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Abstract Cellular senescence is considered an important tumour suppression mechanism in response to damage and oncogenic stress in early lesions. However, when senescent cells are not immune-cleared and persist in the tumour microenvironment, they can drive a variety of tumour-promoting activities, including cancer initiation, progression, and metastasis. Additionally, there is compelling evidence demonstrating a direct connection between chemo(radio)therapy-induced senescence and the development of drug resistance and cancer recurrence. Therefore, detection of senescent cells in tissues holds great promise for predicting cancer occurrence earlier, assessing tumour progression, aiding patient stratification and prognosis, and informing about the efficacy of potential senotherapies. However, effective detection of senescent cells is limited by lack of biomarkers and readout strategies suitable for in vivo clinical imaging. To this end, a nanoprobe composed of biocompatible polydopamine (PDA) nanoparticle doped with FDA-approved indocyanine green (ICG) dye, namely PDA-ICG, was designed as a contrast agent for senescence detection using photoacoustic imaging (PAI). In an in vitro model of chemotherapy-induced senescence, PDA-ICG nanoprobe showed an elevated uptake in senescent cells relative to cancer cells. In addition to its improved photostability, 2.5-fold enhancement in photoacoustic signal relative to ICG was observed. Collectively, the results indicate that the PDA-ICG nanoprobe has the potential to be used as a contrast agent for senescence detection of chemotherapy-induced senescence using PAI.

Infectious endocarditis is characterized by dysfunction of heart valves and contribute significantly to the cardiovascular morbidity and mortality worldwide, especially in low- and middle-income countries. Immune response is playing the important role in the pathophysiology of this disease. This work was aimed to study the local cytokine profile in native heart valves obtained from the patients with infectious endocarditis. Cytokine profiling were performed in biopsies of native heart valves explanted from 4 patients with infective endocarditis (experimental group) and 10 patients with rheumatic heart disease (comparison group) by dot blotting using the Proteome Profiler™ Human Cytokine Array Kit (ARY005B). The results of dot blotting were validated by the gene expression profiling using quantitative polymerase chain reaction. MIF, PAI-1, ICAM-1 and CXCL12 were found in the native heart valves explanted from both infective endocarditis and rheumatic heart disease patients. Upon a semi-quantitative assessment, the heart valves explanted from the infective endocarditis patients were characterized by 4-fold increased secretion of PAI-1 and twofold decreased secretion of ICAM-1 and CXCL12 compared to the heart valves ffected by rheumatic heart disease. MIF was expressed on similar levels in the both studied groups. IL-1ra, IL-6, IL-8, IL-16, CCL4, CCL5 and CXCL1 were detected only in heart valves affected by infectious endocarditis. At the gene expression level, MIF, IL6, IL8 genes were upregulated and PAI1, IL1RA, CXCL1 genes were downregulated in heart valves explanted from infectious endocarditis patients compared to the subjects affected by rheumatic heart disease. Native heart valves in cases of infectious endocarditis are characterized by nonspecific local inflammatory response associated with pathogenic bacteremia, along with active neovascularization. The data obtained can help to better understand fundamental pathogenetic mechanisms of infectious endocarditis.

Extracellular vesicles (EVs) show great potential for therapeutic delivery to human cells, with a focus on modulating immune responses. The most promising targets for inducing humoral and cellular immunity against a specific antigen are macrophages (Mϕs) and dendritic cells (DCs). Targeting mannose receptors (CD206), which are highly expressed on these antigen-presenting cells, to promote the presentation of specific antigens through EV-mediated uptake, is a promising strategy in clinical immunotherapy. Our study compares two EV-fused anti-CD206 nanobodies in delivering cargo proteins to human activated antigen-presenting cells. We demonstrated that nanobody-functionalized EVs exhibit enhanced interaction and increased uptake by CD206+ cells compared to non-targeted EVs. Furthermore, replacing the full-length vesicular stomatitis virus protein G (VSV-G) with its truncated form, fused to a monoclonal anti-CD206 nanobody, significantly improves the specificity of EV uptake by CD206+ cells. Our study outlines an optimized platform for the production of targeted EVs designed for specific protein delivery to CD206-positive human cells.

Abstract Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.

