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Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non–small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy. Article highlights Virtually all patients with epidermal growth factor receptor (EGFR) mutations demonstrate some benefit immediately after initiation of EGFR tyrosine kinase inhibitors (TKI) therapy; therefore, EGFR testing is the first and a critical step in treatment planning. However, there is significant interpatient heterogeneity in the degree of the response and its duration. Patients with the EGFR ex19del mutation are more likely to derive a marked benefit from TKI therapy. In contrast, those with the EGFR L858R substitution are generally poor responders. Poor performance status, high number of metastatic sites and the presence of extrathoracic tumor spread are also well-established negative prognostic factors. TP53 is strong negative predictor for response to EGFR TKIs. Genetic alterations in some other genes may affect the efficacy of EGFR TKIs, although none of the proposed predictors has the level of evidence comparable with that of TP53. The predictive value of the baseline ctDNA level may be attributed to its ability to identify particularly aggressive tumors. Measurement of ctDNA may outperform imaging tools for assessment of the tumor volume and spread of NSCLC. Clinical trials comparing the efficacy of combined administration of EGFR TKI and cytotoxic therapy with TKI alone demonstrated significant prolongation of progression-free survival. This outcome is expected, given that both TKIs and chemotherapy are efficacious against EGFR-mutated NSCLC. Synergy between antiangiogenic drugs and EGFR TKIs has been observed. Bevacizumab and ramucirumab seem particularly promising. Combining bevacizumab with TKIs and chemotherapy seems feasible and warrants further study. Patients with poor early response to single-agent EGFR TKIs, as assessed by ctDNA dynamics, are candidates for clinical trials combining EGFR TKIs with other drugs. [ABSTRACT FROM AUTHOR]

Background: Prolgolimab is the first Russian PD-1 inhibitor approved for the first-line treatment of unresectable or metastatic melanoma and advanced non-small cell lung cancer. It was approved in two weight-based regimens of 1 mg/kg Q2W and 3 mg/kg Q3W, but because of re-evaluation of weight-based dosing paradigm, studying of a fixed-dose regimen was considered perspective. Methods: We conducted a multicenter, single-arm, open-label efficacy, pharmacokinetics, and safety study to obtain data that would allow the approval of the new flat dosing regimen of prolgolimab in patients with previously untreated unresectable or metastatic melanoma (BCD-100-8/FLAT, NCT05783882). The primary objective was to prove the non-inferiority of prolgolimab 250 mg Q3W versus prolgolimab 1 mg/kg Q2W for the treatment of patients with unresectable or metastatic melanoma in terms of ORR according to RECIST 1.1. Patients from the MIRACULUM study (BCD-100-2/MIRACULUM, NCT03269565) comprised a historical control group. Results: One hundred fourteen patients received prolgolimab 250 mg Q3W, and 61 patients received prolgolimab (Prolgo) 1 mg/kg Q2W (historical control). Objective response was achieved by 33.3% [95% confidence interval (CI): 24.8, 42.8] of patients in the Prolgo 250 mg group compared with 32.8% (95% CI: 21.3, 46.0) of patients in the Prolgo 1 mg/kg group. Risk difference was 0.00, 95% CI (-0.12; NA), p = 0.0082. Both regimens were well tolerated, and safety profiles were comparable. The pharmacokinetic analysis (PK) showed that the regimen with the fixed dose of 250 mg Q3W was characterized by higher PK parameters. The immunogenicity study did not detect binding antibodies to prolgolimab in any of the subjects. Conclusion: The obtained results showed that the selected fixed dosing regimen of prolgolimab 250 mg Q3W is characterized by efficacy and safety parameters comparable to that observed for the 1 mg/kg Q2W regimen. [ABSTRACT FROM AUTHOR]

Highly diverse phages infecting thermophilic bacteria of the Thermus genus have been isolated over the years from hot springs around the world. Many of these phages are unique, rely on highly unusual developmental strategies, and encode novel enzymes. The variety of Thermus phages is clearly undersampled, as evidenced, for example, by a paucity of phage-matching spacers in Thermus CRISPR arrays. Using water samples collected from hot springs in the Kunashir Island from the Kuril archipelago and from the Tsaishi and Nokalakevi districts in the Republic of Georgia, we isolated several distinct phages infecting laboratory strains of Thermus thermophilus. Genomic sequence analysis of 11 phages revealed both close relatives of previously described Thermus phages isolated from geographically distant sites, as well as phages with very limited similarity to earlier isolates. Comparative analysis allowed us to predict several accessory phage genes whose products may be involved in host defense/interviral warfare, including a putative Type V CRISPR-cas system. [ABSTRACT FROM AUTHOR]

