Controlling the Quality of Nanodrugs According to Their New Property-Radiothermal Emission.

Previous studies have shown that complexly shaped nanoparticles (NPs) have their intrinsic radiothermal emission in the millimeter range. This article presents a method for controlling the quality of nanodrugs-immunobiological preparations (IBPs)-based on the detection of their intrinsic radiothermal emissions. The emissivity of interferon (IFN) medicals, determined without opening the primary package, is as follows (µW/m2): IFN-α2b-80 ± 9 (105 IU per package), IFN-ß1a-40 ± 5 (24 × 106 IU per package), IFN-γ-30 ± 4 (105 IU per package). The emissivity of virus-like particles (VLP), determined using vaccines Gam-VLP-multivac (120 µg) in an injection bottle (crimp cap vials), was as follows: 12 ± 1 µW/m2, Gam-VLP-rota vaccines-9 ± 1 µW/m2. This study shows the reproducibility of emissivity over the course of a year, subject to the storage conditions of the immunobiological products. It has been shown that accelerated aging and a longer shelf life are accompanied by the coagulation of active NPs, and lead to a manyfold drop in emissivity. The dependence of radiothermal emission on temperature has a complex, non-monotonic nature. The emission intensity depends on the form of dosage, but remains within the order of magnitude for IFN-α2b for intranasal aqueous solution, ointments, and suppositories. The possibility of the remote quantitative control of the first phases of the immune response (increased synthesis of IFNs) to the intranasal administration of VLP vaccines has been demonstrated in experimental animals.

Development of a Multi-technique Characterization Portfolio for Stainless Steels Exposed to Magnox Reprocessing Liquors.

AISI Type 304 stainless steel coupons have been exposed to a simulant aqueous environment representative of the Magnox Reprocessing Plant (MRP) at Sellafield, UK. The experiments were performed for extended time periods (up to 420 days) at elevated temperatures to develop a comprehensive understanding of the extent, nature, and depth of contamination for pipework and vessels in Magnox spent nuclear fuel reprocessing environments. This will inform upcoming decommissioning work which represents a major post-operational challenge. Previous relevant literature has focused on developing fundamental understanding of contamination mechanisms of stainless steels in simplistic, single-element systems, which lack elements of industrial relevance. Contamination behavior is expected to be drastically different in these more complex environments. A characterization portfolio has been developed to enable detailed assessment of corrosion and contamination behavior in acidic reprocessing environments. Solution, surface, and depth analysis determined that uptake was dominated by the elements present in highest concentrations within the environment, namely, Mg, Nd, and Cs. Most contaminants were incorporated into a relatively thin surface oxide layer (<100 nm) in metal oxide form, although there were some exceptions (Cs and Sr). Grain boundary etching was present despite very low corrosion rates (3 µm year-1). As a result of this lack of corrosion, diffusion of contaminants beyond the immediate surface (10-20 nm) did not occur, evidenced through depth profiling. As a result of these findings, surface-based decontamination techniques minimizing excess secondary waste generation can be further developed in order to reduce the environmental and economic burden associated with decommissioning activities.

High-Resolution Lacustrine Records of the Late Holocene Hydroclimate of the Sikhote-Alin Mountains, Russian Far East.

There is little information about moisture changes in different altitudinal belts in mountainous regions of the southern Russian Far East. We present ecological and taxonomic compositions of the diatom flora and identify the botanical composition of peat in small mountain lake/mire complexes located in the Central Sikhote-Alin Mountains, within large landslides on the paleovolcanic slopes. Frequent changes in diatom assemblages and peat-forming plants indicate unstable hydroclimatic conditions with varying degrees of wet and dry conditions up to the overgrowth of the lakes. Frequent change in sphagnum mosses with different trophic preferences was identified. The chronology is based on 11 radiocarbon dates. Accumulation rates reached 1.7-1.9 mm/year, and the temporal resolution for the reconstructions was up to 30-40 yr. The tendencies of lake evolution depended on different scale hydroclimatic changes over the last 4400 yr. The most detailed data for the last 2600 yr were obtained from the Nizhnee Lake sequence, which is more sensitive to climatic changes. The main reason for the change in the hydrological regime of the lakes was variations in precipitation during short-term climatic changes. The sediment record of moisture fluctuations is relatively well correlated with regional patterns reflecting summer monsoon intensity and cyclogenesis activity.

Radiothermal Emission of Nanoparticles with a Complex Shape as a Tool for the Quality Control of Pharmaceuticals Containing Biologically Active Nanoparticles.