Abstract The Friendship Paradox is a simple and powerful statement about node degrees in a graph. However, it only applies to undirected graphs with no edge weights, and the only node characteristic it concerns is degree. Since many social networks are more complex than that, it is useful to generalize this phenomenon, if possible, and a number of papers have proposed different generalizations. Here, we unify these generalizations in a common framework, retaining the focus on undirected graphs and allowing for weighted edges and for numeric node attributes other than degree to be considered, since this extension allows for a clean characterization and links to the original concepts most naturally. While the original Friendship Paradox and the Weighted Friendship Paradox hold for all graphs, considering non-degree attributes actually makes the extensions fail around 50% of the time, given random attribute assignment. We provide simple correlation-based rules to see whether an attribute-based version of the paradox holds. In addition to theory, our simulation and data results show how all the concepts can be applied to synthetic and real networks. Where applicable, we draw connections to prior work to make this an accessible and comprehensive paper that lets one understand the math behind the Friendship Paradox and its basic extensions.

Aim. To characterize the association between cardiovascular risk factors and clinical and paraclinical variables with the severity of concomitant carotid and subclavian atherosclerosis in patients with acute coronary syndrome (ACS).Material and methods. Patients with ACS of any type, having obstructive coronary artery disease (CAD) confirmed by coronary angiography, underwent an ultrasound of the carotid and subclavian arteries with quantitative plaque assessment. The most important clinical, echocardiographic, angiographic and laboratory variables that contribute to atherosclerosis and/or affect the cardiovascular prognosis were evaluated. In patients with ACS considered ad the CAD onset, retrospective calculation of Systematic Coronary Risk Evaluation2 (SCORE2) score was performed.Results. A total of 312 patients aged 64 (56, 72) years (male, 69,2%) were studied. The detection rate of carotid/subclavian plaque was 86% and was higher in patients with more severe CAD — 79,4, 87,0, 92,6% in patients with 1-, 2- and 3-vessel disease respectively (p=0,027). However, 20% of patients with 2-/3-vessel CAD had no carotid/ subclavian atherosclerosis. Most of the traditional cardiovascular risk factors and other studied echocardiographic, angiographic, laboratory variables, as well as SCORE2 in patients with CAD onset did not demonstrate independent association with the severity of carotid/ subclavian atherosclerosis. The variability of the total plaque area (TPA) was explained by related multifactor regression model only to a small extent, R2=13%. Age (β 0,76, 95% CI 0,24-1,29, p=0,004), glomerular filtration rate (β -0,44, 95% CI -0,76 — -0,13, p=0,006); peripheral artery disease (β 19,50, 95% CI 1,63-37,37, p=0,033) demonstrated a significant independent association with TPA.Conclusion. In patients with ACS, only age, glomerular filtration rate and history of peripheral artery disease demonstrated the independent associations with carotid/subclavian atherosclerotic burden. Assessed variables explained 13% of TPA variability.

The phylum Actinobacteria includes important human pathogens like Mycobacterium tuberculosis and Corynebacterium diphtheriae and renowned producers of secondary metabolites of commercial interest, yet only a small part of its diversity is represented by sequenced genomes. Here, we present 824 actinobacterial isolate genomes in the context of a phylum-wide analysis of 6,700 genomes including public isolates and metagenome-assembled genomes (MAGs). We estimate that only 30%-50% of projected actinobacterial phylogenetic diversity possesses genomic representation via isolates and MAGs. A comparison of gene functions reveals novel determinants of host-microbe interaction as well as environment-specific adaptations such as potential antimicrobial peptides. We identify plasmids and prophages across isolates and uncover extensive prophage diversity structured mainly by host taxonomy. Analysis of >80,000 biosynthetic gene clusters reveals that horizontal gene transfer and gene loss shape secondary metabolite repertoire across taxa. Our observations illustrate the essential role of and need for high-quality isolate genome sequences.

Introduction. It is proposed to optimize the time of highly qualified engineers working with a building information model (BIM) during the correction of intersection collisions due to mathematical determination of importance of an element in intersection collisions.Materials and methods. The method of frequency analysis is taken as a basis, using the quality coefficient of BIM. The quality coefficient of BIM is determined based on the data about the BIM itself: number of elements, objects and collisions. The calculated coefficients influence the results obtained using the frequency analysis method. As a result, unique values of importance weights for BIM elements are obtained.Results. The weights of the elements found during the study are sorted in descending order, the first 20 % of the elements with the highest weight are the load-bearing structures, indicating that fixing collisions involving them should be a priority. The priority of correcting collisions involving other non-bearing elements of the BIM can be determined by assigning weights to them based on the elements involved in collisions.Conclusions. The results of the study will help to assign priority to the intersection collisions found. This, in turn, will allow highly qualified engineers to fix the most important intersection collisions in a priority order, thereby using their time more efficiently. The resulting element weights can be applied by exporting the collisions found in the project to a tabular data format. Using tabular editors and pivot table functions, you can assign weights to elements and sort collisions.