Recent consumer demand for non-dairy alternatives has forced many manufacturers to turn their attention to cereal-based non-alcoholic fermented products. In contrast to fermented dairy products, there is no defined and standardized starter culture for manufacturing cereal-based products. Since spontaneous fermentation is rarely suitable for large-scale commercial production, it is not surprising that manufacturers have started to adopt centuries-known dairy starters based on lactic acid bacteria (LABs) for the fermentation of cereals. However, little is known about the fermentation processes of cereals with these starters. In this study, we combined various analytical tools in order to understand how the most common starter cultures of LABs affect the most common types of cereals during fermentation. Specifically, 3% suspensions of rice, oat, and wheat flour were fermented by the pure cultures of 16 LAB strains belonging to five LAB species—Lacticaseibacillus paracasei, Lactobacillus delbrueckii, Lactobacillus helveticus, Streptococcus thermophilus, and Lactococcus lactis. The fermentation process was described in terms of culture growth and changes in the pH, reducing sugars, starch, free proteins, and free phenolic compounds. The organoleptic and rheological features of the obtained fermented products were characterized, and their functional properties, such as their antioxidant capacity and angiotensin-converting enzyme inhibitory activity, were determined. [ABSTRACT FROM AUTHOR]

The productivity of microalgal cultures and their resilience to unfavorable conditions is largely determined by the availability of mineral nutrients, particularly nitrogen. Nitrogen starvation is a strong stressor that induces a broad range of responses in microalgae at the cell and cell population (culture) levels. These responses such as lipogenesis and secondary carotenogenesis are widely used in biotechnology to obtain valuable secondary metabolites of microalgae. It was believed that microalgal cells lack specific structures that function as long-term nitrogen depot, but recent studies assigned this role to microcrystalline inclusions constituted by nitrogenous bases (most often guanine). It is also known that purine microcrystals are biophotonic structures widespread in nature. These structures modify the intensity and spectral composition of radiation in illuminated cells and tissues of living organisms. In this regard, we studied (i) the dynamics of the formation of guanine crystals in the cells of green carotenogenic microalgae from the genus Coelastrella (C. thermophila NAMSU CM1/23 and C. rubescens IPPAS C-2066) depending on the availability of nitrogen in the medium and (ii) the effect of the presence of these crystals on cell resilience to high light intensity. Nitrogen-rich crystal inclusions were accumulated in cells when the cultures reached the stationary growth phase in a medium with ample nitrate nitrogen. During rapid growth, these inclusions were hardly detectable in the cells and disappeared during cultivation in the absence of nitrogen. Optical polarization microscopy and Raman microspectroscopy demonstrated that these nitrogen-rich inclusions are birefringent microcrystals composed of guanine. C. thermophila cells harboring abundant guanine crystals showed resistance to short-term (10–15 min) exposure to high-intensity light (600 µmol PAR quanta/m2/s). The results obtained are discussed in the context of the multifaceted role of guanine crystals in the stress tolerance of microalgae. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are of growing interest in the context of screening for highly informative cancer markers. We have previously shown that uterine aspirate EVs (UA EVs) are a promising source of ovarian cancer (OC) diagnostic markers. In this study, we first conducted an integrative analysis of EV-miRNA profiles from UA, malignant ascitic fluid (AF), and a conditioned medium of cultured ascites cells (ACs). Using three software packages, we identified 79 differentially expressed miRNAs (DE-miRNAs) in UA EVs from OC patients and healthy individuals. To narrow down this panel and select miRNAs most involved in OC pathogenesis, we aligned these molecules with the DE-miRNA sets obtained by comparing the EV-miRNA profiles from OC-related biofluids with the same control. We found that 76% of the DE-miRNAs from the identified panel are similarly altered (differentially co-expressed) in AF EVs, as are 58% in AC EVs. Interestingly, the set of miRNAs differentially co-expressed in AF and AC EVs strongly overlaps (40 out of 44 miRNAs). Finally, the application of more rigorous criteria for DE assessment, combined with the selection of miRNAs that are differentially co-expressed in all biofluids, resulted in the identification of a panel of 29 miRNAs for ovarian cancer screening. [ABSTRACT FROM AUTHOR]

Many different strains of Streptococcus thermophilus are commonly used as starter cultures, and search for new safe strains with desired industrial and probiotic properties is an important issue. In this article, genomes of two new S. thermophilus strains—Str16t and Str159—were sequenced, and the main genome characteristics were determined. In silico analysis of the sequenced genomes revealed the absence of transmissible antibiotic resistance genes, virulence genes associated with pathogenicity, and integrated plasmids; gene clusters encoding class I and class II bacteriocins were found. In vitro tests showed phosphatase, peptidase, β-galactosidase, and esterase activity of both strains. Both strains were capable of fermenting glucose, lactose, sucrose, and ribose; in addition, Str16t fermented mannose. In conclusion, it was demonstrated that both Str16t and Str159 are promising strains for application as starter and probiotic cultures. [ABSTRACT FROM AUTHOR]