It has recently been shown that the titer of the SARS-CoV-2 virus decreases in a cell culture when the cell suspension is irradiated with electromagnetic waves at a frequency of 95 GHz. We assumed that a frequency range in the gigahertz and sub-terahertz ranges was one of the key aspects in the "tuning" of flickering dipoles in the dispersion interaction process of the surfaces of supramolecular structures. To verify this assumption, the intrinsic thermal radio emission in the gigahertz range of the following nanoparticles was studied: virus-like particles (VLP) of SARS-CoV-2 and rotavirus A, monoclonal antibodies to various RBD epitopes of SARS-CoV-2, interferon-α, antibodies to interferon-γ, humic-fulvic acids, and silver proteinate. At 37 °C or when activated by light with λ = 412 nm, these particles all demonstrated an increased (by two orders of magnitude compared to the background) level of electromagnetic radiation in the microwave range. The thermal radio emission flux density specifically depended on the type of nanoparticles, their concentration, and the method of their activation. The thermal radio emission flux density was capable of reaching 20 µW/(m2 sr). The thermal radio emission significantly exceeded the background only for nanoparticles with a complex surface shape (nonconvex polyhedra), while the thermal radio emission from spherical nanoparticles (latex spheres, serum albumin, and micelles) did not differ from the background. The spectral range of the emission apparently exceeded the frequencies of the Ka band (above 30 GHz). It was assumed that the complex shape of the nanoparticles contributed to the formation of temporary dipoles which, at a distance of up to 100 nm and due to the formation of an ultrahigh strength field, led to the formation of plasma-like surface regions that acted as emitters in the millimeter range. Such a mechanism makes it possible to explain many phenomena of the biological activity of nanoparticles, including the antibacterial properties of surfaces.

Studying the Effect of Amino Acid Substitutions in the M2 Ion Channel of the Influenza Virus on the Antiviral Activity of the Aminoadamantane Derivative In Vitro and In Silico.

Purpose: The aminoadamantane derivative of L-histidyl-1-adamantayl ethylamine hydrochloride (HCl*H-His-Rim) has showed a high inhibition level against influenza A virus strains in vitro. The aim of this work is to search and establish evidence of the direct effect of the drug on influenza A virus proton channel M2. Methods: The compound HCl*H-His-Rim was obtained by classical peptide synthesis methods. Influenza A virus mutants of A/PuertoRico/8/34(H1N1) strain were obtained by reverse genetics methods. The mutant samples of the virus were cultured on chicken embryos with a virus titer in the hemagglutination test. ELISA was carried out on Madin-Darby canine kidney (MDCK) monolayer cells when multiplying the virus 10-4-10-6. The binding stability of HCl*H-His-Rim was compared to those of M2 (S31N) and M2 (S31N_A30T) channels by molecular dynamic (MD) modeling. The calculation was performed taking into account the interaction with the model lipid bilayer (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) in the presence of water molecules in accordance with the three-center model. Results: It was found that HCl*H-His-Rim is a direct action drug against influenza A. The most likely conformation of drug binding to target protein has been shown. It has been found that the A30T mutation reduces the binding energy of the drug, and the results obtained in vitro have confirmed the data calculated in silico. Conclusion: The mechanism of action of HCl*H-His-Rim is directly related to the suppression of the function of the proton channel M2 of influenza A virus.

Nanodispersions of Polyelectrolytes Based on Humic Substances: Isolation, Physico-Chemical Characterization and Evaluation of Biological Activity.

Natural polyelectrolytes, including in the form of complexes with colloidal particles, are increasingly used in pharmacy due to the possibility of regulated attachment of medicinal substances and their targeted delivery to the target organ. However, the formation, stability, and molecular-mass characteristics of polyelectrolyte nanodispersions (ND) vary depending on the nature and composition of the medium of their origin. This is due to the lack of standardized approaches to quality control and regulatory documentation for most natural ND. In this paper, we first introduced the isolation, followed by investigations into their physico-chemical properties and bioactivity. Using the dried droplet method, we were able to detect the "coffee ring effect". Fractographic studies of the surface structure of EHA and FA dried samples using SEM showed its heterogeneity and the presence of submicron particles encapsulated in the internal molecular cavities of polyelectrolyte. FTIR spectroscopy revealed the ND chemical structure of benzo-α-pyron and benzo-γ-pyron, consisting of nanoparticles and a branched frame part. The main elements detected by X-ray fluorescence in humic substance extract and fulvic acid include Si, P, S, K, Ca, Mn, Fe, Cu, Zn, whereas Fe is in high concentrations. The UV-spectra and fluorescent radiation demonstrated the possibility of studying the effect of the fulvate chromone structure on its optical properties. It is shown that dilution of the initial solutions of polyelectrolytes 1:10 contributes to the detection of smaller nanoparticles and an increase in the absolute value of the negative ζ-potential as a factor of ND stability. A study of the EHS effect on the SARS-CoV-2 virus infectious titer in the Vero E6 cell showed the effective against virus both in the virucidal scheme (the SI is 11.90-22.43) and treatment/prevention scheme (the SI is 34.85-57.33). We assume that polyelectrolyte ND prevent the binding of the coronavirus spike glycoprotein to the receptor. Taking into account the results obtained, we expect that the developed approach can become unified for the standardization of the ND natural polyelectrolytes complex, which has great prospects for use in pharmacy and medicine as a drug with antiviral activity.

