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The aim: to study the indices of stress-deforming state of biomechanical system «bone — hybrid anchor» in proximal humerus fractures. Material and Methods. The study of anchorage stiffness in juxta-articular fracture (type 11A3 by AO/ASIF) through applying three load types: axial (200 N), transverse (30 N) and torsional (5 N*m) was conducted followed by CAD modeling in SolidWorks and the analysis of stress-deforming state of the system «bone — anchor». Results. While studying the stability of «bone — anchor» system it was found that a new device for proximal humerus fracture ostheosynthesis under the applied loads do not decompose with maximal translocations of bone fragments and maximums of equivalent stress being present under torsional load and comprise 1.6 mm. and 152 Mpa respectively. Conclusion. The application of hybrid devices for juxta-articular fractures of humerus allows carrying out minimally traumatic anchorage with the following early functionality of the injured segment.

The aim: to identify the efficiency of the improved technology of treatment of tibia marginal defects with the use of granular composite osteoplastic materials during external fixation of fragments. Material and Methods. The observation group was made up of 12 patients with the consequences of lower extremity traumas who had undergone osteosyn-thesis of fractures by an external fixation device with defect alloplasty We used clinical and ray-tracing testing methods and also standardized system of assessment of outcomes of bone fractures and their consequences to control the processes of restoration of bone structure integrity. Results. According to the standardized system of assessment of outcomes in 12-18 months in the course of the rehabilitation measures degree of restoration of anatomic functional indices was 92±5%. Bone density made up 91,3±0,54 HU (p

The study aimed to improve the efficiency of detecting and mapping felling using satellite imagery, in order to identify violations of environmental regulations. Traditional remote sensing data interpretation methods are labor-intensive and require high operator expertise. To automate the satellite image interpretation process, numerous approaches have been developed, including those leveraging advanced deep machine learning technologies. The presented work conducted a comparative analysis of convolutional and transformer neural network models for the segmentation of felling in summer Sentinel-2 satellite imagery. The convolutional models evaluated included U-Net++, MA-Net, 3D U-Net, and FPN-ConvLSTM, while the transformer models were SegFormer and Swin-UperNet. A key aspect was the adaptation of these models to analyze pairs of multi-temporal, multi-channel satellite images. The data preprocessing, training sample generation, and model training and evaluation procedures using the F1 metric are described. The modeling results were compared to traditional visual interpretation methods using GIS tools. Experiments on the territory of the Khanty-Mansiysk Autonomous Okrug showed that the F1 accuracy of the different models ranged from 0.409 to 0.767, with the SegFormer transformer model achieving the highest performance and detecting felling missed by human interpretation. The processing time for a 100 × 100 km2 image pair was 15 minutes, 16 times faster than manual methods — an important factor for large-scale forest monitoring. The proposed SegFormer-based felling segmentation approach can be used for rapid detection and mapping of illegal logging. Further improvements could involve balancing the training dataset to include more diverse clearing shapes and sizes as well as incorporating partially cloudy images.

Introduction: The study of the competitive environment in the pharmaceutical market is an element of the analysis of the drug supply system. The purpose of the study is to analyze the dynamics of concentration levels in the wholesale segment of the regional pharmaceutical market. Materials and methods: Data on market shares of key players were collected and summarized based on the executed contracts (461 contracts in total) for the supply of pharmaceutical products in the model region. For the competitive analysis of pharmaceutical distributors, the Herfindahl-Hirschman Index (HHIn) calculation method was used. We also used the method of constructing the SV matrix, which has the form of a graph consisting of four quadrants divided on the abscissa scale by the obtained values of market concentration ratios (CRSV) and on the ordinate scale by the values of Hall-Teidman indices (HTSV). Results: Market concentration indicators in the wholesale segment of the regional pharmaceutical market indicate the formation of oligopoly. The constructed SV matrix demonstrated the dynamics of market concentration levels corresponding to the changing economic situation. Based on the results of the analysis, proposals to improve the competitiveness of regional pharmaceutical distributors were formed. Conclusion: The study of the dynamics of market concentration indicators allowed to analyze their state, establish the vectors of their drift, and propose measures to optimize the wholesale supply of pharmaceutical goods.

