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BACKGROUND: The shoulder joint provides the greatest degree of freedom in movement, making it one of the most unstable and frequently dislocated joints, accounting for almost 50% of large-joint dislocations. Recurrent instability of the shoulder joint develops in 96%100% of children and adolescents, making it important to accurately diagnose possible anatomical causes of persistent pain syndrome violating the habitual function of the shoulder. At the same time, the symptoms of intra-articular injuries of the shoulder joint are often vague, and a definitive diagnosis cannot be made without the use of instrumental research methods. AIM: To compare the diagnostic value of clinical examination and magnetic resonance imaging in detecting intra-articular pathology in adolescents with anterior instability of the shoulder joint of traumatic origin. MATERIALS AND METHODS: This retrospective study included parameters of clinical examination and instrumental methods of investigation of 72 children (72 shoulder joints) with habitual shoulder dislocation of traumatic origin. The age of the examined persons ranged from 13 to 17 years. Magnetic resonance, clinical, arthroscopic, and statistical methods of research were employed in this work. The arthroscopic method was considered as a reference research method for assessing the sensitivity and specificity of clinical examination and magnetic resonance imaging. Sensitivity and specificity were evaluated, followed by an assessment of the prognoses of positive and negative results for MRI data and clinical research methods. RESULTS: The MRI data was characterized by a significantly greater sensitivity and specificity in detecting lesions (95.4% and 71.4%) than those of clinical examination (79.1% and 60%). Thus, MRI is better at detecting damage to the fibrous-cartilaginous lip in traumatic instability in adolescents than clinical examination. CONCLUSIONS: In our opinion, for the most reliable preoperative planning of surgical treatment of children, a full-fledged clinical examination should be used and data from instrumental research methods should be included, considering the advantages and disadvantages of each method.

Aim of the study was to analyze the frequency and nature of cardiovascular complications in influenza A/H1N1/09 in Zabaykalsky Krai from 2018 to 2019. Material and methods. 86 cases of severe influenza A/H1N1/09 were analyzed. Results. The patients were divided into 2 groups, comparable by gender and age. The first group consisted of patients with cardiovascular complications of influenza A/H1N1 / 09 (41 people). The second group consisted of patients without complicated flu (45 people). The average age of patients in the first group was 60 ± 13.7 years. According to the ECG results, sinus tachycardia with a heart rate of 94 ± 14.2 beats/min was dominant, in combination with various rhythm and conduction disorders: supraventricular extrasystole – in 5 (12 %) patients, acute (paroxysmal) atrial fibrillation – in 19 (46 %), ventricular extrasystole – in 7 (17 %), complete right and left bundle branch block – in 7 (17 %) and 7 (17 %), respectively, atrioventricular block of the 1st degree – in 1 (2 %) patients. Long QT syndrome was revealed in 5 patients (12 %). The severe cardiovascular system complications were: myopericarditis in 2 (5 %) people, decompensation of chronic heart failure in 4 (10 %) people, pulmonary embolism in 1 (2 %), acute myocardial infarction in 11 (27 %). The mortality rate in this group was 12 (29 %) cases from hospitalized patients. The average age of patients in the second group was 58 ± 14.1 years. According to the ECG results, sinus tachycardia with a heart rate of 91 ± 9.4 beats/min was detected in 98 % of cases, 3 (7 %) patients had complete left bundle branch block, 1 (2 %) patient had atrial fibrillation. No other rhythm or conduction disturbances were detected. No organic heart pathology was detected in this group of patients. The mortality rate was 5 (11 %) people. Conclusion. The analysis of 86 cases showed that elderly patients with a heavy premorbid background prevailed. The severe cardiovascular system complications were mainly represented by cardiac arrhythmias and the development of acute myocardial infarction. The fatal outcome occurred on the 8th-22nd day from the onset of the disease. The presence of cardiovascular complications doubles the mortality rate.

A balanced immune response is a cornerstone of healthy aging. Here, we uncover distinctive features of the long-lived blind mole-rat (Spalax spp.) adaptive immune system, relative to humans and mice. The T-cell repertoire remains diverse throughout the Spalax lifespan, suggesting a paucity of large long-lived clones of effector-memory T cells. Expression of master transcription factors of T-cell differentiation, as well as checkpoint and cytotoxicity genes, remains low as Spalax ages. The thymus shrinks as in mice and humans, while interleukin-7 and interleukin-7 receptor expression remains high, potentially reflecting the sustained homeostasis of naive T cells. With aging, immunoglobulin hypermutation level does not increase and the immunoglobulin-M repertoire remains diverse, suggesting shorter B-cell memory and sustained homeostasis of innate-like B cells. The Spalax adaptive immune system thus appears biased towards sustained functional and receptor diversity over specialized, long-lived effector-memory clones—a unique organizational strategy that potentially underlies this animal’s extraordinary longevity and healthy aging. Investigation of the long-lived blind mole rat adaptive immune system reveals that they do not accumulate large memory T-cell clones and effector programs with aging. Such organization could relieve the burden of inflammaging triggered by persistent clonal expansions and contribute to the long and healthy Spalax lifespan.