A modified method for culturing, concentrating, and purifying phage ϕ24B preparations was developed. In particular, a new lysogenic phage-producing strain lacking flagella was used, induction conditions were optimized, and purification in a sucrose gradient followed by concentration by deposition on a Freon 113 cushion were used. Using this method, a preparation of the Stx-converting bacteriophage ϕ24B was obtained, suitable for CryoEM direct analysis. Based on CryoEM data for this phage, the first primary three-dimensional reconstruction of its virions was performed. The structure of the phage ϕ24B tail is described. It was shown that the adsorption apparatus of this virus is represented by six thin lateral fibrils, and an axial fibril located at the end of the tail. This arrangement of the tail structure is consistent with the previously proposed hypothesis based on analysis of the receptor binding proteins (RBPs) of this bacteriophage. [ABSTRACT FROM AUTHOR]

Objective: Isolation of bacteria and fungi from porcine nasal microbiome and evaluation of antibioticproducing potential among them. Methods: Conventional isolation using Sabouraud and Mueller-Hinton nutrient media was carried out for collected samples. The isolated strains were subjected to antibiotic susceptibility testing and antimicrobial activity screening. Results and Discussion: Taxonomy positions of the 20 isolated strains (18 bacteria, 1 yeast, 1 fungus) were determined by phylogenetic analysis, morphological study and a substrate utilization assay. Pseudomonas aeruginosa SM-11 was found to produce 4 known antibacterial molecules (pyocyanine, pyochelin, pyoluteorin, monorhamnolipid). Production of pyocyanine was induced by cocultivation with test microorganisms. Conclusions: The mammal microbiota might serve as a valuable source of antimicrobialproducing strains, including those of rare taxa. Cocultivation techniques are a promising approach to exploring antimicrobials from silent biosynthetic gene clusters. [ABSTRACT FROM AUTHOR]

This paper presents the results of MHD simulations of astrophysical and laboratory supersonic jets under a superposition of poloidal ( , ) and toroidal () magnetic fields. It is shown that the escaping matter is quickly collimated by the magnetic field. A shock wave of an elongated shape is formed, which moves from the target to the boundary of the chamber, leaving behind a stable flow. A periodic shock wave structure is observed inside the main conical expanding shock wave. It is shown that the toroidal component of the magnetic field remains in the region throughout the entire calculation and plays a role in the collimation of the flow. The poloidal magnetic field decreases in the region of the jet cone, but remains in the simulation region throughout the calculation and also participates in flow collimation. Thus, both components and take part in the collimation of the flow by the magnetic field. The width of the jet and the opening angle of the cone depend on the magnitude of the magnetic field induction. As the field increases, the jet becomes narrower and the cone angle decreases. Initially, we do not specify the rotation of the jet . However, due to the presence of the field, the substance acquires angular velocity and twists along the axis. The simulation results are in agreement with laboratory jets arising in the experiment at the Neodymium laser installation, and with the previously obtained results of MHD modeling of jet formation separately, in poloidal or toroidal magnetic field. [ABSTRACT FROM AUTHOR]

Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine that include many products of the endogenous or bacteria-mediated decarboxylation of amino acids. A family of G protein-coupled trace amine-associated receptors (in humans, TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) that senses trace amines was discovered relatively recently. They are mostly investigated for their involvement in the olfaction of volatile amines encoding innate behaviors and their potential contribution to the pathogenesis of neuropsychiatric disorders, but the expression of the TAAR family of receptors is also observed in various populations of cells in the immune system. This review is focused on the basic information of the interaction of trace amines and their receptors with cells of the general immune systems of humans and other mammals. We also overview the available data on TAARs' role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in immune functions and on uncovering the contribution of these processes to the pathogenesis of the immune response, a significant advance in the field could be expected. Furthermore, the determination of the molecular mechanisms of TAARs' involvement in immune system regulation and the further investigation of their potential chemotactic role could bring about the development of new approaches for the treatment of disorders related to immune system dysfunctions. [ABSTRACT FROM AUTHOR]

The experiments on medium-size stellarator Uragan-2M (U-2M) in Kharkiv, Ukraine, are carried on in support of the Wendelstein 7-X (W7-X) experimental program. The scenario ion cyclotron frequency range (ICRF) plasma production at the hydrogen minority regime had been experimentally tested on U-2M and was qualified at the Large Helical Device (LHD). The paper presents the results of further research on the ICRF plasma production. The ICRF discharge studies were carried out in a H2 + He mixture with a controlled hydrogen concentration ranging from few percents to 75%. The two-strap like antenna mimicks the W7-X antenna operated in monopole phasing. The applied RF power was in the range of ∼100 kW. Relatively dense plasma of up to Ne ∼ 1019 m−3 was produced near the first harmonic of the hydrogen cyclotron frequency. The maximum temperature of the electrons and ions was not more than a few tens of electron volt. The characteristic features of RF plasma production and the propagation of electromagnetic waves in the experimental conditions are discussed. The experiments on U-2M and LHD indicate that the minority scenario of ICRF plasma production appears to be scalable and could be used in large stellarator machines. This is, in particular, important for the future experiments ICRF production of target plasma in W-7X in conditions where electron cyclotron resonance heating start-up is not possible. [ABSTRACT FROM AUTHOR]