AIM OF STUDY. The study was aimed to evaluate the effectiveness of treating acute pancreatitis by early enteral nutrition and selective introduction of nutritional mixtures directly into the initial sections of the jejunum, bypassing the duodenum.MATERIAL AND METHODS. A comprehensive treatment method for acute pancreatitis was developed based on the use of a pancreatoduodenal catheter. The method focuses on preventing intestinal failure syndrome by isolating the duodenum and preventing any liquid from entering it while ensuring the selective introduction of glucose-saline solutions and/or enteral nutritional mixtures directly into the initial sections of the jejunum. Several Russian clinics are currently conducting the research approved by local ethics committees. This article presents preliminary results from the data analysis. The study included moderate to severe forms (according to the 2012 Atlanta classification) of acute biliary pancreatitis without indications for endoscopic retrograde cholangiopancreatography, as well as alimentary-alcoholic pancreatitis. The first group of patients received standard therapy according to the 2020 clinical guidelines of the Russian Society of Surgeons. The second group received standard therapy combined with the new selective enteral nutrition method. The observation period lasted until the end of the hospital treatment, including five mandatory visits and a final visit to the physician. A follow-up survey was conducted three months or more after discharge to identify delayed episodes of acute pancreatitis complications, focusing on the incidence of infectious complications and surgical interventions.RESULTS. A total of 148 patients were treated. Patients were evenly distributed by etiology, gender, age, and body mass index. The analysis revealed that the number of patients with infectious complications decreased from 19.3% in the comparison group to 6.67% in the study group (p=0.041). The number of patients requiring surgical interventions was 5.0% in the study group compared to 19.3% in the comparison group (p=0.017).CONCLUSIONS. The study demonstrated that the use of the new method in the comprehensive treatment of acute pancreatitis, including early enteral feeding at the onset of the disease, may improve the course of the disease by reducing the incidence of infectious complications and the number of necessary surgical interventions.

Keratins 6, 16, and 17 occupy unique positions within the keratin family. These proteins are not commonly found in the healthy, intact epidermis, but their expression increases in response to damage, inflammation, and hereditary skin conditions, as well as cancerous cell transformations and tumor growth. As a result, there is an active investigation into the potential use of these proteins as biomarkers for different pathologies. Recent studies have revealed the role of these keratins in regulating keratinocyte migration, proliferation, and growth, and more recently, their nuclear functions, including their role in maintaining nuclear structure and responding to DNA damage, have also been identified. This review aims to summarize the latest research on keratins 6, 16, and 17, their regulation in the epidermis, and their potential use as biomarkers in various skin conditions.

Introduction. The article discusses the current state of the possibilities to improve the efficiency of construction processes by using fibre-reinforced concrete in the construction of transport and utility tunnels, as well as other critical building structures. The authors present foreign experience with widespread use of fibre-reinforced concrete in transport construction, as well as few such cases for domestic practice. The inconsistency of domestic experience with the modern state of art has been noted. The main blockers in the development of the issue are under consideration, the theoretical approach and practical application are presented. Materials and methods. The principal aspects of the current approach to the quality indicators of fibre-reinforced concrete and the classification principles of fibre-reinforced concrete based on quality criteria, which are the basis for the normalization of material characteristics, are described. The continuity of domestic and European regulatory documents is shown. Results. Illustrated examples of the possibilities of an optimization approach to the selection of structural solutions in the design of transport construction facilities used in international practice are described. Conclusion. The argumentation in favor of technology development is shown. This opens up possibilities for significant cost reduction justified by a scientific approach. In conclusion, the authors provide recommendations on the general application of the promising material in the domestic practice

The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

The paper describes an algorithm for the design of axial and radial-axial type turbines. The algorithm is based on using mathematical models of various levels of complexity – from 1D to 3D. Flow path geometry is described by means of analytical methods of profiling using a limited number of parameters. 3D turbulent flow model is realised in the program complex IPMFlow, developed based on the earlier codes FlowER and FlowER-U. Examples of developed or modernized turbines for differentpurpose power machines are presented. They are: an expansion turbine, ORC turbine and cogeneration mediumpressure turbine.

The article deals with new treatment technique in fractures of shin bones. It combines ideal reduction of damaged bone with reposition device without transition of transosseous elements through muscular masses, adequate fixation of bone fragments and change of biomechanical efforts in apparatus according to reparative osteogenesis phases. It is performed due to application of external fixation apparatus

