K-space description in which the spectral representation is used to describe both the axial and lateral structure of the illuminating/received OCT signals. Along with the majority of descriptions of OCT-image formation, the discussed approach relies on the basic principle of OCT operation, in which ballistic backscattering of the illuminating light is assumed. This single-scattering assumption is the main limitation, whereas in other aspects, the presented approach is rather general. In particular, it is applicable to arbitrary beam shapes without the need for paraxial approximation or the assumption of Gaussian beams. The main result of this study is the use of the proposed K-space description to analytically derive a filtering function that allows one to digitally transform the initial 3D set of complex-valued OCT data into a desired (target) dataset of a rather general form. An essential feature of the proposed filtering procedures is the utilization of both phase and amplitude transformations, unlike conventionally discussed phase-only transformations. To illustrate the efficiency and generality of the proposed filtering function, the latter is applied to the mutual transformation of non-Gaussian beams and to the digital elimination of arbitrary aberrations at the illuminating/receiving aperture. As another example, in addition to the conventionally discussed digital refocusing enabling depth-independent lateral resolution the same as in the physical focus, we use the derived filtering function to perform digital "super-refocusing." The latter does not yet overcome the diffraction limit but readily enables lateral resolution several times better than in the initial physical focus.

Cyclops States in Repulsive Kuramoto Networks: The Role of Higher-Order Coupling.

Repulsive oscillator networks can exhibit multiple cooperative rhythms, including chimera and cluster splay states. Yet, understanding which rhythm prevails remains challenging. Here, we address this fundamental question in the context of Kuramoto-Sakaguchi networks of rotators with higher-order Fourier modes in the coupling. Through analysis and numerics, we show that three-cluster splay states with two distinct coherent clusters and a solitary oscillator are the prevalent rhythms in networks with an odd number of units. We denote such tripod patterns cyclops states with the solitary oscillator reminiscent of the Cyclops' eye. As their mythological counterparts, the cyclops states are giants that dominate the system's phase space in weakly repulsive networks with first-order coupling. Astonishingly, the addition of the second or third harmonics to the Kuramoto coupling function makes the cyclops states global attractors practically across the full range of coupling's repulsion. Beyond the Kuramoto oscillators, we show that this effect is robustly present in networks of canonical theta neurons with adaptive coupling. At a more general level, our results suggest clues for finding dominant rhythms in repulsive physical and biological networks.

Immunologic Heterogeneity in 2 Cartilage-Hair Hypoplasia Patients With a Distinct Clinical Course.

BACKGROUND AND OBJECTIVE: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease. To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH. METHODS: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects. RESULTS: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation. CONCLUSION: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome.

Analysis of Experimental Data on Changes in Various Structures and Functions of the Rat Brain following Intranasal Administration of Fe2O3 Nanoparticles.

Particulate matter, including iron nanoparticles, is one of the constituents of ambient air pollution. We assessed the effect of iron oxide (Fe2O3) nanoparticles on the structure and function of the brain of rats. Electron microscopy showed Fe2O3 nanoparticles in the tissues of olfactory bulbs but not in the basal ganglia of the brain after their subchronic intranasal administration. We observed an increase in the number of axons with damaged myelin sheaths and in the proportion of pathologically altered mitochondria in the brains of the exposed animals against the background of almost stable blood parameters. We conclude that the central nervous system can be a target for toxicity of low-dose exposure to Fe2O3 nanoparticles.

The Automatic Design of Multimode Resonator Topology with Evolutionary Algorithms.