Characteristics are analyzed of the electrical component of auroral kilometric radiation (AKR), measured by the ERG satellite in the Earth's inner magnetosphere and the WIND satellite in the solar wind. It is shown that the radiation spectrum changes when AKR propagates in plasma channels, and high frequencies are suppressed. Results are presented from calculations based on the model that confirm these measurements. [ABSTRACT FROM AUTHOR]

The problem of eutrophication of water objects as a global process is analyzed. The volumes of increasing planetary use of N and P, the dispersion of which together with climate warming leads to an increase in the nutrient content of lakes and rivers, are shown. The results of original studies of remote lakes of the Arctic zone are provided. The tendency toward an increase in the contents of N and P, as well as organic matter in water lakes even in case of the absence of anthropogenic impact, is revealed. It is proved that the climate warming mostly affects the increase in the nutrient content and the trophic status of lakes. [ABSTRACT FROM AUTHOR]

Article: —This article describes the construction, principles of operating, and characteristics of the TOTEM- electron spectrometer developed for the Strannik complex of scientific instruments for the Resonance-MKA space project. In the article, analytical characteristics are presented of the qualification model of the instrument, which fully corresponds to the flight unit, and the procedure for functional tests of the instrument is described. The article also describes the structure and principles of functioning of the hardware and software laboratory facility developed for ground calibrations and tests of such a type of instruments. The design of the TOTEM-E instrument offers a new approach to measuring particle fluxes, which allows the accuracy and speed of measurements to be increased. A feature of the proposed scheme is the possibility of simultaneous measurement of electron fluxes in a plane section in the velocity space in the energy range from E0 to 6.5 × E0, where E0 is the minimum particle energy recorded by the instrument. This is achieved by using two conical electrostatic mirrors that take electrons from a flat 360° flow section for subsequent energy analysis and using a coordinate-sensitive detector for simultaneous particle registration. [ABSTRACT FROM AUTHOR]

Contributions of anthropogenic and wetland methane emissions in Northern Eurasia (>40° N) and Russia into the near-surface CH4 abundance are quantified using GEOS-chem global chemical transport model at ZOTTO, Teriberka, and Tiksi measurement sites. Numerical results agree well with the proposed semianalytical solution, in which the total contribution (atmospheric response) in the CH4 level at a given site is decomposed into direct (synoptic) and global terms. On an advection timescale corresponding to a synoptic time interval, the annual average direct contribution of Russian anthropogenic emissions into the CH4 mixing ratio measured at ZOTTO (38.6 ppbv) is more than twice as large as that for Western Europe sources (17.7 ppbv). For the Arctic sites, the anthropogenic inputs from Russian and European sources are roughly similar (19.5 and 12.4 ppbv, respectively). The input from continental sources into near-surface methane abundance and its annual variations at the Arctic sites are generally lower compared to those at the ZOTTO site due to larger transport times from upstream CH4 source regions. Model-based atmospheric responses in methane levels at the Teriberka and Tiksi sites to continental CH4 sources are found to be very close owing to the relatively homogeneous (circumpolar) spatial distributions of the anthropogenic and biogenic signals at high latitudes. [ABSTRACT FROM AUTHOR]

As a toxic xenobiotic compound, the anthraquinone dye Remazol Brilliant Blue R (RBBR) poses a serious threat to aquatic ecosystems. In the present study, the ability of Trametes hirsuta to remove RBBR from the medium was investigated, and the role of adsorption by fungal mycelium and biodegradation by fungal enzymes was evaluated. It was shown that the whole fungal culture was able to remove up to 97% of the dye within the first four hours of incubation. Based on enzymatic activities in the culture broth, laccases were proposed to be the main enzymes contributing to RBBR degradation, and RT-qPCR measurements demonstrated an increase in transcription for the two laccase genes—lacA and lacB. Composite mycelial pellets of T. hirsuta with improved adsorption ability were prepared by adding activated carbon to the growth medium, and the induction of laccase activity by carbon was shown. For composite pellets, the RBBR decolorization degree was about 1.9 times higher at 1 h of incubation compared to carbon-free pellets. Hence, it was shown that using fungal mycelium pellets containing activated carbon can be an effective and economical method of dye removal. [ABSTRACT FROM AUTHOR]