BACKGROUND: Time in range (TIR) is a promising indicator of glycemic control used for evaluation of continuous glucose monitoring (CGM) for patients with diabetes mellitus (DM). The current problem is the assessment and prediction of TIR for patients who use self-monitoring of blood glucose (SМBG) corresponding low CGM availability for the majority of diabetic patients.AIM: To develop a predictive model of TIR for patients with T1DM based on data of the experimental mobile application.MATERIALS AND METHODS: An analysis of 1253 professional CGM profiles of patients with T1DM was performed. On the base of included records, TIR(CGM) was calculated and training models of 7-point SMBG profiles were generated. SMBG profiles’re loaded into the developed experimental mobile application that calculated standard glycemic control parameters. The dataset was divided into main and test samples (80 and 20%). For the main sample, the following methods’re used to develop predictive models: simple linear regression (SLR), multiple linear regression (MLR), artificial neural network (ANN). The effectiveness of the developed models was assessed on the test sample with the calculation of the mean absolute error (MAE), the root mean square error (RMSE).RESULTS: The 568 CGM profiles’re included in the study. TIR in the main group (n=454) — 45 [33; 65]%, in the test group (n=114) — 43 [33; 58]%. The most significant predictors of the regression models were the derived TIR (dTIR), p

The aim: is to compare short-term results of home-based and outpatient programs of physical therapy among patients with frozen shoulder and concomitant thoracic myofascial pain syndrome. Materials and methods. The study involved 80 patients. The range of motion in the shoulder joint affected by capsulitis was assessed. A numerical pain scale was used to assess pain sensations when pressing on trigger points. Functional limitations in the shoulder were measured by means of the Oxford Shoulder Score (before and 1.5 months after the end of the physical therapy). Participants were divided into two groups: home-based group (HG) and outpatient group (ОG). All the patients were consulted by a physical therapist. ОG patients received end-range mobilization with the assistance of a physical therapist 5 times a week to improve shoulder joint mobility. Most of ОG participants received 15 procedures (3 weeks). Patients HG performed therapeutic exercises without any assistance at home. (twice a day, 3 weeks). In terms of trigger points therapy, the patients performed ischemic compression without any assistance. Results. Patients of both groups demonstrated positive dynamics of the studied indicators. Comparison of the short-term results of the therapy according to range of motion and pain showed better indicators in the ОG. Comparison of the initial results of the groups in Oxford Shoulder Score items did not reveal any significant differences. Total score was 18.2±6.5 points in ОG and 17.6±7.5 points in HG (p=0.715). Me (25%; 75%) values were 17.5 (12.5; 23.8) and 18 (13; 23.5) points, respectively. Comparison of the final results of the groups in Oxford Shoulder Score items revealed significant differences. Total score was 47 (47; 48) points in ОG and 33 (31; 35.75) points in HG (p

Abstract The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4–6 nM IC50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in the open configuration. Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi.

The thermal scheme of a power generating plant with a remote heat exchanger operating according to the Brayton cycle with energy recuperation is considered. It is assumed that the plant will work on non-certified (cheap) biofuel. It is shown that, in contrast to the usual Brayton cycle, in the cycle with energy recuperation, the greatest influence on the thermal efficiency is the heating temperature of the working medium and the internal efficiency of the main components of the plant, such as the compressor and the turbine. Also, in contrast to the usual Brayton cycle, a higher efficiency of the plant is achieved with smaller degrees of pressure reduction (increase) in the turbine (compressor). It was established that even at a relatively low temperature of the working medium heating (500 ºC), with high efficiency of the compressor and turbine, it is possible to achieve good characteristics of the power plant as a whole. At a temperature of up to 850 ºC, a thermal efficiency of 40% is achieved, but in this case the cost of materials and production increases. For a final conclusion about the possibility of using the proposed plant and its efficiency, it is necessary to conduct additional studies, in particular, of its main elements, such as a compressor, turbine, heat exchanger and others.

Approximately 50% of tumors carry mutations in TP53; thus, evaluation of the features of mutant p53 is crucial to understanding the mechanisms underlying cell transformation and tumor progression. HaCaT keratinocytes represent a valuable model for research in this area since they are considered normal, although they bear two gain-of-function mutations in TP53. In the present study, transcriptomic and proteomic profiling were employed to examine the functions of mutant p53 and to investigate the impact of its complete abolishment. Our findings indicate that CRISPR-mediated TP53 knockout results in significant changes at the transcriptomic and proteomic levels. The knockout of TP53 significantly increased the migration rate and altered the expression of genes associated with invasion, migration, and EMT but suppressed the epidermal differentiation program. These outcomes suggest that, despite being dysfunctional, p53 may still possess oncosuppressive functions. However, despite being considered normal keratinocytes, HaCaT cells exhibit oncogenic properties.

