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Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6βrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

BackgroundThe Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.ResultsPerformance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.ConclusionsResults show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.

A new pyridine-fused selenodiazolium salt, 3-(phenylselanyl)[1,2,4]selenadiazolo[4,5-a]pyridin-4-ylium chloride dichloromethane 0.352-solvate, C12H9N2Se2+·Cl−·0.352CH2Cl2, was obtained from the reaction between 2-pyridylselenenyl chloride and phenylselenocyanate. Single-crystal structural analysis revealed the presence of C—H...N, C—H...Cl−, C—H...Se hydrogen bonds as well as chalcogen–chalcogen (Se...Se) and chalcogen–halogen (Se...Cl−) interactions. Non-covalent interactions were explored by DFT calculations followed by topological analysis of the electron density distribution (QTAIM analysis). The structure consists of pairs of selenodiazolium moieties arranged in a head-to-tail fashion surrounding disordered dichloromethane molecules. The assemblies are connected by C—H...Cl− and C—H...N hydrogen bonds, forming layers, which stack along the c-axis direction connected by bifurcated Se...Cl−...H—C interactions.

In this clinical case, a patient who had an instrumentally detected aneurysm with the lumen expanding up to 60 mm underwent a surgically flawless prosthetic replacement of the ascending aorta. This treatment led to decreased exercise tolerance, decreased contractile function of the left ventricular myocardium at rest, and enlarged pulmonary artery. The leading factor was a decrease in the volume of systolic expansion of the aorta down to 5 mL (at the initial 13 mL), despite a noticeable increase in the extensibility and a decrease in mechanical stiffness compared with initial indexes of the affected aortic wall. In the literature review, considering mechanical extensibility and elasticity, problems in creating aortic prostheses equivalent to those for healthy biological tissues were discussed.

BACKGROUND: Magnetic resonance imaging is one of the leading imaging modalities of the musculoskeletal system. However, when imaging the hand, major problems in magnetic resonance imaging include the lack of specialized coils and reliable fixation devices for the hand, uncomfortable patient posture, motion artifacts, and small anatomical structures in the wrist. These factors inevitably lead to incorrect interpretation. AIM: To improve the quality of magnetic resonance imaging of the hand by developing an approach to coil selection, scanning protocol, and hand positioning and fixation. MATERIALS AND METHODS: A positioning device was developed to prevent hand movements. Two types of coils were evaluated. Magnetic resonance images were evaluated comparatively, as well as by a musculoskeletal radiologist. RESULTS: А head coil is more appropriate when scanning the entire hand, for example, in rheumatic diseases. A knee coil is more appropriate when studying smaller anatomical structures (including the wrist) owing to a smaller field of view and higher resolution. Based on the obtained data, guidelines for the selection of scanning parameters, sequences, and coils for magnetic resonance imaging of the hand were formulated. To prevent motion artifacts, a special fixation device of the patient’s hand was introduced. CONCLUSION: Certain factors directly affect the qualitative magnetic resonance imaging study of the hand, such as safety protocols, scanning parameters, and hand fixation. The guidelines presented in this study and the use of the developed specialized fixation device may improve the quality of magnetic resonance imaging of the hand.

Introduction. The relevance of the study is due to the increasing importance and complexity of horizontal public relations in socio-political processes, an increase in the number of practices of grassroots civic activity at the regional and local levels, including the use of new information and communication technologies. The purpose of the article is to identify the causes of initiation, the specifics of the organization and practical implementation of grassroots civic activity, as well as the specifics of the interaction of its key actors in modern socio-political conditions in the Yaroslavl region. Materials and Methods. The empirical basis of the study is 21 practices of grassroots civic engagement in the Yaroslavl region, the analysis of which was carried out by the case-study method with elements of comparative analysis. The case-study method made it possible to study these practices of grassroots civic engagement in their complexity and integrity, and also identified their key characteristics and factors influencing them. Results. A comparison of the main practices of grassroots civic engagement that have taken place in the Yaroslavl region in recent years has been made. The main mechanisms and subjects of grassroots civic engagement, processes of interaction between actors are identified. The role of information and communication technologies in the organization of grassroots civic engagement was determined. The problems of grassroots civic engagement organization and interaction of its key actors were also outlined. Discussion and Сonclusion. The study revealed the key characteristics of grassroots civic activity: significant actors, theirs goals, motives, resources and methods of action, features of media coverage and the use of information and communication technologies. The results of the study will be useful for improving the efficiency of the work of local authorities with various formal and informal organizations and associations of citizens. They will help to build work with these groups, taking into account the identified features in the implementation of practices of grassroots civil initiatives in the Yaroslavl region.

