Search

Introduction. A vaccine against hepatitis C has not yet been developed. Recombinant proteins and plasmids encoding hepatitis C virus (HCV) proteins, the components of candidate vaccines, induce a weak immune response and require the use of adjuvants. The aim of the work was to study the adjuvant action of an aqueous solution of fullerene C60 during immunization of mice with HCV recombinant protein NS5B (rNS5B) that is an RNA-dependent RNA polymerase, or with NS5B-encoding pcNS5B plasmid. Materials and methods. An aqueous solution of dispersed fullerene (dnC60) was obtained by ultrafiltration. C57BL/6 mice were immunized with rNS5B subcutaneously, pcNS5B intramuscularly mixed with different doses of dnC60 three times, then the humoral and cellular response to HCV was evaluated. Results. Mice immunization with rNS5B in a mixture with dnC60 at doses of 250 g/mouse significantly induced humoral response: a dose-dependent increase in IgG1 antibody titers was 720 times higher than in the absence of fullerene. There was no increase in the cellular response to rNS5B when administered with dnC60. The humoral response to DNA immunization was weak in mice of all groups receiving pcNS5B. The cellular response was suppressed when the plasmid was injected in a mixture with dnC60. Conclusions. Dispersed fullerene dnC60 is a promising adjuvant for increasing the immunostimulating activity of weakly immunogenic proteins including surface and other HCV proteins, important for a protective response. Further research is needed to enhance the ability of dnC60 to boost the cellular immune response to the components of the candidate vaccine.

Targeted treatment with somatostatin analogues (SA) in acromegaly and neuroendocrine neoplasms may have some benefits compared to curative treatments, because these agents decrease excessive hormone secretion and exert a tumor-suppressive effect. Monotherapy and combination therapy with SA is well tolerated and bears no risk of debilitating iatrogenic complications. In acromegaly caused by somatotropin producing pituitary tumor, first generation SA are treatment of choice after non-radical adenomectomy, as well as in the cases when patients reject surgery. Treatment efficacy depends on the pathomorphological types of somatotropic tumors, which are different in their receptor phenotype, clinical scenario and proliferative activity. The first generation SA are successfully used for medical treatment of other pituitary tumors (thyrotropic, corticotropic, gonadotropic, lactotropic with resistance to dopamine agonists), as well as for adjuvant therapy of neuroendocrine and non-endocrine neoplasms and elimination of various gastrointestinal disorders. The anti-secretory and anti-tumor effects of SA have been proven for gastroenteropancreatic tumors (carcinoid syndrome, vipomas, gastrinomas, insulinomas, glucagonomas, somatostatinomas). Targeted selection of patients for treatment with first generation SA based on the receptor phenotypes of malignant cells would facilitate more rapid achievement of biochemical remission, improvement of quality of life and survival.

Metabolic syndrome (MS) is a widespread polyethiological clustering characterized by metabolic, hormonal disorders and clinical manifestations that significantly increase the risk of developing cardiovascular diseases, atherosclerosis, type II diabetes and other pathological conditions. An important role in the development of MS is assigned to the intestinal microbiota. To develop new therapeutic agents for correction of MS manifestations, it is necessary to develop adequate experimental models. In this paper, comparative studies were conducted to assess the parameters of lipid metabolism, the content of peptide hormones, morphological changes in liver tissue, and the quantitative and generic composition of the intestinal microbiota of mice. Experimental models of experimental hyperlipidemia (HL) caused by the introduction of poloxamer 407 (Pol407) and alimentary MS (a diet with fructose and the addition of cholesterol to the feed) were used. Significant increase in the levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) was found in the group of mice treated with Pol407 injections. To assess the indicators of carbohydrate metabolism in blood serum, the following markers were determined: insulin, adiponectin, leptin. In the alimentary MS model a decrease in adiponectin in the blood serum, while insulin level was increased. In both experimental models, significant changes in the gut microbiota of mice were observed. They were associated with the manifestation of metabolic dysbiosis - an increase in the representation of Firmicutes (staphylococci, streptococci, enterococci) in the biomaterial, changes among representatives of both facultative (E. coli), and transient (Enterobacter bacteria) microflora. In addition, dystrophic, as well as morphological changes and signs of inflammation in the liver tissue were noted in both groups.

