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Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies. Here, we explored aminomethylmorpholino and aminomethylmorpholino glycine nucleosides as inhibitors of PARP1 and PARP2, using different enzymatic assays. The compounds bearing thymine or 5-Br(I)-uracil bases displayed the highest inhibition potency, with all of them being more selective toward PARP1. Interaction of the inhibitors with the NAD+ binding cavity of PARP1 (PARP2) suggested by the mixed-type inhibition was demonstrated by molecular docking and the RoseTTAFold All-Atom AI-model. The best PARP1 inhibitors characterized by the inhibition constants in the range of 12–15 µM potentiate the cytotoxicity of hydrogen peroxide by displaying strong synergism. The inhibitors revealed no impact on PARP1/PARP2 affinity for DNA, while they reduced the dissociation rate of the enzyme–DNA complex upon the autopoly(ADP-ribosyl)ation reaction, thus providing evidence that their mechanism of action for PARP trapping is due primarily to catalytic inhibition. The most active compounds were shown to retain selectivity toward PARP1, despite the reduced inhibition potency in the presence of histone PARylation factor 1 (HPF1) capable of regulating PARP1/PARP2 catalytic activity and ADP-ribosylation reaction specificity. The inhibitors obtained seem to be promising for further research as potential drugs. [ABSTRACT FROM AUTHOR]

The first data on the diversity and structure of bacterial communities in the Selenga River, its tributaries, and delta waters (Selenga shallows) during the summer high-water period of 2021 were obtained. The chemical indices (alkalinity, mineralization, as well as concentrations of sulfate and chloride ions) in the Russian part of the Selenga River exhibited a tendency to decrease gradually in the downstream direction. As before, the chemical composition of the Selenga River waters was determined by water content and anthropogenic pressures, while the effect of tributary waters was local. At a distance of 1 km from the mouths in the mixing zone of river water and lake water, the chemical composition and taxonomic structure of bacterial communities were close to those observed in the pelagic zone of Lake Baikal. In all analyzed 16S rRNA gene libraries, nine common bacterial phyla were identified, with a predominance of Pseudomonadota (51.71–76.83%) in river communities and Actinomycetota (17.28–66.32%) in the communities of the Selenga shallows. The most significant differences in the taxonomic composition of bacterial communities were noted at the genus level. We suggest that a stable bacterial community exists throughout the Selenga River course, with dominant members representing the bacterial genera Limnohabitans, Pseudarcicella, Rhodoluna, and Polynucleobacter. The same genera also predominated in the small rivers of South Baikal. A comparative analysis of the diversity of tributary communities did not reveal any significant impact on the microbiomes of the Selenga River and Lake Baikal. Only a few riverine bacterial taxa were identified in the littoral and pelagic zones of the lake. [ABSTRACT FROM AUTHOR]

Cationic antimicrobial peptides (AMPs), also called host defence peptides, have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were conjugated to L-K6, a lysine/leucine-rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components. [ABSTRACT FROM AUTHOR]

Four new glycosides of polyhydroxysteroids, ceramasterosides A, B, D, and E (1–4), and two previously known compounds, ceramasteroside C1 (5) and attenuatoside B-I (6), were isolated from an extract of a deep-sea sea star species, the orange cookie star Ceramaster patagonicus. The structures of 1–4 were elucidated by the extensive NMR and ESIMS methods. Steroid monoglycosides 1 and 2 had a common 3β,6α,8,15β,16β-pentahydroxysteroid nucleus and a C–29 oxidized stigmastane side chain and differed from each other only in monosaccharide residues. Ceramasteroside A (1) contained 3-O-methyl-4-O-sulfated β-D-xylopyranose, while ceramasteroside B (2) had 3-O-methyl-4-O-sulfated β-D-glucopyranose, recorded from starfish-derived steroid glycosides for the first time. Their biological activity was studied using a model of lipopolysaccharide-induced (LPS) inflammation in a SIM-A9 murine microglial cell line. During the LPS-induced activation of microglial cells, 1, 3, and 5, at a non-toxic concentration of 1 µM, showed the highest efficiency in reducing the production of intracellular NO, while 4 proved to be most efficient in reducing the extracellular nitrite production. All the test compounds reduced the LPS-induced malondialdehyde (MDA) production. The in vitro experiments have demonstrated, for the first time, the antioxidant activity of the compounds under study. [ABSTRACT FROM AUTHOR]

Buckingham [(2024). J. Acoust. Soc. Am. 155, 1285–1296] analyzed the dependence of the reflection coefficient on the grazing angle in two-layer marine sediment model. The upper layer in his model consists of a fine-grained material (mud), while seawater and the basement below the mud layer are treated as homogeneous halfspaces. Buckingham's analyses revealed several narrow spikes in this dependence that appeared only in the presence of a sound velocity gradient in the mud layer, a phenomenon he called acoustic glint. His derivation was accomplished for certain specific dependencies of the sound velocity on the depth. Surprisingly, the authors appear to reach the conclusion that for a slightly different vertical sound speed profile in the mud layer the spikes are no longer present in the dependence of the reflection coefficient on the grazing angle. More precisely, the same problem is examined in this letter for the case of an n 2 -linear layer (often called Airy medium). Acoustic glint effect is therefore very sensitive to the exact parametrization of the mud layer. [ABSTRACT FROM AUTHOR]