Background. The problem of concept formation in the visual modality remains largely unexplored. There are many studies on the formation of verbal concepts in the learning process. However, it has not yet been fully investigated how concept formation occurs in conditions when both the signified and the signifier (sign) are represented only in the visual modality and what brain mechanisms are involved in this process. Objectives. The aim of the present work was to identify the brain mechanisms of visual concepts formation, on the basis of EEG registration with subsequent localization of the sources of electrical activity. Another task is to evaluate the possibility of actualizing the process of indirect learning in the formation of visual concepts. Study Participants. 26 Russian-speaking subjects without neurological disorders: 10 males and 16 females (aged 18 to 40 years, mean age 22.92 years, SD = 6.38) participated in the study. Methods. Chinese hieroglyphs, unfamiliar to the subjects, were taken as signs. The designated ones were emoticons (schematic faces expressing various emotions). A total of 10 pairs of stimuli sign-designated were presented. A 19-channel electroencephalogram (EEG) was recorded in three successive series: 1) the initial perception of hieroglyphic signs without assigning them a category; 2) categorization of these signs in the process of associative learning, with only 8 designating stimuli-signs directly associated with the designated stimulus, while 2 stimuli-signs were never associated with the stimulus-designator, their meaning was established indirectly; 3) subsequent perception of signs with the meaning already assigned to them. All stimuli were presented to the subjects visually. A new method of localization of brain activity, “Virtually implanted electrode”, developed by A.V. Vartanov (patent RU No. 2 785 268) was applied. Results. The analysis of the subjects' responses showed that during the learning process all signs (including those formed indirectly) were assigned a certain meaning (designated). Differences in event-related potentials (ERP) were found in leads C3 and CZ. Significant differences in ERP as a result of learning were revealed in a number of brain structures. It was found that a number of functional connections between the left area of the secondary visual cortex and the right part of the cerebellum changed significantly as a result of learning. Conclusions. The development of visual categories is ensured by the coordinated work of the right part of the cerebellum, parahippocampal gyrus and primary visual cortex, which is confirmed by the discovered differences in the corresponding ERPs.

In connection with the beginning transition of mass-produced battery electric vehicle (BEV) powertrains from single-gear gearboxes to specially configured automatic transmissions (AT), the number of publications devoted to justification and research of their architecture, as well as optimization of applied design solutions, is rapidly increasing. A large number of publications focus on dual-clutch AT (i. e. DCT) with two clutches (or frictions) in the first stage application. A clear recent trend in their subject matter is a shift of interest in DCT control, especially in transient automatic gear shifting with joint control of the motorgenerator (MG) and frictions in an integrated powertrain. It is shown that smoothness of shifting here is of no less importance than in classical AT, not only because of shift shocks, which deteriorate comfort, but also because of the possibility of excitation of oscillating modes in the electric drive. The paper analyzes several published variants of a strategy for controlling such shifting processes and their computer and physical implementation. We believe that, given the lack of Russian-language materials on this subject, this information is published for the first time.

The results of previously performed studies are summarized, and a methodology for estimating the lifetime consumption of fire tankers is presented. The proposed methodology takes into account the specific features of the practical operation of a fire truck, as well as its integral part — the tank, which has a significant impact on the loss of the lifetime of the vehicle as a whole. The methodology combines computational and statistical methods, and also develops an approach based on taking into account two interdependent factors: mileage and operating time. In combination, this makes it possible to differentially determine the lifetime consumption of fire tankers, taking into account the weighted average consumption of the lifetime potential of their main components. At the same time, to the known five typical groups of the main parts of the vehicle, which have a similar nature of lifetime loss depending on mileage (conditions, nature of loading and damage processes) and operating time, in the case of a tanker truck, it is proposed to add another characteristic group, tanks, using a dependence for assessing its lifetime, taking into account the lifetime consumption for corrosion wear. An example of calculating the lifetime consumption of a fire tanker is given. The results obtained show values corresponding to the actual processes of obsolescence. Scope of application of the results obtained is: assessment of the condition of a fire truck and its tank after long-term storage; extension of the operation of a fire tanker after the expiration of the established service life; extension of the service life after major repairs; extension of the service life after the main lifetime work out; decision on the expediency of repair or decommissioning of a tanker truck.