Background. Pancreatic head cancer ranks 6–7th among oncologic diseases and 4–5th among causes of mortality, with only 5% of patients achieving 5-year survival rate to date. Despite the successes of modern diagnostics and surgical treatment, the problem of early detection, staging of oncologic process and, as a consequence, combined treatment of pancreatic head cancer remains actual.Objective: increasing the accuracy of diagnostics and estimation of resectability of the pancreatic head cancer on the basis of the complex use of the radiation methods of investigation with pancreaticoduodenal zone 3D-reconstructions.Material and methods. The study included 93 patients (44 (47.31%) males and 49 (52.69%) females) with complicated pancreatoduodenal masses treated from 2019 to 2022 at the Surgical Department of the City Mariinsky Hospital. The patients’ age varied from 44 to 90 years, the mean age was 67±0.74 years. All patients underwent magnetic resonance imaging (MRI) on an Ingenia MR tomograph (Philips Medical Systems, Netherlands) with a magnetic field induction of 3 Tesla. The native examination of the abdomen and retroperitoneum, supplemented with MR-cholangiopancreatography protocol, and dynamic contrast enhancement with data collection in arterial, portal, and delayed phases were carried out. T2-weighted images were then performed using turbospin-echo technology, including fat-suppressed images, to evaluate structural changes and the presence of fluid in fascial spaces. Patients also underwent endoscopic ultrasound of the pancreaticoduodenal zone using the push and pull method, and abdominal multislice computed tomography (MSCT). To build 3D models, we used free 3D-slicer and Mimics programs, which allowed to build semi-automatic model for further evaluation of anatomo-topographic relations.Results. MSCT 3D modeling revealed tumor invasion into the superior mesenteric vein in 6 (23.06%) patients, whereas MRI models showed tumor invasion in 4 (15.38%) patients, intraoperatively the results were confirmed in 5 patients (19.23%). According to both MSCT and MRI modeling data, the invasion of the ventral trunk occurred in 1 (5.2%) case, which was confirmed intraoperatively. Inferior vena cava invasion on MSCT and MRI models was detected in 3 (11.54%) patients, whereas intraoperatively – in 4 (15.38%) patients. The MSCT and MRI 3D models coincided with the data on invasion of the ventral trunk in 1 (3.85%) patient and the superior mesenteric artery in 2 (7.69%) patients, which was fully confirmed intraoperatively.Conclusion. 3D modeling on the basis of MRI and MSCT studies is an informative method in preoperative staging of pancreatic head cancer and its resectability. This method allows to objectively determine the localization and prevalence of the tumor process on adjacent anatomical structures, as well as visually demonstrate the metastatic lesion of regional lymph nodes. By the parameters of diagnostic efficiency, 3D models are maximally close to the intraoperative picture, which allows planning both the volume and the course of surgical intervention.

Purpose of the study. Сomparing and evaluating the prognostic potential of the CORONET online risk assessment tool and the Charlson Comorbidity Index in predicting mortality in cancer patients with COVID-19.Materials and methods. The results are drawn from the data of 168 case histories of cancer patients who were undergoing inpatient treatment for COVID-19 at the University Clinical Hospitals of Sechenov University between March 2020 and February 2022. The study was conducted as part of the program of the world-class research center “Digital Biodesign and Personalized Healthcare” of Sechenov University, with participation in the ESMO-CoCARE Registry project. Patients with a history of solid or hematologic malignancies were included in the study; their treatment period before the study was 5 years or less. The age ranged from 37 to 100 years, the median age was 69 years. The CORONET online risk assessment tool and the Charlson comorbidity index were used to objectify the severity of multimorbidity status and prognosis of fatal outcomes in cancer patients with COVID-19.Results. It was demonstrated that statistically significant effects on the prognosis of mortality in patients with cancer were: age, percentage of saturation on admission, treatment in intensive care units (ICU), National Early Warning Score 2 (NEWS2) distress syndrome severity scale score, computed tomography (CT) assessment of disease course severity, decreased blood albumin and platelet counts, and increased blood neutrophil counts in both categorical and immediate indicator value formats. In addition, it was determined that as the number of comorbidities increased, the probability of mortality increased significantly, odds ratio (OR) = 2.162 (CI 95 % 1.016–4.600; p = 0.045). The CORONET calculator score yields one of the highest OR values among all established statistically significant predictors, 20.410 (CI 95 % 4.894–85.113; p < 0.001). For oncopathology in COVID-19 patients, the Charlson index score shows statistical significance as a predictor of mortality, OR =1.396 (CI 9 5 % 1.105–1.765; p = 0.005).Conclusion. The obtained advantages in using the CORONET online decision support tool over the Charlson comorbidity index in predicting mortality in cancer patients with COVID-19 are recognized as convincing.