The possibility of using the universal software ANSYS to study the concentration of interlaminar stresses near the free edges of laminated composites in a two-dimensional finite element formulation is considered. In this case, the cross-section of a rectangular four-layer composite plate of finite width with free side edges subject to uniform axial deformation is simulated. To create it, an original technique is proposed which consists in using thermal stress. The presented calculation results are in good agreement with the results of other authors.

This work considers numerical modeling of the stress-strain state of a homogeneous rectangular thin plate after a thermal shock. The presented solution is implemented in the finite element (FEM) package ANSYS Mechanical APDL 2020 R2. The task to be considered is a two-dimensional problem with the initial deflection of the plate. It is considered that the plate is cantilevered only at one end, but the other three edges are free. At the moment of a temperature shock, the plate acquires a curved shape. Within the framework of the heat conduction problem, two heat flows are taken into account. The first flow goes from the surface layer subjected to thermal shock deep into the plate. The second flow spreads parallel to its longitudinal axis. This axis is perpendicular to the plate embedding line. The dependencies of the temperature field of the plate are built. A comparative analysis was carried out with approximate analytical dependencies obtained in other works. The dependencies of the projections of the displacement vector of the plate points are obtained only in the case when the longitudinal displacement is small. There is also an analysis of the applicability of the results for practical purposes. For example, it is proposed to use the results obtained to assess the significance of the impact of thermal shock of solar panels on the motion of a small satellite.

Introduction. The application of information modelling (BIM) and augmented reality (AR) technologies at the stage of construction and subsequent operation of capital construction facilities (CCF) is analyzed.Materials and methods. Potential possibilities of optimization of work of installation and construction teams or carrying out of project expertise using information modelling (BIM) technologies are shown. Due to the application of this technology: the terms of installation works at the construction site are reduced (as a result, costs are reduced and labour efficiency is increased); the terms of the project expertise are reduced (at the stage of construction object commissioning). The main idea is to combine BIM technology at the construction stage and augmented reality technology. Combination of these technologies will make it easier to identify deviations from the project and reduce the labour intensity of installation works.Results. The proposed information tables for visualization of elements of the information model of the construction object and the key principles of their filling with data on the example of a pipeline on the basis of given points of the constructed three-dimensional model are of great importance for the construction practice. Examples of AR application at the operation stage on the example of a water meter and an electric meter are considered.Conclusions. Types and content of information visualization tables of the main pipeline are formulated and determined on the basis of which the construction of a three-dimensional model of the pipeline at the construction stage of the facility is carried out. An example of the content of the information table of visualization of individual elements of the information model of the construction object at the operational stage is given on the example of a water and electric meter. The directions of further research are given.

The virions of plant viruses and their structurally modified particles (SP) represent valuable platforms for recombinant vaccine epitopes and antitumor agents. The possibility of modifying their surface with biological compounds makes them a tool for developing medical biotechnology applications. Here, we applied a new type of SP derived from virions and virus-like particles (VLP) of Alternanthera mosaic virus (AltMV) and well-studied SP from Tobacco mosaic virus (TMV). We have tested the ability of SP from AltMV (AltMV SPV) and TMV virions also as AltMV VLP to bind to and penetrate Ewing sarcoma cells. The adsorption properties of AltMV SPV and TMV SP are greater than those of the SP from AltMV VLP. Compared to normal cells, AltMV SPV adsorbed more effectively on patient-derived sarcoma cells, whereas TMV SP were more effective on the established sarcoma cells. The AltMV SPV and TMV SP were captured by all sarcoma cell lines. In the established Ewing sarcoma cell line, the effectiveness of AltMV SPV penetration was greater than that of TMV SP. The usage of structurally modified plant virus particles as a platform for drugs and delivery systems has significant potential in the development of anticancer agents.