Experimental diagrams of limiting states of active systems under conditions of mechano-sliding fatigue are presented, as well as their analytical description. A graphical representation of the proposed equations for limit stresses (limits of mechano-sliding fatigue) is given based on the energy criterion of limiting states in the form of multicriteria diagrams of limiting states of various active systems (the ordinate axis on them serves as a strength scale, and the abscissa axis – as a tribological scale). Analysis of the proposed equations for limiting stresses, experimental diagrams of limiting states of different active systems showed that: 1) processes of friction and wear, depending on the conditions of their implementation, can significantly reduce, as well as significantly increase, the fatigue resistance of the active system; 2) cyclic stresses, depending on the test conditions, can both significantly reduce and increase the wear resistance of the active system.

Abstract Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.

Problem description. One of the areas of digital transformation of Russian society is the development and implementation of the National Digital Ruble System (DR) in the credit and financial sphere (CFS) of the economy of the Russian Federation. The National DR system should be based on the information technology infrastructure (ITI) for ensuring information security (IS). In fact, the ITI for ensuring IS is a trust infrastructure (ITIT) based on the public key infrastructure (PKI). ITIT should have a number of functional properties, including identification and authenti­cation of objects and subjects of electronic financial transactions, protection of the integrity and confidentiality of data and the electronic financial transactions themselves, implementation of the principle of non-repudiation of the parties to information interaction. At the same time, the absence of ITIT in the National DR System can completely discredit the very idea of digitalization of the CFS, associated with the absence of any guarantees of reliability and trust in the National DR System, based on the implementation of the entire range of methods and means of cryptographic protection of information (electronic financial transactions), including systems for managing cryptographic keys. The absence of comprehensive protection of the National DR System will entail risks and problems in ensuring IS, which can negatively affect individuals, groups, organizations, sectors of the economy and society as a whole. Goals. To propose and analyze a heuristic model of DR and a model of functional and structural ITIT, which solves the main problems of ensuring IS of the National DR System, associated primarily with confirmation of the authenticity and ownership of DR, as well as the protection of electronic payment transactions and the possibility of withdrawing (withdrawing from circulation) DR immediately (on-line) after detection of its compromise. Results. The article presents a heuristic (hypothetical) model of C₽ and describes the DR format (as an information object) that includes cryptographically linked information blocks and public key certificates issued by accredited certification authorities using electronic signatures. A functional and structural model of the ITIT of the National DR System is proposed. The composition, main elements of the ITIT structure, as well as their goals and implemented functions are described. The results of the analysis of trust assurance based on the PKI of the Bank of Russia (BR) are presented. Practical significance. The heuristic (hypothetical) model of DR, the functional and structural model of the ITIT of the National DR System and the results of the analysis of trust assurance based on the PKI of the BR are of great practical significance in the development and implementation of the National DR System in the CFS of the Russian Federation economy. Conclusions. The results obtained will increase the level of security and trust in the National DR System of the citizens, businesses and credit and financial institutions.