Background. The frequency of occurrence of dislocation of the shoulder joint is the highest among that for all other limb joints. Simultaneously, recurrent instability of the shoulder joint develops majorly in children and adolescents, which, in the future, lead to the development of persistent pain syndrome. Past evidence indicate that the features of the spatial positioning of the articular process of the scapula can be considered as a risk factor toward the development of instability in the shoulder joint among adult patients. However, there is no reliable data in the literature regarding the influence of tilt and rotation of the shoulder blade glenoid on the occurrence of instability in the shoulder joint among children and adolescents. Encouraged, we undertook this subject for our study. Aim. To clarify the impact of changes in the version and inclination of the glenoid on the instability of the shoulder joint among children. Materials and methods. We analyzed the survey data of 42 children with a habitual dislocation of the shoulder of traumatic and atraumatic origins. The average ages of the examined children were 15.57 1.75 and 15.07 1.64 years, respectively, for those with shoulder instability of traumatic and atraumatic origins, respectively. Results. Statistical data processing revealed no significant differences in the versioning and inclination of the glenoid process between the groups with traumatic and atraumatic instabilities of the shoulder joint. Notably, the average values of versioning and inclination indicators were in the normal range. Conclusion. Based on our results, we suggest that, in the childhood, the dynamic and static soft tissue stabilizers of the shoulder joint play the leading role in the formation of instability of the shoulder joint.

The article critically analyses the phenomenon of global digital platforms, which have become key actors in the international movement of factors of production and studies the approaches to their management. The methodological basis of the research includes the main provisions of the emerging theory of ecosystems and digital platforms, questioning the postulates of theories of international business and strategic management. The article uses the methods of comparative, structural and system-based analysis in the context of their application for assessing digital transformation and managing global digital platforms. The study shows that universal determinants and competitive advantages of global digital platforms are the following: the ability to overcome trade barriers; providing liquidity through transactions; low marginal cost; more efficient use of assets and attraction of investments; and the ability to significantly enhance international specialization. The authors propose an approach for differentiating traditional business models and platform business models based on avoiding linear optimization of internal processes and centralized exchange of value. We establish the conceptual aspects of the expansion of global digital platforms’ business activities. This is due to the emergence of new components of the digital infrastructure that modifies the principles of international business and the administration methods of transnational corporations, which are no longer focused on location. The paper identifies the management problems and risks experienced by traditional companies when creating platforms: dependence on key platforms, increasing costs incurred in market entry, and difficulties when functioning within the lightweight asset model. The formation and development of global platforms not only affect the system of economic relations, but also stimulate changes in corporate governance models and technologies.

The article discusses the problems of international fragmentation of production and global value chains and how they relate to modern aspects, trends and challenges of international trade development. Methodologically the research rests upon the key principles of classical and alternative theories of international trade, the theory of value chains and the basic theories of foreign investment. In the course of the study, the authors apply both general theoretical (formalization, synthesis, analysis) and particular (measurement, comparison, observation) research methods. The main results of the research are as follows: a conceptual rethink of the nature of today’s international trade in terms of influencing factors of global production decomposition; theoretical justification and criticism of contemporary approaches to the organization of value chains between developed and developing countries; the formulation of measures to modify trade and economic policy in the current system-related and structural challenges of value chains’ transformation. The authors conclude that instability of modern global value chains in the world production and international trade is due to the unsteady dynamics of the global economy, industrial differentiation of global value chains, changes in international strategies of multinational companies, innovation and digitalization of global production networks.