This study presents correction factors for the Norwegian fatigue load model for railway bridges. The fundamental idea of a correction factor is to ensure that the load model induces the same fatigue damage as actual traffic. Load measurements from traffic on a representative line on the Norwegian railway network are used to propose correction factors for improved fatigue life estimation with freight and passenger trains. Correction factors improve the accuracy of the estimated fatigue life and reduce the conservatism of the load model. The validity and conservatism of the most damaging train assumption for fatigue load modeling is also considered. The suitability and consequences of using the proposed correction factors for other lines and historic traffic are discussed. [ABSTRACT FROM AUTHOR]

We have started a measurement campaign of numerous methanol isotopologs in low-lying torsional states in order to provide extensive line lists for radio astronomical observations from an adequate spectroscopic model and to investigate how the intricate vibrationtorsion-rotation interactions manifest themselves in the spectra of different isotopic species. After CD3OH and CD3OD, we turn our focus to CH3OD, which is an important species for studying deuteration in prestellar cores and envelopes that enshroud protostars. Notably, deuteration is frequently viewed as a diagnostic tool for star formation. The measurements used in this study were obtained in two spectroscopic laboratories and cover large fractions of the 34 GHz-1.35 THz range. As done in previous studies, we employed a torsion-rotation Hamiltonian model for our analysis that is based on the rho-axis method. The resulting model describes the ground and first excited torsional states of CH3OD well up to quantum numbers J ⩽ 51 and Ka ⩽ 18. We derived a line list for radio astronomical observations from this model that is accurate up to at least 1.35 THz and should be sufficient for all types of radio astronomical searches for this methanol isotopolog in these two lowest torsional states. This line list was applied to a reinvestigation of CH3OD in data from the Protostellar Interferometric Line Survey of IRAS 16293–2422 obtained with the Atacama Large Millimeter/submillimeter Array. The new accurately determined value for the column density of CH3OD implies that the deuteration in methanol differs in its two functional groups by a factor of ~7.5. [ABSTRACT FROM AUTHOR]

Monitoring wildlife exposure to biological hazards is a critical component of the wildlife risk assessment. In this study 38 hair samples were collected from 8 different species from ten districts of Russian Far East and Siberia and analysed for the presence of organochlorine pesticides (OCP). 50% of the samples were contaminated with - p, p’-DDT, α-HCH and DDD. DDT was the main contaminant found in 13 sample at concentrations range of 14.3 to 369.5 pg/mg hair, mean 91.9 ± 89.7 pg/mg. α-HCH was detected in three samples with the concentrations range 29.9–180.2 pg/mg. The p, p’-DDD was found only in one hair sample of Siberian roe deer from Altai region at 52.6 pg/mg. The exposure level is depended on animals habitat location. The most contaminated region is Terney district which is in the proximity to the borders with China and North Korea where OCP are still in use. [ABSTRACT FROM AUTHOR]

Despite great advances in the treatment of oncological diseases, the development of medical technologies to prevent or reduce complications of therapy, in particular, those associated with surgery and the introduction of antibiotics, remains relevant. The aim of this study is to evaluate the effectiveness of the use of autoprobiotics based on indigenous non-pathogenic strains of Enterococcus faecium and Enterococcus hirae as a personalized functional food product (PFFP) in the complex therapy of colorectal cancer (CRC) in the early postoperative period. A total of 36 patients diagnosed with CRC were enrolled in the study. Study group A comprised 24 CRC patients who received autoprobiotic therapy in the early postoperative period, while the control group C included 12 CRC patients without autoprobiotic therapy. Prior to surgery and between days 14 and 16 post-surgery, comprehensive evaluations were conducted on all patients, encompassing the following: stool and gastroenterological complaints analysis, examination of the gut microbiota (bacteriological study, quantitative polymerase chain reaction, metagenome analysis), and analysis of interleukins in the serum. Results: The use of autoprobiotics led to a decrease in dyspeptic complaints after surgery. It was also associated with the absence of postoperative complications, did not cause any side effects, and led to a decrease in the level of pro-inflammatory cytokines (IL-6 and IL-18) in the blood serum. The use of autoprobiotics led to positive changes in the structure of escherichia and enterococci populations, the elimination of Parvomonas micra and Fusobacterium nucleatum, and a decrease in the quantitative content of Clostridium perfringens and Akkermansia muciniphila. Metagenomic analysis (16S rRNA) revealed an increase in alpha diversity. Conclusion: The introduction of autoprobiotics in the postoperative period is a highly effective and safe approach in the complex treatment of CRC. Future studies will allow the discovery of additional fine mechanisms of autoprobiotic therapy and its impact on the digestive, immune, endocrine, and neural systems. [ABSTRACT FROM AUTHOR]

