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Abstract The Aria cryogenic distillation plant, located in Sardinia, Italy, is a key component of the DarkSide-20k experimental program for WIMP dark matter searches at the INFN Laboratori Nazionali del Gran Sasso, Italy. Aria is designed to purify the argon, extracted from underground wells in Colorado, USA, and used as the DarkSide-20k target material, to detector-grade quality. In this paper, we report the first measurement of argon isotopic separation by distillation with the 26 m tall Aria prototype. We discuss the measurement of the operating parameters of the column and the observation of the simultaneous separation of the three stable argon isotopes: $${}^{36}\hbox {Ar}$$ 36 Ar , $${}^{38}\textrm{Ar}$$ 38 Ar , and $${}^{40}\textrm{Ar}$$ 40 Ar . We also provide a detailed comparison of the experimental results with commercial process simulation software. This measurement of isotopic separation of argon is a significant achievement for the project, building on the success of the initial demonstration of isotopic separation of nitrogen using the same equipment in 2019.

Abstract Aria is a plant hosting a $${350}\,\hbox {m}$$ 350 m cryogenic isotopic distillation column, the tallest ever built, which is being installed in a mine shaft at Carbosulcis S.p.A., Nuraxi-Figus (SU), Italy. Aria is one of the pillars of the argon dark-matter search experimental program, lead by the Global Argon Dark Matter Collaboration. It was designed to reduce the isotopic abundance of $${^{39}\hbox {Ar}}$$ 39 Ar in argon extracted from underground sources, called Underground Argon (UAr), which is used for dark-matter searches. Indeed, $${^{39}\hbox {Ar}}$$ 39 Ar is a $$\beta $$ β -emitter of cosmogenic origin, whose activity poses background and pile-up concerns in the detectors. In this paper, we discuss the requirements, design, construction, tests, and projected performance of the plant for the isotopic cryogenic distillation of argon. We also present the successful results of the isotopic cryogenic distillation of nitrogen with a prototype plant.

Background. Antigen-presenting cells (APCs), especially macrophages, play an important role in the body defense against various pathogens. Their dysfunction and polarization are associated with most inflammatory and autoimmune diseases. The inflammatory process is regulated by activation and / or inhibition of genes differentially expressed by macrophages. Successful correction of inflammation leads firstly to elimination of inflammatory stimuli and then to remodeling and restoration of tissues and organs. It was experimentally confirmed that silvercontaining bionanocomposites based on natural humic substances (HS) obtained from coal of different origin, as well as initial matrices of these HS, are capable of activating pro- and anti-inflammatory properties of macrophages.Aim. To study cytotoxic, pyrogenic, and immunomodulatory properties (arginine balance) of initial HS samples and samples of silver nanoparticles ultradispersed in these HS matrices (HS-AgNPs) in the cell culture of peritoneal macrophages, as well as their effect on pro- and anti-inflammatory properties of APCs.Materials and methods. Cultural and biochemical methods were used in the study.Results. The study showed that the samples CHE-K, CHE-AgNPs, CHS-K, and CHP-K increased M1 macrophage polarization due to stimulation of the NO-synthase activity and inhibition of arginase. The samples CHI-K, CHIAgNPs, CHP-AgNPs, and CHS-AgNPs modulated an alternative M2 or M2-like state of macrophage activation. At the same time, HS are not cytotoxic at effective concentrations, and three out of four studied samples did not contain pyrogenic impurities.Conclusion. The use of HS and their silver-containing bionanocomposites, which have the ability to greatly affect the polarization of antigen-presenting cells, is a promising research area in correction of the inflammatory response for solving an important social and medical problem of treating chronic wounds.

Introduction. Silver nanoparticles are promising agents for suppressing resistant strains of microorganisms and accelerating the purulent wounds healing. Oxidative stress disrupts normal wound healing processes, which leads to the formation of chronic non-healing wounds. Therefore, the determination of the ability of new wound healing agents to decrease the production of reactive oxygen species is a relevant task.Aim. The aim of the current study was to investigate the effect of silver-containing bionanocompositions based on humic substances on the basal and tert-butyl hydroperoxide-stimulated production of reactive oxygen species at the normal fibroblasts 3T3-L1 cell culture in vitro.Materials and methods. The study was carried out on 7 samples of initial humic substances and biomaterials with silver nanoparticles synthesized in the Laboratory of Natural Humic Systems, Faculty of Chemistry, Moscow State University named after M. V. Lomonosov. The intracellular production of reactive oxygen species was assessed using a 2,7-dichlorodihydrofluorescein diacetate fluorescent probe. Cells were cultured with samples for 24 h; tret-butyl hydroperoxide was used to stimulate the production of reactive oxygen species. Detection was performed fluorometrically using a microplate reader.Results and discussion. The most pronounced antioxidant activity was demonstrated by three samples of biomaterials with silver nanoparticles ultradispersed in humic substances matrices (CHS-AgNPs, CHP-AgNPs and CHE-AgNPs), which allows us to consider them as the most promising pharmaceutical agents for the treatment of purulent-inflammatory processes. The most probable mechanism of the high antioxidant activity of the studied biomaterials in relation to intracellular reactive oxygen species is the intrinsic activity of humic substances to bind reactive oxygen species, while silver nanoparticles in biomaterials catalyze the reduction processes of their interaction with reactive oxygen species.Conclusion. For the studied samples of biomaterials with silver nanoparticles ultradispersed in matrices of humic substances pronounced antioxidant activity was shown. Together with antibacterial properties, it makes it possible to consider them as potential agents for purulent wounds healing accelerating.