Symmetry aspects of the periodic model of a crystal with a point defect (a supercell model or a extended unit cell (EUC) model) are considered; splitting of the Wyckoff positions in a primitive crystal cell with the introduction of supercell and the change of the one-electron states classification over k-vector (Brillouin zone folding) are discussed. When considering a point defect in a crystal in the supercell model, it is necessary to take into account the symmetry of the one-electron states of the original crystal at the top of the valence band and at the bottom of the conduction band. The selected supercell should reproduce these states. Each specific selection of a supercell corresponds to a specific splitting of the Wyckoff positions of the original crystal and, as a result, the possibility to place a defect in positions with different point symmetry and to perform a calculation without taking into account the point symmetry of the crystal with a defect at all (site symmetry method). By the results of the calculation of a crystal with a defect in the supercell model, taking into account site symmetry, it is possible to determine the real symmetry of the crystal with a defect, which is essential for the interpretation of experimental data. A copper impurity in a lithium node in a LiCl crystal retains the cubic symmetry of the atom being replaced; the impurity of an iron atom in a titanium site with cubic local symmetry in a SrTiO3 crystal lowers the symmetry to tetragonal; and the H site in the CsPbI3 crystal is characterized by the complete removal of point symmetry with the formation of an $${\text{I}}_{2}^{ - }$$ ion.

Objective The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. Methods The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). Results CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. Conclusion In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

The results of three-year research on the use of allogeneic mesenchymal stem cells of adipose tissue (AMSCs) in the treatment of skin burns of II-III degree are presented. in a complex with wounds dressing of nanofibers chitosan and copolyamide, hyaluronic acid. It was found that with surgical necrectomy, introduction of AMSCs and substitution of defects with natural polymer coatings, the healing time is reduced by 89% (p < 0.05). Isolated administration of MSC reduces the healing period by no more than 5% (p > 0.05). The combined use of wounds dressings of nanofibers chitosan and copo lyamide with MSC accelerates the regeneration process by 26% (p < 0.05), with the introduction of AMSCs accelerating the development of granulation tissue by the fifth day of observation by 83% (p < 0.01). Joint use of wound coverings on the basis of hyaluronic acid with AMSCs is accompanied by an increase in the number of vessels of the microcirculatory bed in the defect area by 185% (p < 0.01). Clinical evaluation of the effectiveness of drugs with stem cells – a gel for topical application and a suspension of MSC LC for injection administration demonstrate their ability to optimize regeneration in the burn zone. Application of gel with AMSCs reduces the duration of epithelialization of border (dermal) burns by 2.2-2.4 times, with the final healing period being reduced by 59% (p < 0.01) and the suppuration frequency by 30% (p < 0.05). The introduction of a suspension of AMSCs into the zone of deep burn increases the frequency of engraftment of autografts, stimulates angiogenesis and proliferation of fibroblasts in the superficial and deep layers of the dermis. In the area of MSC administration, the LC perfusion level and the amplitude of blood flow fluctuation are twice as high as the values in the zones without the introduction of cells.

A force field is proposed that reproduces with a high accuracy a large number of properties of the bulk crystal MoS2 phases, monolayers, and nanotubes. The reproduced values are both the experimental results and the results of quantum chemical calculations. The elaborated interaction potential can be useful primarily for investigation of multiwall MoS2 nanotubes and their thermodynamic properties, especially, since the potential is able to reproduce the frequencies of the crystal phonon spectrum. In this study the proposed potential is applied to simulate the temperature dependence of a number of properties of the armchair and zigzag nanotubes. The calculations have been performed using molecular mechanics method within the framework of quasi harmonic approximation which is carried out through the estimation of the temperature dependence of the Helmholtz free energy.

In the last decade there has been a tendency to move away from the symptomatic treatment and embrace targeted therapies. This process is underpinned by the accumulated knowledge of the mechanisms underlying the pathogenesis of diseases and driven by the advances in biotechnologies. T-cell receptors with variable TRBV9 β-chain regions have been recently associated with spondyloarthritis including its subtype, ankylosing spondylitis. The aim of this work was to engineer a chimeric monoclonal antibody targeting the variable region of the T-cell receptor β-chain encoded by the TRBV9 gene segment and assess its specificity and cytotoxicity. Using flow cytometry and next generation sequencing, we demonstrate that the engineered chimeric antibody is highly specific and exhibits cytotoxic activity against its target. Approaches based on the use of therapeutic chimeric antibodies against pathogenic T-clones may hold great promise for the therapy of autoimmune disorders in general and AS in particular.

MoS2 nanostructures, especially mono-, multilayer nanothin films as well as single- and multiwall nanotubes are rather interesting popular objects in nanomaterials chemistry. The thermodynamic properties of inorganic nanotubes, and the temperature dependence of their properties can be efficiently investigated by first-principles and molecular mechanics methods in the framework of harmonic approximation. At the same time, only thin single-wall nanotubes are available for the first-principles calculations. The classical mechanics is suitable to simulate very large atomic systems and their phonon frequencies, but developing sufficiently accurate force field is rather tedious work. Herein, we report the force field fitted to the experimental and first-principles data on the structure of 2H- and 3RMoS2 polytypes of bulk crystal, structure of monolayer and several bilayers, vibrational frequencies of 2HMoS2 bulk and monolayer, relative energetic stability of polytypes experimental and first-principles data, elastic constants, strain energy of a (12, 12) MoS2 nanotube. The thermodynamic functions and their temperature dependence for the armchair and zigzag nanotubes are calculated within the formalism of molecular mechanics using elaborated interatomic potential. The results of molecular mechanics and first-principles method application to the thinnest nanotubes are compared.

