Adaptive Role of Cell Death in Yeast Communities Stressed with Macrolide Antifungals.

Microorganisms cooperate with each other to protect themselves from environmental stressors. An extreme case of such cooperation is regulated cell death for the benefit of other cells. Dying cells can provide surviving cells with nutrients or induce their stress response by transmitting an alarm signal; however, the role of dead cells in microbial communities is unclear. Here, we searched for types of stressors the protection from which can be achieved by death of a subpopulation of cells. Thus, we compared the survival of Saccharomyces cerevisiae cells upon exposure to various stressors in the presence of additionally supplemented living versus dead cells. We found that dead cells contribute to yeast community resistance against macrolide antifungals (e.g., amphotericin B [AmB] and filipin) to a greater extent than living cells. Dead yeast cells absorbed more macrolide filipin than control cells because they exposed intracellular sterol-rich membranes. We also showed that, upon the addition of lethal concentrations of AmB, supplementation with AmB-sensitive cells but not with AmB-resistant cells enabled the survival of wild-type cells. Together, our data suggest that cell-to-cell heterogeneity in sensitivity to AmB can be an adaptive mechanism helping yeast communities to resist macrolides, which are naturally occurring antifungal agents. IMPORTANCE Eukaryotic microorganisms harbor elements of programmed cell death (PCD) mechanisms that are homologous to the PCD of multicellular metazoa. However, it is still debated whether microbial PCD has an adaptive role or whether the processes of cell death are an aimless operation in self-regulating molecular mechanisms. Here, we demonstrated that dying yeast cells provide an instant benefit for their community by absorbing macrolides, which are bacterium-derived antifungals. Our results illustrate the principle that the death of a microorganism can contribute to the survival of its kin and suggest that early plasma membrane permeabilization improves community-level protection. The latter makes a striking contrast to the manifestations of apoptosis in higher eukaryotes, the process by which plasma membranes maintain integrity.

[Functional diseases of the gastrointestinal tract in the context with overlapping functional disorders: current status of the problem].

Functional diseases of the gastrointestinal tract cause significant damage to the health care system. Their frequent combination in the same patient with the migration of clinical symptoms throughout the digestive tube is accompanied by continuous exacerbations, refractory to the therapy and severe psychosocial disorders. This review provides data on the main etiopathogenetic factors, clinical manifestations, course features and management tactics for patients with overlapping for the most common functional diseases of the gastrointestinal tract.

[Diseases of biliary tract in the context of association with oncological diseases of the digestive system].

Cancers of the gastrointestinal tract are widespread among the population and cause significant damage to the health care system. In order to improve the strategy of preventive measures and the detection of oncological diseases at the early stages, it is necessary to provide timely impact on possible risk factors contributing to the onset and progression of malignant neoplasms. This review demonstrates the association between the pathology of the biliary tract and oncological diseases of the digestive system, discusses the possible mechanisms of the influence of cholelithiasis and cholecystectomy on the development of malignant neoplasms of various parts of the gastrointestinal tract.

NSAID-induced enteropathy: the current state of the problem.

The review analyzes the main etiological and pathogenetic mechanisms of the development of NSAID-enteropathy. Particular attention is paid to the role of intestinal microbiota in the manifestation and progression of NSAID-enteropathy. The special role of probiotics in the prevention and treatment of NSAIDs enteropathy is considered.

Optimizing therapy of liver diseases not associated with viral infection.

The review demonstrated results and prospects of non-pharmacological and drug therapy patients with liver disease, not associated with a viral infection. The presented data emphasize the relevance of studying the problem of effective therapy of diseases of the liver and its role in improving the course and outcomes of liver disease.

Comparative effectiveness of vitamin-mineral complexes with iron in correcting iron deficiency in women in the outpatient setting.