Prevalence and Genetic Diversity of Group A Rotavirus Genotypes in Moscow (2019-2020).

Group A rotavirus (RVA) infection is the leading cause of hospitalization of children under 5 years old, presenting with symptoms of acute gastroenteritis. The aim of our study was to explore the genetic diversity of RVA among patients admitted to Moscow Infectious Disease Clinical Hospital No. 1 with symptoms of acute gastroenteritis. A total of 653 samples were collected from May 2019 through March 2020. Out of them, 135 (20.67%) fecal samples were found to be positive for rotavirus antigen by ELISA. RT-PCR detected rotavirus RNA in 80 samples. Seven G-genotypes (G1, G2, G3, G4, G8, G9, and G12) and three P-genotypes (P[8], P[4], and P[6]) formed 9 different combinations. The most common combination was G9P[8]. However, for the first time in Moscow, the combination G3P[8] took second place. Moreover, all detected viruses of this combination belonged to Equine-like G3P[8] viruses that had never been detected in Russia before. The genotype G8P[8] and G9P[4] rotaviruses were also detected in Moscow for the first time. Among the studied rotaviruses, there were equal proportions of Wa and DS-1-like strains; previous studies showed that Wa-like strains accounted for the largest proportion of rotaviruses in Russia.

[Epidemiology, clinical manifestations and efficiency of different methods of treatment of acromegaly according to the United Russian Registry of Patients with Pituitary Tumors].

BACKGROUND: The registry is the main source of information about patients with acromegaly for assessing the quality of medical care, effectiveness of treatment, determining the compliance of real clinical practice with existing standards and patient management protocols. AIMS: To evaluate epidemiological, demographic and clinical characteristics of acromegaly in Russian Federation and effectiveness of treatment modalities. MATERIALS AND METHODS: The object of the study was the database of the united Russian registry of patients with pituitary tumors with specific analysis of patients with acromegaly only. We analyzed the data of 4114 patients with acromegaly stored on the online system in February 2019. RESULTS: Based on the data 32% of patients had complete clinical and laboratory remission of acromegaly; the percentage of patients with no remission was 68%, among them 22.5% had significant improvements in clinical symptoms and a decrease in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) without IGF-1 normalization. The average age of patients at the onset of the disease was 42.7 years and at diagnosis – 45.8 years. The ratio of men to women was 1:2.6. In patients with acromegaly hypopituitarism was registered in 14.7% of cases and among them hypothyroidism (66%) and hypogonadism (52%) were registered more often. Among other complications the leading were diabetes mellitus (15.7%) and acromegalic arthropathy (15%). The proportion of patients receiving neurosurgical treatment increased from 35.7% to 49.6% in 2012–2019; the portion of patients undergoing radiation therapy decreased significantly from 17.7% in 2012 to 0.8% in 2019. Remission was achieved in 40.47% after neurosurgery and 28.95% after medical treatment as a first line therapy p<0.01. The number of patients receiving medical treatment at the time of the study was 1209. Among them 51% of patients treated with long-acting lanreotide and 24% receiving long-acting octreotide achieved remission (p<0.0001) CONCLUSIONS: The remission rate of acromegaly remains suboptimal despite increased surgical activity, which corresponds to global trends. Long-acting lanreotide was significantly superior versus long-acting octreotide in the rate of acromegaly remission, which does not correspond with clinical trials.

Treatment of high fracture risk patients in routine clinical practice.