Aim. Evaluation of comorbid pathology in SARS-CoV-2 infected in cancer practice as a predictor of severe outcomes. Testing the COVID-19 risk assessment tool in oncology (CORONET), to predict the likely severity of COVID-19 course in cancer patients on inpatient treatment. Materials and methods. A retrospective analysis of 173 cancer patient disease stories was conducted. The study was conducted as part of the program of the World-Class Research Center “Digital Biodesine and Personalized Health Care” of the University of Sechenov, with participation in the ESMO-CoCARE Register project. Based on the ESMO COVID-19 and CAncerREgistry (ESMO-CoCARE) registry, taking into account the entered our patient sample (n=173), a COVID-19 risk assessment tool in oncology (CORONET) was developed. Results. Cancer patients with comorbid pathology have been shown to have an increased risk of COVID-19 course of the disease from this sample by CORONET (mean conclusion score CORONET 2.44 pointsseverity). Prognosis of probable severity of outcomes in cancer patients infected with SARS-CoV-2 depends on associated diseases. The presence of a history of ≥3 comorbid pathologies in COVID-19 patients was detected in 106 people (61.27%). 15 patients were included in the risk of severe course. Retrospective analysis obtained actual confirmation of the prognosis of severe course of the disease in this group followed by death in all these patients (71.42% of all deaths). Indicators such as low albumin levels, high levels of C-reactive protein and neutrophils showed high prognostic significance of the likely severity of coronavirus infection in cancer patients on inpatient treatment for COVID-19. The mortality rate of patients admitted with COVID-19 and cancer was 12.14%. Conclusion. The most informative predictors of severe outcomes in COVID-19 in inpatient cancer patients to assess the prognosis of disease severity are: number of comorbidities, age, NEWS2 scale, ECOG patient activity status, albumin level, C-reactive protein level and absolute neutrophil level. The benefits gained in the use of the online decision support tool CORONET are considered convincing not only during the decision-making phase of hospitalization, but also in cancer patients on inpatient treatment.

Background: Alzheimer’s disease (AD) develops as a result of oxidative damage to neurons and chronic inflammation of microglia. These processes can be influenced by the use of a conditioned medium (CM) derived from mesenchymal stem cells (MSCs). The CM contains a wide range of factors that have neurotrophic, antioxidant, and anti-inflammatory effects. In addition, the therapeutic potential of the CM can be further enhanced by pretreating the MSCs to increase their paracrine activity. The current study aimed to investigate the neuroprotective effects of CM derived from MSCs, which were either activated by a TLR3 ligand or exposed to CoCl2, a hypoxia mimetic (pCM or hCM, respectively), in an in vitro model of AD. Methods: We have developed a novel in vitro model of AD that allows us to investigate the neuroprotective and anti-inflammatory effects of MSCs on induced neurodegeneration in the PC12 cell line and the activation of microglia using THP-1 cells. Results: This study demonstrates for the first time that pCM and hCM exhibit more pronounced immunosuppressive effects on proinflammatory M1 macrophages compared to CM derived from untreated MSCs (cCM). This may help prevent the development of neuroinflammation by balancing the M1 and M2 microglial phenotypes via the decreased secretion of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased secretion of IL-4, as well as the expression of IL-10 and TGF-β by macrophages. Moreover, a previously unknown increase in the neurotrophic properties of hCM was discovered, which led to an increase in the viability of neuron-like PC12 cells under H2O2-induced oxidative-stress conditions. These results are likely associated with an increase in the production of growth factors, including vascular endothelial growth factor (VEGF). In addition, the neuroprotective effects of CM from preconditioned MSCs are also mediated by the activation of the Nrf2/ARE pathway in PC12 cells. Conclusions: TLR3 activation in MSCs leads to more potent immunosuppressive effects of the CM against pro-inflammatory M1 macrophages, while the use of hCM led to increased neurotrophic effects after H2O2-induced damage to neuronal cells. These results are of interest for the potential treatment of AD with CM from preactivated MSCs.

