Forecasting risk of bankruptcy for machine-building plants

The paper presents an overview of well-known bankruptcy risk forecasting models, elaborated as by Russian so by foreign authors, on the basis of the data about financial and business activities of the biggest machine-building Russian plants. The authors substantiate and confirm appropriateness of a fuzzy set model to the problem of bankruptcy risk forecasting. This model is worked out on the basis of 10 most important factors, which have the greatest influence on sales proceeds as the main financial source for a production plant

Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson\u27s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells

CRISPR/Cas-edited pigs for personalized medicine: more than preclinical test-system

Novel CRISPR-Cas-based genome editing tools made it feasible to introduce a variety of precise genomic modifications in the pig genome, including introducing multiple edits simultaneously, inserting long DNA sequences into specifically targeted loci, and performing nucleotide transitions and transversions. Pigs serve as a vital agricultural resource and animal model in biomedical studies, given their advantages over the other models. Pigs share high similarities to humans regarding body/organ size, anatomy, physiology, and a metabolic profile. The pig genome can be modified to carry the same genetic mutations found in humans to replicate inherited diseases to provide preclinical trials of drugs. Moreover, CRISPR-based modification of pigs antigen profile makes it possible to offer porcine organs for xenotransplantation with minimal transplant rejection responses. This review summarizes recent advances in endonuclease-mediated genome editing tools and research progress of genome-edited pigs as personalized test-systems for preclinical trials and as donors of organs with human-fit antigen profile. Graphical abstract

Atherosclerosis is a side effect of cellular senescence

Atherosclerosis is a systemic autoimmune disease of the arterial wall characterized by chronic inflammation, high blood pressure, oxidative stress, and progressive loss of cell and organ function with aging. An imbalance of macrophage polarization is associated with many aging diseases, including atherosclerosis. The polarization toward the pro-inflammatory M1 macrophage is a major promoter of the atheroma formation. It is known that efferocytosis, or ingestion of apoptotic cells, is stimulated by M2 macrophage polarization. A failure of efferocytosis leads to the prolongation of chronic pathology in tissue. In addition, fat-laden macrophages contribute to the plague progression by transforming into foam cells in response to excess lipid deposition in arteries. In spite of the generally accepted theory that macrophages capture oxidized low-density lipoprotein by phagocytosis and become foam cells, we postulate that the main source of lipid accumulation in foam cells are senescent erythrocytes. Senescent erythrocytes lose their plasticity, which affects the rheological blood properties. It is known that their membrane contains high levels of cholesterol. There is evidence that senescent erythrocytes play a pathogenic role in the atheroma formation after breaking down during flowing through an artery bifurcation. Here we review the current knowledge on the impact of age-associated immune cells and red blood cells modifications on atherogenesis. Graphical abstract

Effect of recombinant Sox9 protein on the expression of cartilage-specific genes in human dermal fibroblasts cell culture

Introduction: Damage to the hyaline layer of large joints resulting from injuries or age-related changes restricts their mobility. The repair of these disorders is an actual issue in medicine. One of the promising therapies is the usage of cell engineering constructs based on a biodegradable scaffold and a modified cell culture. A frequently used method to modify the proliferation of cell culture for tissue engineering of hyaline cartilage, which makes it possible to introduce an experimental technique into clinical practice, is the application of recombinant proteins that affect chondrogenesis and lead to increase synthesis of extracellular matrix proteins. The goal of this work was to elucidate the effect of the key transcription factor in the chondrogenesis process – Sox9 protein – on the expression of genes responsible for chondrogenesis (Tgfβ3, Sox9, Acan, Comp, Col2a1). Materials and methods: Human dermal fibroblasts were used as a cell culture; recombinant Sox9 was added at each change of medium; the modification was carried out for 21 days, and difference in gene expression was determined by real-time PCR and -ΔΔCt method. Results and discussion: To assess the effectiveness of fibroblast modification, we analyzed the changing of expression of genes responsible for chondrogenesis (Tgfß3, Sox9, Col2a1, Acan, Comp). We studied the direct effect of different concentrations of the recombinant Sox9 protein on the proliferation of dermal fibroblasts in the chondrogenic direction. We showed that the addition of the recombinant Sox9 protein in various concentration did not significantly change the expression of both the genes encoding proteins of the extracellular matrix of hyaline cartilage (Acan, Col2a1, Comp) and the genes encoding chondrogenesis inducers (Tgfß3, Sox9). Conclusion: As a result of the experiments, it was shown that the recombinant Sox9 protein has practically no effect on chondrogenic differentiation and does not significantly change the expression of chondrogenesis genes

