Modeling hepatitis A epidemiological profiles and estimating the pediatric vaccination threshold in the Russian Federation.

Background: To combat the hesitancy towards implementing a hepatitis A universal mass vaccination (UMV) strategy and to provide healthcare authorities with a comprehensive analysis of the potential outcomes and benefits of the implementation of such a vaccination program, we projected HAV seroprevalence and incidence rates in the total population of the Russian Federation and estimated the pediatric vaccination threshold required to achieve an incidence level of less than 1 case per 100,000 using a new mathematical model. Methods: A dynamic age-structured SEIRV (susceptible-exposed-infectious-recovered-vaccinated) compartmental model was developed and calibrated using demographic, seroprevalence, vaccination, and epidemiological data from different regions of the Russian Federation. This model was used to project various epidemiological measures. Results: The projected national average age at the midpoint of population immunity increases from 40 years old in 2020 to 50 years old in 2036 and is shifted even further to the age of 70 years in some regions of the country. An increase of varying magnitude in the incidence of symptomatic HAV infections is predicted for all study regions and for the Russian Federation as a whole between 2028 and 2032, if the HAV vaccination coverage level remains at the level of 2022. The national average vaccination coverage level required to achieve a symptomatic HAV incidence rate below 1 case per 100,000 by 2032 was calculated to be 69.8% if children aged 1-6 years are vaccinated following the implementation of a UMV program or 34.8% if immunization is expanded to children aged 1-17 years. Conclusion: The developed model provides insights into a further decline of herd immunity to HAV against the background of ongoing viral transmission. The current favorable situation regarding hepatitis A morbidity is projected to be replaced by an increase in incidence rates if vaccination coverage remains at the current levels. The obtained results support the introduction of a hepatitis A UMV strategy in the Russian Federation.

Two Types of Survival Curves of Different Lines of Progeric Mice.

For most of their lifespan, the probability of death for many animal species increases with age. Gompertz law states that this increase is exponential. In this work, we have compared previously published data on the survival kinetics of different lines of progeric mice. Visual analysis showed that in six lines of these rapidly aging mutants, the probability of death did not strictly depend on age. In contrast, ten lines of progeric mice have survival curves similar to those of the control animals, that is, in agreement with Gompertz law, similar to the shape of an exponential curve upside down. Interestingly, these ten mutations cause completely different cell malfunctions. We speculate that what these mutations have in common is a reduction in the lifespan of cells and/or an acceleration of the transition to the state of cell senescence. Thus, our analysis, similar to the conclusions of many previously published works, indicates that the aging of an organism is a consequence of the aging of individual cells.

Metabolomic Profile and Functional State of Oat Plants (Avena sativa L.) Sown under Low-Temperature Conditions in the Cryolithozone.

Oats are one of the most useful and widespread cereal crops in the world. In permafrost conditions (Central Yakutia), based on metabolic changes in late summer-sown oat plants (Avena sativa L.), the key processes involved in the cold acclimation of a valuable cereal species were identified. During the onset of low ambient temperatures, metabolites from leaf samples were profiled using gas chromatography with mass spectrometry (GC-MS) and were analyzed using principal component analysis (PCA). A total of 41 metabolites were identified in oat leaves. It was found that acclimation to suboptimal temperatures during the fall period leads to biochemical (accumulation of mono- and disaccharides and decrease in fatty acids and polyols) as well as physiological and biophysical changes (decrease in leaf PRI reflectance indices and chlorophyll a fluorescence). Therefore, the study contributes to a more holistic understanding of oat metabolism under low-temperature cryolithozone stress. It is believed that the analysis of changes in leaf reflection properties and JIP-test parameters of chlorophyll a fluorescence using leaf metabolomic profiling can be used in the selection of valuable varieties of cereal crops to obtain plant fodders with high nutrient contents under conditions of a sharply continental climate.

The Imidazolium Ionic Liquids Toxicity is Due to Their Effect on the Plasma Membrane.