Microwave electromagnetic devices have been used for many applications in tropospheric communication, navigation, radar systems, and measurement. The development of the signal preprocessing units including frequency-selective devices (bandpass filters) determines the reliability and usability of such systems. In wireless sensor network nodes, filters with microstrip resonators are widely used to improve the out-of-band suppression and frequency selectivity. Filters based on multimode microstrip resonators have an order that determines their frequency-selective properties, which is a multiple of the number of resonators. That enables us to reduce the size of systems without deteriorating their selective properties. Various microstrip multimode resonator topologies can be used for both filters and microwave sensors, however, the quality criteria for them may differ. The development of every resonator topology is time consuming. We propose a technique for the automatic generation of the resonator topology with required frequency characteristics based on the use of evolutionary algorithms. The topology is encoded into a set of real valued parameters, which are varied to achieve the desired features. The differential evolution algorithm and the genetic algorithm with simulated binary crossover and polynomial mutation are applied to solve the formulated problem using the dynamic penalties method. The experimental results show that our technique enables us to find microstrip resonator topologies with desired amplitude-frequency characteristics automatically, and manufactured devices demonstrate characteristics very close to the results of the algorithm. The proposed algorithmic approach may be used for automatically exploring the new perspective topologies of resonators used in microwave filters, radar antennas or sensors, in accordance with the defined criteria and constraints.

Structure-Function Relationships in Temperature Effects on Bacterial Luciferases: Nothing Is Perfect.

The evaluation of temperature effects on the structure and function of enzymes is necessary to understand the mechanisms underlying their adaptation to a constantly changing environment. In the current study, we investigated the influence of temperature variation on the activity, structural dynamics, thermal inactivation and denaturation of Photobacterium leiognathi and Vibrio harveyi luciferases belonging to different subfamilies, as well as the role of sucrose in maintaining the enzymes functioning and stability. We used the stopped-flow technique, differential scanning calorimetry and molecular dynamics to study the activity, inactivation rate, denaturation and structural features of the enzymes under various temperatures. It was found that P. leiognathi luciferase resembles the properties of cold-adapted enzymes with high activity in a narrow temperature range and slightly lower thermal stability than V. harveyi luciferase, which is less active, but more thermostable. Differences in activity at the studied temperatures can be associated with the peculiarities of the mobile loop conformational changes. The presence of sucrose does not provide an advantage in activity but increases the stability of the enzymes. Differential scanning calorimetry experiments showed that luciferases probably follow different denaturation schemes.

Immunization of Mice with Gold Nanoparticles Conjugated to Thermostable Cancer Antigens Prevents the Development of Xenografted Tumors.

Gold nanoparticles as part of vaccines greatly increase antigen stability, antigen accumulation in the lymph nodes, and antigen uptake by antigen-presenting cells. The use of such particles as part of anticancer vaccines based on heat shock proteins to increase vaccine effectiveness is timely. We prepared and characterized nanoconjugates based on 15-nm gold nanoparticles and thermostable tumor antigens isolated from MH22a murine hepatoma cells. The whole-cell lysate of MH22a cells contained the main heat shock proteins. BALB/c mice were injected with the conjugates and then received transplants of MH22a cells. The highest titer was produced in mice immunized with the complex of gold nanoparticles + antigen with complete Freund's adjuvant. The immunized mice showed no signs of tumor growth for 24 days. They also showed a decreased production of the INF-γ, IL-6, and IL-1 proinflammatory cytokines compared to the mice immunized through other schemes. This study is the first to show that it is possible in principle to use gold nanoparticles in combination with thermostable tumor antigens for antitumor vaccination. Antitumor vaccines based on thermostable tumor antigens can be largely improved by including gold nanoparticles as additional adjuvants.

Manifestation of apomictic potentials in the line AS-3 of Sorghum bicolor (L.) Moench.