The competitiveness of individual companies is related not only to their own characteristics, but also to the institutional and economic characteristics of the home countries of these companies. How the business environments of countries affect the results of applying management practices in different companies is a complex research issue, as managerial practices have many characteristics. Nevertheless, Russian enterprises have to use new technologies to increase competitiveness in the world market. We analysed both the sector of transportation where geographic closeness is a key indicator of competition, and transportation facilities where incremental costs and savings can be implemented to build variables of the market structures. The research sample includes 210 specialized logistic firms with variation of ownership structure and collateral agreements. We have examined firms in two markets: Russian and German ones. The analysis is based on the data from 7 Russian regions, and 6 German federal states. We have found that the quality of managerial practices — estimated by using a new survey instrument — is strongly linked with commercial ratios such as a rate of fail to deliver and a rate of consumer satisfaction. A high level of competitiveness is demonstrated by a greater number of companies in the same region. We have found that this is positively correlated with increased quality of managerial capabilities. This correlation is reinforced when we quantify the number of local firms with local logistic infrastructure. This paper reveals that the increasing the effectiveness of managerial practices are due to the characteristics of the country of origin. The results allow to develop recommendations for policy-makers to improve the business environment.

This article discusses the results of a continuous study of Russian domestic air carriers conducted in 2006-2016 and analyzes the main barriers to entry into the passenger air travel market and their impact on competition in this field. There are significant structural barriers that prevent companies from entering this market. This situation challenges the existing concept and the idea of the domestic air transportation market as a quasi-competitive one. To describe the structure of the Russian passenger air transport market, we introduce the notion of “discrete competition,” reflecting shifted density of market concentration towards small regional airlines. The latter are usually united by ownership mechanisms or affiliation with an airport. They possess considerable market power, but at the same time have an insignificant market share in the overall Russian passenger air market. Administrative barriers also play a crucial role in restraining competition. Furthermore, current institutional conditions are favourable for vertical "airport - airline" integration which results in a fundamental transformation, as described by Williamson, and can be detrimental to competition. As our research findings have shown, there is a trade-off between existing vertically integrated structures in the air passenger market and public welfare.

For the first time, the structural and stability properties of multi-walled GaS, GaTe, and Janus Ga2STe nanotubes have been simulated using molecular-mechanics calculations. The armchair and zigzag nanotubes with different wall numbers and diameters have been considered. The force field used for GaS, GaTe and Ga2STe multi-walled nanotubes is based on the interaction potentials recently developed to describe monolayers of the transition and post-transition metal chalcogenides. The Buckingham potentials have been introduced to model the interlayer and interwall interactions. The results of quantum mechanical calculations for a number of bulk crystals, mono and bilayers, as well as small diameter single-wall nanotubes have been employed to check the validity of the proposed force field. With the help of an adapted force field, large eight-walled nanotubes with an outer diameter of 32 nm were simulated, which at present cannot be studied using the first principles of quantum mechanical methods. Molecular mechanics simulations predict the faceted structure of armchair GaS, GaTe, and Ga2STe multi-walled nanotubes with a sufficiently large diameter and a cylindrical structure for all zigzag nanotubes. The Janus nanotubes' stability is superior to that of binary nanotubes and may probably achieve a maximum at certain wall numbers and diameters.

The results of the application of cold atmospheric plasma are discussed in the experimental study. The effectiveness of an experimental wound dressing based on chitosan nanofibers and copolyamide and a commercial wound dressing material based on hyaluronic acid hydrogel in the treatment of third-degree skin burns (ICD-10) is also evaluated. During the first phase of the study, an original method of inflicting thermal burn on the skin of small laboratory animals (rodents) was developed. The temperature of dehaired skin and the temperature of skin heated by resistive electrical element metal plate were obtained through a digital thermometer sensor. The source for the generation of cold atmospheric plasma was made by specialists of St. Petersburg Polytechnic University of Peter the Great. Biopsy material for histological assay was taken 3, 7, 12, 15, 21, and 28 days after treatment. Paraffinic microscopic sectioning was performed with hematoxylin and eosin; after this, microscopic assay was done. The use of cold atmospheric plasma decreases the frequency of purulent complications and also helps reduce the recovery time of the skin by 20% (p < 0.05) but is not sufficient to achieve the result that has been proclaimed after an early escharectomy and replacement of surgical defects by wound dressing materials based on natural polymers. It was demonstrated that the wound dressing based on aliphatic copolyamide and chitosan and hyaluronic acid hydrogel can help significantly accelerate the process of reparative regeneration and histogenesis in the heat-affected zone after escharectomy for up to 14.6%-46% (p < 0.05).