The ab-plane optical conductivity of the Weyl semimetal TaP is calculated from the band structure and compared to the experimental data. The overall agreement between theory and experiment is found to be best when the Fermi level is slightly (20 to 60 meV) shifted upwards in the calculations. This confirms a small unintentional doping of TaP, reported earlier, and allows a natural explanation of the strong low-energy (50 meV) peak seen in the experimental ab-plane optical conductivity: this peak originates from transitions between the almost parallel non-degenerate electronic bands split by spin-orbit coupling. The temperature evolution of the peak can be reasonably well reproduce by calculations using an analog of the Mott formula., Deutsche Forschungsgemeinschaft

The paper studies the effect of the RVI biocomposite material belonging to the group of osteoplastic biocomposite materials, the RV-2 immunomodulator – a synthetic dipeptide inducing an immunocorrective effect, and combinations of these drugs on the reparative histogenesis of bone tissue in femoral fractures in rats. It was found that the remodeling of the primary bone callus into the secondary one in the fracture of the studied animals was of a diverse nature. This process was the most pronounced in the group where the components were used in complex, i.e. the bone defect was filled with RVI during the surgery, as well as RV-2 was injected intramuscularly to rats at a dose of 10 mcg per 1 kg of live weight for five days, starting immediately after the surgery. Well-formed coarse-fibrous connective tissue callus was recorded in animals of this group. The connective tissue was stained more intensely which indicates a denser arrangement of fibers in the callus. Focal cartilage tissue spanning bone fragments was observed within the callus. At the periphery of the site the cartilaginous callus was subjected to endochondral ossification with replacement by coarse-fibrous trabeculae with elements of lamellar bone tissue having haversian canals in the center. The inter-girdle spaces were filled with elements of the myeloid bone marrow in the forming bone tissue. Markedly proliferated osteoblasts were visible in the cambial layer of the periosteum. The bone tissue ratio increased up to (60.21 ± 2.62)%, which significantly exceeded the same indicator in the control group and in all experimental groups. The low content of connective tissue and the high ratio of bone tissue indicated more active osteogenesis processes and reparative regeneration in comparison with other groups.

В статье рассмотрена проблема неинвазивной и скрытой диагностики деструктивного поведения. В качестве трансдиагностического биомаркера предлагается измерение вариабельности сердечного ритма. Разработаны авторские алгоритмы, на основании которых целесообразно проводить скрининг определенных групп, например подростковых коллективов.

Hepatitis C virus (HCV) is one of the basic culprits behind chronic liver disease, which may result in cirrhosis and hepatocarcinoma. In spite of the extensive research conducted, a vaccine against HCV has not been yet created. We have obtained human mesenchymal stem cells (hMSCs) and used them for expressing the HCV NS5A protein as a model vaccination platform. Sixteen hMSC lines of a different origin were transfected with the pcNS5A-GFP plasmid to obtain genetically modified MSCs (mMSCs). The highest efficiency was obtained by the transfection of dental pulp MSCs. C57BL/6 mice were immunized intravenously with mMSCs, and the immune response was compared with the response to the pcNS5A-GFP plasmid, which was injected intramuscularly. It was shown that the antigen-specific lymphocyte proliferation and the number of IFN-γ-synthesizing cells were two to three times higher after the mMSC immunization compared to the DNA immunization. In addition, mMSCs induced more CD4+ memory T cells and an increase in the CD4+/CD8+ ratio. The results suggest that the immunostimulatory effect of mMSCs is associated with the switch of MSCs to the pro-inflammatory phenotype and a decrease in the proportion of myeloid derived suppressor cells. Thus, the possibility of using human mMSCs for the creation of a vaccine against HCV has been shown for the first time.