Ionic liquids (ILs) are organic salts with a low melting point. This is due to the fact that their alkyl side chains, which are covalently connected to the ion, hinder the crystallization of ILs. The low melting point of ILs has led to their widespread use as relatively harmless solvents. However, ILs do have toxic properties, the mechanism of which is largely unknown, so identifying the cellular targets of ILs is of practical importance. In our work, we showed that imidazolium ILs are not able to penetrate model membranes without damaging them. We also found that inactivation of multidrug resistance (MDR) pumps in yeast cells does not increase their sensitivity to imidazolium ILs. The latter indicates that the target of toxicity of imidazolium ILs is not in the cytoplasm. Thus, it can be assumed that the disruption of the barrier properties of the plasma membrane is the main reason for the toxicity of low concentrations of imidazolium ILs. We also showed that supplementation with imidazolium ILs restores the growth of cells with kinetically blocked glycolysis. Apparently, a slight disruption of the plasma membrane caused by ILs can, in some cases, be beneficial for the cell.

Unlocking the Potential of CuAgZr Metallic Glasses: A Comprehensive Exploration with Combinatorial Synthesis, High-Throughput Characterization, and Machine Learning.

In this work, the CuAgZr metallic glasses (MGs) are investigated, a promising material for biomedical applications due to their high strength, corrosion resistance, and antibacterial activity. Using an integrated approach of combinatorial synthesis, high-throughput characterization, and machine learning (ML), the mechanical properties of CuAgZr MGs are efficiently explored. The investigation find that post-deposition oxidation in inter-columnar regions with looser packing causes high oxygen content in Cu-rich regions, significantly affecting the alloys' mechanical behavior. The study also reveals that nanoscale structural features greatly impact plastic yielding and flow in the alloys. ML algorithms are tested, and the multi-layer perceptron algorithm produced satisfactory predictions for the alloys' hardness of untested alloys, providing valuable clues for future research. The work demonstrates the potential of using combinatorial synthesis, high-throughput characterization, and ML  techniques to facilitate the development of new MGs with improved strength and economic feasibility.

Six Functions of Respiration: Isn't It Time to Take Control over ROS Production in Mitochondria, and Aging Along with It?

Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function #6, which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation. Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.

Structural Role of Plasma Membrane Sterols in Osmotic Stress Tolerance of Yeast Saccharomyces cerevisiae.

Yeast S. cerevisiae has been shown to suppress a sterol biosynthesis as a response to hyperosmotic stress. In the case of sodium stress, the failure to suppress biosynthesis leads to an increase in cytosolic sodium. The major yeast sterol, ergosterol, is known to regulate functioning of plasma membrane proteins. Therefore, it has been suggested that the suppression of its biosynthesis is needed to adjust the activity of the plasma membrane sodium pumps and channels. However, as the sterol concentration is in the range of thirty to forty percent of total plasma membrane lipids, it is believed that its primary biological role is not regulatory but structural. Here we studied how lowering the sterol content affects the response of a lipid bilayer to an osmotic stress. In accordance with previous observations, we found that a decrease of the sterol fraction increases a water permeability of the liposomal membranes. Yet, we also found that sterol-free giant unilamellar vesicles reduced their volume during transient application of the hyperosmotic stress to a greater extent than the sterol-rich ones. Furthermore, our data suggest that lowering the sterol content in yeast cells allows the shrinkage to prevent the osmotic pressure-induced plasma membrane rupture. We also found that mutant yeast cells with the elevated level of sterol accumulated propidium iodide when exposed to mild hyperosmotic conditions followed by hypoosmotic stress. It is likely that the decrease in a plasma membrane sterol content stimulates a drop in cell volume under hyperosmotic stress, which is beneficial in the case of a subsequent hypo-osmotic one.

Hydrogeochemistry and stable isotopes in radon-rich thermal waters of Belokurikha (Altai, Russia).