Origanum vulgare ssp. hirtum essential oil (OEO) is a natural oil with high therapeutic potential. For some applications, however, the development of novel formulations is still needed to improve the bioavailability and stability of OEO. In this study, we describe the fabrication of an original nanocomposite hydroxypropyl cellulose (HPC) physical hydrogel, containing OEO-loaded polymeric micelles, for topical delivery. The concentration of the main active compounds of OEO—carvacol and thymol—was determined using gas chromatography (GC) analysis. OEO was first encapsulated into Pluronic F127 micelles, and then embedded into HPC gel. Micellar and gel formulations of pure polymers and OEO-containing systems were characterized by dynamic light scattering (DLS) and rheology measurements, respectively. Selected formulations were evaluated for cytotoxicity and antiproliferative activity. The hydrogel formulation of HPC with micellar OEO (8% HPC, 2% F127, 1% OEO) exhibited sustained release of the oil and selectivity towards SH-4 tumor cells (an in vitro model of melanoma).

AbstractThe present study aimed to evaluate the genetic diversity and differentiation of Pinus nigra Arnold, the European black pine, populations located in protected forested areas in three countries from the Balkan and Mediterranean region: Bulgaria, Greece, and Cyprus. Totally, 175 DNA samples from P. nigra plants collected from eight populations in these countries were analyzed using three SRAP primer pairs. The applied SRAP markers demonstrated high-resolution power, resulting in the identification of an average of 215 ± 67 polymorphic loci per SRAP primer pair. The analysis of molecular variance (AMOVA) showed that 82% of the observed variation was due to intra-population variation, while 18% was due to inter-population variation. The overall analysis of the population structure suggested low (Fst ≤ 0.01) intra-country differentiation for the populations from Bulgaria and Cyprus and moderate (0.15 ≤ Fst ≤ 0.17) inter-country differentiation. On the contrary, high differentiation between the populations (0.06 ≤ Fst ≤ 0.20) and complex genetic structure were characteristic of the three populations from Greece, relatively closely located in the area of the Pindos National Park. Analysis of the population structure also revealed that one of the Pindos populations belonged to the cluster of Bulgarian populations (Fst ≤ 0.01), showing moderate (Fst ≤ 0.11) to high (Fst ≤ 0.20) genetic differentiation from the other analyzed Pindos populations. The further use of SRAP markers for mapping the genetic diversity among P. nigra populations and identification of local populations diverted from the overall phylogeography-driven pattern in the studied region are discussed.

Abstract Background Mesenchymal stromal cells (MSCs) have regenerative and immunomodulatory properties, making them suitable for cell therapy. Toll-like receptors (TLRs) in MSCs respond to viral load by secreting immunosuppressive or proinflammatory molecules. The expression of anti-inflammatory molecules in MSCs can be altered by the concentration and duration of exposure to the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)). This study aimed to optimize the preconditioning of MSCs with poly(I:C) to increase immunosuppressive effects and to identify MSCs with activated TLR3 (prMSCs). Methods Flow cytometry and histochemical staining were used to analyze MSCs for immunophenotype and differentiation potential. MSCs were exposed to poly(I:C) at 1 and 10 μg/mL for 1, 3, and 24 h, followed by determination of the expression of IDO1, WARS1, PD-L1, TSG-6, and PTGES2 and PGE2 secretion. MSCs and prMSCs were cocultured with intact (J−) and activated (J+) Jurkat T cells. The proportion of proliferating and apoptotic J+ and J− cells, IL-10 secretion, and IL-2 production after cocultivation with MSCs and prMSCs were measured. Liquid chromatography–mass spectrometry and bioinformatics analysis identified proteins linked to TLR3 activation in MSCs. Results Poly(I:C) at 10 μg/mL during a 3-h incubation caused the highest expression of immunosuppression markers in MSCs. Activation of prMSCs caused a 18% decrease in proliferation and a one-third increase in apoptotic J+ cells compared to intact MSCs. Cocultures of prMSCs and Jurkat cells had increased IL-10 and decreased IL-2 in the conditioned medium. A proteomic study of MSCs and prMSCs identified 53 proteins with altered expression. Filtering the dataset with Gene Ontology and Reactome Pathway revealed that poly(I:C)-induced proteins activate the antiviral response. Protein‒protein interactions by String in prMSCs revealed that the antiviral response and IFN I signaling circuits were more active than in native MSCs. prMSCs expressed more cell adhesion proteins (ICAM-I and Galectin-3), PARP14, PSMB8, USP18, and GBP4, which may explain their anti-inflammatory effects on Jurkat cells. Conclusions TLR3 activation in MSCs is dependent on exposure time and poly(I:C) concentration. The maximum expression of immunosuppressive molecules was observed with 10 µg/mL poly(I:C) for 3-h preconditioning. This priming protocol for MSCs enhances the immunosuppressive effects of prMSCs on T cells.