Indoloterpenoids of the paxilline type belong to a large family of secondary metabolites that exhibit unique molecular architectures and a diverse set of biological activities. More than 100 congeners identified to date share a common structural motif that contains an indole moiety fused to a rearranged diterpenoid fragment. The representative physiological and cellular effects attributed to this family of natural products include neurological and insecticidal activities, modulation of lipid balance, and inhibition of mitosis. The uniting polycyclic motif combined with the diversity of individual structural features of paxilline indoloterpenoids and the broad scope of their biological activities have fascinated organic chemists for the past four decades and have led to the development of numerous syntheses. In this Account, we describe our contributions to this field and how they in turn shape new directions that are developing in our laboratory. We begin with the discussion of our strategy for the synthesis of the shared indoloterpenoid core. To address stereochemical challenges encountered in earlier reports, we planned to leverage a suitably substituted cyclopentanone in a polycyclization to form the desired trans-decalin motif. This polycyclization relied on a radical-polar crossover cascade initiated by hydrogen atom transfer. The original process exhibited poor diastereoselectivity, but we discovered an efficient solution to this problem that took advantage of intramolecular tethering effects, culminating in short synthesis of emindole SB. During these studies, we also identified indium-mediated alkenylation of silyl enol ethers with alkynes as a suitable method for the synthesis of highly substituted β,γ-unsaturated ketones that was critical to achieving brevity of our route. We subsequently developed a catalytic version of this transformation that allowed for a formal bimolecular ene reaction that exhibited unusual and potentially useful selectivity in construction of quaternary centers. To test the scope and limitations of our approach to paxilline indoloterpenoids and identify potential improvements, we developed a synthesis of the more complex congener nodulisporic acid C. The convergent assembly of this natural product was enabled by identification of new elements of stereocontrol in the radical-polar crossover polycyclization en route to the polycyclic terpenoid motif and development of a highly diastereoselective enyne cycloisomerization to access the indenopyran motif and a ketone arylation protocol to unite the two complex fragments. In subsequent studies, we expanded the radical-polar crossover cascade underlying our approach to paxilline indoloterpenoids to a bimolecular setting, which allowed for annulation of two unsaturated carbonyl components to produce functionalized cyclohexanes. This transformation is particularly well suited for installation of fully substituted carbons and can be complementary to the venerable Diels–Alder reaction. The utility of the new annulation was tested in the synthesis of forskolin, allowing for rapid construction of the complex polycyclic motif in this densely functionalized labdane diterpenoid. Over the past five years, our initial forays into the synthesis of paxilline indoloterpenoids have grown into a program that incorporates development of new synthetic methods and pursues artificial assembly of terpenoid natural products from several different families. We are encouraged by the increasing diversity of structural motifs made accessible by application of this chemistry and continue to discover new aspects of the underlying reactivity.

To cut the amount of machine time spent on designing systems with electric machines and semiconductor converters, it is proposed to describe processes using smooth current and voltage constituents. It is also proposed to use dual system models that combine the simulation using smooth components of curves with the simulation of systems by interconnected subsystems. This allows reconciling the requirements on the speed and accuracy of calculating long-time processes. An example of creating a dual solid-state drive model with a PMAC motor is provided.

Synthesis of a potent inhibitor of bacterial protein synthesis, pleuromutilin, is described. Assembly of the critical cyclooctane fragment relies on an oxidative ring-expansion, and complete stereochemical relay in the synthetic sequence is enabled by the judicious choice of tactics. The requisite connectivity pattern of the perhydroindanone motif is rapidly established in a sequence of cycloaddition and radical cyclization events. Application of this strategy allows for preparation of the target natural product in 16 steps from commercially available material.

Covering: up to 2021Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field.

