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Emile R Zakiev,1 Igor A Sobenin,1,2 Vasily N Sukhorukov,1 Veronika A Myasoedova,1 Ekaterina A Ivanova,3 Alexander N Orekhov1,4 1Laboratory of Angiopathology, Institute for General Pathology and Pathophysiology, 2Laboratory of Medical Genetics, Russian Cardiology Research and Production Complex, Moscow, Russia; 3Department of Development and Regeneration, KU Leuven, Leuven, Belgium; 4Skolkovo Innovative Center, Institute for Atherosclerosis Research, Moscow, Russia Abstract: Atherogenic modification of low-density lipoprotein (LDL) plays a crucial role in the pathogenesis of atherosclerosis, as modified LDL, but not native LDL, induces pronounced accumulation of cholesterol and lipids in the arterial wall. It is likely that LDL particles undergo multiple modifications in human plasma: desialylation, changes in size and density, acquisition of negative electric charge, oxidation, and complex formation. In a total LDL preparation isolated from pooled plasma of patients with coronary atherosclerosis and from healthy subjects, two subfractions of LDL could be identified: desialylated LDL bound by a lectin affinity column and normally sialylated (native) LDL that passed through the column. The desialylated LDL subfraction therefore represents circulating modified LDL. In this work, we performed a careful analysis of LDL particles to reveal changes in the composition of glycoconjugates associated with proteins and lipids. Protein fraction of LDL from atherosclerotic patients contained similar amounts of glucosamine, galactose, and mannose, but a 1.6-fold lower level of sialic acid as compared to healthy donors. Lipid-bound glycoconjugates of total LDL from patients with coronary atherosclerosis contained 1.5–2-fold less neutral monosaccharides than total LDL from healthy donors. Patient-derived LDL also contained significantly less sialic acid. Our results demonstrate that carbohydrate composition of LDL from atherosclerotic patients was altered in comparison to healthy controls. In particular, prominent decrease in the sialic acid content was observed. This strengthens the hypothesis of multiple modification of LDL particles in the bloodstream and underscores the clinical importance of desialylated LDL as a possible marker of atherosclerosis progression. Keywords: atherosclerosis, low density lipoprotein, LDL, modified LDL, desialylation

Ekaterina A Ivanova,1 Yuri V Bobryshev,2,3 Alexander N Orekhov2,4,5 1Department of Pediatric Nephrology and Growth and Regeneration, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium; 2Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Sciences, Moscow, Russia; 3Faculty of Medicine, School of Medical Sciences, University of New South Wales, Kensington, Sydney, NSW, Australia; 4Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia; 5Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia Abstract: High cardiovascular risk conditions are frequently associated with altered plasma lipoprotein profile, such as elevated low-density lipoprotein (LDL) and LDL cholesterol and decreased high-density lipoprotein. There is, however, accumulating evidence that specific subclasses of LDL may play an important role in cardiovascular disease development, and their relative concentration can be regarded as a more relevant risk factor. LDL particles undergo multiple modifications in plasma that can lead to the increase of their negative charge. The resulting electronegative LDL [LDL(−)] subfraction has been demonstrated to be especially atherogenic, and became a subject of numerous recent studies. In this review, we discuss the physicochemical properties of LDL(−), methods of its detection, atherogenic activity, and relevance of the LDL electronegativity index as a potential independent predictor of cardiovascular risk. Keywords: low-density lipoprotein, LDL, LDL electronegativity index, cardiovascular disease, atherosclerosis

Affinity chromatography is a widely used technique for antibody isolation. This article presents the successful synthesis of a novel affinity resin with a mutant form of protein A (BsrtA) immobilized on it as a ligand. The key aspect of the described process is the biocatalytic immobilization of the ligand onto the matrix using the sortase A enzyme. Moreover, we used a matrix with primary amino groups without modification, which greatly simplifies the synthesis process. The resulting resin shows a high dynamic binding capacity (up to 50 mg IgG per 1 mL of sorbent). It also demonstrates high tolerance to 0.1 M NaOH treatment and maintains its effectiveness even after 100 binding, elution, and sanitization cycles.

Acute nociceptive pain in mice caused by subcutaneous (intraplantar) injection of TRPV1 ion channel agonist capsaicin (1.6 μg/mouse) and the effects of protein kinase A inhibitor H-89 (0.05 mg/mouse, intraplantar injection) and NMDA receptor channel antagonists MK-801 (7.5 and 15 μg/mouse, topical application) and hemantane (0.5 mg/mouse, topical application) on the pain were assessed. MK-801 and hemantane were found to reduce the duration of the pain response. H-89 did not significantly affect the pain in animals, but preliminary administration of this drug abolished the antinociceptive effect of MK-801 (7.5 μg/mouse) and weakens the effect of hemantane (0.5 mg/mouse)., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Burial mounds represent a challenge for microbiologists. Could ancient buried soils preserve microbiomes as they do archaeological artifacts? To investigate this question, we studied the soil microbiome under a burial mound dating from 2500 years ago in Western Kazakhstan. Two soil profile cuts were established: one under the burial mound and another adjacent to the mound surface steppe soil. Both soils represented the same dark chestnut soil type and had the same horizontal stratification (A, B, C horizons) with slight alterations. DNA samples isolated from all horizons were studied with molecular techniques including qPCR and high throughput sequencing of amplicon libraries of the 16S rRNA gene fragment. The taxonomic structure of the microbiome of the buried horizons demonstrated a deep divergence from ones of the surface, comparable to the variation between different soil types (representatives of the soil types were included in the survey). The cause of this divergence could be attributed to diagenetic processes characterized by the reduction of organic matter content and changes in its structure. Corresponding trends in the microbiome structure are obvious from the beta-diversity pattern: the A and B horizons of the buried soils form one cluster with the C horizons of both buried and surface soil. This trend could generally be designated as 'mineralization'. Statistically significant changes between the buried and surface soils microbiomes were detected in the number of phylogenetic clusters, the biology of which is in the line of diagenesis. The trend of 'mineralization' was also supported by PICRUSt2 functional prediction, demonstrating a higher occurrence of the processes of degradation in the buried microbiome. Our results show a profound shift in the buried microbiome relatively the "surface" microbiome, indicating the deep difference between the original and buried microbiomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The effect of a single injection of doxorubicin, 8-day administration of two 5-hydroxypyrimidine derivatives, SNK-411 (2-Isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (hydrochloride of 2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine), on metastases, lifespan and serum cytokines has been investigated in С57ВL/6 mice after removal of a primary tumor node of Lewis lung carcinoma (LLC). LLC cells (1×106) were injected in the footpad of right hind feet of mice in control and experimental groups; after 14 days of tumor development the hind feet with the tumor were amputated at the ankle level. One hour before the amputation mice received a single injection of doxorubicin (4 mg/kg) and 8-day therapy with the 5-hydroxypyrimidine derivatives started. SNK-578 monotherapy was performed at a dose of 10 mg/kg administered intraperitoneally (i.p.). SNK-411 was administered per os at a dose of 25 mg/kg. In the case of combined therapy mice also received a single injection of doxorubicin (4 mg/kg; i.p.). The metastasis inhibition index in mice-treated with SNK-411 and SNK-578 were 53.3% as compared with control mice (with removed tumor). The mice-treated with SNK-411, doxorubicin, and the combination SNK-578 + doxorubicin had lifespan increased by 60.2%, 53.9%, and 42.9%, respectively. A single injection of doxorubicin, the course administration of the 5-hydroxypyrimidine derivative alone and in combination with single injection of doxorubicin completely decreased serum levels of the prooncogenic Th2-cytokines IL-4, and IL-6 and significantly decreased the level of the Th2-cytokine IL-5. Administration of doxorubicin, SNK-411 and SNK-578 did not influence serum concentration of Th1-cytokine interferon gamma (IFN-γ). These data confirm our previous findings that administration of the compounds studied decreased concentrations of prooncogenic IL-4 and IL-6 in tumor-bearing mice with LLC and had no effect on concentrations of the Th1-cytokine IFN-γ.