Simple Summary: The life expectancy of Drosophila melanogaster evolves in the laboratory in a downward direction over time. The comparison of two old laboratory-adapted strains, Canton-S and Harwich, suggested that they may be used as a multicellular eukaryote model for studying the effects of individual difference in aging processes on the physiological responses to various environmental factors, including low and high temperature, carbohydrate-heavy food, and caffeinated food in the presence of light-dark cyclicity and constant darkness. We found that the accelerated aging in Harwich was associated with a shorter lifespan, lower fecundity, faster rate of development, smaller body weight, lower concentrations of two main insect sugars, reduced locomotor activity, and larger amount of sleep. Such findings imply that, in the experimental studies of the aging accelerated effects of various adverse factors, the results obtained with only one of the laboratory-adapted strains cannot be generalized to other strains. The documented individual and strain-associated differences in the responses of their daily rhythms to aging and age-accelerated factors allow the recommendation to use at least two distinct strains characterized by a relatively fast and relatively slow aging processes, for the experimental elaboration of relationships between genes, environment, behavior, physiology, and health. Background: Drosophila melanogaster provides a powerful platform to study the physiology and genetics of aging, i.e., the mechanisms underpinnings healthy aging, age-associated disorders, and acceleration of the aging process under adverse environmental conditions. Here, we tested the responses of daily rhythms to age-accelerated factors in two wild-type laboratory-adapted strains, Canton-S and Harwich. Methods: On the example of the 24 h patterns of locomotor activity and sleep, we documented the responses of these two strains to such factors as aging, high temperature, carbohydrate diet, and diet with different doses of caffeine-benzoate sodium. Results: The strains demonstrated differential responses to these factors. Moreover, compared to Canton-S, Harwich showed a reduced locomotor activity, larger amount of sleep, faster rate of development, smaller body weight, lower concentrations of main sugars, lower fecundity, and shorter lifespan. Conclusions: It might be recommended to use at least two strains, one with a relatively fast and another with a relatively slow aging process, for the experimental elaboration of relationships between genes, environment, behavior, physiology, and health. [ABSTRACT FROM AUTHOR]

The international sanctions on Russian industry necessitate the study of consumer behavior in such conditions. Legal aspects of economic regulation are reviewed. Analysis of what is entailed in protecting the social and economic rights of Russian citizens permits clearer understanding of the sanctions' influence on consumer behavior. Measures to stabilize the Russian economy are evaluated, and the current circumstances of industry and citizens are discussed. [ABSTRACT FROM AUTHOR]

Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC50 values in the submicromolar range. Furthermore, methyl esters 4d–e, as well as their acid counterparts 3d–e, inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d–e and 4d–e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that can reduce the efficacy of some anticancer drugs targeting topoisomerase 1 (TOP1) making it a promising target for antitumor therapy when combined with TOP1 poisons. Here we describe the synthesis of a number of adamantane-monoterpene conjugates 20a–g and 21a–g connected through a 1,3,4-thiadiazol-2(3H)-imine linker, where acyclic, monocyclic, and bicyclic structural types of monoterpenes were used. All the synthesized compounds demonstrated activity against TDP1 in micromolar range, with the most potent inhibitor being compound 21a (IC50 1.2 μM). The cytotoxic effects of these compounds determined in the HEK293A and HeLa cell lines were low to moderate. These findings imply that such compounds are promising for further development of new TDP1 inhibitors with favorable physicochemical properties. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives: tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer. [ABSTRACT FROM AUTHOR]

This article delves into the profound impact of postmodernism on the trajectory and evolution of future public administration. The 20th century witnessed radical changes in worldview, marking the transition from modernity to postmodernity. The basic principles of postmodernism, encompassing deconstruction, fragmentation, future shock, and cultural relativism, have instigated a paradigm shift challenging traditional administrative frameworks (M. Foucault, J.-F. Lyotard, A. Toffler, etc.). The article explores how these postmodern tenets influence administrative practices, power structures, and the very nature of governance. Postmodernity is characterized by a unique attitude towards truth, acknowledging its relativity, and by decentration, the absence of a single center, replaced by multipolarity and globalization. "Post-truth" replaces truth, posing new challenges to the future of public administration. The public administration of the future will be shaped by existing trends, including Public-Private Partnerships (PPP), Non-Governmental Organizations (NGOs), Corporate Social Responsibility (CSR), etc. It will also depend on modern technologies such as artificial intelligence, blockchain, data analysis, and data-driven decision-making, as underscored by the need for digitalization in response to the pandemic (according to EIB). However, alongside advantages, there are also challenges, such as issues of liability in the use of AI for future public administration. These risks can be mitigated through collaborative and participatory governance models, adaptive leadership, an emphasis on inclusivity, diversity, and social equity, addressing environmental concerns, advanced training courses, and other strategic measures. [ABSTRACT FROM AUTHOR]

This is the first report on the application of metagenomic analysis of the microbiome of Lake Baikal bottom sediments in order to assess the community structure and metabolic potential of the microorganisms inhabiting the upper sediment horizon at the site of a deep-water station. Compared to the metagenome of near-bottom water, relative abundance of the phyla Methylomirabilota, Chloroflexota, and Acidobacterota was found to increase, as well as that of the genes for the pathways of methane, sulfur, and thiosulfate oxidation and of nitrate reduction. Genomes of members of 12 phyla forming the basis of the studied microbiome were assembled. Reconstruction of the metabolic pathways indicated the possible coexistence of microorganisms capable of gaining carbon and energy due to oxidation of carbohydrates, methane, thiosulfate, and ammonia, as well as via anaerobic processes of fermentation, denitrification, and (to a lesser degree) sulfate reduction. [ABSTRACT FROM AUTHOR]