Effect of recombinant Sox9 protein on the expression of cartilage-specific genes in human dermal fibroblasts cell culture

Introduction: Damage to the hyaline layer of large joints resulting from injuries or age-related changes restricts their mobility. The repair of these disorders is an actual issue in medicine. One of the promising therapies is the usage of cell engineering constructs based on a biodegradable scaffold and a modified cell culture. A frequently used method to modify the proliferation of cell culture for tissue engineering of hyaline cartilage, which makes it possible to introduce an experimental technique into clinical practice, is the application of recombinant proteins that affect chondrogenesis and lead to increase synthesis of extracellular matrix proteins. The goal of this work was to elucidate the effect of the key transcription factor in the chondrogenesis process – Sox9 protein – on the expression of genes responsible for chondrogenesis (Tgfβ3, Sox9, Acan, Comp, Col2a1). Materials and methods: Human dermal fibroblasts were used as a cell culture; recombinant Sox9 was added at each change of medium; the modification was carried out for 21 days, and difference in gene expression was determined by real-time PCR and -ΔΔCt method. Results and discussion: To assess the effectiveness of fibroblast modification, we analyzed the changing of expression of genes responsible for chondrogenesis (Tgfß3, Sox9, Col2a1, Acan, Comp). We studied the direct effect of different concentrations of the recombinant Sox9 protein on the proliferation of dermal fibroblasts in the chondrogenic direction. We showed that the addition of the recombinant Sox9 protein in various concentration did not significantly change the expression of both the genes encoding proteins of the extracellular matrix of hyaline cartilage (Acan, Col2a1, Comp) and the genes encoding chondrogenesis inducers (Tgfß3, Sox9). Conclusion: As a result of the experiments, it was shown that the recombinant Sox9 protein has practically no effect on chondrogenic differentiation and does not significantly change the expression of chondrogenesis genes

Search for Structural Basis of Interactions of Biogenic Amines with Human TAAR1 and TAAR6 Receptors

The identification and characterization of ligand-receptor binding sites are important for drug development. Trace amine-associated receptors (TAARs, members of the class A GPCR family) can interact with different biogenic amines and their metabolites, but the structural basis for their recognition by the TAARs is not well understood. In this work, we have revealed for the first time a group of conserved motifs (fingerprints) characterizing TAARs and studied the docking of aromatic (β-phenylethylamine, tyramine) and aliphatic (putrescine and cadaverine) ligands, including gamma-aminobutyric acid, with human TAAR1 and TAAR6 receptors. We have identified orthosteric binding sites for TAAR1 (Asp68, Asp102, Asp284) and TAAR6 (Asp78, Asp112, Asp202). By analyzing the binding results of 7500 structures, we determined that putrescine and cadaverine bind to TAAR1 at one site, Asp68 + Asp102, and to TAAR6 at two sites, Asp78 + Asp112 and Asp112 + Asp202. Tyramine binds to TAAR6 at the same two sites as putrescine and cadaverine and does not bind to TAAR1 at the selected Asp residues. β-Phenylethylamine and gamma-aminobutyric acid do not bind to the TAAR1 and TAAR6 receptors at the selected Asp residues. The search for ligands targeting allosteric and orthosteric sites of TAARs has excellent pharmaceutical potential