Atomistic model has been proposed to describe the structure, phonon frequencies, and thermodynamic properties of multi-walled nanotubes based on molybdenum disulfide.

Background:Recently a group of T-cell clones with characteristic T-cell receptor (TCR) motif was identified in peripheral blood and synovial fluid of HLA-B*27+ patients with ankylosing spondylitis (AS) [1-2] - a prototypic disease from a wider group of spondyloarthropathies (SpAs). Extraarticular manifestations of AS could involve skin, intestine or eye. Emerging data indicate linkage between intestinal and joint inflammation, including expression of gut-associated integrins on synovial T-cells [3-4]. However, clonal T-cell composition and presence of identical clones in different inflamed sites in SpAs remains poorly studied.Objectives:To investigate clonal T-cell repertoire and presence of AS-related TCR motif in different sites of inflammation of patients with SpA.Methods:Samples of synovial fluid (SF) were obtained from HLA-B*27+ and HLA-B*27- patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA), as well as gut biopsy samples from patients with AS and Crohn’s disease (AS/CD) or ulcerative colitis (AS/UC), and conjunctival swabs from patients with uveitis (Uv) and with or without articular manifestations (Table 1). Also SF and gut biopsy samples were obtained from HLA-B*27+ patients with juvenile idiopathic arthritis (JIA). For one patient PsA patient paired samples of SF and gut biopsy were obtained.Table 1.Detection of the AS-related motif TRBV9_CASS[V/A/L/P][G/A] [L/T/V][F/Y]STDTQYF_TRBJ2-3 in bTCR repertoires of samples from different inflamed sites of patients with SpATissueDiagnosisB27+B27-AS-related TCR motif+ among all samples from B27+ donorsSynovial fluidAS2012PsAJIAIntestinal biopsyAS/CD433 / 4AS/UCJLAConjunctival swabUv804 / 8SF and gut samples were processed to isolate mononuclear cells, while conjunctival swabs were directly lysed in the lysis buffer. CD3+ β7-intergin+ cells were isolated from SF by fluorescence-activated cell sorting. Deep TCR repertoire profiling was carried out using UMI-based cDNA library preparation technology [1].Results:Identical T-cell clonotypes were detected between paired SF and gut samples of the same patient with psoriatic arthritis and intestinal inflammation. The subpopulation of β7-intergin+ SF T-cells shared significantly more identical clonotypes with gut biopsy repertoire compared to the bulk SF T-cell repertoire.Clonotypes belonging to the AS-related TCR beta motif TRBV9_CASS[V/A/L/P][G/A][L/T/V][F/Y]STDTQYF_TRBJ2-3 were detected in all inflamed tissues tested: synovial fluid, intestinal biopsies and conjunctival swabs of SpA patients (Table 1). Importantly, we observed these clonotypes exclusively in samples from HLA-B*27+ donors (n=26), but not in HLA-B27- context (n=15) with comparable analysis depth, thus confirming strong HLA-B*27-restriction of the clonotypes. The AS-related clonotypes were detected in the subpopulation of β7-intergin+ SF T-cells from HLA-B*27+ patients with PsA.Conclusion:For the first time we directly report the T-cell clonal sharing between synovial fluid and inflamed gut tissue of SpA patients. In sum our data suggests involvement of identical T-cell clones in inflammation in different anatomical sites in SpA.References:[1]Komech et al. Rheumatology (Oxford). 2018;57(6):1097-1104.[2]Faham et al. Arthritis Rheumatol. 2016;11(10):300-308.[3]Guggino et al.Ann Rheum Dis. Published Online First: 18 October 2019.doi:10.1136/annrheumdis-2019-216456.[4]Qaiyum et al Ann Rheum Dis. 2019;78(11):1566-1575.Acknowledgements:We thanks all the patients and medical personnel involved in the studyDisclosure of Interests:None declared