We introduce eco4cast,1 an open-source package aimed to reduce carbon footprint of machine learning models via predictive cloud computing scheduling. The package is integrated with machine learning models and employs an advanced temporal convolution neural network to forecast daily carbon dioxide emissions stemming from electricity generation.The model attains remarkable predictive accuracy by accounting for weather conditions, acknowledged for their robust correlation with carbon energy intensity. The hallmark of eco4cast lies in its capability to identify periods of temporal minimal carbon intensity. This enables the package to manage cloud computing tasks only during these periods, significantly reducing the ecological impact. Our contribution represents a compelling fusion of sustainability and computational efficiency. The code and documentation of the package are hosted on GitHub under the Apache 2.0 license. [ABSTRACT FROM AUTHOR]

The purpose of this research was to investigate and identify by tandem mass spectrometry the polyphenolic complexes and other biologically active compounds present in the leaves and stems of Ledum palustre L. Carbon dioxide, compressed to a supercritical state, was used for the most environmentally friendly extraction of polyphenolic complexes and other biologically active compounds from Ledum palustre L. The most effective extraction characteristics (pressure 350 bar, temperature 60°C, extraction time 1 h, co-solvent MeOH 3.5%) of supercritical CO2 extraction of L. palustre were determined empirically. To identify target analytes in the supercritical extracts, high performance liquid chromatography (HPLC) in combination with a BRUKER DALTONIKS ion trap was used. The results showed the presence of 61 biologically active compounds corresponding to the Rhododendron species, of which 32 were identified for the first time in L. palustre. These are flavanols dihydrokaempferol, quercetin arabinoside, myricetin galactoside; flavones diosmetin, nevadensin, cirsimaritin; flavanone naringenin; anthocyanins delphinidin, petunidin, cyanidin pentoside, delphinidin pentoside, peonidin 3-(6-O-acetyl) glucoside, peonidin-3-O-malonylglucoside, cyanidin-3-rutinoside, peonidin 3-O-glucoside; ellagic acid; lignan medioresinol; a type A procyanidin dimer; sterols fucosterol and avenasterol, etc. [ABSTRACT FROM AUTHOR]

New imidazolidine-2,4,5-triones with norabietic, nordehydroabietic, and adamantane substituents were synthesized by reacting oxalyl chloride and the corresponding ureas, providing good yields. Bioisosteric replacement of the ureide group with a parabanic acid fragment made it possible to increase the solubility of compounds and conduct biological studies. The compounds inhibit the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 in submicromolar concentrations. Cytotoxic concentrations were also studied on the glioblastoma cell line SNB19. [ABSTRACT FROM AUTHOR]

Porous calcium phosphate coatings (C-P) with ZnO nanoparticles were obtained via the micro-arc oxidation method on a titanium substrate. ZnO nanoparticles were added to the C-P coatings to change the zeta potential and improve the coatings' bioactivity and antibacterial properties. The samples with coatings were studied via scanning electron microscopy (SEM), X-ray diffraction, energy dispersive microanalysis, potentiodynamic polarization, and zeta potential measurement. The coatings modified with ZnO nanoparticles showed improved physical, electrochemical, and electrical properties, compared to the initial unmodified coatings. Modification with ZnO nanoparticles contributed to an increase in zeta potential from −60 mV to −53 mV. Functionalization of the coatings with ZnO nanoparticles allowed us to increase the anticorrosion characteristics by about 30%. The biological studies showed that the coatings had no cytotoxic effect on L929 fibroblast cells. The antibacterial activity of the coating rose by 99% after the addition of ZnO nanoparticles against the bacterium Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

The article deals with the problem of automation and decision-making support in forming sustainable assortments of plant species for landscaped areas of cities, taking into account environmental factors, conditions of growing, properties of plant species, and landscaping practices adopted in the region. The automation of plant species and composition planning for planted territories requires formation of a knowledge base and output algorithms, as well as consideration of specific landscaping practices and techniques adopted in the region. It also requires the application of new modeling methods in combination with methods of spatial analysis, which together with the database of available regional plant species forms a recommendation system and provides decision support in the tasks of landscaping for city planners. The feature of the proposed method based on network analysis is the combination and composition of plant species, as well as the properties of invasive species, which require the use of graph models to form a knowledge base. The proposed method can be useful for forming sustainable assortments of plant species for landscaping squares, boulevards, small courtyards in the city, technical areas and other cases that do not involve the creation of individual complex landscape design. As part of the testing of the proposed method, the authors have formed a unique information base of species. The use of such a database, together with the method of selecting the species composition based on their resistances and interspecies compatibility will ensure the expansion of the diversity of species in the created ecosystem, which will make green areas more resistant to external anthropogenic factors and diseases, as well as preventing the spread of species invasive to the region. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (−)-usnic acid. Both (+)- and (−)-enantiomers of compounds act equally effectively against Tdp1 with IC50 values in the range of 0.02–0.2 μM; only (−)-enantiomers inhibited Tdp2 with IC50 values in the range of 6–9 μM. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide (CC50 3.0–3.9 μM in the presence of compounds and 2.4 μM the presence of DMSO) but potentiate it against Tdp2 knockout cells (CC50 1.2–1.6 μM in the presence of compounds against 2.3 μM in the presence of DMSO). We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with the effective inhibition of Tdp1, which could take over the functions of Tdp2. [ABSTRACT FROM AUTHOR]