A retrospective cohort study determined the high incidence of recurrent fractures in osteoporotic patients with high fracture risk during the observation. The strategy of starting treatment with more potent regimens (zoledronic acid, denosumab and/or teriparatide) seems to have the best secondary fracture prevention efficacy. OBJECTIVE: This paper describes the various medical therapy regimens prescribed to osteoporotic patients with high fracture risk and the result of treatment. METHODS: We carried out a retrospective cohort study in selected Osteoporosis Centers. Patients were considered to have high fracture risk in case of a history of a low-energy hip fracture or two or more vertebral or other site fractures. A total of 812 subjects (768 women and 44 men) aged 36-95 years were included. The observation period was 2285.1 patient-years. Demographic data, clinical findings, and BMD data obtained by DXA, as well as a history of fractures that had occurred during the follow-up, were included in the analysis. RESULTS: Overall, at baseline, there were 637 non-vertebral fractures including 104 hip fractures. A total of 590 patients had vertebral fractures; of these, 69% suffered multiple fractures. Being on treatment, 119 (14.7%) patients developed new vertebral and non-vertebral fractures. The incidence of new non-vertebral fractures and hip fractures was 39.4 and 13.1 per 1000 patient-years. The total number of vertebral fractures increased by 24.8% from 1353 to 1689. The best results of the treatment were achieved in patients who were started on zoledronic acid, denosumab, or teriparatide and had an adequate duration of treatment. Although these patients had significantly lower BMD values at the time of diagnosis compared with other patients, they showed a lower incidence of new vertebral and hip fractures, during the follow-up. CONCLUSION: Therapy of patients at high risk of fractures started with more potent treatment regimens (zoledronic acid, denosumab and/or teriparatide) of adequate duration was more effective in terms of prevention of new vertebral and hip fractures as compared with other treatment options. However, treatment appears to be challenging given the number of recurrent fractures in patients on treatment and the frequency of drug withdrawal or replacement.

Dependence of Biocatalysis on D/H Ratio: Possible Fundamental Differences for High-Level Biological Taxons.

The kinetics of biological reactions depends on the deuterium/protium (D/H) ratio in water. In this work, we describe the kinetic model of biocatalytic reactions in living organisms depending on the D/H ratio. We show that a change in the lifetime or other characteristics of the vital activity of some organisms in response to a decrease or increase in the content of deuterium in the environment can be a sign of a difference in taxons. For animals-this is a curve with saturation according to the Gauss's principle, for plants-it is the Poisson dependence, for bacteria a weakly saturated curve with a slight reaction to the deuterium/protium ratio toward increasing deuterium. The biological activity of the aquatic environment with reduced, elevated, and natural concentrations of deuterium is considered. The results of the study are presented in different vital indicators of some taxons: the bacteria kingdom-the colony forming units (CFU) index (Escherichia coli); animals-the activation energy of the death of ciliates (Spirostomum ambiguum), embryogenesis of fish (Brachydanio rerio); plants-germination and accumulation of trace elements Callisia fragrans L., sprouting of gametophores and peptidomics of moss Physcomitrella patens. It was found that many organisms change their metabolism and activity, responding to both high and low concentrations of deuterium in water.

A registry for patients with chronic hypoparathyroidism in Russian adults.

Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017-2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.

Effect of the deuterium on efficiency and type of adipogenic differentiation of human adipose-derived stem cells in vitro.

In this study, we performed an adipogenic differentiation of human adipose-derived stem cells (ADSCs) in vitro with different deuterium content (natural, low and high) in the culture medium during differentiation process with parallel analysis of the gene expression, metabolic activity and cell viability/toxicity. After ADSCs differentiation into adipocytes we have done the analysis of differentiation process efficiency and determined a type of resulting adipocytes (by morphology, gene expression, UCP1 protein detection and adipokine production analysis). We have found that high (5 × 105 ppm) deuterium content significantly inhibit in vitro adipogenic differentiation of human ADSCs compared to the groups with natural (150 ppm) and low (30 ppm) deuterium content. Importantly, protocol of differentiation used in our study leads to white adipocytes development in groups with natural (control) and high deuterium content, whereas deuterium-depleted differentiation medium leads to brown-like (beige) adipocytes formation. We have also remarked the direct impact of deuterium on the cellular survival and metabolic activity. Interesting, in deuterium depleted-medium, the cells had normal survival rate and high metabolic activity, whereas the inhibitory effect of deuterated medium on ADSCs differentiation at least was partly associated with deuterium cytotoxicity and inhibitory effect on metabolic activity. The inhibitory effect of deuterium on metabolic activity and the subsequent decrease in the effectiveness of adipogenic differentiation is probably associated with mitochondrial dysfunction. Thus, deuterium could be considered as an element that affects the substance chirality. These findings may be the basis for the development of new approaches in the treatment of obesity, metabolic syndrome and diabetes through the regulation of adipose-derived stem cell differentiation and adipocyte functions.

First detection and full genome sequence of porcine circovirus type 3 in Russia.