Objective: To study the effect of ethylmethylhydroxypyridine succinate (EMHPS) on the analgesic effect of the non-selective cyclooxygenase (COX) inhibitor diclofenac sodium and the selective COX-2 inhibitor etoricoxib in models of acute visceral and somatic pain and to evaluate the possibility of using EMHPS in combination with COX inhibitors to reduce their doses while maintaining analgesic efficiency., Material and Methods: We studied the effect of EMHPS with a single oral administration on the analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs): the non-selective COX inhibitor diclofenac sodium and the selective COX-2 inhibitor etoricoxib - on models of acute visceral (vinegar writhing test) and somatic pain (formalin test and mechanical hyperalgesia during inflammation) in an experiment on mice and rats., Results: In a model of acute visceral pain in mice, EMGPS (25-100 mg/kg) does not have a significant effect on its severity, but enhances the analgesic effect of diclofenac sodium (0.5 mg/kg) and etoricoxib (1 mg/kg). In the formalin test in rats, which simulates pain during surgical incisions (trauma), EMGPS (25 mg/kg) increases the severity of the analgesic effect of COX inhibitors (1 mg/kg), primarily by reducing pain in the acute phase caused by the effect of formalin on afferent neurons. In a model of mechanical hyperalgesia in rats caused by exudative inflammation after injection of a carrageenan solution into the paw, EMHPS enhances the effect of diclofenac to a greater extent than etoricoxib., Conclusion: The data obtained indicate the feasibility of a clinical study of the use of EMGPS in combination with NSAIDs for visceral and somatic pain in order to assess its ability to increase the therapeutic effect of NSAIDs.

NMDA glutamate receptors play an important role in normal and pathophysiological nociception. At the periphery, they can interact with TRPV1 ion channels. The blockade of TRPV1 ion channels decreases NMDA-induced hyperalgesia, and NMDA receptor antagonists suppress the pain response to the TRPV1 agonist capsaicin. Since TRPV1 ion channels and NMDA receptors can functionally interact at the periphery, it would be interesting to investigate the possibility that they interact in the CNS. A single subcutaneous injection of 1 mg/kg of capsaicin was found to raise the thermal pain threshold in the tail flick test in mice, which reproduces the spinal flexion reflex, owing to the ability of capsaicin to cause long-term desensitization of nociceptors. Preventive administration of either noncompetitive NMDA receptor antagonists (high-affinity MK-801 20 μg/kg and 0.5 mg/kg subcutaneously; low-affinity hemantane 40 mg/kg intraperitoneally) or the selective TRPV1 antagonist BCTC (20 mg/kg intraperitoneally) inhibit the capsaicin-induced increase in the pain threshold. Capsaicin (1 mg/kg, subcutaneous injection) induces transient hypothermia in mice, which is brought about by hypothalamus-triggered vegetative reactions. This effect is prevented by BCTC but not by the noncompetitive NMDA receptor antagonists., (Copyright ® 2023 National Research University Higher School of Economics.)

The aim of the study is to develop a method for early diagnosis of intrauterine infection (IUI). A study of markers of inflammation in the venous blood of 60 pregnant women was conducted. The study was followed by a retrospective assessment of the outcomes of pregnancies and childbirth. Of these, 33 patients with a gestation period of more than 37 weeks (full-term pregnancy) and, accordingly, 27 patients from whom the blood sample was taken at a period of less than 37 weeks - patients with the threat of premature birth (PB). PB is the main factor contributing to the development of IUI. 27 patients were diagnosed with premature rupture of the membranes (PROM). Of these, 15 are with the threat of PB. 8 of them had a diagnosed IUI. In all cases of diagnosed PROM, including those with IUI, the concentration of nitrite and nontiolate nitroso compounds (NO2-+RNO) in the mother's blood plasma was 2.3±1.2 µM, while normally it does not exceed 0.1 µM (p<0.001). Regardless of the duration of pregnancy. The use of antibiotics in the case of PROM contributed to the normalization of the concentration (NO2-+RNO). Therefore, increasing of this indicator is result of bacterial infection. Indications of other markers of inflammation: the number of leukocytes in venous blood and in a smear of vaginal contents, the level of C-RB did not significantly change in both PROM and IUI (p>0.1). Since the concentration index (NO2-+RNO) increased in almost all cases of PREM, unlike all other clinical and biochemical indicators used in modern medicine, there is an obvious sense of its use for the current monitoring of the health of pregnant women. But it is still impossible to say unequivocally about the possibility of monitoring the fetal health by concentration (NO2-+RNO) in the mother's blood., Competing Interests: The authors declare no conflict of interest.

Prostate cancer is a clinically heterogeneous disease, and accurate risk stratification of patients is becoming a key clinical task. This is the most common malignant neoplasm and the leading cause of cancer death in men worldwide. Genomic markers include tools and technologies that can predict the probability of an initial positive biopsy, reduce the number of unnecessary repeated biopsies, identify tumors with low, medium and high risk, classify the degree of disease, as well as predict and monitor the clinical response to intervention. Variants of the PTEN gene are of great interest as genetic markers of the risk of developing prostate malignancies.

