Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a malignant neoplasm characterized by extremely low curability and survival. The inflammatory microenvironment and maturation (differentiation) of AML cells induced by it contribute to the evasion of these cells from effectors of antitumor immunity. One of the key molecular effectors of immune surveillance, the cytokine TRAIL, is considered a promising platform for developing selective anticancer drugs. Previously, under in vitro conditions of the inflammatory microenvironment (a three-dimensional high-density culture of THP-1 AML cells), we demonstrated the emergence of differentiated macrophage-like THP-1ad clones resistant to TRAIL-induced death. In the present study, constitutive activation of proinflammatory signaling pathways, associated transcription factors, and increased expression of the anti-apoptotic BIRC3 gene were observed in TRAIL-resistant macrophage-like THP-1ad AML cells. For the first time, a bioinformatic analysis of the transcriptome revealed the main regulator, the IL1B gene, which triggers proinflammatory activation and induces resistance to TRAIL in THP-1ad macrophage-like cells.

Coronavirus Infections in Animals: Risks of Direct and Reverse Zoonoses.

The publications on animal coronavirus infections that have the greatest emerging potential, as well as official data from the World Organization for Animal Health (OIE) on cases of animal infection with COVID-19, are analyzed. Like most infectious diseases common to humans, coronavirus infections were first discovered in animals. Due to the increased rate of replication and recombination activity compared to other viruses, mutations occur more often in the genome of coronaviruses, which contribute to the acquisition of new qualities in order to consolidate in the host organism. Examples of cross-species transmission are not only SARS-CoV, MERS-CoV, and SARS-CoV-2, which are dangerous to humans, but also coronaviruses of agricultural and domestic animals, between which there is a genetic relationship. There are several known cases of zoo, wild, domestic, and farm animals displaying symptoms characteristic of COVID-19 and identification of the genome of the SARS-CoV-2 virus in them. The issue of cross-species transmission of coronavirus infections, in particular the reverse zoonosis of SARS-CoV-2 from animals to humans, is widely discussed. According to the conclusions of many researchers, including OIE experts, there is no direct evidence base for infection of humans with COVID-19 from animals. However, people with suspected COVID-19 and with a confirmed diagnosis are still advised to isolate not only from people but also from animals. A number of methods for specific prevention, diagnosis, and immunization against a wide range of coronavirus infections are being developed at the All-Russia Research Institute for Animal Protection.

Structure and Functions of Gap Junctions and Their Constituent Connexins in the Mammalian CNS.

Numerous data obtained in the last 20 years indicate that all parts of the mature central nervous system, from the retina and olfactory bulb to the spinal cord and brain, contain cells connected by gap junctions (GJs). The morphological basis of the GJs is a group of joined membrane hemichannels called connexons, the subunit of each connexon is the protein connexin. In the central nervous system, connexins show specificity and certain types of them are expressed either in neurons or in glial cells. Connexins and GJs of neurons, combining certain types of inhibitory hippocampal and neocortical neuronal ensembles, provide synchronization of local impulse and rhythmic activity, thalamocortical conduction, control of excitatory connections, which reflects their important role in the processes of perception, concentration of attention and consolidation of memory, both on the cellular and at the system level. Connexins of glial cells are ubiquitously expressed in the brain, and the GJs formed by them provide molecular signaling and metabolic cooperation and play a certain role in the processes of neuronal migration during brain development, myelination, tissue homeostasis, and apoptosis. At the same time, mutations in the genes of glial connexins, as well as a deficiency of these proteins, are associated with such diseases as congenital neuropathies, hearing loss, skin diseases, and brain tumors. This review summarizes the existing data of numerous molecular, electrophysiological, pharmacological, and morphological studies aimed at progress in the study of the physiological and pathophysiological significance of glial and neuronal connexins and GJs for the central nervous system.

Biocompatible dextran-coated gadolinium-doped cerium oxide nanoparticles as MRI contrast agents with high T1 relaxivity and selective cytotoxicity to cancer cells.

Gd-based complexes are widely used as magnetic resonance imaging (MRI) contrast agents. The safety of previously approved contrast agents is questionable and is being re-assessed. The main causes of concern are possible gadolinium deposition in the brain and the development of systemic nephrogenic fibrosis after repeated use of MRI contrasts. Thus, there is an urgent need to develop a new generation of MRI contrasts that are safe and that have high selectivity in tissue accumulation with improved local contrast. Here, we report on a new type of theranostic MRI contrast, namely dextran stabilised, gadolinium doped cerium dioxide nanoparticles. These ultra-small (4-6 nm) Ce0.9Gd0.1O1.95 nanoparticles have been shown to possess excellent colloidal stability and high r1-relaxivity (3.6 mM-1 s-1). They are effectively internalised by human normal and cancer cells and demonstrate dose-dependent selective cytotoxicity to cancer cells.