Introduction. The article considers the issue of modifying the initial chrysotile fiber and its bundles by the action of hydration products of Portland cement and various acidity value of the treated medium. A brief justification of the relevance of the research topic is provided. It is noted that recently, issues of production of composite materials based on natural and man-made raw materials, which are a promising area of modern economics, have aroused great scientific and practical interest. The availability and low cost of raw materials, as well as low energy, transportation, and overhead costs, contribute to reducing the cost of composite materials. At the same time, the high contractual prices and strong demand in both domestic and foreign markets provide incentives for increasing production volumes. The aim of the research is to study the behavior of the initial chrysotile fibers and their aggregates in the composition of the cement component under the influence of different acidity of the treated medium. Research objective: to investigate the behavior of chrysotile cement dust components under an aggressive environmental condition with electron microscopy examination; calculation of the number and dimensional characteristics of nanofibers and dust particles under the influence of various exposure times of the aggressive factor; microdifraction studies of the nanostructure of the studied samples after exposure to acidic media. Materials and methods. The materials used in the research and their characteristics are given, in particular, chrysotile cement dust containing fibers of commercial chrysotile, acidity of the medium, exposure time, micro- and nanofibers obtained after exposure to aggressive medium. Samples of chrysotile cement dust were taken at the slate production No.1 of JSC “BelACI” and collected at the place of sawing of chrysotile cement products, underwent the stage of dispersion using a centrifugal separator. In the work chrysotile cement dust was used as an object of environmental pollution and its further use in the production of composite chrysotile cement products. Results. The results of studies on the influence of aggressive environment on the components of chrysotile-cement dust, their size characteristics, and structural nano-changes are presented. The studied samples have been examined in a scanning ion-electron microscope at magnifications of 200x, 500x, 5000x, 10000x, and their chemical composition have been analyzed. Discussion. The results of analysis of the obtained experimental data are given. Quantitative composition of fibers and aggregates of fibers in chrysotile cement dust changes after its exposure in acidic medium in comparison with their quantity in initial chrysotile cement dust, and the quantity of separate thin fibers increases, it is explained by the fact that in acidic medium there is not only destruction of cement stone, but also splitting of bundles of chrysotile fibers into micro- and nanofibers. Conclusions. Electron microscopic examination of initial commercial chrysotile fibers and their bundles in cement dust have shown changes in their dimensional and quantitative characteristics, including the products of Portland cement hydration under the influence of the factor of aggressiveness of the environment

Background and Objectives: Silicon is the main semiconductor material used in many areas of human life. It is used in the creation of solar cells, various electronic devices, sensors etc. Also of particular interest is such an actively developing area as flexible electronics. It finds its application in the electronic devices. Thus, it becomes important to study ways to create polycrystalline films of semiconductor materials such as silicon on flexible substrates. The biggest problem with silicon crystallization on flexible substrates is that these substrates are low-melting, and traditional methods of silicon crystallization have an intense thermal effect on the crystallized material, which leads to destruction of the substrate. Materials and Methods: To create the samples, consecutive magnetron sputtering deposition of a silicon layer and then a tin layer onto a polyimide substrate was used. Silicon was crystallized using an infrared pulsed laser due to high absorption in tin layer. The structure of silicon during its bending deformation was studied using Raman spectroscopy. Results: As a result of the study, the sizes of silicon crystallites after crystallization, as well as the stresses in the films during bending, have been determined.

Abstract Background The previously underestimated effects of commensal gut microbiota on the human body are increasingly being investigated using omics. The discovery of active molecules of interaction between the microbiota and the host may be an important step towards elucidating the mechanisms of symbiosis. Results Here, we show that in the bloodstream of healthy people, there are over 900 peptides that are fragments of proteins from microorganisms which naturally inhabit human biotopes, including the intestinal microbiota. Absolute quantitation by multiple reaction monitoring has confirmed the presence of bacterial peptides in the blood plasma and serum in the range of approximately 0.1 nM to 1 μM. The abundance of microbiota peptides reaches its maximum about 5 h after a meal. Most of the peptides correlate with the bacterial composition of the small intestine and are likely obtained by hydrolysis of membrane proteins with trypsin, chymotrypsin and pepsin – the main proteases of the gastrointestinal tract. The peptides have physicochemical properties that likely allow them to selectively pass the intestinal mucosal barrier and resist fibrinolysis. Conclusions The proposed approach to the identification of microbiota peptides in the blood, after additional validation, may be useful for determining the microbiota composition of hard-to-reach intestinal areas and monitoring the permeability of the intestinal mucosal barrier.