Microbial communities of terrestrial mud volcanoes are involved in aerobic and anaerobic methane oxidation, but the biological mechanisms of these processes are still understudied. We have investigated the taxonomic composition, rates of methane oxidation, and metabolic potential of microbial communities in five mud volcanoes of the Taman Peninsula, Russia. Methane oxidation rates measured by the radiotracer technique varied from 2.0 to 460 nmol CH4 cm−3 day−1 in different mud samples. This is the first measurement of high activity of microbial methane oxidation in terrestrial mud volcanos. 16S rRNA gene amplicon sequencing has shown that Bacteria accounted for 65–99% of prokaryotic diversity in all samples. The most abundant phyla were Pseudomonadota, Desulfobacterota, and Halobacterota. A total of 32 prokaryotic genera, which include methanotrophs, sulfur or iron reducers, and facultative anaerobes with broad metabolic capabilities, were detected in relative abundance >5%. The most highly represented genus of aerobic methanotrophs was Methyloprofundus reaching 36%. The most numerous group of anaerobic methanotrophs was ANME-2a-b (Ca. Methanocomedenaceae), identified in 60% of the samples and attaining relative abundance of 54%. The analysis of the metagenome-assembled genomes of a community with high methane oxidation rate indicates the importance of CO2 fixation, Fe(III) and nitrate reduction, and sulfide oxidation. This study expands current knowledge on the occurrence, distribution, and activity of microorganisms associated with methane cycle in terrestrial mud volcanoes.

Combining new therapeutics with all-trans-retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and K562 cells exposed to ATRA for 3–72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).

AbstractThe content of linalyl acetate and the ratio of linalool to linalyl acetate (L/LA ratio) are one of the important parameters that determine the quality of lavender oil. The characterization of a segregating population derived from a self-pollinated Lavandula angustifolia var. Hemus resulted in the identification of a single quantitative trait locus controlling the L/LA ratio (L/LA-QTL) and located on chromosome 8 of the lavender reference genome. The L/LA data analysis demonstrated that plants homozygous for one of the L/LA-QTL alleles had significantly higher linalool content, lower linalyl acetate content and higher L/LA ratio, than the plants which were either heterozygous or homozygous for the other allele. No significant difference was observed for the sum of linalool and linalyl acetate content among these three groups of plants, suggesting that the identified L/LA-QTL is related to an enzyme conversion of linalool to linalyl acetate. The BLAST search revealed that the L/LA-QTL region included a sequence of the LiAAT4 gene of monoterpene acetyltransferase, considered as a candidate gene for the L/LA-QTL locus. Sequence analysis of the LiAAT4 gene of var. Hemus revealed the presence of two alleles differing in two nucleotides and predicted amino acid substitutions. The comparison of the allele configurations of SSR, SRAP and LiAAT4 loci and the L/LA ratio of plants showing recombination in the L/LA-QTL region provided further support that LiAAT4 is a candidate gene underlying the identified L/LA-QTL and controlling the L/LA ratio. The application of molecular markers for the identified L/LA-QTL is discussed.

The rates of oxygenic and anoxygenic photosynthesis, the microorganisms responsible for these processes, and the hydrochemical characteristics of the sulfide-containing karst lakes, Black Kichier and Big Kichier (Mari El Republic), were investigated. In these lakes, a plate of anoxygenic phototrophic bacteria (APB) is formed at the upper boundary of sulfide occurrence in the water. The phototrophic community of the chemocline zone was analyzed using a combination of high-throughput sequencing of the 16S rRNA gene fragments and light and electron microscopic techniques. Green-colored Chlorobium clathratiforme were absolutely predominant in both lakes. The minor components included green sulfur bacteria (GSB) Chlorobium spp., symbiotic consortia Chlorochromatium magnum and Pelochromatium roseum, purple sulfur bacteria (PSB) Chromatium okenii, and unidentified phylotypes of the family Chromatiaceae, as well as members of the Chloroflexota: Chloronema sp. and Oscillochloris sp. Based on the results of the molecular analysis, the taxonomic status of Ancalochloris perfilievii and other prosthecate GSB, as well as of the PSB Thiopedia rosea, which were visually revealed in the studied freshwater lakes, is discussed.

The article discusses the issue of application of fire escape chutes and rigid fire escape chutes to rescue people from low heights in case of fire. These rescue means are compared according to the main characteristics. Recommendations for practical use are indicated.