MAIN CONCLUSION: AS-3 line of Sorghum bicolor possesses functional components of apomixis-apospory, parthenogenesis and autonomous endospermogenesis. The data obtained indicate efficiency of selection for apomixis components in diploid species of cultivated crops. Apomixis (seed formation without fertilization) is one of most attractive phenomena in plant biology. In this paper, we provide the results of long-term selection for apomixis components in the progeny of grain sorghum (Sorghum bicolor (L.) Moench) hybrid plants with male sterility mutation. Selection was carried out for a high frequency of aposporous embryo sacs (ESs), autonomous pro-embryos, and the presence of maternal-type plants in test crosses with the line Volzhskoe-4v (V4v) homozygous for the Rs1 genes determining the red color of the leaves and stem of the hybrids. As a result of using this approach, the line, AS-3, was created, in which the frequency of ovaries with parthenogenetic embryos reached 42-45%. The autonomous development of embryos and endosperm was observed in the panicles of each of the 10 cytologically studied plants of this line. The frequency of parthenogenesis positively correlated with the high average daily air temperature during the first five out of 10 days preceding the onset of flowering (r = 0.75; P > 0.01). Genotyping of the plants from the progeny of hand-emasculated panicles of AS-3 pollinated with V4v performed using co-dominant SSR markers revealed that the F1 hybrids carrying the Rs1 gene (chromosome 6) possessed both paternal and maternal alleles of Sb1-10 (chromosome 4) and Xtxp320 (chromosome 10) markers, while in the maternal-type plants (rs1rs1), only the maternal alleles of these markers were present. In the endosperm of the kernels from which the maternal-type seedlings were obtained, only the maternal alleles were present, while in the endosperm of the kernels that produced hybrid seedlings, both the paternal and maternal alleles were observed. The data obtained indicate the presence of functional components of apomixis (apospory, parthenogenesis, autonomous endospermogenesis) in the grain sorghum line AS-3, and the efficiency of selection for apomixis in functionally diploid species of cultivated crops.

Appearance of chaos and hyperchaos in evolving pendulum network.

The study of deterministic chaos continues to be one of the important problems in the field of nonlinear dynamics. Interest in the study of chaos exists both in low-dimensional dynamical systems and in large ensembles of coupled oscillators. In this paper, we study the emergence of chaos in chains of locally coupled identical pendulums with constant torque. The study of the scenarios of the emergence (disappearance) and properties of chaos is done as a result of changes in (i) the individual properties of elements due to the influence of dissipation in this problem and (ii) the properties of the entire ensemble under consideration, determined by the number of interacting elements and the strength of the connection between them. It is shown that an increase of dissipation in an ensemble with a fixed coupling force and a number of elements can lead to the appearance of chaos as a result of a cascade of period-doubling bifurcations of periodic rotational motions or as a result of invariant tori destruction bifurcations. Chaos and hyperchaos can occur in an ensemble by adding or excluding one or more elements. Moreover, chaos arises hard since in this case, the control parameter is discrete. The influence of the coupling strength on the occurrence of chaos is specific. The appearance of chaos occurs with small and intermediate coupling and is caused by the overlap of the existence of various out-of-phase rotational mode regions. The boundaries of these areas are determined analytically and confirmed in a numerical experiment. Chaotic regimes in the chain do not exist if the coupling strength is strong enough. The dimension of an observed hyperchaotic regime strongly depends on the number of coupled elements.

Mechanisms of Viscous Media Effects on Elementary Steps of Bacterial Bioluminescent Reaction.

Enzymes activity in a cell is determined by many factors, among which viscosity of the microenvironment plays a significant role. Various cosolvents can imitate intracellular conditions in vitro, allowing to reduce a combination of different regulatory effects. The aim of the study was to analyze the media viscosity effects on the rate constants of the separate stages of the bacterial bioluminescent reaction. Non-steady-state reaction kinetics in glycerol and sucrose solutions was measured by stopped-flow technique and analyzed with a mathematical model developed in accordance with the sequence of reaction stages. Molecular dynamics methods were applied to reveal the effects of cosolvents on luciferase structure. We observed both in glycerol and in sucrose media that the stages of luciferase binding with flavin and aldehyde, in contrast to oxygen, are diffusion-limited. Moreover, unlike glycerol, sucrose solutions enhanced the rate of an electronically excited intermediate formation. The MD simulations showed that, in comparison with sucrose, glycerol molecules could penetrate the active-site gorge, but sucrose solutions caused a conformational change of functionally important αGlu175 of luciferase. Therefore, both cosolvents induce diffusion limitation of substrates binding. However, in sucrose media, increasing enzyme catalytic constant neutralizes viscosity effects. The activating effect of sucrose can be attributed to its exclusion from the catalytic gorge of luciferase and promotion of the formation of the active site structure favorable for the catalysis.