Abstract Segregation is a threat to the aspirations of producing a cohesive society and modelling its dynamics can be done in order to help design preventative measures. This work explores the question of whether the network topologies of urban spaces can affect the pace at which populations can become segregated. The simulation dynamics employed augment the canonical Schelling model in such a way that it also captures the affinity for agents to prefer denser regions which also offer sufficient local homogeneity. It is shown that different networks synthetically generated and from real city maps can alter the rate of segregation. The results also show that using the entropy trace on the distribution of agent edge degree across all agents correlates with the segregation reinforcing the relevance of physics inspired modeling of social systems. This investigation shows that it is possible to explore and select network arrangements which can be less conducive towards segregation movements during the stages of urban planning so that the rate is reduced. An additional finding is that the entropic measure is closely associated with the common statistic for such modeling efforts.

In recent years, the collection of eggs of stink bugs (Pentatomidae) has intensified because of the attention given to egg parasitoids in classical biological control strategies against Halyomorpha halys (Stål) in Europe. Several specimens belonging to the genus Telenomus Haliday emerged from field-collected pentatomid eggs. Taxonomic knowledge to date has not been sufficient to enable the research community to identify these specimens to species level. Three species of scelionid wasps (Scelionidae) associated with Pentatomidae, Telenomus gifuensis Ashmead, Telenomus truncatus (Nees von Esenbeck) and Telenomus turesis Walker, have been characterized on a morphological basis. A COI barcode analysis confirmed the genetic distance between the latter two species. An identification key to the three Telenomus species occurring in the Palearctic region associated with stink bugs is provided. Telenomus heydeni Mayr is here considered conspecific with Telenomus truncatus (Nees von Esenbeck).

Abstract As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels.

Abstract When an electromagnetic (EM) wave propagates in a medium whose properties are varied abruptly in time, the wave experiences refractions and reflections known as time-refractions and time-reflections, both manifesting spectral translation as a consequence of the abrupt change of the medium and the conservation of momentum. However, while the time-refracted wave continues to propagate with the same wave-vector, the time-reflected wave propagates backward with a conjugate phase despite the lack of any spatial interface. Importantly, while time-refraction is always significant, observing time-reflection poses a major challenge – because it requires a large change in the medium occurring within a single cycle of the EM wave. For that reason, time-reflection of EM waves was observed only recently. Here, we present the observation of microwave pulses at the highest frequency ever observed (0.59 GHz), and the experimental evidence of the phase-conjugation nature of time-reflected waves. Our experiments are carried out in a periodically-loaded microstrip line with optically-controlled picosecond-switchable photodiodes. Our system paves the way to the experimental realization of Photonic Time-Crystals at GHz frequencies.

Abstract This study introduces a novel approach in the realm of liquid biopsies, employing a 3D Mueller-matrix (MM) image reconstruction technique to analyze dehydrated blood smear polycrystalline structures. Our research centers on exploiting the unique optical anisotropy properties of blood proteins, which undergo structural alterations at the quaternary and tertiary levels in the early stages of diseases such as cancer. These alterations manifest as distinct patterns in the polycrystalline microstructure of dried blood droplets, offering a minimally invasive yet highly effective method for early disease detection. We utilized a groundbreaking 3D MM mapping technique, integrated with digital holographic reconstruction, to perform a detailed layer-by-layer analysis of partially depolarizing dry blood smears. This method allows us to extract critical optical anisotropy parameters, enabling the differentiation of blood films from healthy individuals and prostate cancer patients. Our technique uniquely combines polarization-holographic and differential MM methodologies to spatially characterize the 3D polycrystalline structures within blood films. A key advancement in our study is the quantitative evaluation of optical anisotropy maps using statistical moments (first to fourth orders) of linear and circular birefringence and dichroism distributions. This analysis provides a comprehensive characterization of the mean, variance, skewness, and kurtosis of these distributions, crucial for identifying significant differences between healthy and cancerous samples. Our findings demonstrate an exceptional accuracy rate of over $$90\%$$ 90 % for the early diagnosis and staging of cancer, surpassing existing screening methods. This high level of precision and the non-invasive nature of our technique mark a significant advancement in the field of liquid biopsies. It holds immense potential for revolutionizing cancer diagnosis, early detection, patient stratification, and monitoring, thereby greatly enhancing patient care and treatment outcomes. In conclusion, our study contributes a pioneering technique to the liquid biopsy domain, aligning with the ongoing quest for non-invasive, reliable, and efficient diagnostic methods. It opens new avenues for cancer diagnosis and monitoring, representing a substantial leap forward in personalized medicine and oncology.