Despite the achievements of modern cardiology, the cardiovascular morbidity and mortality in most countries of the world remains high, which motivates the wider use of additional (alternative) preventive and therapeutic approaches, one of which is hypoxytherapy. Over several decades of using this method, a large amount of data has been accumulated that allows us to state the beneficial effect of various hypoxytherapy regimens on the clinical course of cardiovascular diseases and can potentially improve prognosis of them. The use of hypoxytherapy is associated with an improvement in blood pressure circadian rhythm, flow-dependent vasodilation, an insulin resistance decrease, a vascular wall stiffness redaction, an improvement in blood rheology, endothelial function and nitric oxide system, a decrease of proinflammatory and prothrombotic cytokines levels. A number of modern experts consider hypoxytherapy as an affordable and perspective method of prevention and treatment of cardiovascular disease, effectively supporting traditional non-drug and drug-based approaches. Contemporary data indicate serious future perspectives for an expanded study of the hypoxytherapy possibilities in cardiac patients, including through the State research programmes. This review is devoted to the discussion of the physiological effects of hypoxytherapy, the possibilities of its application in cardiological practice, including with the analysis of own data, as well as precautions during its implementation.

The failure of heart valve bioprostheses, requiring repeated intervention to replace them, is a serious drawback that narrows the scope of such devices. The present study demonstrates the experimental investigation of a medical device designed to partially solve the problem of repeated interventions on heart valves, primarily with an emphasis on reducing the duration and trauma of such procedures due to the sutureless balloon implantation method of the «valvein- valve» method.Material and methods. The paper presents a series of in silico, in vitro and in vivo experiments to evaluate various aspects of the device under development. Numerical modeling of the final shape setting to the supporting frame of the heart valve prosthesis to select the most promising concept for prototyping was carried out in the Abaqus/CAE (Dassault Systèmes, France) based on the finite element method. The selected optimal support frame model was prototyped in the form of a series of prosthesis samples of four standard sizes for hydrodynamic studies of quantitative characteristics in vitro. The study was carried out in the Vivitro Labs unit (Vivitro Labs, Canada), imitating the physiological mode of the heart, the prostheses were examined for the mitral position. The developed prototypes of the device were supplemented with related products, an implant holder and a balloon catheter, after which the proposed method of sutureless fixation was validated in an in vitro implantation procedure on a bovine heart model and a series of in vivo (n = 3) chronic experiments on animals.Results. In the course of numerical simulation, it was shown that in Model No. 3 of the supporting frame of the prosthesis, the smallest stresses occur – with an amplitude of up to 490 MPa. For other concepts (Models No. 1 and No. 2), this indicator was significantly higher, 543 and 514 MPa, respectively. Prototypes obtained on the basis of the selected shape of the support frame demonstrated satisfactory hydrodynamic characteristics: effective hole area 190-261 mm2, regurgitation volume 6–9 ml/cycle, average transprosthetic gradient 4.4–6.4 mmHg, depending on size. The study of the technology of sutureless balloon implantation in an in vitro model of the heart and the subsequent chronic experiment on sheep confirmed the main idea of the system – the possibility of a significant reduction in the duration of repeated prosthetics. It has been shown that the time of suture implantation of the “classic” frame prosthesis of the mitral valve is 23–29 minutes, with a total access time of 41–52 minutes. When implanting the experimental device, the sutureless prosthesis itself took 4–6 minutes, access time 24–29 minutes. At the same time, one-month results of an echocardiographic study of the operation of the prosthesis demonstrated satisfactory hemodynamics.Conclusions. This work demonstrates a consistent series of tests of the system being developed for repeated heart valve replacement, which substantiates some design solutions, confirms the effectiveness and viability of the chosen approach to sutureless minimally invasive implantation.

In the planar hydraulics, the problems with previously unknown boundaries are most difficult. The best adequacy in terms of flow parameters is provided by simplified analytical methods based on a potential flow model. A mathematical model of a stationary, potential, 2D planar high-velocity open water flow of an ideal fluid, freely spreading back from a non-pressure orifice is studied. The boundary problem of flow free spreading in plane were formulated. Studying the system of dimensionless equations of motion resulted in identification of the criteria influencing the process of flow spreading. A critical analysis was carried out and a description of various methods for solving the problem of free spreading of a high-velocity water flow was given. The problem in an analytical form was solved in the velocity hodograph plane. All flow parameters are determined in the physical plane. For the first time, the conjugating flow "simple wave" was applied. The proposed analytical method for solving the problem of flow free spreading is effective, unambiguous and has no singularities and discontinuities, particularly, at the outlet of a non-pressure pipe. The adequacy of the mathematical model was verified on a test example. The relative error of the flow parameters does not exceed 10 % compared to the experimental data.