Bacterial Luciferases from Vibrio harveyi and Photobacterium leiognathi Demonstrate Different Conformational Stability as Detected by Time-Resolved Fluorescence Spectroscopy.

Detecting the folding/unfolding pathways of biological macromolecules is one of the urgent problems of molecular biophysics. The unfolding of bacterial luciferase from Vibrio harveyi is well-studied, unlike that of Photobacterium leiognathi, despite the fact that both of them are actively used as a reporter system. The aim of this study was to compare the conformational transitions of these luciferases from two different protein subfamilies during equilibrium unfolding with urea. Intrinsic steady-state and time-resolved fluorescence spectra and circular dichroism spectra were used to determine the stages of the protein unfolding. Molecular dynamics methods were applied to find the differences in the surroundings of tryptophans in both luciferases. We found that the unfolding pathway is the same for the studied luciferases. However, the results obtained indicate more stable tertiary and secondary structures of P. leiognathi luciferase as compared to enzyme from V. harveyi during the last stage of denaturation, including the unfolding of individual subunits. The distinctions in fluorescence of the two proteins are associated with differences in the structure of the C-terminal domain of α-subunits, which causes different quenching of tryptophan emissions. The time-resolved fluorescence technique proved to be a more effective method for studying protein unfolding than steady-state methods.

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.

Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8+ and CD4+ T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8+ T cells from all patients demonstrated significantly reduced IFN-γ production. When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

Heart Transplantation in the USSR and Former Soviet Countries.

Experimental and clinical heart transplantation programs in the USSR, Russia, and post-Soviet states are described, including information about early experimental studies conducted by Russian and Soviet scientists in the early to mid-20th century. The novel research of V.P. Demikhov, a Soviet transplantologist famous for performing the first experimental heart transplantations and coronary artery bypass surgeries in the world is highlighted. In addition, the preparation and implementation of the USSR's first clinical heart transplantations during the pre-cyclosporine era (1960-1970s) are described, and the features of anesthesia, cardiopulmonary bypass, and graft protection, as well as causes of heart failure are analyzed. Furthermore, information about the first successful heart transplantation performed by V.I. Shumakov (1987), the first successful heart transplantation programs in the USSR and Russia during the cyclosporine era (after 1980), and anesthesiologic developments for heart transplantation are presented. The current status, modern research, and prospects of heart transplantation in Russia and the implementation of heart transplantation programs in Lithuania, Ukraine, Latvia, Republic of Belarus, and Kazakhstan also are described.

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis.

The antigenic specificity of T cells occurs via generation and rearrangement of different gene segments producing a functional T cell receptor (TCR). High-throughput sequencing (HTS) allows in-depth assessment of TCR repertoire patterns. There are limited data concerning whether TCR repertoires are altered in inflammatory bowel disease. We hypothesized that pediatric ulcerative colitis (UC) patients possess unique TCR repertoires, resulting from clonotypical expansions in the gut. Paired blood and rectal samples were collected from nine newly diagnosed treatment-naive pediatric UC patients and four healthy controls. DNA was isolated to determine the TCR-ß repertoire by HTS. Significant clonal expansion was demonstrated in UC patients, with inverse correlation between clinical disease severity and repertoire diversity in the gut. Using different repertoire variables in rectal biopsies, a clear segregation was observed between patients with severe UC, those with mild-moderate disease and healthy controls. Moreover, the overlap between autologous blood-rectal samples in UC patients was significantly higher compared with overlap among controls. Finally, we identified several clonotypes that were shared in either all or the majority of UC patients in the colon. Clonal expansion of TCR-ß-expressing T cells among UC patients correlates with disease severity and highlights their involvement in mediating intestinal inflammation.