The paper is devoted to anthropogenic and biogeochemical processes that effect the formation of the water and bottom sediment (BS) of subarctic Imandra Lake. The data of long-term observations are presented that show changes in the chemical composition of the water during the period of maximum pollution and after the reduction in the anthropogenic load over the past 30 years. The concentrations of toxic metals in the water has decreased, but climate warming has increased the inflow of organic matter and nutrients, and this intensified the production processes. The enrichment of the water in heavy metals during the period of intense pollution resulted in the accumulation of these metals in the bottom sediments, with the highest concentrations of the metals found in the uppermost layers accumulated during the modern sedimentation period. The development of anoxic conditions in the bottom water horizons due to sedimentation and oxidation of organic matter leads to the circulation of metals and hampers their burial. Physicochemical and biogeochemical processes are considered as explaining the diffusion of metals to the surface of the bottom sediments and the accumulation of anomalously high concentrations of metals in the surface layers of BS despite the significant decrease in the concentrations of metals in water. A hypothesis is suggested for the beginning of initial diagenesis stage in bottom sediments. [ABSTRACT FROM AUTHOR]

Magnetorotational processes can significantly affect the dynamics of core-collapse supernovae, resulting to magnetically driven jet-like explosions. The magnetic field topology of progenitor stellar cores is believed to be quite complex and is not known precisely. Such complex structures may differ substantially from usual dipole or quadrupole field, which may cause to additional anisotropy of magnetorotational explosions. The latter is a result of mirror symmetry violation of the progenitor magnetic field. Here we report the results of two- dimensional MHD modelling of the collapse and further magnetorotational explosion of a rotating magnetized stellar core. We consider the models with different magnetic field configurations with and without mirror symmetry in the progenitor magnetic field respectively to the equatorial plane. In this work, we study the explosion asymmetry as well as the possibility of a protoneutron star kick formation during the explosion phase. [ABSTRACT FROM AUTHOR]

Cell-to-cell transport of plant viruses through plasmodesmata (PD) requires viral movement proteins (MPs) often associated with cell membranes. The genome of the Hibiscus green spot virus encodes two MPs, BMB1 and BMB2, which enable virus cell-to-cell transport. BMB2 is known to localize to PD-associated membrane bodies (PAMBs), which are derived from the endoplasmic reticulum (ER) structures, and to direct BMB1 to PAMBs. This paper reports the fine structure of PAMBs. Immunogold labeling confirms the previously observed localization of BMB1 and BMB2 to PAMBs. EM tomography data show that the ER-derived structures in PAMBs are mostly cisterns interconnected by numerous intermembrane contacts that likely stabilize PAMBs. These contacts predominantly involve the rims of the cisterns rather than their flat surfaces. Using FRET-FLIM (Förster resonance energy transfer between fluorophores detected by fluorescence-lifetime imaging microscopy) and chemical cross-linking, BMB2 is shown to self-interact and form high-molecular-weight complexes. As BMB2 has been shown to have an affinity for highly curved membranes at cisternal rims, the interaction of BMB2 molecules located at rims of adjacent cisterns is suggested to be involved in the formation of intermembrane contacts in PAMBs. [ABSTRACT FROM AUTHOR]

Regulatory adenine nucleotide-binding cystathionine β-synthase (CBS) domains are widespread in proteins; however, information on the mechanism of their modulating effects on protein function is scarce. The difficulty in obtaining structural data for such proteins is ascribed to their unusual flexibility and propensity to form higher-order oligomeric structures. In this study, we deleted the most movable domain from the catalytic part of a CBS domain-containing bacterial inorganic pyrophosphatase (CBS-PPase) and characterized the deletion variant both structurally and functionally. The truncated CBS-PPase was inactive but retained the homotetrameric structure of the full-size enzyme and its ability to bind a fluorescent AMP analog (inhibitor) and diadenosine tetraphosphate (activator) with the same or greater affinity. The deletion stabilized the protein structure against thermal unfolding, suggesting that the deleted domain destabilizes the structure in the full-size protein. A "linear" 3D structure with an unusual type of domain swapping predicted for the truncated CBS-PPase by Alphafold2 was confirmed by single-particle electron microscopy. The results suggest a dual role for the CBS domains in CBS-PPase regulation: they allow for enzyme tetramerization, which impedes the motion of one catalytic domain, and bind adenine nucleotides to mitigate or aggravate this effect. [ABSTRACT FROM AUTHOR]