Cardioncology has emerged as a new field at the intersection of cardiology and oncology. Despite the fact that improving efficiency of antitumor treatment increased the survival of oncological hematological patients, the long-term cardiovascular consequences of this treatment have become more clinically significant.Despite the effectiveness of modern methods of treatment, some drugs, such as Bcr-Abl kinase inhibitors, anthracyclines, HER2/Erbb2 inhibitors, vascular endothelial growth factor inhibitors, fluoropyrimidines, as well as radiation therapy can have a pronounced effect on the cardiovascular system. These toxic effects lead to cardiac arrhythmia, heart failure, vascular toxicity and even death. It is important for hematologists, oncologists and cardiologists to understand the basic diagnostic and treatment strategies that should be used in the event of toxicity of this kind. At a time when, due to the developed cardiotoxicity, antitumor therapy should be discontinued, in some cases, it is possible to consider continuing treatment with caution and careful monitoring.

The crystal structure of the title compound, [Ag2(VO2F2)2(C9H9N3)4], is presented. The molecular complex is based on the heterobimetallic AgI—VV fragment {AgI2(VVO2F2)2(tr)4} supported by four 1,2,4-triazole ligands [4-benzyl-(4H-1,2,4-triazol-4-yl)]. The triazole functional group demonstrates homo- and heterometallic connectivity (Ag—Ag and Ag—V) of the metal centers through the [–NN–] double and single bridges, respectively. The vanadium atom possesses a distorted trigonal–bipyramidal coordination environment [VO2F2N] with the Reedijk structural parameter τ = 0.59. In the crystal, C—H...O and C—H...F hydrogen bonds as well as C—H...π contacts are observed involving the organic ligands and the vanadium oxofluoride anions. A Hirshfeld surface analysis of the hydrogen-bonding interactions is also described.

Origanum vulgare ssp. hirtum essential oil (OEO) is a natural oil with high therapeutic potential. For some applications, however, the development of novel formulations is still needed to improve the bioavailability and stability of OEO. In this study, we describe the fabrication of an original nanocomposite hydroxypropyl cellulose (HPC) physical hydrogel, containing OEO-loaded polymeric micelles, for topical delivery. The concentration of the main active compounds of OEO—carvacol and thymol—was determined using gas chromatography (GC) analysis. OEO was first encapsulated into Pluronic F127 micelles, and then embedded into HPC gel. Micellar and gel formulations of pure polymers and OEO-containing systems were characterized by dynamic light scattering (DLS) and rheology measurements, respectively. Selected formulations were evaluated for cytotoxicity and antiproliferative activity. The hydrogel formulation of HPC with micellar OEO (8% HPC, 2% F127, 1% OEO) exhibited sustained release of the oil and selectivity towards SH-4 tumor cells (an in vitro model of melanoma). [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) develops as a result of oxidative damage to neurons and chronic inflammation of microglia. These processes can be influenced by the use of a conditioned medium (CM) derived from mesenchymal stem cells (MSCs). The CM contains a wide range of factors that have neurotrophic, antioxidant, and anti-inflammatory effects. In addition, the therapeutic potential of the CM can be further enhanced by pretreating the MSCs to increase their paracrine activity. The current study aimed to investigate the neuroprotective effects of CM derived from MSCs, which were either activated by a TLR3 ligand or exposed to CoCl2, a hypoxia mimetic (pCM or hCM, respectively), in an in vitro model of AD. Methods: We have developed a novel in vitro model of AD that allows us to investigate the neuroprotective and anti-inflammatory effects of MSCs on induced neurodegeneration in the PC12 cell line and the activation of microglia using THP-1 cells. Results: This study demonstrates for the first time that pCM and hCM exhibit more pronounced immunosuppressive effects on proinflammatory M1 macrophages compared to CM derived from untreated MSCs (cCM). This may help prevent the development of neuroinflammation by balancing the M1 and M2 microglial phenotypes via the decreased secretion of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and increased secretion of IL-4, as well as the expression of IL-10 and TGF-β by macrophages. Moreover, a previously unknown increase in the neurotrophic properties of hCM was discovered, which led to an increase in the viability of neuron-like PC12 cells under H2O2-induced oxidative-stress conditions. These results are likely associated with an increase in the production of growth factors, including vascular endothelial growth factor (VEGF). In addition, the neuroprotective effects of CM from preconditioned MSCs are also mediated by the activation of the Nrf2/ARE pathway in PC12 cells. Conclusions: TLR3 activation in MSCs leads to more potent immunosuppressive effects of the CM against pro-inflammatory M1 macrophages, while the use of hCM led to increased neurotrophic effects after H2O2-induced damage to neuronal cells. These results are of interest for the potential treatment of AD with CM from preactivated MSCs. [ABSTRACT FROM AUTHOR]