OX40 receptor-expressing regulatory T cells (Tregs) populate tumors and suppress a variety of immune cells, posing a major obstacle for cancer immunotherapy. Different ways to functionally inactivate Tregs by triggering OX40 receptor have been suggested, including anti-OX40 antibodies and Fc:OX40L fusion proteins. To investigate whether the soluble extracellular domain of OX40L (OX40Lexo) is sufficient to enhance antitumor immune response, we generated an OX40Lexo-expressing CT26 colon carcinoma cell line and studied its tumorigenicity in immunocompetent BALB/c and T cell deficient nu/nu mice. We found that soluble OX40L expressed in CT26 colon carcinoma favors the induction of an antitumor response which is not limited just to cells co-expressing EGFP as an antigenic determinant, but also eliminates CT26 cells expressing another fluorescent protein, KillerRed. Tumor rejection required the presence of T lymphocytes, as indicated by the unhampered tumor growth in nu/nu mice. Subsequent re-challenge of tumor-free BALB/c mice with CT26 EGFP cells resulted in no tumor growth, which is indicative of the formation of immunological memory. Adoptive transfer of splenocytes from mice that successfully rejected CT26 OX40Lexo EGFP tumors to naïve mice conferred 100% resistance to subsequent challenge with the CT26 EGFP tumor.

The properties of multi-walled MoS2 nanotubes have been investigated by the first principles calculations and by molecular mechanics (MM) simulations using a revised three-body force field. The density functional theory (DFT) calculations have been performed on single-, double- and triple-walled MoS2 nanotubes. The new version of the force field is able to reproduce the structure integrity of the MoS2 nanotubes at temperatures up to 700 K through the molecular dynamics simulations. Comparison of the results of first principles and MM simulations of the multi-walled nanotubes demonstrates satisfactory agreement. The results of DFT and MM simulations indicate that the difference between chirality indices of adjacent shells of a multi-walled nanotube is the main factor that determines a possibility of the nanotube to be synthesized. The structure of zigzag 12-walled nanotubes with chirality indices difference 12 and 13, simulated by MM method and using the proposed force field, is the most close to the structure of experimentally detected nanotubes.

Numerous studies have demonstrated that the percentage of naïve T cells and diversity of T cell receptor (TCR) repertoire decrease with age, with some findings likewise suggesting that increased repertoire diversity may be associated with longer lifespan and healthy aging. In this work, we have analyzed peripheral TCR diversity from humans, mice, and blind mole-rats (Spalax spp.)—long-lived, hypoxia- and cancer-tolerant rodents. We employed a quantitative approach to TCR repertoire profiling based on 5’RACE with unique molecular identifiers (UMI) to achieve accurate comparison of repertoire diversity, which also required development of specific wet lab protocol and TCR gene reference for Spalax. Our direct comparison reveals a striking phenomenon. Whereas TCR diversity of mice and humans decreases with age, resulting primarily from the shrinkage of the naive T cell pool, Spalax TCR diversity remains stable even for the animals that reach extreme old age (15-17 years). This indicates that T cell immunity does not meaningfully age in long-lived rodents, at least in terms of the classical understanding of immunosenescence, which is associated with the accumulation of large numbers of memory clones. We suggest that the extraordinary longevity of Spalax may be attributable at least in part to the distinctive organization of their T cell immunity. Our findings should therefore encourage a close re-examination of the contribution of immunosenescence to life span in mammals.

Temperature dependence of the Young’s modulus of cylindrical single-wall nanotubes with zigzag and armchair chiralities and consolidated-wall nanotubes has been studied by the molecular mechanics method with the use of the atom–atom potential. The nanotubes have been obtained by rolling up of crystal layers (111) of TiO2 with fluorite structure. Calculations have been performed for isothermal conditions on the basis of calculating the Helmholtz free energy of the system. The dependence of the Helmholtz free energy of nanotubes on the period has been calculated in the quasi-harmonic approximation as a result of calculation of phonon frequencies. It has been shown that the temperature dependence of the stiffness of nanotubes is determined by their chirality, and some nanotubes exibit anomalous behavior of both the Young’s modulus and the period of unit cell with variation in temperature.

The article is devoted to the assessment of influence of budgetary restrictions and economic sanctions on investment policy of a region. The paper studies the bilateral negative effect on socio-economic development of regions from both the external sanctions and braking mechanism of economic development within the country. On the basis of the comparative and statistical analysis, the need to change focus of investment policy from the growth in volumes to qualitative perfecting is proved. The new direction of investment policy connected with the import substitution process realization, its combination with acceleration of innovative development on the certain example of Sverdlovsk region is analyzed. The conclusions and offers stated in the article are applicable to the public authorities of subjects of the Russian Federation, experts in the sphere of regional investment policy and improvement of investment climate, and also the specialized organizations specialized in attracting investment and work with investors in regions of Russia.