Porcine circovirus type 3 (PCV3) was firstly detected in 2016 in USA. Later PCV3 was discovered in Asia, Europe, and South America. The present investigation demonstrates for the first time the circulation of PCV3 among pigs in Russia. The viruses were detected at two geographically distant unrelated commercial farms with records of reproductive failure (abortions, stillbirth), porcine dermatitis, and nephropathy syndrome (PDNS). The two farms were located in the region of Smolensk (western part of Russia) and the region of Tyumen (West Siberia, Russia). We investigated samples collected from pigs of different ages. We performed PCR for the PCV3 DNA detection. The DNA of PCV3 was detected in serum, kidney, heart, spleen, pleural effusion, and peritoneal cavity fluid samples. Two viral genomes were sequenced and the corresponding strains were named PCV3-RU/SM17 (the strain from Smolensk region) and PCV3-RU/TY17 (the strain from Tyumen region). The full genome sequences of both strains were 2000 nucleotides in length and contained at least two ORFs, encoding the Cap and Rep proteins. Full sequence alignment revealed a 99.3% identity between the PCV3-RU/SM17 and PCV3-RU/TY17 strains. Molecular analysis showed that the two strains from Russia are highly homologous to viruses identified in other countries, with a 98.5-99.6% homology for PCV3-RU/TY17 and 97.9-99.0 for PCV3-RU/SM17. The PCV3-RU/SM17 and PCV3-RU/TY17 strains were found to form a monophyletic group in a phylogenetic tree based on PCV3 complete genome sequences.

Effects of active acromegaly on bone mRNA and microRNA expression patterns.

OBJECTIVE: To evaluate the response of bone to chronic long-term growth hormone (GH) and insulin-like growth factor-1 (IGF1) excess by measuring the expression of selected mRNA and microRNA (miR) in bone tissue samples of patients with active acromegaly. DESIGN: Case-control study. METHODS: Bone tissue samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 14 patients with clinically and biochemically confirmed acromegaly and 10 patients with clinically non-functioning pituitary adenoma (NFPA) matched by sex and age. Expression of genes involved in the regulation of bone remodeling was studied using quantitative polymerase chain reaction (qPCR). RESULTS: Of the genes involved in osteoblast and osteoclast activity, only alkaline phosphatase (ALP) mRNA was 50% downregulated in patients with acromegaly. GH excess caused increased expression of the Wnt signaling antagonists (DKK1) and agonists (WNT10B) and changes in the levels of miR involved in mesenchymal stem cell commitment to chondrocytes (miR-199a-5p) or adipocytes (miR-27-5p, miR-125b-5p, miR-34a-5p, miR-188-3p) P < 0.05; q < 0.1. Relevant compensatory mechanisms were found through the changes in miR involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p), but the expression of TWIST1 was 50% downregulated and RUNX2 was unchanged. CONCLUSIONS: Acromegaly had minimal effects on tested mRNAs specific to osteoblast or osteoclast function except for downregulated ALP expression. The expressions of miR known to be involved in mesenchymal stem cell commitment and downregulated TWIST1 expression suggest acromegaly has a negative effect on osteoblastogenesis.

Genetic and pathogenic characterization of a Russian subtype 2 PRRSV-1 isolate.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes reproductive failure and respiratory problems. Data about the virulence and pathogenicity of subtype 2 PRRSV-1 strains are limited. The main purposes of this investigation were to characterize the full genome sequence of the subtype 2 PRRSV-1 WestSib13 strain and to compare the pathogenicity with that of the subtype 1 PRRSV-1 Lelystad strain. Comparison of the whole genome sequence of the WestSib13 strain with that of PRRSV-1 prototype strains revealed a 76.2% (subtype 1 Lelystad virus) and 79.0% (subtype 3 Lena virus) identity, respectively The virulence and pathogenicity of the European subtype 2 PRRSV strain WestSib13 and the European subtype 1 PRRSV strain Lelystad were compared in 3-week-old piglets upon inoculation of 105.4 TCID50 of virus. Non-infected animals (control group) as well as animals infected with the Lelystad strain were clinically healthy until 14days post challenge. In contrast, animals infected with the WestSib13 strain demonstrated dyspnea starting at 3days post-inoculation (dpi). All piglets in this group died between 5 and 8 dpi. During that period, fever was not observed in WestSib13-infected animals. Viremia was detected in animals from both infected groups starting from 2 dpi. Viral loads in serum and lungs upon euthanasia were significantly higher (3 log10) in the WestSib13-infected than in the LV-infected animals. Taken together, this study provides the full genome sequence and the unusual virological and clinical outcome (high level viremia without fever) of the novel WestSib13 strain.