AIM: To compare the efficacy of prophylactic administration of mineral-vitamin complexes "Feroglobin-B12" and "Complivit iron" with different degrees of Fe valence. MATERIALS AND METHODS: 120 female subjects were examined. To determine the quality of life, the SF-36 questionnaire was used. The presence of anxiety was determined on the Spielberger-Khanin Alarm Scale. 30 women with a deficit of Fe were divided into 2 groups of 15 people each. The first group received "Ferroglobin-B12", the second - "Complivit iron" for a month. RESULTS: In a month after the initiation of preventive therapy in women of the 1 group the content of Fe serum was normalized. In the second group, its concentration approached the control values. The difference in Fe content in the 1 and 2 groups was of a reliable nature. CONCLUSION: The intake of "Ferroglobin-B12" was not accompanied by side effects, and performance indicators, social activity and mental health reached control values, unlike the group of patients taking Complivit iron.

[PROSPECTS FOR CLINICAL APPLICATION OF STATINS IN GASTROENTEROLOGY].

We present the analytical review of non-cardial effects of statins used in gastroenterology with the data illustrating their high antibacterial activity as exemplified by combined therapy of conditions associated with Helicobacter pylori infection. Special emphasis is laid on anti-inflammatory and oncoprotective mechanisms of statin action that are successfully made use of for the treatment of liver, pancreas, gallbladder, and biliary system diseases. Prophylactic aspects of statin application to overcome an addiction to fast food are discussed.

[DIFFUSE NEUROENDOCRINE SYSTEM OF THE STOMACH AND CHARACTERISTICS OF PROLIFERATION IN REALIZATION OF CORREA'S CASCADE IN DISEASES ASSOCIATED WITH HELICOBACTER PYLORI].

AIM: To study the role of the vascular endothelial growth factor (VEGF), Ki-67, BCL-2, and endocrine cells (EC) of gastric mucosa producing somatostatin (SS), glucagon (GL), and pancreatic polypeptide (PP) in diseases associated with Helicobacter pylori. To use the data obtained to develop early diagnostic criteria for the progress of structural changes in gastric mucosa of the patients with stomach ulcer disease [SUD), chronic atrophic gastritis (CAG), gastric adenomatous polyps (GAP), and gastric cancer (GC) before and after surgical intervention and eradication of H. pylori. MATERIALS AND METHODS: We examined 104 patients with gastric pathology associated with Helicobacter pylori including 30 with SUD, 30 with CAG, 20 with GAP and CAG, 24 with stage II noncardia GC. The effectiveness of the treatment was evaluated 2 months after alleviation of inflammation in the stomachfollowing polypectomy in case of GAP or gastrectomy in case of GC. Material for immunohistochemical studies was taken from the fundus. Monoclonal antibodies against VEGF SS, GL, PP Ki-67, BCL-2 (1:100, Novocastra) were used. Histobacterioscopy was conducted using antral mucosal smears stained by the Romanowsky-Giemsa procedure. RESULTS: Exacerbation of SUD was accompanied by a decrease in the number of epithelial cells and EC producing VEGF glucagon (GL), and pancreatic polypeptide (PP) with the increase in the number of SS-secreting EC along with intensification of proliferative processes determined from the number of Ki-67 and BCL-2 immunopositive epithelial cells. CAG and GC were associated with persistence of H. pylori, hyperplasia of EC producing VEGF glucagon (GL), pancreatic polypeptide (PP) and hypoplasia of SS-secreting EC along with high proliferative activity of epitheliocytes expressed via Ki-67 and BCL-2. CONCLUSION: Endothelial growth factor (VEGF), somatostatin (SS), glucagon (GL), and pancreatic polypeptide (PP) are of importance for the prognostication of development and clinical course of diseases associated with Helicobacter pylori since their pathological properties are realized either directly or indirectly through H. pylori, Ki-67 and BCL-2. Eradication of H. pylori does not result in the disappearance of intestinal metaplasia.

[The role of gastric APUD system in progression of chronic Helicobacter gastritis].