Biocidal coatings are of great interest to the healthcare system. In this work, the biocidal activity of coatings based on a complex biocide containing polymer and inorganic active antibacterial components was studied. Silver oxide was distributed in a matrix of a positively charged interpolyelectrolyte complex (IPEC) of polydiallyldimethylammonium chloride (PDADMAC) and sodium polystyrene sulfonate (PSS) using ultrasonic dispersion, forming nanoparticles with an average size of 5–6 nm. The formed nanoparticles in the matrix are not subject to agglomeration and changes in morphology during storage. It was found that the inclusion of silver oxide in a positively charged IPEC allows a more than 4-fold increase in the effectiveness of the complex biocide against E. coli K12 in comparison with the biocidal effect of PDADMAC and IPEC. Polycation, IPEC, and the IPEC/Ag2O ternary complex form coatings on the glass surface due to electrostatic adsorption. Adhesive and cohesive forces in the resulting coatings were studied with micron-scale coatings using dynamometry. It was found that the stability of the coating is determined primarily by adhesive interactions. At the macro level, it is not possible to reliably identify the role of IPEC formation in adhesion. On the other hand, use of the optical tweezers method makes it possible to analyze macromolecules at the submicron scale and to evaluate the multiple increase in adhesive forces when forming a coating from IPEC compared to coatings from PDADMAC. Thus, the application of ternary IPEC/Ag2O complexes makes it possible to obtain coatings with increased antibacterial action and improved adhesive characteristics. [ABSTRACT FROM AUTHOR]

The T5 family of viruses are tailed bacteriophages characterized by a long non-contractile tail. The bacteriophage DT57C is closely related to the paradigmal T5 phage, though it recognizes a different receptor (BtuB) and features highly divergent lateral tail fibers (LTF). Considerable portions of T5-like phages remain structurally uncharacterized. Here, we present the structure of DT57C determined by cryo-EM, and an atomic model of the virus, which was further explored using all-atom molecular dynamics simulations. The structure revealed a unique way of LTF attachment assisted by a dodecameric collar protein LtfC, and an unusual composition of the phage neck constructed of three protein rings. The tape measure protein (TMP) is organized within the tail tube in a three-stranded parallel α-helical coiled coil which makes direct contact with the genomic DNA. The presence of the C-terminal fragment of the TMP that remains within the tail tip suggests that the tail tip complex returns to its original state after DNA ejection. Our results provide a complete atomic structure of a T5-like phage, provide insights into the process of DNA ejection as well as a structural basis for the design of engineered phages and future mechanistic studies. The authors present the nearly-complete structure of the DT57C bacteriophage of the Siphovirus family, revealing the molecular architecture of its capsid, neck, tail and tail tip, and providing insights into the process of DNA ejection. [ABSTRACT FROM AUTHOR]

The paper reports an example of a successful upgrade of the JEOL JEM-2100 analytical transmission electron microscope to a low-resolution cryo-electron microscope, which can be used to optimize sample preparation and to assess preparation quality. As a result of the instrument upgrade, it is possible to obtain subnanometer resolution of protein molecule reconstructions (within 8 Å). The role of graphene and amorphous carbon substrates in preventing the effect of preferential orientation of protein particles in a frozen sample is discussed. [ABSTRACT FROM AUTHOR]

In this work, conditions were selected for obtaining a sample of eukaryotic chaperonin TRiC suitable for studying by cryo-electron microscopy. Using the method of differential scanning (time-resolved) fluorimetry, the temperature stability of protein samples at different concentrations of salt and glycerol was compared, and then the selected conditions were used to prepare the sample for microscopy. As a result, the structure of bovine TRiC in an open conformation was obtained at 4.42 Å resolution. [ABSTRACT FROM AUTHOR]

The architecture of DNA in the dormant cells was studied by synchrotron radiation diffraction and transmission electron microscopy. Diffraction experiments indicate the appearance of a periodic ordered organization of DNA. Transmission electron microscopy made it possible to visualize information about the type of DNA condensation. Intracellular nanocrystalline, liquid-crystalline and folded nucleosome-like structures of DNA have been found. Next, we studied changes in DNA architecture under stress of exposure to a chemical analogue of the anabiosis autoinducer (4-hexylresorcinol). Studies of the DNA architecture in the anabiotic and mummified states show the identity of the DNA structure in the anabiotic state and in the dormant state under starvation stress. The architecture of DNA in a mummified state is very different from that of DNA in an anabiotic state. [ABSTRACT FROM AUTHOR]

Cryo-electron microscopy (cryo-EM) is indispensable for the structural studies of enveloped viruses: dangerous pathogens of humans and animals. Yet, it requires highly specialized equipment as well as careful sample preparation. In this work, the capabilities of a JEOL JEM-2100 transmission electron microscope equipped with a cryo-transfer holder are used, and preliminary cryo-EM data for influenza A and B virus strains and SARS-CoV-2 inactivated with beta-propiolactone are presented. Image analysis allows us to (1) distinguish "empty" viral particles from "full" ones (containing nucleocapsid); (2) visualize the lipid bilayer of the viral envelope; (3) identify influenza virus surface antigens and the M1 protein layer combined with the inner lipid monolayer; and (4) distinguish different morphology of S-spikes on the surface of inactivated SARS-CoV-2 virions. The developed approach provides good image quality for both fundamental and applied research. [ABSTRACT FROM AUTHOR]