Alzheimer's disease (AD) is a neurodegenerative disease that causes dementia in half of the cases. Asthma is usually found in people over 65 years of age. The etiopathogenesis of the disease is multifactorial and includes genetic factors, nutritional disorders, mitochondrial dysfunction, oxidative stress, and aging. Sex hormones have an important influence on the development of AD, as evidenced by a higher incidence in women than in men. Considering the significant influence of T on the maintenance of normal brain function, the present study is aimed at evaluating the impact of androgen deprivation therapy (ADT), as well as testosterone therapy, on the risk of AD development and progression. Although there is some clinical inconsistency between studies, androgens have a significant effect on brain function and are beneficial for AD patients. Low levels of circulating androgens should be considered as a significant risk factor for the development of AD and memory loss. With a reduced level of T in the plasma of men, its administration improves cognitive performance and memory, treatment should be started at an early stage of the disease. In men and women with AD, androgens improve mental state and slow the progression of the disease, providing a protective effect. In the future, it is necessary to conduct studies on a large population, taking into account personality factors and a more specific approach to assessing cognitive functions and the causal relationship of T administration in AD.

The main manifestations of metabolic syndrome (MS) are disorders of carbohydrate and lipid metabolism and their hormonal regulation. The combined nature of metabolic disorders can significantly affect the course and prognosis of CHF in elderly people with metabolic syndrome. To determine the features of the combined effect of metabolic laboratory parameters and biological active factors of adipose tissue in patients with CHF and metabolic syndrome on the course of the disease. A comparison was made between a group of patients with CHF complicated by MS(n=37) and a group of patients with CHF without MS (n=37). The parameters of lipid metabolism (cholesterol CH and lipoproteins LP), the lipid transport system (ApoA1 and ApoB), leptin, adiponectin and resistin and their mutual relations were studied. The ratio of ApoB/ApoAI levels was indicative, which was 0.80±0.32 in patients with CHF without MS, and 1.12±0.46 in patients with CHF with MS (p <0.05). A significant correlation was found between the ratio of ApoB/ApoA1 levels and abdominal obesity (r=0.42, p<0.05), functional class of CHF (r=0.463, p<0.05), LDL-C level (r=0.518, p<0.05), and triglycerides (r=0.476, p<0.05). Also, significant results were obtained for the leptin/adiponectin ratio. For this ratio, 4 ranks were derived depending on the value of the leptin (ng/ml)/adiponectin (mcg/ml) ratio: less than 1 - rank 0 was assigned, with values of the ratio in the range 1 - 3 - rank 1, in the range 3.1 - 6 - rank 2, and above the value 6 - rank 3. Of the 22 patients who had improved CHF at the end of hospitalization, all at the beginning of hospitalization had a rank 0 or 1 ApoB/ApoA1 ratio. Thus, ranking the values of the ratio of ApoB/ApoA1 levels, and especially leptin/adiponectin, can suggest the probability of successful treatment of CHF or the probability of deterioration of the patient's condition, up to a fatal outcome., Competing Interests: The authors declare no conflict of interest.

Drosophila melanogaster is one of the most famous insects in biological research. It is widely used to analyse functions of different genes. The phosphatidylcholine lysophospholipase gene swiss cheese was initially shown to be important in the fruit fly nervous system. However, the role of this gene in non-nervous cell types has not been elucidated yet, and the evolutional explanation for the conservation of its function remains elusive. In this study, we analyse expression pattern and some aspects of the role of the swiss cheese gene in the fitness of Drosophila melanogaster . We describe the spatiotemporal expression of swiss cheese throughout the fly development and analyse the survival and productivity of swiss cheese mutants. We found swiss cheese to be expressed in salivary glands, midgut, Malpighian tubes, adipocytes, and male reproductive system. Dysfunction of swiss cheese results in severe pupae and imago lethality and decline of fertility, which is impressive in males. The latter is accompanied with abnormalities of male locomotor activity and courtship behaviour, accumulation of lipid droplets in testis cyst cells and decrease in spermatozoa motility. These results suggest that normal swiss cheese is important for Drosophila melanogaster fitness due to its necessity for both specimen survival and their reproductive success.

Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese ( sws )-the evolutionarily conserved ortholog of human NTE/PNPLA6- in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

Human gut microbiota is a dynamic and variable system that can change over time and in response to different diets and treatments. There is currently no doubt that gut microbiota can provide interesting therapeutic opportunities, since it can metabolize biologically active molecules, drugs, and their precursors, and control their bioavailability. Moreover, it can produce both beneficial and dangerous metabolites that influence host's health. In this review, we summarize the current knowledge on the involvement of gut microbiota in two chronic human pathologies that represent the greatest challenges of modern medicine: atherosclerosis and cancer. Interesting parallels are observed between the mechanisms and possible treatment approaches of these pathologies. Some of the common effects of therapeutic agents targeting both pathologies, such as anti-inflammatory activity, are partially mediated by the gut microbiota. We will discuss the effects of common drugs (metformin, statins and aspirin) and various nutraceuticals on gut microbiota and outline the pathways of microbial involvement in mediating the pleiotropic beneficial effects of these agents in atherosclerosis and cancer., (Copyright © 2020. Published by Elsevier Ltd.)

Glia are crucial for the normal development and functioning of the nervous system in many animals. Insects are widely used for studies of glia genetics and physiology. Drosophila melanogaster surface glia (perineurial and subperineurial) form a blood-brain barrier in the central nervous system and blood-nerve barrier in the peripheral nervous system. Under the subperineurial glia layer, in the cortical region of the central nervous system, cortex glia encapsulate neuronal cell bodies, whilst in the peripheral nervous system, wrapping glia ensheath axons of peripheral nerves. Here, we show that the expression of the evolutionarily conserved swiss cheese gene is important in several types of glia. swiss cheese knockdown in subperineurial glia leads to morphological abnormalities of these cells. We found that the number of subperineurial glia nuclei is reduced under swiss cheese knockdown, possibly due to apoptosis. In addition, the downregulation of swiss cheese in wrapping glia causes a loss of its integrity. We reveal transcriptome changes under swiss cheese knockdown in subperineurial glia and in cortex + wrapping glia and show that the downregulation of swiss cheese in these types of glia provokes reactive oxygen species acceleration. These results are accompanied by a decline in animal mobility measured by the negative geotaxis performance assay.