We resolve the real-time coherent rotational motion of isolated water molecules encapsulated in fullerene-C60 cages by time-domain terahertz (THz) spectroscopy. We employ single-cycle THz pulses to excite the low-frequency rotational motion of water and measure the subsequent coherent emission of electromagnetic waves by water molecules. At temperatures below ~ 100 K, C60 lattice vibrational damping is mitigated and the quantum dynamics of confined water are resolved with a markedly long rotational coherence, extended beyond 10 ps. The observed rotational transitions agree well with low-frequency rotational dynamics of single water molecules in the gas phase. However, some additional spectral features with their major contribution at ~2.26 THz are also observed which may indicate interaction between water rotation and the C60 lattice phonons. We also resolve the real-time change of the emission pattern of water after a sudden cooling to 4 K, signifying the conversion of ortho-water to para-water over the course of 10s hours. The observed long coherent rotational dynamics of isolated water molecules confined in C60 makes this system an attractive candidate for future quantum technology., Deutsche Forschungsgemeinschaft, EPSRC-UK, Projekt DEAL

We have studied the contrast sensitivity of the visual system in various ranges of the spatial frequencies in “dry” immersion conditions that simulate the physiological effects of microgravity. The contrast sensitivity in the range of low and high spatial frequencies is indicative of the functional state of the magnocellular and parvocellular neuronal pathways that form the dorsal and ventral information flows from the occipital to the frontal lobes. The study involved ten volunteers who were exposed to “dry” immersion for 21 days. The contrast sensitivity of the visual system was recorded with a method of visocontrastometry. The Gabor elements were used as stimuli. An increase in contrast sensitivity was registered in the low spatial frequency range with specific sensitivity of the magnocellular pathway to these frequencies on the third day of immersion and 1 day after the end of the experiment, compared to the background values. The contrast sensitivity in the high spatial frequency range with specific sensitivity of the parvocellular pathway to these frequencies in the experiment remained unchanged. Thus, our findings have shown that the magnocellular neuronal pathway is involved in the processes of adaptation to extreme ambient conditions.

Introduction. Acromegaly is a severe multi-organ disease that negatively affects the quality and life expectancy of patients. The continuing complexity of acromegaly curation is due to the multiplicity of pathomorphological variants growth hormone-secreting adenomas and the lack of differentiated approach in choosing a therapeutic strategy. The high percentage of non-radical adenomectomy, due to the large size and invasive growth of somatotropin, involves the operative connection of adequate secondary drug therapy.Purpose. The aim of the study is to compare the effectiveness of different classes of drugs, as well as algorithms of their combined use in the treatment of acromegaly.Methods of treatment. The review uses information on factors affecting the results of clinical use of modern pharmacological preparations (somatostatin analogues, dopamine agonists, growth hormone receptor antagonists) used in secondary drug therapy of acromegaly. The indications for the administration of a drug are discussed taking into account the features of the pathomorphological structure of the tumor tissue, as well as the tactics of the therapeutic allowance in absolute or relative resistance to somatostatin analogues of the 1st generation (octreotide and lanreotide) and dopamine agonists (cabergoline). Data on efficiency of the new drug – pegvisomant providing stable control of acromegaly irrespective of secretory activity and receptor phenotype of tumor tissue are summed up.Results. Interim reports of the ACROSTUDY observational project and other clinical studies regarding the therapeutic efficacy and safety of pegvisomant are presented. A relatively low risk of continued growth of tumor tissue and other adverse reactions against the background of treatment with this drug is shown. Prognostic factors of insufficient efficiency of pegvisomant include young age, increased BMI, high initial level of ИРФ-1, presence of diabetes mellitus. There is an advantage of combined use of pegvisomant and somatostatin analogues to maintain acromegaly control and prevent tumor growth. The topic of primary therapy of pegvisomant is touched upon. Based on the results of real clinical practice, modern international recommendations are presented, which indicate the place of pegvisomant in the algorithm of secondary drug therapy.Conclusions. Due to the introduction into clinical practice of various therapeutic agents, which allow, regardless of the activity of the disease, the specificity of the pathomorphological structure of tumor tissue and somatic status, to achieve stable maintenance of biochemical remission, patients have real opportunities for improving the quality and life expectancy.