The study included 60 patients with chronic Halicobacter gastritis (30 with chronic non-atrophic and 30 with atrophic Halicobacter gastritis (CNAHG and CAHG)). The control group was comprised of 15 practically healthy subjects. The aim of the work was to elucidate the role of Helicobacter infection, disturbances of regeneration, endothelin-1 and melatonin-secreting neuroendocrine cells of gastric antrum in progression of chronic Helicobacter gastritis (CHG). It was shown that CHG is due to H. pylori persistence and that patients with CNAHG undergo grade III microbial contamination while in CAHG patients atrophic changes are accompanied by metaplasia of gastric mucosa (GM) and inflammation of different severity. Patients with CNAHG has an increased number of melatonin-positive gastric cells and enhanced apoptotic activity of GM epitheliocytes. Patients with CAHG experience a reduction of melatonin-positive cells correlated with enhanced apoptotic activity of GM epitheliocytes. The number of endothelin-1 positive cells in patients with CNAHG and CAHG was similar to that in controls. Adequate eradication promoted normalization of the number of gastric endothelin-1 and melatonin-secreting neuroendocrine cells in patients with CHG. The apoptotic index reached the control value within 1 month after eradication in CNAHG patients but remained relatively high in CAHG patients.

Towards in silico identification of the human ether-a-go-go-related gene channel blockers: discriminative vs. generative classification models.

HERG potassium channels have a critical role in the normal electrical activity of the heart. The blockade of hERG channels in heart cells can result in a potentially fatal disorder called long QT syndrome. HERG channels can be blocked by compounds with diverse structures belonging to several drug classes. Presented herein are generative (Generative Topographic Maps) and discriminative (Support Vector Machines) classification models to categorize the compounds in silico into active and inactive classes by using different types of descriptors. The predictive performance of discriminative and generative classification models has been compared. Here, the possibility of using Generative Topographic Maps as an approach for applicability domain analysis and to generate probability-based descriptors was demonstrated to our knowledge for the first time. Comparison of obtained results with the models developed by other teams on the same data set has been performed.

[The influence of melatonin included in the combined treatment of antichelicobaterial therapy on immunohistochemical characteristics of gastric epitheliocytes from patients with duodenal ulcer].

The study included 100 patients with duodenal ulcer (DU), 30 with chronic non-atrophic gastritis (CNAG), 30 with chronic atrophic gastritis (CAG) and 12 practically healthy subjects. All patients with DU and CNAG had morphologically confirmed H. pylori infection. The patients with DU were divided into 2 groups each including age-matched subjects with endoscopically, morphologically, immunohistochemically identical characteristics. Those of group 1 underwent eradication of H. pylori by a traditional 7-day procedure including the use of omeprazole (20 mg BID), claritromycin (500 mg BID) and amoxicillin (1000 mg BID). In group 2 this scheme was supplemented by melatonin (3 mg before bedtime). Patients of group 1 continued to use omeprazole and those in group 2 omeprazole + melatonin till the end of the second month. Healthy subjects and patients with CAG served as controls. All patients underwent FGDS on weeks 2 and 4, immunohistochemical study was conducted to detect endothelin-1 and melatonin-positive cells, apoptotic activity of mucosal epitheliocytes from gastric antrum was determined before and 6 weeks after the onset of therapy. It was shown that introduction of melatonin in the scheme of eradication therapy increases efficacy of H. pylori elimination and accelerates DU cicatrization. Two-month therapy with omeprazole + melatonin more effectively normalizes immunohistochemical parameters (endothelin-1 and melatonin-positive cells) and epitheliocyte apoptotic activity, than omeprazole alone.

Generative Topographic Mapping (GTM): Universal Tool for Data Visualization, Structure-Activity Modeling and Dataset Comparison.

Here, the utility of Generative Topographic Maps (GTM) for data visualization, structure-activity modeling and database comparison is evaluated, on hand of subsets of the Database of Useful Decoys (DUD). Unlike other popular dimensionality reduction approaches like Principal Component Analysis, Sammon Mapping or Self-Organizing Maps, the great advantage of GTMs is providing data probability distribution functions (PDF), both in the high-dimensional space defined by molecular descriptors and in 2D latent space. PDFs for the molecules of different activity classes were successfully used to build classification models in the framework of the Bayesian approach. Because PDFs are represented by a mixture of Gaussian functions, the Bhattacharyya kernel has been proposed as a measure of the overlap of datasets, which leads to an elegant method of global comparison of chemical libraries.

[Changes in coagulation hemostasis in patients after coronary bypass surgery].