The effects of intraperitoneal administration of SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) in a dose of 25 mg/kg (the total dose of 350 mg/kg) and SNK-578 (hydrochloride of 2-isobutyl-4,6-dimethyl-5- hydroxypyrimidine) in a dose of 10 mg/kg (the total dose of 140 mg/kg) on tumor growth and concentration of cytokines in the blood serum were studied in female CBA mice. Substances were administrated from the 2nd to 15th days of tumor development. Tumor growth inhibition (TGI) and serum cytokine level were studied on the 7th day after the end of compounds administration (21st day of tumor growth). In intact control group (n=10) median tumor mass was 1255 mg. TGI in the group of animals treated with SNK-411 was 47%; in the group of mice treated with SNK-578 TGI was 87%, tumor mass demonstrated 7.4-fold reduction. Serum concentrations of cytokines (IL-6, IL-10, IL-17A and IFN-γ) in tumor-bearing group of mice were higher versus the intact control group by 229%, 40%, 60% and 81%, respectively. Highly active SNK-578 decreased concentrations of prooncogenic IL-10, IL-17A and proinflammatory IL-6, by 61%, 70% and 29% as compared to tumor-bearing control group. SNK-411 decreased concentrations of prooncogenic IL-10 and IL-17A by 48% and 60%, respectively, and did not affect concentration of IL-6. Taking into consideration that IL-6 participates in autoimmune reactions, we can assume that the immune control is one of the crucial mechanisms of antitumor effect of SNK-578. All results are statistically significant.

Mitochondrial dysfunction and ubiquitin-proteasome system (UPS) failure contribute significantly to the development of Parkinson's disease (PD). The proteasome subunit Rpn13 located on the regulatory (19S) subparticle play an important role in the delivery of proteins, subjected to degradation, to the proteolytic (20S) part of proteasome. We have previously found several brain mitochondrial proteins specifically bound to Rpn13 (Buneeva et al. (2020) Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 14, 297-305). In this study we have investigated the effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroprotector isatin on the mitochondrial subproteome of Rpn13-binding proteins of the mouse brain. Administration of MPTP (30 mg/kg) to animals caused movement disorders typical of PD, while pretreatment with isatin (100 mg/kg, 30 min before MPTP) reduced their severity. At the same time, the injection of MPTP, isatin, or their combination (isatin + MPTP) had a significant impact on the total number and the composition of Rpn13-binding proteins. The injection of MPTP decreased the total number of Rpn13-binding proteins in comparison with control, and the injection of isatin prior to MPTP or without MPTP caused an essential increase in the number of Rpn13-binding proteins, mainly of the functional group of proteins participating in the protein metabolism regulation, gene expression, and differentiation. Selected biosensor validation confirmed the interaction of Rpn13 subunit of proteasome with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) revealed while proteomic profiling. The results obtained testify that under the conditions of experimental MPTP-induced parkinsonism the neuroprotective effect of isatin may be aimed at the interaction of mitochondria with the components of UPS.

High-throughput 16S rRNA sequencing was performed to compare the microbiomes inhabiting two contrasting soil types-sod-podzolic soil and chernozem-and the corresponding culturome communities of potentially cellulolytic bacteria cultured on standard Hutchinson media. For each soil type, soil-specific microorganisms have been identified: for sod-podzolic soil-Acidothermus, Devosia, Phenylobacterium and Tumebacillus, and for chernozem soil-Sphingomonas, Bacillus and Blastococcus. The dynamics of differences between soil types for bulk soil samples and culturomes varied depending on the taxonomic level of the corresponding phylotypes. At high taxonomic levels, the number of common taxa between soil types increased more slowly for bulk soil than for culturome. Differences between soil-specific phylotypes were detected in bulk soil at a low taxonomic level (genus, species). A total of 13 phylotypes were represented both in soil and in culturome. No relationship was shown between the abundance of these phylotypes in soil and culturome., Competing Interests: The authors have declared that no competing interests exist.

Background: Atrial fibrillation (AF) can be maintained by localized intramural reentrant drivers. However, AF driver detection by clinical surface-only multielectrode mapping (MEM) has relied on subjective interpretation of activation maps. We hypothesized that application of machine learning to electrogram frequency spectra may accurately automate driver detection by MEM and add some objectivity to the interpretation of MEM findings., Methods: Temporally and spatially stable single AF drivers were mapped simultaneously in explanted human atria (n=11) by subsurface near-infrared optical mapping (NIOM; 0.3 mm 2 resolution) and 64-electrode MEM (higher density or lower density with 3 and 9 mm 2 resolution, respectively). Unipolar MEM and NIOM recordings were processed by Fourier transform analysis into 28 407 total Fourier spectra. Thirty-five features for machine learning were extracted from each Fourier spectrum., Results: Targeted driver ablation and NIOM activation maps efficiently defined the center and periphery of AF driver preferential tracks and provided validated annotations for driver versus nondriver electrodes in MEM arrays. Compared with analysis of single electrogram frequency features, averaging the features from each of the 8 neighboring electrodes, significantly improved classification of AF driver electrograms. The classification metrics increased when less strict annotation, including driver periphery electrodes, were added to driver center annotation. Notably, f1-score for the binary classification of higher-density catheter data set was significantly higher than that of lower-density catheter (0.81±0.02 versus 0.66±0.04, P <0.05). The trained algorithm correctly highlighted 86% of driver regions with higher density but only 80% with lower-density MEM arrays (81% for lower-density+higher-density arrays together)., Conclusions: The machine learning model pretrained on Fourier spectrum features allows efficient classification of electrograms recordings as AF driver or nondriver compared with the NIOM gold-standard. Future application of NIOM-validated machine learning approach may improve the accuracy of AF driver detection for targeted ablation treatment in patients.