Coronavirus Infections of Animals: Future Risks to Humans.

Coronaviruses have tremendous evolutionary potential, and three major outbreaks of new human coronavirus infections have occurred in the recent history of humankind. In this paper, the patterns of occurrence of new zoonotic coronavirus infections and the role of bioveterinary control in preventing their potential outbreaks in the future are determined. The possibility of SARS-CoV-2 infection in companion animals is considered. Diverse human activities may trigger various interactions between animal species and their viruses, sometimes causing the emergence of new viral pathogens. In addition, the possibility of using probiotics for the control of viral infections in animals is discussed.

[Pharmacotherapy of inflammatory bowel diseases: efficacy performance and safety management].

Treatment of inflammatory bowel diseases IBD (Crohns disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.

Ceria-Containing Hybrid Multilayered Microcapsules for Enhanced Cellular Internalisation with High Radioprotection Efficiency.

Cerium oxide nanoparticles (nanoceria) are believed to be the most versatile nanozyme, showing great promise for biomedical applications. At the same time, the controlled intracellular delivery of nanoceria remains an unresolved problem. Here, we have demonstrated the radioprotective effect of polyelectrolyte microcapsules modified with cerium oxide nanoparticles, which provide controlled loading and intracellular release. The optimal (both safe and uptake efficient) concentrations of ceria-containing microcapsules for human mesenchymal stem cells range from 1:10 to 1:20 cell-to-capsules ratio. We have revealed the molecular mechanisms of nanoceria radioprotective action on mesenchymal stem cells by assessing the level of intracellular reactive oxygen species (ROS), as well as by a detailed 96-genes expression analysis, featuring genes responsible for oxidative stress, mitochondrial metabolism, apoptosis, inflammation etc. Hybrid ceria-containing microcapsules have been shown to provide an indirect genoprotective effect, reducing the number of cytogenetic damages in irradiated cells. These findings give new insight into cerium oxide nanoparticles' protective action for living beings against ionising radiation.

Opposite effects of low intensity light of different wavelengths on the planarian regeneration rate.

Planarian freshwater flatworms have the unique ability to regenerate due to stem cell activity. The process of regeneration is extremely sensitive to various factors, including light radiation. Here, the effect of low-intensity LED light of different wavelengths on regeneration, stem cell proliferation and gene expression associated with these processes was studied. LED matrices with different wavelengths (red (λmax = 635 nm), green (λmax = 520 nm) and blue (λmax = 463 nm), as well as LED laser diodes (red (λmax = 638.5 nm), green (λmax = 533 nm) and blue (λmax = 420 nm), were used in the experiments. Computer-assisted morphometry, whole-mount immunocytochemical study and RT-PCR were used to analyze the biological effects of LED light exposure on the planarian regeneration in vivo. It was found that a one-time exposure of regenerating planarians with low-intensity red light diodes stimulated head blastema growth in a dose-dependent manner (up to 40%). The green light exposure of planarians resulted in the opposite effect, showing a reduced head blastema growth rate by up to 21%. The blue light exposure did not lead to any changes in the rate of head blastema growth. The maximum effects of light exposure were observed at a dose of 175.2 mJ/cm2. No significant differences were revealed in the dynamics of neoblasts' (planarian stem cells) proliferation under red and green light exposure. However, the RT-PCR gene expression analysis of 46 wound-induced genes revealed their up-regulation upon red LED light exposure, and down-regulation upon green light exposure. Thus, we have demonstrated that the planarian regeneration process is rather sensitive to the effects of low-intensity light radiation of certain wavelengths, the biological activity of red and green light being dictated by the different expression of the genes regulating transcriptional activity.

Influence of electromagnetic waves, with maxima in the green or red range, on the morphofunctional properties of multipotent stem cells.

This paper examines the effect of electromagnetic waves, with maxima in the green or red regions of the spectrum, on the morphofunctional state of multipotent mesenchymal stromal cells. The illumination regimes used in our experiments did not lead to any substantial heating of the samples; the physical parameters of the lighting were carefully monitored. When the samples were illuminated with a green light, no significant photostimulatory effect was observed. Red light, on the other hand, had an evident photostimulatory effect. It is shown that photostimulation with a red light decreases the enzymatic activities of mitochondrial dehydrogenases and enhances the viability of cells, their proliferative activity, and their ability to form bone tissue. It is also established that red light stimulates cell proliferation, while not activating the genes that increase the risk of the subsequent malignant transformation of cells or their death. This paper discusses the possible role of hydrogen peroxide in the processes examined.

Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response.