The present study deals with a new highly effective functional product, a dietary supplement, to improve gut biocenosis and support metabolic detoxification. The supplement includes the following ingredients (mg per capsule): postbiotic metafiltrate -200; natural zeolite -130.36; polysorbovit - 105 (soluble dietary fiber - 100); silicon dioxide - 14.46; lipase - 10; bromelain - 10; papain - 10; cellulase - 10; rutin - 6; chitosan - 5; lysozyme hydrochloride - 5. The supplement is considered innovative as capsules have a special enteric coating to provide successive and targeted delivery of ingredients to the gastrointestinal tract cells while preserving safety and bioactivity. The antimicrobial and antifungal activity of the postbiotic metafiltrate has been studied. The mechanism of endotoxin neutralization and biocenosis normalization is characterized by the following factors: the destruction of toxic peptidoglycans of the bacterial cell wall and proteins and peptides with different chain lengths; elimination of Candida albicans cells by destroying bonds in the beta-glycan molecule of the fungal cell wall; cleavage of toxic lipid A of lipopolysaccharides; the influence of the culture fluid metabolites of probiotic microorganisms; high sorption capacity and selectivity for endotoxins, toxic metabolites, pathogenic microorganisms, free radicals, allergens, and antigens. The product has been included in the volunteers' diet and its efficacy has been assessed. The product's role in metabolic detoxification and biocenosis normalization has been studied. The recommended dosage is 1 capsule twice a day with a meal for 30 days. [ABSTRACT FROM AUTHOR]

Clinical blood analysis, combined with cytomorphological examination is an important diagnostic tool for assessing the physiological state of animals. The cytomorphological features of blood cells have been described for terrestrial mammals, and well-illustrated veterinary atlases have been created, in which normal and pathological forms of animal blood cells are displayed. However, such information is virtually nonexistent for marine mammals. In this article, we present the results of a study of the morphology of the blood cells of the beluga (also known as "white") whale Delphinapterus leucas, obtained by supravital staining of blood smear preparations with Brilliant Cresyl Blue, Methylene Blue, and utilizing the standard Romanowsky–Giemsa staining technique. We describe the main types of blood cells of marine mammals: erythrocytes, segmented neutrophils, eosinophils, monocytes, lymphocytes, and band neutrophils, as well as rare basophils. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is an important enzyme in the DNA repair system. The ability of the enzyme to repair DNA damage induced by a topoisomerase 1 poison such as the anticancer drug topotecan makes TDP1 a promising target for complex antitumor therapy. In this work, a set of new 5-hydroxycoumarin derivatives containing monoterpene moieties was synthesized. It was shown that most of the conjugates synthesized demonstrated high inhibitory properties against TDP1 with an IC50 in low micromolar or nanomolar ranges. Geraniol derivative 33a was the most potent inhibitor with IC50 130 nM. Docking the ligands to TDP1 predicted a good fit with the catalytic pocket blocking access to it. The conjugates used in non-toxic concentration increased cytotoxicity of topotecan against HeLa cancer cell line but not against conditionally normal HEK 293A cells. Thus, a new structural series of TDP1 inhibitors, which are able to sensitize cancer cells to the topotecan cytotoxic effect has been discovered. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) dysregulation is well-documented in psychiatric disease, but miRNA dynamics remain poorly understood during adolescent and early adult brain maturation, when symptoms often first appear. Here, we use RNA sequencing to examine miRNAs and their mRNA targets in cortex and hippocampus from early-, mid-, and late-adolescent and adult mice. Furthermore, we use quantitative proteomics by tandem mass tag mass spectrometry (TMT-MS) to examine protein dynamics in cortex from the same subjects. We found that ~25% of miRNAs' 3' ends shorten with age due to increased 3' trimming and decreased U tailing. Particularly, shorter but functionally competent isoforms (isomiRs) of miR-338-3p increase up to 10-fold during adolescence and only in brain. MiRNAs that undergo 3' shortening exhibit stronger negative correlations with targets that decrease with age and stronger positive correlations with targets that increase with age, than miRNAs with stable 3' ends. Increased 3' shortening with age was also observed in available mouse and human miRNA-seq data sets, and stronger correlations between miRNAs that undergo shortening and their mRNA targets were observed in two of the three available data sets. We conclude that ageassociated miRNA 3' shortening is a well-conserved feature of postnatal brain maturation. [ABSTRACT FROM AUTHOR]

The purpose of this work was a comparative metabolomic study of extracts of from Siberian breeds of the Solanum tuberosum L.: Tuleevsky, Kuznechanka, Memory of Antoshkina, Tomichka, Hybrid 15/F-2-13, Hybrid 22103-10, Hybrid 17-5/6-11, and Sinilga from the collection of Siberian Federal Scientific Centre of Agrobiotechnology of the Russian Academy of Sciences. HPLC was used in combination with ion trap to identify target analytes in extracts of tuber part of a potato. The results showed the presence of 87 target analytes corresponding to S. tuberosum. In addition to the reported metabolites, a number of metabolites were newly annotated in S. tuberosum. There were essential amino acid L-Tryptophan, L-glutamate, L-lysine, Nordenine; flavones Ampelopsin; Chrysoeriol, Diosmetin, Diosmin, Myricetin; flavanones Naringenin and Eriodictyol-7-O-glucoside; dihydrochalcone Phlorizin; oligomeric proanthocyanidin (Epi)afzelechin-(epi)afzelechin; Shikimic acid; Hydroxyphenyllactic acid; Fraxidin; Myristoleic acid; flavan-3-ols Epicatechin, Gallocatechin, Gibberellic acid, etc. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that removes various adducts from the 3' end of DNA. Such adducts are formed by enzymes that introduce single-strand breaks in DNA during catalysis (for example, topoisomerase 1) and a number of anticancer drugs with different mechanisms of action. Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes posttranslational modification (PARylation) of various targets and thus controls many cell processes, including DNA repair. Tdp1 is a PARP1 target, and its PARylation attracts Tdp1 to the site of DNA damage. Olaparib is a PARP1 inhibitor used in clinical practice to treat homologous recombination-deficient tumors. Olaparib inhibits PARylation and, therefore, DNA repair. The Tdp1 inhibitor OL7-43 was used in combination with olaparib to increase the antitumor effect of the latter. Olaparib cytotoxicity was found to increase in the presence of OL7-43 in vitro. OL7-43 did not exert a sensitizing effect, but showed its own antitumor and antimetastatic effects in Lewis and Krebs-2 carcinoma models. [ABSTRACT FROM AUTHOR]