Materials and methods. 18 native humic acids (HAs) were received from nine representative types of peat of the Tomsk region. Two extraction methods were used: sodium hydroxide and sodium pyrophosphate. Molecular structure parameters were investigated by IR-spectroscopy. The assessement of qualitative and quantitative features of the IR-spectra of 18 different humic acids was made. When HAs with mouse macrophages were cultured their ability to influence the NO-stimulation was determined. Thus, the biological activity of HAs and its dependence on the parameters of the molecular structure were studied.Results. The results of infrared spectroscopy showed that the HAs of upland types of peat contain more carbonyl, carboxyl, and ester groups, and HAs of lowland types of peat contain more aromatic carbon, phenolic and alcoholic hydroxyl, ether and carbohydrate fragments. The results of biological activity showed that HAs from upland types of peat induce the formation of nitrogen oxide, wherein the cell activation decreases with HAs obtained by alkali. All types of HAs from lowland types of peat contain an admixture of endotoxin. Some HAs obtained by sodium pyrophosphate have higher immunotropic activity; the HAs can cause antigen-specific stimulation of cells. The activity of HAs does not depend on endotoxin admixture. The results of molecular spectroscopy showed that the most biologically active HAs have higher aromaticity and higher concentration of oxygen-containing functional groups. This result can be used as a marker factor in the standardization of HAs.

The earlier pathomorphological studies of toxic properties of peat humic acids (PHAs) at intraperitoneal injection revealed that one of the causes of lethality is the direct cardiotoxic action of PHAs. For the further study of the mechanism of cardiotoxic action, electrocardiogram was recorded and ventricular fibrillation threshold was determined in male rats after intraperitoneal injection of humic acids in knowingly lethal dose – 480 mg/kg bwt. A single intraperitoneal injection of PHA to rats in knowingly lethal dose caused a significant decrease of the ventricular fibrillation threshold in comparison with intact animals. It was found that the PHA injection exerted no significant effect on the heart rate in rats and change of the PQ, QT, and QTc intervals. At the same time, the significant shortening of the QRS complex in comparison with intact animals was observed. Judging from the results obtained, the single injection of humic acids in the lethal dose induced a decrease in the electrical stability of heart, as evidenced by the drop of the ventricular fibrillation threshold. This decrease of the electrical stability of heart can be a cause of sudden cardiac death of trial rats. Disorder of the heart electrical stability is likely connected with the ionophoric action of humic acids and change of electrophysiological properties of cell membranes.

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Aim. To assess the effect of iron-rich humic substances on hematological parameters in acute post-hemorrhagic and iron deficiency anemia.Materials and methods. Materials for the study were samples of iron-rich active pharmaceutical ingredients based on humic substances (Fe(III) hydroxide complexes with humic substances and polymaltose): HA-Fe3+, HA-PMFe3+, FA-Fe3+, and FA-PM-Fe3+. The anti-anemic activity of the substances was studied on 53 female Wistar rats of the conventional rat line in the model of acute posthemorrhagic and iron deficiency anemia. Anti-anemic activity was assessed by the hemoglobin level, erythrocyte count, hematocrit, and serum iron level.Results. The studied substances HA-Fe3+ and FA-Fe3+ are the most effective in correcting the consequences of both experimental acute posthemorrhagic anemia and iron deficiency anemia. Their effect is comparable to that of the positive control drug Ferrum Lek.Conclusion. Fe(III) hydroxide complexes stabilized by humic and fulvic acids exhibit anti-anemic activity.

Introduction. Macrophages occupy a special place in the formation and coordination of the immune response, their population is characterized by heterogeneity, however, two main types are distinguished among them: pro-inflammatory (classically activated) macrophages M1, which are activated by interferon-γ (IFN-γ) or lipopolysaccharide (LPS) of bacteria, produce pro-inflammatory cytokines, nitric oxide (NO) and initiate an immune response, and anti-inflammatory (alternatively activated) macrophages M2, which are activated by such cytokines as interleukin 1 (IL-1), IL-10 or IL-13 and are associated with suppression of the immune response and tissue healing. The proinflammatory properties of macrophages are most often associated with the activation of an intracellular signaling cascade with the participation of the IKK-2 kinase complex and nuclear factor-κB (NF-κB), which is the most important signal transduction molecule. Previously, the authors showed that humic acids (HA) of peat cause the appearance of pro-inflammatory properties in macrophages; however, the intracellular mechanisms of such activation have not been studied.Aim. Study of the contribution of the intracellular signaling cascade IKK-2/NF-κB to the activation of pro-inflammatory properties of macrophages by humic acids of peat.Materials and methods. The studies were carried out using cultural methods and western blotting.Results and discussion. It was shown that the addition of the IKK-2 inhibitor to the macrophage culture reduced the ability of HA to stimulate the production of nitric oxide by the cells. Western blotting revealed that after 30 minutes simultaneous incubation of HA with macrophages, the content of the NF-κB p65 molecule in the cells increased, after 60 minutes it decreased to the values of intact control, and after 17 hours it decreased 3 times compared to the control level. However, the IKK-2 inhibitor after a 30-minutes incubation did not have a blocking effect on the IKK kinase, whereas in an hour of the co-incubation of the cells with the inhibitor and substances, a decrease in the level of NF-κB p65 was observed. This trend continued in 17 hours.Conclusion. The stimulating effect of peat humic acids on macrophages is realized, among other things, due to the activation of the IKK-2 kinase complex with further release of the p65 subunit of the NF-κB molecule. The dependence of the degree of NF-κB activation on the period of interaction of the cell with activating agents is traced. HA start the intracellular signaling cascade of the nuclear factor NF-κB already within the first 30 minutes.