We have hypothesized that the adaptive response to low doses of ionizing radiation (IR) is mediated by oxidized cell-free DNA (cfDNA) fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production), induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs) with low doses of IR (10 cGy) leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR.

Reaction of Lymphoid Organs to Injection of Iron-Carbon Nanoparticles.

The distribution of iron-carbon nanoparticles in FeC-DSPE-PEG-2000 modification (micellar particles with structure (Fe) core-carbon shell; PEG-based coating) is studied. The greater part of the nanoparticles accumulated in the spleen and liver, a small amount in the lungs, and the minimum amount in the thymus. The structural changes in the lymphoid organs were minor and involved only the microcirculatory bed. Analysis of the peripheral blood showed manifest anemia, thrombocytopenia, and leukocytosis.

The geomorphology of Ceres.

Analysis of Dawn spacecraft Framing Camera image data allows evaluation of the topography and geomorphology of features on the surface of Ceres. The dwarf planet is dominated by numerous craters, but other features are also common. Linear structures include both those associated with impact craters and those that do not appear to have any correlation to an impact event. Abundant lobate flows are identified, and numerous domical features are found at a range of scales. Features suggestive of near-surface ice, cryomagmatism, and cryovolcanism have been identified. Although spectroscopic analysis has currently detected surface water ice at only one location on Ceres, the identification of these potentially ice-related features suggests that there may be at least some ice in localized regions in the crust.

Cratering on Ceres: Implications for its crust and evolution.

Thermochemical models have predicted that Ceres, is to some extent, differentiated and should have an icy crust with few or no impact craters. We present observations by the Dawn spacecraft that reveal a heavily cratered surface, a heterogeneous crater distribution, and an apparent absence of large craters. The morphology of some impact craters is consistent with ice in the subsurface, which might have favored relaxation, yet large unrelaxed craters are also present. Numerous craters exhibit polygonal shapes, terraces, flowlike features, slumping, smooth deposits, and bright spots. Crater morphology and simple-to-complex crater transition diameters indicate that the crust of Ceres is neither purely icy nor rocky. By dating a smooth region associated with the Kerwan crater, we determined absolute model ages (AMAs) of 550 million and 720 million years, depending on the applied chronology model.

Dawn arrives at Ceres: Exploration of a small, volatile-rich world.

On 6 March 2015, Dawn arrived at Ceres to find a dark, desiccated surface punctuated by small, bright areas. Parts of Ceres' surface are heavily cratered, but the largest expected craters are absent. Ceres appears gravitationally relaxed at only the longest wavelengths, implying a mechanically strong lithosphere with a weaker deep interior. Ceres' dry exterior displays hydroxylated silicates, including ammoniated clays of endogenous origin. The possibility of abundant volatiles at depth is supported by geomorphologic features such as flat crater floors with pits, lobate flows of materials, and a singular mountain that appears to be an extrusive cryovolcanic dome. On one occasion, Ceres temporarily interacted with the solar wind, producing a bow shock accelerating electrons to energies of tens of kilovolts.

A partially differentiated interior for (1) Ceres deduced from its gravity field and shape.

Remote observations of the asteroid (1) Ceres from ground- and space-based telescopes have provided its approximate density and shape, leading to a range of models for the interior of Ceres, from homogeneous to fully differentiated. A previously missing parameter that can place a strong constraint on the interior of Ceres is its moment of inertia, which requires the measurement of its gravitational variation together with either precession rate or a validated assumption of hydrostatic equilibrium. However, Earth-based remote observations cannot measure gravity variations and the magnitude of the precession rate is too small to be detected. Here we report gravity and shape measurements of Ceres obtained from the Dawn spacecraft, showing that it is in hydrostatic equilibrium with its inferred normalized mean moment of inertia of 0.37. These data show that Ceres is a partially differentiated body, with a rocky core overlaid by a volatile-rich shell, as predicted in some studies. Furthermore, we show that the gravity signal is strongly suppressed compared to that predicted by the topographic variation. This indicates that Ceres is isostatically compensated, such that topographic highs are supported by displacement of a denser interior. In contrast to the asteroid (4) Vesta, this strong compensation points to the presence of a lower-viscosity layer at depth, probably reflecting a thermal rather than compositional gradient. To further investigate the interior structure, we assume a two-layer model for the interior of Ceres with a core density of 2,460-2,900 kilograms per cubic metre (that is, composed of CI and CM chondrites), which yields an outer-shell thickness of 70-190 kilometres. The density of this outer shell is 1,680-1,950 kilograms per cubic metre, indicating a mixture of volatiles and denser materials such as silicates and salts. Although the gravity and shape data confirm that the interior of Ceres evolved thermally, its partially differentiated interior indicates an evolution more complex than has been envisioned for mid-sized (less than 1,000 kilometres across) ice-rich rocky bodies.