Prospects for the use of spherical gold nanoparticles in immunization.

Recent years have seen extremely fast development of new viral nanovaccines and diagnostic agents using nanostructures prepared by biological and chemical synthesis. We used spherical gold nanoparticles (average diameter, 15 nm) as a platform for the antigen for swine transmissible gastroenteritis virus (TGEV). The literature data demonstrate that immunization of animals with the TGEV antigen coupled to gold nanoparticles (GNPs) not only activates antigen-presenting cells but also increases the proliferative activity of splenic lymphoid (antibody-forming) cells. The contents of γ-IFN, IL-1ß, and IL-6 in animals immunized with GNP-antigen conjugates were found to be higher than those in intact animals or in animals given the antigen alone. The increased concentration of IL-1ß in the immunized animals directly correlated with the activity of macrophages and stimulated B cells, which produce this cytokine when activated. The increased concentration of IL-6 indicates that the injected preparations are stimulatory to cellular immunity. Immunization with the TGEV antigen conjugated to GNPs as a carrier activates the respiratory activity of lymphoid cells and peritoneal macrophages, which is directly related to their transforming activity and to the activation of antibody generation. Furthermore, the use of this conjugate allows marked improvement of the structure of the animals' immune organs and restores the morphological-functional state of these organs. The microanatomical changes (increased number of follicles) indicate the activation of the B-dependent zone of the spleen and, consequently, the development of a humoral-type immunological reaction. The degradative processes observed in the animals immunized with TGEV antigen alone are evidence of weak resistance to pathogen attack. These results can be used to develop vaccines against this infection by employing TGEV antigen coupled to gold nanoparticles as a carrier.

Natriuretic Peptides in Cardiac Anesthesia and Intensive Care.

Natriuretic peptides, predominantly B-type, are widely used in cardiology as prognostic and diagnostic biomarkers or, much less often, as a substantive treatment tool. They are hormones that are produced mainly in the myocardium in response to overload and ischemia, and their level quite accurately reflects the degree of myocardial dysfunction. Although their use in cardiac anesthesia and intensive care setting seems to be very beneficial for assessing the risk of acute disturbance of myocardial function or its laboratory monitoring, the actual significance of natriuretic peptides in this area is not yet recognized. This is due to the lack of clear diagnostic and prognostic values for these biomarkers supported by high-quality researches. On the basis of the available data, main advantages, existing difficulties, and most effective ways of using natriuretic peptides for determining the risk of heart surgery and assessing the severity of sepsis, pneumonia, and other critical conditions have been discussed in this review. In addition, the expediency of using natriuretic peptides as target parameters for goal-oriented therapy and as a substantive tool for treatment is considered.

Fifteen Years of Transesophageal Echocardiography in Cardiac Anesthesia in Russia.

Transesophageal echocardiography was first introduced in Russia as a component of anesthesiology monitoring in 2003 following its successful implementation in the practice of cardiac anesthesia in the United States and Western Europe. This novel opportunity for perioperative hemodynamic evaluation was enthusiastically adopted at several cardiac surgical clinics despite the presence of critical barriers. The most important of these were the lack of certification programs for anesthesiologists, limited equipment, and a lack of understanding of the responsibility of the anesthesiologist as the coordinator of perioperative therapeutic decisions. Although intraoperative transesophageal echocardiography as a part of the anesthesiology protocol has been introduced in less than 10% of Russian cardiac surgery clinics, a group of interested anesthesiologists has formed over the last 15 years. Both the technical conditions and professional mentality of anesthesiologists need to be changed substantially for successful further development of intraoperative echocardiography. This review aims to highlight the milestones, successes, and challenges in the implementation of intraoperative echocardiography in the practice of cardiac anesthesiology in Russia, which may be interesting to a wide range of cardiac anesthesiologists.