Heart and skeletal muscle inflammation (HSMI) is one of the most widespread economically relevant diseases of farmed Atlantic salmon (Salmo salar), and it poses serious danger to its aquaculture. The disease was first reported in Norway in 1999. In 2006, the Norwegian researchers demonstrated its viral etiology. Heart and skeletal muscle inflammation is a novel and understudied highly contagious transboundary disease of Salmonidae characterized by erythrocyte damage, blood circulation failure, jaundice and aggregated signs of heart and skeletal muscle inflammation. The disease associated economic damage to aquaculture is enormous. Total cumulative mortality can reach 30% and morbidity can amount to 100%. Loss of quality of the commercial fish products due to melanised foci in the salmons’ muscles further increases the disease-associated economic losses. Aquacultured Atlantic salmon is the most susceptible to HSMI. Rainbow trout, chub salmon and bull trout are also susceptible species and the list is still being continued. The disease is caused by the virus belonging to genusOrthoreovirusin the familyReoviridae. Currently Piscine orthoreovirus demonstrates the tendency towards its global spread. The virus-induced disease is reported in Norway, Scotland, Ireland, Iceland, France, Germany, Italy, Denmark and Alaska. The majority of the outbreaks are registered in Central and Northern parts of Norway, which borders the Murmansk Oblast. The vicinity of the affected areas to Russia, the Gulf Stream passing the Norwegian shore while moving towards the Murmansk Oblast as well as wildSalmonidaemigration to the Barents Sea, White Sea and Pechora Sea through the Norwegian territorial waters coupled with high stability of the virus compose high threat of Piscine orthoreovirus introduction to the Russian Federation from the adjacent countries.

At present, Miramistin drug (benzyldimethyl [3-(myristoylamino) propyl] ammonium chloride monohydrate), which has a broad bactericidal effect, is used in veterinary practice. This antiseptic is active against most viruses, mycoplasmas, bacteria, fungi and protozoa. According to toxicometric parameters, Miramistin is classified as a low-hazard substance. Use of cell structures as test systems for assessing the toxicity of pharmacological substances instead of conventional tests on experimental animals allows us to better clarify the possible mechanism of the effect of the investigated substance. Since many types of mycoplasmas affect the genitourinary system organs, to assess the cytotoxicity of Miramistin kidney mammalian cells of various mammals can be used as test systems, in particular, the newborn Syrian hamster (VNK-21), Siberian mountain ibex (PSGK-30), and others. The possibility of using BHK-21 and PSGK-30 cell monolayer as test systems for assessing the baseline cytotoxicity of Miramistin was shown. When studying toxicity of the drug, the effect of its various concentrations on the cell morphology was studied, the number of viable cells and the total protein content were determined as an indicator of the cell mass increase. The results of a cytomorphological study indicate that the Miramistin maximum permissible concentration of for BHK-21 and PSGK-30 cell monolayer is 25 μg/cm3. The use of this antibacterial drug in higher concentrations caused the appearance and increased signs of endogenous intoxication and degeneration. When evaluating the proliferative activity of cells under the influence of the Miramistin antibiotic in different concentrations, it was found that increasing the dose to 50, 75, 100, 125, 150 μg/cm3 leads to decrease in the rate of cell growth compared to the control. The Miramistin content in the growth medium in an amount of up to 25 μg/cm3 did not affect the intensity of protein synthesis. Presence of Miramistin in the culture medium at the maximum permissible concentration causes a slight decrease in the reproduction of foot and mouth disease virus in BHK-21 and PSGK-30 cell cultures by 4.5 and 4.0%, respectively, compared with the control without antibiotic. Since mycoplasmas are the most common contaminants of cell cultures, further studies will be aimed at exploring the possibility of using Miramistin for decontamination of BHK-21 and PSGK-30 cell monolayers.

The structures of systems with high-voltage cascade frequency converters containing multi-winding transformers and low-voltage low-power converters connected in series at each output phase of the load are considered. Low-voltage blocks contain three-phase diode or active rectifiers, DC capacitor filters, single-phase stand-alone voltage inverters and block disconnecting devices in partial modes (in case of failure when part of the blocks are disconnected). The possibilities of operation of cascade converters are determined, equations for correcting tasks to units in partial modes are given, tables of correction of tasks with estimates of achievable load characteristics are proposed. The results of experiments on the model of a powerful installation with a cascade frequency converter are presented, confirming the possibility of ensuring the symmetry of the load currents when disconnecting part of the blocks and the asymmetry of the circuit.