Incorporation of probiotic Lacticaseibacillus paracasei into a standard yogurt starter culture can drastically improve its health promoting properties. However, besides being an advantage in itself, the incorporation of a new probiotic strain can significantly affect the overall composition of fermented milk. In this article, the effect of incorporation of the L. paracasei probiotic strains (KF1 and MA3) into several standard yogurt starter cultures (consisting of the following strains: Streptococcus thermophilus 16t and either Lactobacillus delbrueckii Lb100 or L. delbrueckii Lb200) was investigated. Such parameters as the degree of proteolysis, antioxidant activity, ACE-inhibitory activity, content of organic acids, profile of FAs and profile of volatile organic compounds were measured, and the influence of the starter culture composition on these parameters was described. It was demonstrated that, at least in the case of the studied strains, yogurt with L. paracasei had an advantage over the standard yogurt in terms of the content of acetoin, acetic acid, butyric acid and conjugated linoleic acid. Moreover, the incorporation of L. paracasei KF1 significantly improved the hypotensive properties of the resulting yogurt. Thus, the presented study provides insight into the bioactive molecules of probiotic yogurt and may be useful for both academia and industry in the development of new dairy-based functional products. [ABSTRACT FROM AUTHOR]

Modeling of the dynamics of the nickel concentration in soils, water, and bottom sediments of lakes, caused by emissions into the atmosphere from the Pechenga Nickel Plant (Kola Peninsula) over the entire period of its operation, is considered. The technology of balanced identification, which makes it possible based on mathematical description of inhomogeneous geochemical processes occurring in ecosystems to combine heterogeneous experimental data and to develop a computer model with an optimal balance of complexity and closeness to the data, is used. The results including estimates of the retrospective state of the simulated objects and a forecast of their dynamics until 2030 are presented and discussed. According to model calculations, the intensity of Ni accumulation in the soil was 2.4 and it was twice as high as in bottom sediments during the periods of maximum deposition (1980–2005). According to the forecast model, after the shutdown of the plant, Ni accumulation in bottom sediments will begin to decrease and Ni will slowly leach from the soil with an intensity of 0.2 mg/(m2 yr). [ABSTRACT FROM AUTHOR]

The interest in peroxidases of the basidiomycete secreted enzyme complex is due to their wide substrate specificity and the ability of these enzymes to participate in the biodegradation of such difficult to degrade biopolymers as lignin. However, due to the difficulty of isolating these enzymes from native sources, their study is difficult. In this work, expression vectors were created that carried the sequence encoding the T. hirsuta LE-BIN072 versatile peroxidase VP2, which was transformed into the genome of the P. canescens strain. Screening of transformants showed the presence of peroxidase activity up to 1 U/mL. Fragments of the target protein in the culture liquids of the selected transformants were identified by mass spectrometric analysis. A new strain, P. canescens pVP2D-6, a producer of the recombinant versatile peroxidase VP2 of T. hirsuta LE-BIN072, was obtained for the first time, and the ability of the enzyme complex secreted by it to modify alkaline lignin was shown. [ABSTRACT FROM AUTHOR]

Prions form an infectious version of amyloid; they are involved in the pathogenesis of some human neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Yeast prions, in particular, the Sup35 protein, serve an effective model for studying the basic properties of amyloids. Strain versions of the prion form of Sup35 lie in the basis of the conformational diversity of the amyloid structures formed by it, which exhibit different biological properties. The spatial organization of the Sup35 prion has not yet been established. The structure of the strain version W of Sup35 prion protein, isolated ex vivo from yeast Saccharomyces cerevisiae, was studied by transmission electron microscopy (TEM). The parameters of the fibril were estimated, and its structure was reconstructed with a low resolution. [ABSTRACT FROM AUTHOR]

A central event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-β (Aβ) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that Aβ augmented AChE activity in vitro, maximum activation of 548 ± 5% was achieved following 48 h of incubation with 10 μM of Aβ1–40, leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by Aβ1–40 was associated with increased Vmax and unchanged Km. Although BChE activity also increased following incubation with Aβ1–40, this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 μM of Aβ1–40 significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters. [ABSTRACT FROM AUTHOR]