Objective. The risk of AS is associated with genomic variants related to antigen presentation and specific cytokine signalling pathways, suggesting the involvement of cellular immunity in disease initiation/progression. The aim of the present study was to explore the repertoire of TCR sequences in healthy donors and AS patients to uncover AS-linked TCR variants. Methods. Using quantitative molecular-barcoded 50-RACE, we performed deep TCR beta repertoire profiling of peripheral blood (PB) and SF samples for 25 AS patients and 108 healthy donors. AS-linked TCR variants were identified using a new computational approach that relies on a probabilistic model of the VDJ rearrangement process. Results. Using the donor-agnostic probabilistic model, we reveal a TCR b motif characteristic for PB of AS patients, represented by eight highly homologous amino acid sequence variants. Some of these variants were previously reported in SF and PB of patients with ReA and in PB of AS patients. We demonstrate that identified AS-linked clones have a CD8(+) phenotype, present at relatively low frequencies in PB, and are significantly enriched in matched SF samples of AS patients. Conclusion. Our results suggest the involvement of a particular antigen-specific subset of CD8+ T cells in AS pathogenesis, confirming and expanding earlier findings. The high similarity of the clonotypes with the ones found in ReA implies common mechanisms for the initiation of the diseases.

Tumor-targeted delivery of cytotoxins presents considerable advantages over their passive transport. Chemical conjugation of cytotoxic module to antibody is limited due to insufficient reproducibility of synthesis, and recombinant immunotoxins are aimed to overcome this disadvantage. We obtained genetically encoded immunophotosensitizer 4D5scFv-miniSOG and evaluated its photocytotoxic effect in vitro. A single-chain variable fragment (scFv) of humanized 4D5 antibody was used as a targeting vehicle for selective recognition of the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu) overexpressed in many human carcinomas. As a phototoxic module we used a recently described photoactivated fluorescent flavoprotein miniSOG. We found that recombinant protein 4D5scFv-miniSOG exerts a highly specific photo-induced cytotoxic effect on HER2/neu-positive human breast adenocarcinoma SK-BR-3 cells (IC50= 160 nM). We demonstrated that the 4D5scFv-miniSOG specifically binds to HER2-positive cells and internalizes via receptor-mediated endocytosis. Co-treatment of breast cancer cells with 4D5scFv-miniSOG and Taxol or junction opener protein JO-1 produced remarkable additive effects.

This paper reports the results of a classical molecular dynamics (CMD) study of molecular water adsorption on MO2- and SrO-terminated SrMO3 (001) surfaces (M = Ti, Zr) at 300 K with ½ ML and 1 ML coverage. Models of the force fields for the water–crystalline oxide interfaces have been proposed. These force fields describe the oxide–oxide, water–oxide and water–water interactions, as well as interactions within the water molecule itself. The water–water and flexible water intramolecular potentials have been adopted from Toukan and Rahman (Phys. Rev. B 31 (1985) 2643–2648). The results of CMD simulations of the structure of the water layers at the oxide surfaces are discussed in terms of the most probable configurations. The power spectra of the water hydrogen velocity autocorrelation functions have been calculated using the CMD trajectories. The calculated power spectra permit us to consider the vibrational modes of the different structural species formed by the water molecules at the oxide surfaces and to analyse the level of binding of these species, both between themselves and to the surface.

The accuracy with which DNA polymerase can replicate a template DNA sequence is an extremely important property that can vary by an order of magnitude from one enzyme to another. The rate of nucleotide misincorporation is shaped by multiple factors, including PCR conditions and proofreading capabilities, and proper assessment of polymerase error rate is essential for a wide range of sensitive PCR-based assays. In this paper, we describe a method for studying polymerase errors with exceptional resolution, which combines unique molecular identifier tagging and high-throughput sequencing. Our protocol is less laborious than commonly-used methods, and is also scalable, robust and accurate. In a series of nine PCR assays, we have measured a range of polymerase accuracies that is in line with previous observations. However, we were also able to comprehensively describe individual errors introduced by each polymerase after either 20 PCR cycles or a linear amplification, revealing specific substitution preferences and the diversity of PCR error frequency profiles. We also demonstrate that the detected high-frequency PCR errors are highly recurrent and that the position in the template sequence and polymerase-specific substitution preferences are among the major factors influencing the observed PCR error rate.

Single-molecule localization microscopy relies on either controllable photoswitching of fluorescent probes or their robust blinking. We have found that blinking of monomeric red fluorescent proteins TagRFP, TagRFP-T, and FusionRed occurs at moderate illumination power and matches well with camera acquisition speed. It allows for super-resolution image reconstruction of densely labelled structures in live cells using various algorithms.