The missing large impact craters on Ceres.

Asteroids provide fundamental clues to the formation and evolution of planetesimals. Collisional models based on the depletion of the primordial main belt of asteroids predict 10-15 craters >400 km should have formed on Ceres, the largest object between Mars and Jupiter, over the last 4.55 Gyr. Likewise, an extrapolation from the asteroid Vesta would require at least 6-7 such basins. However, Ceres' surface appears devoid of impact craters >∼280 km. Here, we show a significant depletion of cerean craters down to 100-150 km in diameter. The overall scarcity of recognizable large craters is incompatible with collisional models, even in the case of a late implantation of Ceres in the main belt, a possibility raised by the presence of ammoniated phyllosilicates. Our results indicate that a significant population of large craters has been obliterated, implying that long-wavelength topography viscously relaxed or that Ceres experienced protracted widespread resurfacing.

[MONITORING OF THE CONTENT OF HEAVY METALS AND ELEMENTS IN THE SNOW COVER IN AGRICULTURAL SOILS AT THE TERRITORY OF THE MOSCOW REGION].

The monitoring of snow cover pollution by heavy metals and elements (zinc, copper, lead, cadmium, arsenic, nickel, chromium, strontium, manganese, fluorine, lithium) was performed in 20 districts of the Moscow region in 2009, 2012 and 2013. The assessment of the levels of contamination by heavy metals and elements was given by means of comparison of them with the average values in the snow cover near Moscow in the end of the last century and in some areas of the world, that no exposed to technological environmental impact. 7 districts of Moscow region were characterized by a high content of lead and cadmium in the snow water. It requires the control of water, soil and agricultural products pollution.

Evaluation of Biodistribution of Functionalized Magnetic Core/Carbon-Shell Nanoparticles in Systemic Method of Administration.

We studied new magnetic nanocomposites consisting of a core(Fe) and carbon-shell inert to biological media. Iron-carbon nanoparticles circulate in the bloodstream for several minutes and are primarily accumulated in the liver; less intensive accumulation was found in the spleen and minimum in the lungs, kidneys, and heart. Accumulation of nanoparticles in the liver leads to the development of destructive processes and is accompanied by activation of compensatory-adaptive mechanisms. In the liver and spleen, structural changes are mild and mainly relate to changes in the microvasculature. In 6 months, the total content of nanoparticles in all tissues decreased due to their elimination from the body and the structure of the organs returned to normal.

[THE NEW APPROACH TO EVALUATION OF ENDOTHELIUM DYSFUNCTION: DETECTION OF NUMBER OF CIRCULATING ENDOTHELIUM CELLS USING FLOW CYTOMETRY TECHNIQUE].

The endothelium dysfunction takes leading place in pathogenesis of development of cardiovascular diseases. The circulating endothelium cells of peripheral blood can act as a direct cell marker of damage and remodeling of endothelium. The study was carried out to develop a new approach to diagnose of endothelium dysfunction by force of determination of number of circulating endothelium cells using flow cytometry technique and to apply determination of circulating endothelium cells for evaluation of risk of development of ischemic heart disease in women of young and middle age. The study embraced 62 female patients with angiography confirmed ischemic heart disease, exertional angina pectoris at the level of functional class I-II (mean age 51 ± 6 years) and 49 women without anamnesis of ischemic heart disease (mean age 52 ± 9 years). The occurrence of more than three circulating endothelium cells by 3 x 105 leukocytes in peripheral blood increases relative risk of development of ischemic heart disease up to 4 times in women of young and middle age and risk of development of acute myocardial infarction up to 8 times in women with ischemic heart disease. The study demonstrated possibility to apply flow cytometry technique to quantitatively specify circulating endothelium cells in peripheral blood and forecast risk of development of ischemic heart disease in women of young and middle age depending on level of circulating endothelium cells.

Structural organization of glial cells at the border between the neurotransplant and recipient brain.

Integration of fetal hippocampal dentate fascia neurotransplants with the neocortical somatosensory region in adult rats was studied by electron microscopy. The growth of nerve fiber through the neurotransplant/brain border formed by the glial cells was studied. The interface zone was organized by various astrocyte subpopulations and ependymocytes forming multilamellar accumulations in some sites of the interface. These conglomerations of the glial cells and their processes did not prevent the growth of axonal and axodendritic bundles; moreover, fibrous astrocyte axons accompanied them. Under conditions of immature nervous tissue transplantation to the focus of mature brain damage, the glial cells created a substrate in the interface permeable for nerve fibers, thus promoting the functional integration of the neurotransplant.