The first integrated isotope and chemistry results have been obtained for radon-rich thermal waters from the Belokurikha field which are used at a large spa resort in Altai, Russia. The waters reside in an unconfined aquifer composed of Quaternary soft sediments and in a confined (artesian) aquifer of monolithic to weathered Upper Paleozoic granites. The waters belong to three geochemical groups: low-radon nitrogen-silicic interstitial waters in weathered Paleozoic granites; groundwaters of REE-enriched and background compositions; surface waters of the Belokurikha River. The interstitial waters in granites have HCO3-SO4 Na and SO4-HCO3 Na major-ion chemistry, total salinity from 198 to 257 mg/L, pH = 8.6-9.6, silica contents of 19.8 to 24.6 mg/L, and 222Rn activity from 160 to 360 Bq/L (290 Bq/L on average). Judging by their oxygen and hydrogen (deuterium) isotope compositions (-17.5 to -14.2 ‰ and -126.9 to -102.7 ‰, respectively), the Belokurikha aquifers recharge with infiltrating meteoric water, especially the winter precipitation. The carbon isotope composition of dissolved inorganic carbon (-9.7 to -25.6 ‰ δ13СDIC) corresponds to biogenic origin. Comparison of radon-rich mineral waters from different areas of southern Siberia shows that the change from oxidized to reduced environments leads to 232Th/238U increase from 4.20∙10-5-7.39∙10-2 to 0.0022-26, respectively, with an intermediate range of 2.63∙10-5-0.20 in transitional conditions.

Cytostatic effects of structurally different ginsenosides on yeast cells with altered sterol biosynthesis and transport.

Triterpene glycosides are a diverse group of plant secondary metabolites, consisting of a sterol-like aglycon and one or several sugar groups. A number of triterpene glycosides show membranolytic activity, and, therefore, are considered to be promising antimicrobial drugs. However, the interrelation between their structure, biological activities, and target membrane lipid composition remains elusive. Here we studied the antifungal effects of four Panax triterpene glycosides (ginsenosides) with sugar moieties at the C-3 (ginsenosides Rg3, Rh2), C-20 (compound K), and both (ginsenoside F2) positions in Saccharomyces cerevisiae mutants with altered sterol plasma membrane composition. We observed reduced cytostatic activity of the Rg3 and compound K in the UPC2-1 strain with high membrane sterol content. Moreover, LAM gene deletion reduced yeast resistance to Rg3 and digitonin, another saponin with glycosylated aglycon in the C-3 position. LAM genes encode plasma membrane-anchored StARkin superfamily-member sterol transporters. We also showed that the deletion of the ERG6 gene that inhibits ergosterol biosynthesis at the stage of zymosterol increased the cytostatic effects of Rg3 and Rh2, but not the other two tested ginsenosides. At the same time, in silico simulation revealed that the substitution of ergosterol with zymosterol in the membrane changes the spatial orientation of Rg3 and Rh2 in the membranes. These results imply that the plasma membrane sterol composition defines its interaction with triterpene glycoside depending on their glycoside group position. Our results also suggest that the biological role of membrane-anchored StARkin family protein is to protect eukaryotic cells from triterpenes glycosylated at the C-3 position.

High-temperature superconductivity on the verge of a structural instability in lanthanum superhydride.

The possibility of high, room-temperature superconductivity was predicted for metallic hydrogen in the 1960s. However, metallization and superconductivity of hydrogen are yet to be unambiguously demonstrated and may require pressures as high as 5 million atmospheres. Rare earth based "superhydrides", such as LaH10, can be considered as a close approximation of metallic hydrogen even though they form at moderately lower pressures. In superhydrides the predominance of H-H metallic bonds and high superconducting transition temperatures bear the hallmarks of metallic hydrogen. Still, experimental studies revealing the key factors controlling their superconductivity are scarce. Here, we report the pressure and magnetic field dependence of the superconducting order observed in LaH10. We determine that the high-symmetry high-temperature superconducting Fm-3m phase of LaH10 can be stabilized at substantially lower pressures than previously thought. We find a remarkable correlation between superconductivity and a structural instability indicating that lattice vibrations, responsible for the monoclinic structural distortions in LaH10, strongly affect the superconducting coupling.

Composite pressure cell for pulsed magnets.