Objective: Myotonia congenita (MC) is a rare muscle disease characterized by sarcolemma over-excitability inducing skeletal muscle stiffness. It can be inherited either as an autosomal dominant (Thomsen's disease) or an autosomal recessive (Becker's disease) trait. Both types are caused by loss-of-function mutations in the CLCN1 gene, encoding for ClC-1 chloride channel. We found a ClC-1 mutation, p.G411C, identified in Russian patients who suffered from a severe form of Becker's disease. The purpose of this study was to provide a solid correlation between G411C dysfunction and clinical symptoms in the affected patient. Methods: We provide clinical and genetic information of the proband kindred. Functional studies include patch-clamp electrophysiology, biotinylation assay, western blot analysis, and confocal imaging of G411C and wild-type ClC-1 channels expressed in HEK293T cells. Results: The G411C mutation dramatically abolished chloride currents in transfected HEK cells. Biochemical experiments revealed that the majority of G411C mutant channels did not reach the plasma membrane but remained trapped in the cytoplasm. Treatment with the proteasome inhibitor MG132 reduced the degradation rate of G411C mutant channels, leading to their expression at the plasma membrane. However, despite an increase in cell surface expression, no significant chloride current was recorded in the G411C-transfected cell treated with MG132, suggesting that this mutation produces non-functional ClC-1 chloride channels. Conclusion: These results suggest that the molecular pathophysiology of G411C is linked to a reduced plasma membrane expression and biophysical dysfunction of mutant channels, likely due to a misfolding defect. Chloride current abolition confirms that the mutation is responsible for the clinical phenotype., (Copyright © 2020 Altamura, Ivanova, Imbrici, Conte, Camerino, Dadali, Polyakov, Kurbatov, Girolamo, Carratù and Desaphy.)

A selective prolyl endopeptidase (PEP) inhibitor benzyloxycarbonyl-prolyl-prolinal (IC50 = 1,61±0,12 nmol/l) and a nonselective PEP inhibitor benzyloxycarbonyl-methionyl-cyanopyrrolidine (IC50 = 2,01±0,14 nmol/l) exhibit a comparable antiexudative effect at single doses of 2 mg/kg and 5 mg/kg (intraperitoneally) in outbred mice with peritonitis induced by 1% acetic acid. However, only benzyloxycarbonyl-methionyl-cyanopyrrolidine at a dose of 5 mg/kg reduces acetic acid induced pain in animals.

Accumulation of essential/beneficial and non-essential chemical elements by submerged (Stuckenia pectinata (L.) Börner) and emergent (Phragmites australis (Cav.) Trin. ex Steud.) rooted macrophytes in three water bodies was studied as dependent on water salinity (specific conductivity) and main environmental factors (temperature, pH of water, growing period, element contents in water and sediments). Inductively coupled plasma optical emission spectrometry (ICP - OES) was used for the element detection in the plants, sediments, and water. Multivariate statistics redundancy analysis (RDA) showed that investigated factors together explained 37.8 - 44.7% and 29.9 - 42.6% of the essential/beneficial and non-essential elements variability, respectively, whereas salinity was one of the main factors determining the accumulation of a number of elements (Mg, S, Na, Li, Sr, Sb) by the macrophytes. A decrease in the essential element contents (K, P, N, Cu, Zn) was observed in both species of the macrophytes during the growing season. Environmental factors (salinity, growing period, and pH) were more significant than the element contents in water and the sediments for the essential/beneficial element accumulation by two species of the macrophytes. The element contents in the sediments to a greater extent determined non-essential element accumulation by P. australis than by S. pectinata. The study showed that the efficiency of using P. australis and S. pectinata for remediation of aquatic ecosystems contaminated by heavy metals should not decrease with a salinity increase., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Efficient diagnostic approaches to detect coronary artery disease (CAD) in elderly patients are necessary to ensure optimal and timely treatment. The population of suspected CAD patients older than 70 years is especially vulnerable and constantly growing. Finding the optimal diagnostic approach is challenging due to certain features of this population, such as high prevalence of comorbidities, existing contraindications to exercise tests or cognitive decline, which hinders correct assessment of the patient's situation. Moreover, some symptoms of CAD can have variable significance in the elderly compared to younger adult groups. In this review, we present current recommendations of the United States (US) and European cardiologists' associations and discuss their applicability for diagnostics in the elderly population. Exercise electrocardiogram (ECG) and exercise stress echocardiography (SE) tests are not feasible for a substantial proportion of elderly patients. Coronary computed tomography angiography (CTA) appears to be an attractive alternative for such patients, but is not universally applicable; for instance, it is problematic in patients with significant calcification of the vessels. Moreover, more studies are needed to compare the results delivered by CTA to those of other diagnostic methods. Future efforts should be focused on comparative studies to better understand the limits and advantages of different diagnostic methods and their combinations. It is possible that some of the currently used diagnostic criteria could be improved to better accommodate the needs of the elderly population.

Purpose of Review: Mutations in both nuclear and mitochondrial genes are associated with the development of atherosclerotic lesions in arteries and may provide a partial explanation to the focal nature of lesion distribution in the arterial wall. This review is aimed to discuss the genetic aspects of atherogenesis with a special focus on possible pro-atherogenic variants (mutations) of the nuclear and mitochondrial genomes that may be implicated in atherosclerosis development and progression., Recent Findings: Mutations in the nuclear genes generally do not cause a phenotype restricted to a specific vascular wall cell and manifest themselves mostly at the organism level. Such mutations can act as important contributors to changes in lipid metabolism and modulate other risk factors of atherosclerosis. By contrast, mitochondrial DNA (mtDNA) mutations occurring locally in the arterial wall cells or in circulating immune cells may play a site-specific role in atherogenesis. The mosaic distribution of heteroplasmic mtDNA mutations in the arterial wall tissue may explain, at least to some extent, the locality and focality of atherosclerotic lesions distribution. The genetic mechanisms of atherogenesis include alterations of both nuclear and mitochondrial genomes. Altered lipid metabolism and inflammatory response of resident arterial wall and circulating immune cells may be related to mtDNA damage and defective mitophagy, which hinders clearance of dysfunctional mitochondria. Mutations of mtDNA can have mosaic distribution and locally affect functionality of endothelial and subendothelial intimal cells in the arterial wall contributing to atherosclerotic lesion development.

The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.

The current view on atherosclerosis positions it as a multifactorial disorder that results from the interplay between lipid metabolism disturbances and inflammatory processes. Oxidative stress is proven to be one of the initiating factors in atherosclerosis development, being implicated both in the inflammatory response and in atherogenic modifications of lipoproteins that facilitate lipid accumulation in the arterial wall. The hallmark of oxidative stress is the elevated level of reactive oxygen species (ROS). Correspondingly, the activity of major ROS-generating enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, and cyclooxygenases, is an important element in atherosclerosis development. In particular, the role of NADPH oxidases in atherosclerosis development has become a subject of intensive research. Aberrant activity of NADPH oxidases was shown to be associated with cardiovascular disease in humans. With regard to atherosclerosis, several important pathological components of the disease development, including endothelial dysfunction, inflammation, and vascular remodeling, involve aberrations in NADPH oxidases functioning. In humans, NADPH oxidases are represented by four isoforms expressed in vascular tissues, where they serve as the main source of ROS during atherogenesis. Moreover, recent studies have demonstrated their impact on vascular remodeling processes. Interestingly, one of the NADPH oxidase isoforms, NOX4, was shown to have an atheroprotective effect. Despite the growing evidence of the crucial involvement of NADPH oxidases in atherosclerosis pathogenesis, the available data still remains controversial. In this narrative review, we summarize the current knowledge of the role of NADPH oxidases in atherosclerosis and outline the future directions of research.

