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Introduction. The concept of appropriateness of professional self-determination is analyzed, approaches to its analysis and measurement are described. Theoretical analysis. The significance of self-assessment of appropriateness of professional self-determination as a condition of sustainability to frequent stresses and prevention of professional burnout, including emotional exhaustion and depersonalization of personnel. Еmpirical analysis. The empirical study presents the results of the validation of the “Appropriateness of professional self-determination” Scale, developed by the author of the article. The empirical research base includes 396 workers, 277 men and 119 women. The performed in the study verification of the factor structure of the Scale confirmed its two-factor structure (subscale “Compliance of personal qualities of the job`s demands” (Cronbach`s α = 0.82) and subscale “Compliance of job of personal qualities” (Cronbach`s α. = 0.63)). The factor structure of the Scale was confirmed by the results of confirmatory factor analysis (RMSEA = 0.061, CFI = 0.964, TLI = 0.906). It was found that male workers and female workers evaluate their own appropriateness of professional self-determination in the same way. Negative correlations of appropriateness of professional self-determination with professional burnout, frequency of stresses and positive correlations with job satisfaction were revealed. Conclusion. The results of the study confirm the validity of the Appropriateness of Professional self-determination Scale, contribute the theoretical reflection of professional self-determination.

With the development of next-generation sequencing (NGS) technologies it became possible to simultaneously analyze millions of variants. Despite the quality improvement, it is generally still required to confirm the variants before reporting. However, in recent years the dominant idea is that one could define the quality thresholds for "high quality" variants which do not require orthogonal validation. Despite that, no works to date report the concordance between variants from whole genome sequencing and their gold-standard Sanger validation. In this study we analyzed the concordance for 1756 WGS variants in order to establish the appropriate thresholds for high-quality variants filtering. Resulting thresholds allowed us to drastically reduce the number of variants which require validation, to 4.8% and 1.2% of the initial set for caller-agnostic (DP, AF) and caller-dependent (QUAL) thresholds, respectively. [ABSTRACT FROM AUTHOR]

A pseudogene is a non-functional copy of a protein-coding gene. Processed pseudogenes, which are created by the reverse transcription of mRNA and subsequent integration of the resulting cDNA into the genome, being a major pseudogene class, represent a significant challenge in genome analysis due to their high sequence similarity to the parent genes and their frequent absence in the reference genome. This homology can lead to errors in variant identification, as sequences derived from processed pseudogenes can be incorrectly assigned to parental genes, complicating correct variant calling. In this study, we quantified the occurrence of variant calling errors associated with pseudogenes, generated by the most popular germline variant callers, namely GATK-HC, DRAGEN, and DeepVariant, when analysing 30x human whole-genome sequencing data (n = 13,307). The results show that the presence of pseudogenes can interfere with variant calling, leading to false positive identifications of potentially clinically relevant variants. Compared to other approaches, DeepVariant was the most effective in correcting these errors. [ABSTRACT FROM AUTHOR]

The extracellular matrix is an organized three-dimensional network of protein-based molecules and other macromolecules that provide structural and biochemical support to tissues. Depending on its biochemical and structural properties, the extracellular matrix influences cell adhesion and signal transduction and, in general, can influence cell differentiation and proliferation through specific mechanisms of chemical and mechanical sensing. The development of body tissues during ontogenesis is accompanied by changes not only in cells but also in the composition and properties of the extracellular matrix. Similarly, tumor development in carcinogenesis is accompanied by a continuous change in the properties of the extracellular matrix of tumor cells, called 'oncomatrix', as the tumor matures, from the development of the primary focus to the stage of metastasis. In this paper, the characteristics of the composition and properties of the extracellular matrix of tumor tissues are considered, as well as changes to the composition and properties of the matrix during the evolution of the tumor and metastasis. The extracellular matrix patterns of tumor tissues can be used as biomarkers of oncological diseases as well as potential targets for promising anti-tumor therapies. [ABSTRACT FROM AUTHOR]