Extreme pressures and high magnetic fields can affect materials in profound and fascinating ways. However, large pressures and fields are often mutually incompatible; the rapidly changing fields provided by pulsed magnets induce eddy currents in the metallic components used in conventional pressure cells, causing serious heating, forces, and vibration. Here, we report a diamond-anvil-cell made mainly out of insulating composites that minimizes inductive heating while retaining sufficient strength to apply pressures of up to 8 GPa. Any residual metallic component is made of low-conductivity metals and patterned to reduce eddy currents. The simple design enables rapid sample or pressure changes, desired by pulsed-magnetic-field-facility users. The pressure cell has been used in pulsed magnetic fields of up to 65 T with no noticeable heating at cryogenic temperatures. Several measurement techniques are possible inside the cell at temperatures as low as 500 mK.

Application of a flexible polymer microECoG array to map functional coherence in schizophrenia model.

Anatomically, connections form the fundamental brain network, functionally the different types of oscillatory electric activities are creating a temporarily connected fraction of the anatomical connectome generating an output to the motor system. Schizophrenia can be considered as a connectome disease, in which the sensory input generates a schizophrenia specific temporary connectome and the signal processing becomes diseased showing hallucinations and adverse behavioral reactions. In this work, flexible, 32-channel polymer microelectrode arrays fabricated by the authors are used to map the functional coherence on large cortical areas during physiological activities in a schizophrenia model in rats.-Fabrication of a flexible microECoG array is shown.-Protocol to use a flexible microECoG is demonstrated to characterize connectome diseases in rats.-Customized method to analyze the functional coherence between different cortical areas during visually evoked potential is detailed.-R-based implementation of the analysis method is presented.

Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow.

Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity.

Protonophore FCCP provides fitness advantage to PDR-deficient yeast cells.

Pleiotropic drug resistance (PDR) plasma membrane transporters mediate xenobiotic efflux from the cells and thereby help pathogenic microorganisms to withstand antimicrobial therapies. Given that xenobiotic efflux is an energy-consuming process, cells with upregulated PDR can be sensitive to perturbations in cellular energetics. Protonophores dissipate proton gradient across the cellular membranes and thus increase ATP spendings to their maintenance. We hypothesised that chronic exposure of yeast cells to the protonophores can favour the selection of cells with inactive PDR. To test this, we measured growth rates of the wild type Saccharomyces cerevisiae and PDR-deficient Δpdr1Δpdr3 strains in the presence of protonophores carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), pentachlorophenol (PCP) and niclosamide (NCA). Although the protonophore-induced respiration rates of these two strains were similar, the PDR-deficient strain outperformed the control one in the growth rate on non-fermentable carbon source supplemented with low concentrations of FCCP. Thus, active PDR can be deleterious under conditions of partially uncoupled oxidative-phosphorylation. Furthermore, our results suggest that tested anionic protonophores are poor substrates of PDR-transporters. At the same time, protonophores imparted azole tolerance to yeasts, pointing that they are potent PDR inducers. Interestingly, protonophore PCP led to a persistent increase in the levels of a major ABC-transporter Pdr5p, while azole clotrimazole induced only a temporary increase. Together, our data provides an insight into the effects of the protonophores in the eukaryotes at the cellular level and support the idea that cells with activated PDR can be selected out upon conditions of energy limitations.

Non-monotonic pressure dependence of high-field nematicity and magnetism in CeRhIn5.

CeRhIn5 provides a textbook example of quantum criticality in a heavy fermion system: Pressure suppresses local-moment antiferromagnetic (AFM) order and induces superconductivity in a dome around the associated quantum critical point (QCP) near pc ≈ 23 kbar. Strong magnetic fields also suppress the AFM order at a field-induced QCP at Bc ≈ 50 T. In its vicinity, a nematic phase at B* ≈ 28 T characterized by a large in-plane resistivity anisotropy emerges. Here, we directly investigate the interrelation between these phenomena via magnetoresistivity measurements under high pressure. As pressure increases, the nematic transition shifts to higher fields, until it vanishes just below pc. While pressure suppresses magnetic order in zero field as pc is approached, we find magnetism to strengthen under strong magnetic fields due to suppression of the Kondo effect. We reveal a strongly non-mean-field-like phase diagram, much richer than the common local-moment description of CeRhIn5 would suggest.