Cases of horizontal transfer of transposable elements (TEs) between species are known for the Drosophilidae family. In the middle of the last century, the case of horizontal transfer of the P-element from the Drosophila willistoni to the D. melanogaster was described. A novel P-element invasion into the D. simulans genome from D. melanogaster occurred approximately 10 years ago. Currently, the P-element has spread across all D. melanogaster population and 30% of D. simulans populations in Europe, Africa and America. In this paper, we investigated the presence of the P-element in D. simulans lines caught in different years in three Asian populations (Tashkent, Nalchik and Sakhalin Island). We also examined the physiological characteristics (cytotype, lifespan, fecundity and locomotor activity) of D. simulans lines with and without the P-element to determine the significance of this new mobile element in the genome. The P-element was found in lines isolated from nature after 2012. The number of P-element copies per genome (two-to-three dozen according to fluorescence in situ hybridization data) was greater than in the American and comparable to the African populations. There were signs of intraspecific hybrid dysgenesis for some pairs of lines. However, in general the presence of the P-element did not adversely affect the physiological characteristics. Either adaptation to the new TE occurs very quickly, or the rate of movement of the P-element is so insignificant that its appearance in the genome remains unnoticed. [ABSTRACT FROM AUTHOR]

The aim: study the effect of the synthetic anabolic steroid 19-nortestosterone on the fractional composition of blood plasma proteins, as well as the total protein and albumin content, indicators of the metabolism of carbohydrates, lipids, macro- and microelements in the fish hepatopancreas. Materials and methods. The experiments were conducted on two-year-old carp (Cyprinus carpio L.), which were kept for 24 hours in aquariums with a volume of 40 dm³ with different concentrations of 19-nortestosterone in water at optimal temperature, oxygen content, and pH. Spectrophotometric methods and an automatic biochemical analyzer were used to determine metabolic indicators in fish, and disk electrophoresis in PAGE was used to determine the fractional composition of proteins. Results. It was established that the steroid hormone 19-nortestosterone, the concentration of which in the water of the fish of the experimental groups was 50 and 200 µg/dm³, respectively, increased the level of total protein and albumin, the concentration of glucose, triglycerides, creatinine, inorganic phosphorus and iron in the hepatopancreas and did not affect the calcium content . In the blood plasma of carp, kept in water with a concentration of 19-nortestosterone of 50 µg/dm³, the content of proteins with a molecular weight of 240-231 increases; 215-179; 169-146 and 105-95 kDa, decreases - 35-33 kDa, fractions of proteins with a molecular weight of 228-220 appear; 116-105 and 48-44 kDa. An increase in the con-centration of 19-nortestosterone in water to 200 µg/dm³ increased the content of proteins with a molecular weight of 240-231 and 215-179 kDa in the blood plasma of fish, and decreased it by 35-33 kDa, causing the redistribution of individual protein fractions due to the appearance of proteins with a molecular weight of 240-228; 116-105 and 48-44 kDa in the absence of proteins 42-41; 38-36 and 24-20 kDa. Conclusions. Based on the obtained results, it was concluded that the anabolic synthetic steroid 19-nortestosterone stimulates the biosynthesis of proteins, the metabolism of carbohydrates and lipids, and its effect on the content of minerals in the hepatopancreas and the fractional composition of blood plasma proteins in carp fish was proven [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3′ end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented. [ABSTRACT FROM AUTHOR]

Topoisomerase 1 (TOP1) is an enzyme that regulates DNA topology and is essential for replication, recombination, and other processes. The normal TOP1 catalytic cycle involves the formation of a short-lived covalent complex with the 3′ end of DNA (TOP1 cleavage complex, TOP1cc), which can be stabilized, resulting in cell death. This fact substantiates the effectiveness of anticancer drugs—TOP1 poisons, such as topotecan, that block the relegation of DNA and fix TOP1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is able to eliminate TOP1cc. Thus, TDP1 interferes with the action of topotecan. Poly(ADP-ribose) polymerase 1 (PARP1) is a key regulator of many processes in the cell, such as maintaining the integrity of the genome, regulation of the cell cycle, cell death, and others. PARP1 also controls the repair of TOP1cc. We performed a transcriptomic analysis of wild type and PARP1 knockout HEK293A cells treated with topotecan and TDP1 inhibitor OL9-119 alone and in combination. The largest number of differentially expressed genes (DEGs, about 4000 both up- and down-regulated genes) was found in knockout cells. Topotecan and OL9-119 treatment elicited significantly fewer DEGs in WT cells and negligible DEGs in PARP1-KO cells. A significant part of the changes caused by PARP1-KO affected the synthesis and processing of proteins. Differences under the action of treatment with TOP1 or TDP1 inhibitors alone were found in the signaling pathways for the development of cancer, DNA repair, and the proteasome. The drug combination resulted in DEGs in the ribosome, proteasome, spliceosome, and oxidative phosphorylation pathways. [ABSTRACT FROM AUTHOR]