The set of three pair atom–atom potentials for zirconia crystals and nano objects was developed. Besides Buckingham potential and Coulomb interaction, these force fields employ the additional functional forms: Fermi-Dirac, Inverse Gaussian or Morse potential. The developed force fields are capable to reproduce the structural, mechanical and thermodynamic properties of five zirconia phases: monoclinic, tetragonal, cubic, brookite and cotunnite with acceptable accuracy. The proposed force fields give monoclinic phase as a ground state structure and predict the correct energy ordering of the phases. The Raman and IR phonon frequencies, temperature dependencies of the thermodynamic properties of monoclinic and tetragonal zirconia are predicted in good and moderate agreement with the experimentally observed data and results of first-principles calculations. To test the transferability of proposed potentials, the zirconia-based nanosheets and nanotubes were simulated. Results of structure optimisation and calculation of the nanotubes’ strain energies are well compared with the corresponding data of the first-principles calculations.

Unique molecular identifiers (UMIs) show outstanding performance in targeted high-throughput resequencing, being the most promising approach for the accurate identification of rare variants in complex DNA samples. This approach has application in multiple areas, including cancer diagnostics, thus demanding dedicated software and algorithms. Here we introduce MAGERI, a computational pipeline that efficiently handles all caveats of UMI-based analysis to obtain high-fidelity mutation profiles and call ultra-rare variants. Using an extensive set of benchmark datasets including gold-standard biological samples with known variant frequencies, cell-free DNA from tumor patient blood samples and publicly available UMI-encoded datasets we demonstrate that our method is both robust and efficient in calling rare variants. The versatility of our software is supported by accurate results obtained for both tumor DNA and viral RNA samples in datasets prepared using three different UMI-based protocols.

Sterically hindered 2,4-disubstituted 3-(1,2,4-oxadiazol-3-yl)-, 3-(imidazol-2-yl)- and 3-(thiazol-2yl)pyridines were synthesized from the corresponding nicotinonitriles via amidoximes, amidines and thioamides, respectively. N-Alkyl- and N-arylamidines were prepared directly from nicotinonitriles using microwave technology. The series of 3-(azolyl)pyridines form a combinatorial library of heterocyclic derivatives of nicotinic acid and were examined by prognostic software PASS.

The diversity, architecture, and dynamics of the TCR repertoire largely determine our ability to effectively withstand infections and malignancies with minimal mistargeting of immune responses. In this study, we have employed deep TCRβ repertoire sequencing with normalization based on unique molecular identifiers to explore the long-term dynamics of T cell immunity. We demonstrate remarkable stability of repertoire, where approximately half of all T cells in peripheral blood are represented by clones that persist and generally preserve their frequencies for 3 y. We further characterize the extremes of lifelong TCR repertoire evolution, analyzing samples ranging from umbilical cord blood to centenarian peripheral blood. We show that the fetal TCR repertoire, albeit structurally maintained within regulated borders due to the lower numbers of randomly added nucleotides, is not limited with respect to observed functional diversity. We reveal decreased efficiency of nonsense-mediated mRNA decay in umbilical cord blood, which may reflect specific regulatory mechanisms in development. Furthermore, we demonstrate that human TCR repertoires are functionally more similar at birth but diverge during life, and we track the lifelong behavior of CMV- and EBV-specific T cell clonotypes. Finally, we reveal gender differences in dynamics of TCR diversity constriction, which come to naught in the oldest age. Based on our data, we propose a more general explanation for the previous observations on the relationships between longevity and immunity.

The bicanonical Monte-Carlo method allows effective computer simulation of free energy, entropy as well as internal energy of ion molecular clusters. The advantages of this method have been exploited to test how much adequately frequently applied pair interaction models reproduce not only energetics, but also statistical properties of the investigated ion–water clusters. In present paper, the series of reproductions of mass spectroscopy data on stepwise binding Gibbs energy, enthalpy and entropy of Ion(H 2 O) n , n = 1 ÷ 6 clusters for a set of monovalent ions has been carried out with the help of bicanonical Monte-Carlo technique. Each reproduction from the series has been performed using one of pair interaction ion–water plus water–water models, the experimental data on free energy, entropy as well as internal energy of ion molecular clusters. Based on the result of the simulations, the quantitative analysis of the investigated pair interaction models accuracy has been accomplished. The accuracy of the pair interaction ion–water plus water–water models has been compared with the accuracy of the one of polarizable models taking into account polarization of ions and water molecules explicitly.

High-throughput sequencing of T cell (TCR) receptor repertoires is a promising approach that can be used to characterize the state and dynamics of adaptive immunity and, potentially, to deduce the antigen specificity of the immune response [1].

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.