Changes in the coagulation link of hemostasis were studied in 37 patients who had undergone coronary bypass surgery using venous and arterial conduits and in 16 healthy individuals of the same age. The recordings of hemostasiograms were examined before and 14 days after surgery. Prior to coronary bypass surgery, the patients with ischemic heart disease were found to have coagulation hemostatic disorders as moderate hyperfibrinogenemia, fibrinolytic suppression, thrombinemia, and elevated D-dimer concentrations. Postoperatively, hypercoagulation substantially increased with suppressed fibrinolysis and decreased anticoagulants in the protein C system. In this connection, it is necessary to longer use anticoagulants in the postoperative period and to thoroughly monitor hemostasiogram recordings after their discontinuance.

[Telomeric oligonucleotide complexes with PGEk protein vector: internalization by target cells and antiproliferative properties].

The recombinant protein PGEk, containing residual of the human epidermal factor (hEGF) bearing DNA binding sequence, retains ability of hEGF to bind with hEGF receptor and to induce cell proliferation was shown. On an example of PGEk complexes with telomeric mimic-oligodeoxyribonucleotide d(TTAGGG)4 and with its thio-analogue we had found such systems can be effectively and selectively internalized by hEGF receptors super expressing cells. The association of this process with a protein/oligonucleotide ratio in complexes was investigated. The intracellular localization of oligonucleotides was explored. We had shown that PGEk not only promotes intensive delivery of oligonucleotides, but also protects them from degradation by nucleases. The oligonucleotides in composition of complexes have considerably more expressed cytotoxic activity in comparison with free oligonucleotides.

[Evaluation of the effect of various methods of oil-polluted soil bioremediation on micromycete complexes].

The influence of remediation of oil-contaminated gray forest, dark gray forest, and black soils by biological preparations Bacispecin, Devoroil, and Belvitamil on the population of opportunistic and phytotoxic fungi was studied. It was found that this population increased after oil pollution and decreased after three months of remediation. The latter is a sign of gradual recovery of soil microbiota.

[Mathematical simulation of accumulation of opportunistic micromycetes in petroleum-polluted soils].

The impact of pollution of different types of soils (leached chernozem, grey wood and dark-grey wood soils) with petroleum and its products on the size, species-specific composition, and accumulation of opportunistic micromycetes was studied in long-term field microallotment and laboratory conditions. Petroleum and its refining products were shown to increase the size of micromycetes and to change their structure and species diversity. A mathematical model has been developed, which describes the time course of changes in the size of mushroom propagules under different environmental conditions.

[Participation of reticular neurons of the cat medulla oblongata in the integration of the respiration center activity]. / Uchastie retikuliarnykh neironov prodolgovatogo mozga koshki v integrativnoi deiatel'nosti dykhatel'nogo tsentra.

Reticular neurons of the respiratory centre are divided into three groups. The 1st one is located in the medial areas and accepts afferents from chemoreceptors. The 2nd one is located in inspiratory and expiratory areas of the centre and take part in integration of afferent signals and activation of the effector mechanism. The 3rd group is present in both areas and organizes the effector activity of the centre. Electrical stimulation of the brain stem nuclei can modify reticular neurons in lateral areas.

[Cyclic AMP-specific nucleotide phosphodiesterase from the insoluble fraction of the human brain]. / cAMP-spetsifichnaia fosfodiésteraza tsiklicheskikh nukleotidov nerastvorimoi fraktsii mozga cheloveka.

The cAMP-specific cyclic nucleotide phosphodiesterase (PDE) from pellet fraction of human brain has been identified. Two alternative methods for isolation and purification of the enzyme are presented. The first method consists of three chromatographic steps (separation on the DEAE-Toyopearl column followed by gel filtrations on AcA-34 and G3000 SW columns) and results in purification of several forms of PDE. One of those is weakly inhibited by cGMP and is insensitive to Ca(2+)-calmodulin or cyclic nucleotides. The second procedure consisting of the chromatographic separation on blue agarose and DEAE-TSK-5PW ion-exchange resin leads to an isolation of several peaks of cAMP-specific PDE. Both methods produce different cAMP-specific forms of PDE with molecular masses ranging from 36 to 47 kDa. These forms differ in kinetic properties (Km = 2.0-7.3 microM, Ki = 1480-5300 microM for cGMP). However, the KicGMP/KmcAMP ratio remains constant for all the peaks of the cAMP-specific enzyme.