Actinidia deliciosa (A. Chev.) C.F. Liang & A.R& Ferguson, 1984 contains a large number of target analytes, which are biologically active compounds. HPLC-ion trap-MS/MS (tandem mass spectrometry) was used to identify target analytes in extracts of A. deliciosa (varieties Abbot, Alison, Bruno, Hayward, Monti), originating from the Adler's Branch of N.I. Vavilov All-Russian Institute of Plant Genetic Resources. Separately, the pulp of the kiwi fruit and its peel were analyzed for the composition of biologically active substances. The richest in the composition of active substances was indicators of the cultivar Monti. The results of initial studies revealed the presence of 56 compounds in the extracts of the peel of A. deliciosa and the presence of 64 compounds in the extracts of berry pulp of A. deliciosa. Forty-three compounds were identified for the first time in family Actinidiaceae. New identified metabolites belonged to 17 classes including 13 flavones, 2 flavonols, 2 flavan-3-ols, 5 stilbenes, 4 lignans, 2 carotenoids, 2 sterols, 3 terpenoids, etc. [ABSTRACT FROM AUTHOR]

Background: Activity plays a very important role in keeping bodies strong and healthy, slowing senescence, and decreasing morbidity and mortality. Drosophila models of evolution under various selective pressures can be used to examine whether increased activity and decreased sleep duration are associated with the adaptation of this nonhuman species to longer or harder lives. Methods: For several years, descendants of wild flies were reared in a laboratory without and with selection pressure. To maintain the "salt" and "starch" strains, flies from the wild population (called "control") were reared on two adverse food substrates. The "long-lived" strain was maintained through artificial selection for late reproduction. The 24 h patterns of locomotor activity and sleep in flies from the selected and unselected strains (902 flies in total) were studied in constant darkness for at least, 5 days. Results: Compared to the control flies, flies from the selected strains demonstrated enhanced locomotor activity and reduced sleep duration. The most profound increase in locomotor activity was observed in flies from the starch (short-lived) strain. Additionally, the selection changed the 24 h patterns of locomotor activity and sleep. For instance, the morning and evening peaks of locomotor activity were advanced and delayed, respectively, in flies from the long-lived strain. Conclusion: Flies become more active and sleep less in response to various selection pressures. These beneficial changes in trait values might be relevant to trade-offs among fitness-related traits, such as body weight, fecundity, and longevity. [ABSTRACT FROM AUTHOR]

Background: Lake Baikal, the world's deepest freshwater lake, contains important numbers of Candidatus Patescibacteria (formerly CPR) in its deepest reaches. However, previously obtained CPR metagenome-assembled genomes recruited very poorly indicating the potential of other groups being present. Here, we have applied for the first time a long-read (PacBio CCS) metagenomic approach to analyze in depth the Ca. Patescibacteria living in the bathypelagic water column of Lake Baikal at 1600 m. Results: The retrieval of nearly complete 16S rRNA genes before assembly has allowed us to detect the presence of a novel and a likely endemic group of Ca. Patescibacteria inhabiting bathypelagic Lake Baikal. This novel group seems to possess extremely high intra-clade diversity, precluding complete genomes' assembly. However, read binning and scaffolding indicate that these microbes are similar to other Ca. Patescibacteria (i.e. parasites or symbionts), although they seem to carry more anabolic pathways, likely reflecting the extremely oligotrophic habitat they inhabit. The novel bins have not been found anywhere, but one of the groups appears in small amounts in an oligotrophic and deep alpine Lake Thun. We propose this novel group be named Baikalibacteria. Conclusion: The recovery of 16S rRNA genes via long-read metagenomics plus the use of long-read binning to uncover highly diverse "hidden" groups of prokaryotes are key strategies to move forward in ecogenomic microbiology. The novel group possesses enormous intraclade diversity akin to what happens with Ca. Patescibacteria at the interclade level, which is remarkable in an environment that has changed little in the last 25 million years. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 μM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1–100 μM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan. [ABSTRACT FROM AUTHOR]

The structure and diversity of microbial communities developing in the combined gradient of temperature (44–19 °C), as well as concentration of oxygen (0–10 mg/L) and hydrogen sulfide (33–0.7 mg/L), were studied in the thermal sulfide spring on the coast of Northern Lake Baikal. The predominance of bacteria participating in sulfur and nitrogen cycles and significant changes in the composition of microbial communities were noted at changing physicochemical conditions. Thiovirga sp. (sulfur-oxidizing bacteria, up to 37%) and Azonexus sp. (nitrogen-fixing bacteria, up to 43%) were dominant at high temperatures and concentrations of hydrogen sulfide in two hydrotherms. In addition, a significant contribution of the Rhodocyclaceae family (up to 51%) which is involved in the denitrification processes, and Acetoanaerobium sp. (up to 20%) fixing carbon oxide were found in the spring water. In the stream, mainly oxygenic cyanobacteria (up to 56%) developed at a temperature of 33 °C, in the presence of hydrogen sulfide and oxygen. In addition, sulfur bacteria of the genus Thiothrix (up to 48%) found in epibiotic communities of benthic animals of Lake Baikal were present here. Thiothrix sp. formed massive fouling in the zone of mixing lake and thermal waters with a significant contribution of hydrogen-oxidizing bacteria of the genus Hydrogenophaga (up to 22.5%). As well as chemolitho- and phototrophic bacteria, chemoorganotrophs (phyla Firmicutes, Chloroflexi, Desulfobacterota, Nitrospirota, Fibrobacterota, etc.) have been identified in all communities. The chemical parameters of water in spring and coastal zones indicate a significant change in the composition of thermal waters occurring with the participation of diverse microbial communities that contribute to the assimilation of inorganic components of mineral thermal waters. [ABSTRACT FROM AUTHOR]