The role of mitochondria in cardiovascular diseases is receiving ever growing attention. As a central player in the regulation of cellular metabolism and a powerful controller of cellular fate, mitochondria appear to comprise an interesting potential therapeutic target. With the development of DNA sequencing methods, mutations in mitochondrial DNA (mtDNA) became a subject of intensive study, since many directly lead to mitochondrial dysfunction, oxidative stress, deficient energy production and, as a result, cell dysfunction and death. Many mtDNA mutations were found to be associated with chronic human diseases, including cardiovascular disorders. In particular, 17 mtDNA mutations were reported to be associated with ischemic heart disease in humans. In this review, we discuss the involvement of mitochondrial dysfunction in the pathogenesis of atherosclerosis and describe the mtDNA mutations identified so far that are associated with atherosclerosis and its risk factors.

The effects of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine chlorohydrate) on the tumor growth and survival of male C57BL/6 mice with transplanted Lewis lung epidermoid carcinoma (LLC) were studied in animals receiving intraperitoneal treatment on days 2-15 of tumor development. Compound SNK-578 in a dose of 10 mg/kg significantly inhibited tumor growth (by 3.6 times; 72.2%) in 7 days after the treatment was discontinued, while compound SNK-411 in a dose of 25 mg/kg only negligibly reduced tumor volume (by 41.7%). A combination of course of SNK-411 (25 mg/kg) and single intraperitoneal dose of doxorubicin (4 mg/kg) significantly inhibited the tumor growth (by 2.2 times; 55.2%), while the combination of SNK-578 (10 mg/kg) with doxorubicin (4 mg/kg) was in fact ineffective. The median survival of animals with untreated LLC was 28 days. Median survival of mice injected with SNK-578 (10 mg/kg) was 43 days, hence, the lifespan of mice with LLC was by 38.6% longer after the treatment. Two of ten mice in this group developed no tumors.

Background: Monopolar energy (ME) is routinely used in appendectomy. This study aimed to investigate the degree of lateral thermal spread generated by ME and to evaluate the thermal injury sustained by the close-lying tissues., Methods: Appendectomy with a monopolar Maryland dissector was performed in 8 rabbits (at 30 and 60 W power settings). A high-resolution infrared camera was used to record tissue heating during the intervention. After autopsy macroscopic changes were evaluated and tissue samples were subjected to myeloperoxidase (MPO) assay and histological examination., Results: No significant differences in the extent of thermal spread, MPO activity and histological signs of inflammation were observed between groups. Regardless of the power settings, the heat spread exceeded 2 cm laterally along the mesoappendix when application time exceeded 3 s. The spread of heat through tubular structures in both groups caused a significant temperature rise in the nearby intestinal loop, resulting in perforation (n = 3) and necrosis (n = 1)., Conclusions: Application time is critical in thermal spread during appendectomy aided by ME. Tubular anatomic structures can enhance thermal injury on distant tissues. The observed effects of ME bear clinical relevance that need further investigation.

Chronification of inflammation is the process that lies at the basis of several human diseases that make up to 80% of morbidity and mortality worldwide. It can also explain a great deal of processes related to aging. Atherosclerosis is an example of the most important chronic inflammatory pathology in terms of public health impact. Atherogenesis is based on the inflammatory response of the innate immunity arising locally or focally. The main trigger for this response appears to be modified low-density lipoprotein (LDL), although other factors may also play a role. With the quick resolution of inflammation, atherosclerotic changes in the arterial wall do not occur. However, a violation of the innate immunity response can lead to chronification of local inflammation and, as a result, to atherosclerotic lesion formation. In this review, we discuss possible mechanisms of the impaired immune response with a special focus on mitochondrial dysfunction. Some mitochondrial dysfunctions may be due to mutations in mitochondrial DNA. Several mitochondrial DNA mutations leading to defective mitophagy have been identified. The regulatory role of mitophagy in the immune response has been shown in recent studies. We suggest that defective mitophagy promoted by mutations in mitochondrial DNA can cause innate immunity disorders leading to chronification of inflammation.

It was shown that finasteride, a 5α-reductase inhibitor (50 mg/kg, intraperitoneally) produced analgesic and antiexudative effects in experimental peritonitis induced by intraperitoneal injection of 1% acetic acid. These results agree with published data on its anti-inflammatory properties and ability to potentiate the analgesic effect of morphine in rodents. New pyrazolo[C] pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]pyridine-3-on, chloral hydrate) injected intraperitoneally in doses of 20-80 mg/kg produced dose-dependent antiexudative effects, but exhibited no analgesic properties.

Cyanopyrrolidine derivatives benzyloxycarbonyl-methionyl-cyanopyrrolidine (ZMetPrdN), benzyloxycarbonylphenylalanyl- cyanopyrrolidine (ZPhePrdN), tert-butyl-hydroxycarbonyl-glycyl-cyanopyrrolidine (BocGlyPrdN), tert-butyl-hydroxycarbonyl-methionyl-cyanopyrrolidine (BocMetPrdN) are inhibitors of prolylendopeptidase (PREP; EC 3.4.21.26) with an IC50 of 2 nM to 12 nM. ZMetPrdN, ZPhePrdN and BocMetPrdN additionally inhibited dipeptidyl peptidase IV (DPP-4; EC 3.4.14.5) with an IC50 of 1100 nM to 3200 nM. All the compounds have antinociceptive properties in the acetic acid writhing test in mice. But only cyanopyrrolidine derivatives with aromatic substituents decrease exudative inflammation. The cyanopyrrolidine derivatives also increase PREP activity and compensatorily reduce DPP-4 activity in the serum of mice three hours after the induction of inflammation. Thus, cyanopyrrolidine derivatives exhibit antinociceptive and antiexudative properties in part via their effect on PREP.