Next-generation sequencing technologies have not only defined a breakthrough in medical genetics, but also been able to enter routine clinical practice to determine individual genetic susceptibilities. Modern technological developments are routinely introduced to genetic analysis overtaking the established approaches, potentially raising a number of challenges. To what extent is the advantage of new methodologies in synthetic metrics, such as precision and recall, more important than stability and reproducibility? Could differences in the technical protocol for calling variants be crucial to the diagnosis and, by extension, the patient's treatment strategy? A regulatory review process may delay the incorporation of potentially beneficial technologies, resulting in missed opportunities to make the right medical decisions. On the other hand, a blind adoption of new technologies based solely on synthetic metrics of precision and recall can lead to incorrect conclusions and adverse outcomes for the specific patient. Here, we use the example of a patient with a WHO-diagnosed desmoplastic/nodular SHH-medulloblastoma to explore how the choice of DNA variant search protocol affects the genetic diagnostics outcome. [ABSTRACT FROM AUTHOR]

Abietane type diterpenic (dehydroabietic, 2,3‐dihydroquinopimaric and maleopimaric) acids were converted by the acid chloride method into a series of aliphatic and heterocyclic amine spacered conjugates. A number of structurally novel derivatives holding 1,2,3‐triazole moieties were designed and synthesized by treating of the propargylated amides and esters with a sugar azides using the Cu(I)‐catalyzed click chemistry approach. The synthesized N‐containing diterpene derivatives were tested for their potential inhibition of influenza A/PuertoRico/8/34 (H1N1) virus in MDCK cell culture and SARS‐CoV‐2 pseudovirus in BHK‐21‐hACE2 cells. Among tested forty‐five compounds ten derivatives were the most efficacious against influenza virus A with IC50 0.7–63.4 μM together with high selectivity index SI value from 11 from 94. Dihydroquinopimaric acid N‐ethylpiperazine‐amide and dehydroabietic acid 1,2,3‐triazoles spacered with glucose and lactose showed anti‐SARS‐CoV‐2 pseudovirus activity with EC50 values of 1.79–25.46 μM. Molecular docking and dynamics modeling investigated the binding mode of the lead compounds into the binding pocket of influenza A virus M2 protein and the RBD domain of SARS‐CoV‐2 spike glycoprotein. [ABSTRACT FROM AUTHOR]

99mTc is a well-known radionuclide that is widely used and readily available for SPECT/CT (Single-Photon Emission Computed Tomography) diagnosis. However, commercial isotope carriers are not specific enough to tumours, rapidly clear from the bloodstream, and are not safe. To overcome these limitations, we suggest immunologically compatible recombinant proteins containing a combination of metal binding sites as 99mTc chelators and several different tumour-specific ligands for early detection of tumours. E1b protein containing metal-binding centres and tumour-specific ligands targeting integrin αvβ3 and nucleolin, as well as a short Cys-rich sequence, was artificially constructed. It was produced in E. coli, purified by metal-chelate chromatography, and used to obtain a complex with 99mTc. This was administered intravenously to healthy Balb/C mice at an activity dose of about 80 MBq per mouse, and the biodistribution was studied by SPECT/CT for 24 h. Free sodium 99mTc-pertechnetate at the same dose was used as a reference. The selectivity of 99mTc-E1b and the kinetics of isotope retention in tumours were then investigated in experiments in C57Bl/6 and Balb/C mice with subcutaneously transplanted lung carcinoma (LLC) or mammary adenocarcinoma (Ca755, EMT6, or 4T1). The radionuclide distribution ratio in tumour and adjacent normal tissue (T/N) steadily increased over 24 h, reaching 15.7 ± 4.2 for EMT6, 16.5 ± 3.8 for Ca755, 6.7 ± 4.2 for LLC, and 7.5 ± 3.1 for 4T1. [ABSTRACT FROM AUTHOR]

In search for new molecules of diterpene origin with promising anticancer activity, two amino‐derivatives (methyl maleopimarate aminoimide and methyl 1β,13‐epoxydihydroquinopimarate C4‐hydrazone) were involved in the 4‐component Ugi reaction (Ugi‐4CR) and pseudo‐7‐component azido‐Ugi condensation (azido‐Ugi‐7CR) to afford a series of adducts holding α‐aminoacylamide and bis‐1,5‐disubstituted tetrazole substituents. The NCI‐60 cancer cell panel screening revealed diterpene‐type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2–15.4 μM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds. [ABSTRACT FROM AUTHOR]

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure–activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI50 = 0.42–3 μM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI50 in the range of 1–17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI50 vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis. [ABSTRACT FROM AUTHOR]