To date, various strategies have been proposed to increase the efficiency of cancer therapy. It is known that the action of DNA repair system can determine the resistance of cancer cells to DNA-damaging chemotherapy and radiotherapy, and one of these ways to increase therapeutic efficiency is the search for inhibitors of enzymes of the DNA repair system. Inhibition of the DNA repair enzyme tyrosyl-DNA phosphodiesterase1 (Tdp1) leads to an increase in the effectiveness of the topoisomerase 1 (Top1) inhibitor, the anticancer drug topotecan. Covalent complexes Top1-DNA, which are normally short-lived and are not a threat to the cell, are stabilized under the influence of topotecan and lead to cell death. Tdp1 eliminates such stabilized complexes and thus weaken the effect of topotecan therapy. We have previously shown that the use of the usnic acid hydrazonothiazole derivative OL9-119 in combination with topotecan increased the antitumor and antimetastatic efficacy of the latter in a mouse model of Lewis lung carcinoma. In this work, it was shown that the combined use of topotecan and Tdp1 inhibitor, the hydrazonothiazole derivative of usnic acid OL9-119, leads to an increase in the DNA-damaging effect of topotecan which is used in the clinic for the treatment of cancer. The study of the proapoptotic effect of the compound OL9-119 showed that the compound itself does not induce apoptosis, but increases the proapoptotic effect of topotecan. The results of the study could be used to improve the effectiveness of anticancer therapy and/or to reduce the therapeutic dose of topotecan and, therefore, the severity of side effects. [ABSTRACT FROM AUTHOR]

The effect of PARP1 knockout in HEK293 cells on the gene expression of DNA base excision repair (BER) proteins was studied. It was shown that the expression of all differentially expressed genes (DEGs) of BER was reduced by knockout. The expression of the DNA glycosylase gene NEIL1, which is considered to be one of the common "hubs" for binding BER proteins, has changed the most. The expression of genes of auxiliary subunits of DNA polymerases δ and ε is also significantly reduced. The PARP1 gene knockout cell line obtained is an adequate cell model for studying the activity of the BER process in the absence of PARP1 and testing drugs aimed at inhibiting repair processes. It has been found for the first time that knockout of the PARP1 gene results in a significant change in the level of expression of proteins responsible for ribosome biogenesis and the functioning of the proteasome. [ABSTRACT FROM AUTHOR]

The use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, that may prevent the action of clinical Topoisomerase 1 (Top1) inhibitors, such as topotecan (Tpc). Tdp1 eliminates covalent Top1-DNA (Top1c) complexes that appear under the action of topotecan and determines the cytotoxic effect of this drug. We hypothesize that Tdp1 inhibition would sensitize cells towards the effect of Tpc. Herein, we report the synthesis and study of lipophilic derivatives of purine nucleosides that efficiently suppress Tdp1 activity, with IC50 values in the 0.3–22.0 μM range. We also showed that this compound class can enhance DNA damage induced by topotecan in vitro by Comet assay on human cell lines HeLa and potentiate the antitumor effect of topotecan in vivo on a mice ascitic Krebs-2 carcinoma model. Thereby, this type of compound may be useful to develop drugs, that sensitize the effect of topotecan and reduce the required dose and, as a result, side effects. [ABSTRACT FROM AUTHOR]

Triticosecale “Bilinda” (cultivar was bred in the laboratories of the Leningrad Research Agriculture Institute, Branch of Russian Potato Research Centre, Leningrad Province) contains a large number of polyphenolic compounds which are biologically active components. The purpose of this work was to conduct a comparative metabolomic study of extracts of Triticosecale cultivar “Bilinda” seeds harvested at different stages of maturation. To identify target analytes in extracts HPLC was used in combination with an ion trap. The results showed the presence of 93 target compounds corresponding to Triticosecale. In addition to the reported polyphenol constituents, 28 polyphenols were newly annotated in grains of Triticosecale. There were 9 flavones, 7 flavonols, 2 flavan-3-ols, 1 flavanone, 5 hydroxybenzoic acids, 1 hydroxycinnamic acid, 1 anthocyanidin, 1 condensed tannin, 1 hydroxycoumarin, 2 triterpenoids; 1 diterpenoid, 6 sterols, 2 isoquinoline alkaloids, 4 carotenoids, 1 hydroquinone derivative and others bioactive compounds. Metabolic analysis showed a significant difference in the classes and amounts of polyphenolic substances identified in the seeds, depending on the time of seed collection. [ABSTRACT FROM AUTHOR]