Background: Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques., Objectives: Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently, there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease., Results: Mitochondria of blood and arterial wall cells appear to be one of the important factors in disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment., Conclusion: Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Isatin (indol-2,3-dione), an endogenous biofactor found in the brain, peripheral tissues and biological body fluids of humans and animals, exhibits a wide range of biological and pharmacological activities. They are realized via interaction with numerous isatin-binding proteins. Some of these proteins identified during proteomic profiling of the brain are involved in the development of neurodegenerative pathology. In the context of the neuroprotective effect, the effect of isatin is comparable to the effects of deprenyl (selegiline), a pharmacological agent used for treatment of Parkinson's disease. In this study, we have investigated the effect of a single dose administration of isatin (100 mg/kg) and deprenyl (10 mg/kg) to mice on the profile of the brain isatin-binding proteins. Comparative proteomic analysis of brain isatin-binding proteins of mice treated with isatin or deprenyl resulted in identification of a representative group of proteins (n=200) sensitive to the administration of these substances. The change in the profile of isatin-binding proteins may be obviously attributed to accumulation of isatin and deprenyl in the brain and their interaction with target proteins; this prevents protein binding to the affinity sorbent. Thus identified brain isatin-binding proteins of the control animals obviously represent specific targets that interact directly with isatin (and also with deprenyl) in vivo . Isatin or deprenyl administered to animals interact with these proteins and thus inhibit their binding to the affinity sorbent (immobilized isatin analogue).

This review summarizes the available data on the combined administration of mexidol with medicines of different pharmacotherapeutic groups. Mexidol has a multifaceted mechanism of action and exhibits a wide range of pharmacological effects. It enhances therapeutic effects of a variety of drugs in research and clinical settings, boosts the effectiveness of therapy prescribed in accordance with the applicable federal standards and contributes to reducing the severity of complications. Effectiveness data and pathogenetic considerations underpinning combination therapy with mexidol and other drugs suggest that this is a viable approach for treating cerebrovascular and cardiovascular diseases, diseases of the nervous system, open-angle glaucoma and alcohol intoxication as well as a number of other diseases.

Methane seepages are widespread in the Black Sea. However, microbiological research has been carried out only at the continental shelf seeps. The present work dealt with coastal gas seepages of the Kalamit Bay (Black Sea). High-throughput 16S rRNA gene sequencing and radiotracer analysis (14С and 35S) were used to determine the composition of the microbial community and the rates of microbial sulfate reduction and methane oxidation. The phylum Proteobacteria, represented mainly by sulfate reducers of the class Deltaproteobacteria, was the predominant in sequence dataset. Bacteroidetes and Planctomycetes were other numerous phyla. Among archaea, the phylum Woesearchaeota and Marine Benthic Group B were predominant in the upper horizons. Relative abundance of Euryarchaeota of the families Methanomicrobiaceae and Methanosarcinaceae (including ANME-3 archaea) increased in deeper sediment layers. Sulfate reduction rate (up to 2.9 mmol/L × day) was considerably higher than the rate of anaerobic methane oxidation (up to 43.4 μmol/L × day), which indicated insignificant contribution of anaerobic methane oxidation to the total sulfide production.

The main goal of modern microbial ecology is to determine the key factors influencing the global diversity of microorganisms. Because of their complexity, soil communities are largely underexplored in this context. We studied soil genesis (combination of various soil-forming processes, specific to a particular soil type) that is driven by microbial activity. To investigate the interrelation between soil type and microbial diversity, we analyzed six soil types that are common in Russia, the Crimea, and Kazakhstan using 16S rDNA pyrosequencing. Soils of different types varied in the taxonomic composition of microbial communities. Their core microbiomes comprised 47 taxa within the orders Solirubrobacteriales and Hyphomicrobiaceae and the Gaiellaceae family. Two species from Bradyrhizobiaceae and Solirubrobactriaceae were present in all samples, whereas most other taxa were soil-type specific. Multiple resampling analysis revealed that two random soil samples from the same soil type shared more taxa than two samples from different types. The differences in community composition were mostly affected by the variation in pH values and exchangeable potassium content. The results show that data on the soil microbiome could be used for soil identification and clarification of their taxonomic position., (Copyright © 2018. Published by Elsevier B.V.)

A quantitative study of lymphoid cells in the B- and T-cell-dependent areas of intestinal lymphoid nodules and mesenteric lymph nodes in behaviorally passive and active rats was performed at various periods after acute stress on the model of 1-h immobilization with simultaneous electrocutaneous stimulation. Stress exposure is accompanied by a decrease in the number of lymphoid cells in immunogenic structures of the gastrointestinal tract. Post-stress changes in the cytoarchitectonics of B- and T-cell-dependent areas in mesenteric lymph nodes of animals are less pronounced than in lymphoid nodules. Quantitative changes in lymphoid cells of B-cell-dependent areas in the small intestine of rats are greater than in T-cell-dependent areas. Changes in the cellular composition of immunogenic structures in the digestive system are most significant at the early stages of the post-stress period (1st week). Passive rats are characterized by significant changes in the cytoarchitectonics of B- and Tcell-dependent areas in the small intestine after extreme exposure, which illustrates functional exhaustion of the lymphoid tissue in stress-predisposed specimens.

Aim: To analyze an efficacy of FT-protocol in patients with acute cholecystitis., Material and Methods: Prospective randomized study included 102 patients (45 of main group (FT) and 57 of control groups). Patients did not differ by TG13 severity index. The protocol included information, antibiotic prophylaxis, restriction of drainage, intraperitoneal anesthesia with long-term anesthetics, low pressure pneumoperitoneum, antiemetics in the presence of risk factors, early activation and feeding of the patient. Pain was assessed by VAS immediately after surgery, and 2, 6 and 12-24 hours postoperatively., Results: Surgery time was similar in both groups. Need for anesthesia and pain severity were significantly lower in the FT group. A total absence of pain (VAS 0-1) on the 1 st postoperative day was noted in 8 (17.7%) of the FT group and 2 (3.5%) patients of the control group (p=0.038). Shoulder pain developed in 4 (8.9%) cases of the main and 22 (38.6%) cases of the control group (p=0.001). Postoperative nausea developed in 13% of the FT group vs 40.5% in the control group (p=0.05). Hospital-stay was 1.29±0.7 days and 2.7±1.6 (p<0.0001), respectively. The time of the first stool was similar. Twenty-four (53.5%) patients of the FT group and 8,9% of the control group were discharged on 1 st postoperative day. There were 2 (IIIA) complications in the main group and 3 - in the control group (IIIA, IIIB and IV). There were no mortality and readmissions., Conclusion: FT protocol in AC reduce postoperative pain, dyspepsia, shoulder pain and in-hospital stay with equal number of postoperative complications.