Far Eastern Scarlet-Like Fever is a Special Clinical and Epidemic Manifestation of Yersinia pseudotuberculosis Infection in Russia.

Pseudotuberculosis in humans until the 1950s was found in different countries of the world as a rare sporadic disease that occurred in the form of acute appendicitis and mesenteric lymphadenitis. In Russia and Japan, the Yersinia pseudotuberculosis (Y. pseudotuberculosis) infection often causes outbreaks of the disease with serious systemic inflammatory symptoms, and this variant of the disease has been known since 1959 as Far Eastern Scarlet-like Fever (FESLF). Russian researchers have proven that the FESLF pathogen is associated with a concrete clonal line of Y. pseudotuberculosis, characterized by a specific plasmid profile (pVM82, pYV 48 MDa), sequence (2ST) and yadA gene allele (1st allele). This review summarized the most important achievements in the study of FESLF since its discovery in the Far East. It has been established that the FESLF causative agent is characterized by a unique phenomenon of psychrophilicity, which consists of its ability to reproduce in the environment with its biologically low and variable temperature (4-12 °C), at which the pathogen multiplies and accumulates while maintaining or increasing its virulence, which ensures the emergence and development of the epidemic process. The key genetic and biochemical mechanisms of Y. pseudotuberculosis adaptation to changing environmental conditions were characterized, and the morphological manifestations of the adaptive variability of these bacteria in different conditions of their habitat were revealed. The main features of the pathogenesis and morphogenesis of FESLF, including those associated with the Y. pseudotuberculosis toxigenicity, were presented. The pathogenetic value of the plasmid PVM82, found only in the FESLF pathogen, was shown.

Cryogenic goniometer for measurements in pulsed magnetic fields fabricated via additive manufacturing technique.

Complex high-precision mechanical devices can be fabricated using a three-dimensional printing technology with the help of computer-aided design. Using 3D stereolithography, we have constructed a cryogenic goniometer for measurements in pulsed magnetic fields of up to 100 T, at temperatures as low as 0.5 K. We review the properties of several materials tested in developing the goniometer and report on its design and performance. The goniometer allows samples to be rotated in situ to a precision of 0.2° so that the field can be applied at many different angles to the samples' symmetry directions. Following its success, we establish that 3D printing is now a viable technology for pulsed field and other cryogenic probes.

Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program.

The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol. One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H+-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation. In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.

Mitochondrial dynamics in yeast with repressed adenine nucleotide translocator AAC2.

The mitochondrial network structure dynamically adapts to cellular metabolic challenges. Mitochondrial depolarisation, particularly, induces fragmentation of the network. This fragmentation may be a result of either a direct regulation of the mitochondrial fusion machinery by transmembrane potential or an indirect effect of metabolic remodelling. Activities of ATP synthase and adenine nucleotide translocator (ANT) link the mitochondrial transmembrane potential with the cytosolic NTP/NDP ratio. Given that mitochondrial fusion requires cytosolic GTP, a decrease in the NTP/NDP ratio might also account for protonophore-induced mitochondrial fragmentation. For evaluating the contributions of direct and indirect mechanisms to mitochondrial remodelling, we assessed the morphology of the mitochondrial network in yeast cells with inhibited ANT. We showed that the repression of AAC2 (PET9), a major ANT gene in yeast, increases mitochondrial transmembrane potential. However, the mitochondrial network in this strain was fragmented. Meanwhile, AAC2 repression did not prevent mitochondrial fusion in zygotes; nor did it inhibit mitochondrial hyperfusion induced by Dnm1p inhibitor mdivi-1. These results suggest that the inhibition of ANT, rather than preventing mitochondrial fusion, facilitates mitochondrial fission. The protonophores were not able to induce additional mitochondrial fragmentation in an AAC2-repressed strain and in yeast cells with inhibited ATP synthase. Importantly, treatment with the ATP synthase inhibitor oligomycin A also induced mitochondrial fragmentation and hyperpolarization. Taken together, our data suggest that ATP/ADP translocation plays a crucial role in shaping of the mitochondrial network and exemplify that an increase in mitochondrial membrane potential does not necessarily oppose mitochondrial fragmentation.