Aim: To analyze outcomes of fast track rehabilitation in patients with acute appendicitis., Material and Methods: Prospective, randomized multi-center trial including 86 patients was conducted. There were 38 patients in the main group and 48 in the control group. All patients underwent laparoscopic appendectomy under endotracheal anesthesia. Protocol included informing, no premedication, glucose infusion prior to surgery, antibiotics administration, mesoappendix excision, limited deployment of drainage tubes, intraabdominal prolonged anesthesia, minimal pneumoperitoneum, limited irrigation, minimum power monopolar electrocautery, antiemetics, early activation and eating (2 and 6 hours after surgery). Pain was evaluated by visual-analogue scale. Auscultative peristalsis was considered every 2 hours after surgery. Cortisol level was assessed preoperatively, in 6 and 12-24 hours after surgery in 11 (29%) and 15 (31%) patients of the main and control groups respectively. Discharge criteria: no leukocytosis, fever and pain syndrome requiring anesthesia, no signs of complications and patient's consent., Results: Terms of disease, gender, age and comorbidities were similar in all patients. Duration of surgery under minimal pneumoperitoneum and standard pressure was also similar: 69.2±3.98 and 70.9±3.89 min (p=0.762). Pain syndrome grade and need for analgesics were significantly lower in the main group within entire follow-up. Pain syndrome was absent at the 1 st postoperative day in 16 (42%) and 2 (4.1%) patients of both groups, respectively (score 0-1). Phrenic nerve syndrome was observed in 36.8% of the main group and 60.4% of the control group (p=0.05). Incidence of dyspepsia and terms of peristalsis onset were similar. Length of hospital-stay was 1.45 days in the main group and 3.15 days in the control group (p=0.002). In the main group 18 (47%) patients were discharged on the first day after surgery. There were only 4 (8.3%) patients with similar hospital-stay in the control group (p<0.001). There were no repeated hospitalizations. Postoperative cortisol concentration was similar in both groups as well as in complicated and uneventful postoperative period. In the main group postoperative intestinal paresis (Clavien-Dindo grade 2) occurred in 1 patient. In the control group 7 patients had postoperative infiltrate and 1 patient - intestinal paresis (Clavien-Dindo grade 2). Postoperative drainage tube was deployed in 3 out of 7 patients with postoperative infiltrates and 6 of them received antibiotic therapy. Medication was successfully applied in all patients with complications., Conclusion: There are some advantages of FTR for AA including reduced pain syndrome, morbidity and less length of hospital-stay. Issue of cortisol concentration requires further trials.

Rats with experimental Parkinson's syndrome induced by seven-day intraperitoneal administration of rotenone at a dose of 2.75 mg/kg have an increased activity of prolylendopeptidase (EC 3.4.21.26, PREP) in blood serum and a decreased activity of adenosine deaminase (EC 3.5.4.4, ADA) in serum and in the prefrontal cortex. PREP and ADA activity in other brain structures (in the striatum, hypothalamus and hippocampus) did not change; dipeptidyl peptidase IV activity (EC 3.4.14.5, DPP-4, CD26) also remained constant in serum and in all the brain structures investigated. Afobazole and levodopa, which exhibit antiparkinsonian activity in this model of Parkinson's syndrome, decrease elevated PREP activity in serum and increase reduced ADA activity in the prefrontal cortex of rats with the experimental pathology. Meanwhile, treatment with the study drugs was associated with a decrease of ADA activity in the other brain structures.

In 60-day-old Wistar rats with fetal valproate syndrome, the brain to body weight ratio was higher by 9.4% and activity of dipeptidyl peptidase IV in the serum and cerebrospinal fluid was higher by 18.4 and 40.6%, respectively, than in healthy controls. Activity of prolylendopeptidase in the serum and cerebrospinal fluid in rats with the fetal valproate syndrome did not differ from the control.

Collagen I gels with protein concentrations of 1, 2, and 3.5 mg/ml were prepared and embedded in a porous polylactide scaffold to reduce their contraction. Concentration of the gel did not affect its degradation. Collagen gels promoted the formation of cell networks. The cells in the collagen gel with a concentration of 1 mg/ml embedded in polylactide scaffold had elongated spindle-like shape, in contrast to flattened cells in collagen gel of the same concentration not embedded in the scaffold. Stabilization of the collagen gel in the polylactide scaffold promoted active synthesis of laminin and fibronectin by cells as soon as on day 5 of culturing in comparison with that in free collagen substrate.

This study is a comparative analysis of samples of archived (stored for over 70-90 years) and modern soils of two different genetic types-chernozem and sod-podzolic soils. We revealed a reduction in biodiversity of archived soils relative to their modern state. Particularly, long-term storage in the museum exerted a greater impact on the microbiomes of sod-podzolic soils, while chernozem samples better preserved the native community. Thus, the persistence of microbial DNA in soil is largely determined by the physico-chemical characteristics that differ across soil types. Chernozems create better conditions for the long-term DNA preservation than sod-podzolic soils. This results in supposedly higher levels of biodiversity conservation in the microbiomes of chernozem with preservation of major microbial taxa dominant in the modern (control) soil samples, which makes archived chernozems a promising object for paleosoil studies.

Modified low-density lipoprotein (LDL) is the main source of lipid accumulation in the arterial wall affected by atherosclerosis. We aimed to compare the properties of apolipoprotein B (apoB) from native and modified LDL. Modified (desialylated) LDL and native LDL were extracted from blood of atherosclerotic patients. We characterized apoB structure of LDL particles in total LDL preparation, circulating modified LDL (cmLDL), and native LDL. Intact cmLDL had a twofold lower content of free amino groups than native LDL. Delipidated apoB from cmLDL also had a lower content of free amino groups. The rates of tryptic hydrolysis and elastase digestion of cmLDL were twofold higher in comparison to native LDL. Therefore, cmLDL from atherosclerotic patients had altered apoB properties. Our observations strengthen the hypothesis of multiple modification of LDL in the bloodstream and underscore the importance of desialylated LDL as a possible marker of atherosclerosis.

Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogs in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose-cysteamine. We demonstrated that the analogs break down into cysteamine extracellularly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown, is necessary to pursue the potential of these analogs as pro-drugs., (Published by Elsevier Ltd.)