The effect of the aluminum layer on the kinetics and mechanism of aluminum-induced crystallization (AIC) of amorphous silicon (a-Si) in (Al/a-Si)n multilayered films was studied using a complex of in situ methods (simultaneous thermal analysis, transmission electron microscopy, electron diffraction, and four-point probe resistance measurement) and ex situ methods (X-ray diffraction and optical microscopy). An increase in the thickness of the aluminum layer from 10 to 80 nm was found to result in a decrease in the value of the apparent activation energy Ea of silicon crystallization from 137 to 117 kJ/mol (as estimated by the Kissinger method) as well as an increase in the crystallization heat from 12.3 to 16.0 kJ/(mol Si). The detailed kinetic analysis showed that the change in the thickness of an individual Al layer could lead to a qualitative change in the mechanism of aluminum-induced silicon crystallization: with the thickness of Al ≤ 20 nm. The process followed two parallel routes described by the n-th order reaction equation with autocatalysis (Cn-X) and the Avrami–Erofeev equation (An): with an increase in the thickness of Al ≥ 40 nm, the process occurred in two consecutive steps. The first one can be described by the n-th order reaction equation with autocatalysis (Cn-X), and the second one can be described by the n-th order reaction equation (Fn). The change in the mechanism of amorphous silicon crystallization was assumed to be due to the influence of the degree of Al defects at the initial state on the kinetics of the crystallization process. [ABSTRACT FROM AUTHOR]

Glycopeptide antibiotics are still in demand in clinical practice for treating infections caused by resistant gram-positive pathogens; however, their use is limited due to severe adverse reactions. Their predominant types of side effects are immunoglobulin E-mediated or nonmediated hypersensitivity reactions. Therefore, the development of new glycopeptide antibiotics with improved toxicity profiles remains an important objective in advancing modern antimicrobial agents. We investigated a new eremomycin aminoalkylamide flavancin, its anaphylactogenic properties, influence on histamine levels in blood plasma, pseudoallergic inflammatory reaction on concanavalin A and the change in the amount of flavancin in the blood plasma after administration. It has been shown that flavancin does not demonstrate anaphylactogenic properties. The injection of flavancin resulted in a level of histamine in the blood three times lower than that caused by vancomycin. The therapeutic dose of vancomycin led to a statistically significant increase in the concanavalin A response index compared to flavancin (54% versus 3.7%). Thus, flavancin does not cause a pseudo-allergic reaction. The rapid decrease in flavancin concentration in the blood and the low levels of histamine in the plasma lead us to assume that any pseudoallergic reactions resulting from flavancin application, if they do occur in clinical practice, will be significantly less compared to the use of vancomycin. [ABSTRACT FROM AUTHOR]

This article discusses a post-authorization safety study (PASS) being conducted in the European Union and the United Kingdom to evaluate the safety profile of selumetinib, a MEK1/2 inhibitor, in pediatric patients with symptomatic inoperable plexiform neurofibromas (PNs) associated with neurofibromatosis type 1 (NF1). The study aims to characterize the long-term safety of selumetinib, including potential developmental effects, in children with NF1-associated PNs. The study will enroll a total of 125 patients and will collect data on safety outcomes such as cardiac function, bone development, muscle function, liver function, eye health, and pubertal development. The results of this study will provide valuable information on the safety of selumetinib in this patient population. [Extracted from the article]

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I–II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I–II treatment options for 34 of them (97%), OncoKB/CGI—for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC—12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I–II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II–IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation. [ABSTRACT FROM AUTHOR]

The paper analyzes the effect of ever increasing anthropogenic impacts on land waters and analyzes V.I. Vernadsky's works on natural waters and their significance for assessing modern biogeochemical processes. The paper demonstrates the scale of the influx of chemical elements and compounds into the modern biosphere as a result of the emission of greenhouse gases, nitrogen and phosphorus dissemination, acid-forming gases, and metals. Key changes in some regions and the biosphere as a whole are highlighted. The consequences of anthropogenically induced processes are illustrated by the example of a remote Arctic region, the northern Kola Peninsula in Russia: the effects of climate warming and the acidification and eutrophication of the waters and their enrichment in metals. In the wake of V.I. Vernadsky's ideas about the role of land waters in supporting the life necessities of the planet's human population, approaches to assessing water quality from the standpoint of the ecological paradigm are described. [ABSTRACT FROM AUTHOR]

Results of the analysis of interannual, seasonal, and diurnal variations in the ratios of the mixture of CH4, CO2, CO, benzene, and δ13C–CH4 in the surface air of Moscow based on the measurements at the station of the Obukhov Institute of Atmospheric Physics, Russian Academy of Sciences (IAP RAS), in 2018–2020 are presented. The annual maximum concentration of CH4, CO2, and CO (>2.2, 430, and 0.20 ppm, respectively) occurs in the winter months due to the seasonal increase in the anthropogenic load from the main sources of urban pollution: motor transport and thermal power plants and a decrease in the role of vertical air mixing. The greatest contribution of local and remote microbial sources to the CH4 concentration is noted in the summer months against the background of low δ13C–CH4 values (–50 to –60‰). In all seasons, CH4, CO2, and CO ground level peaks lasting up to several hours are due to the transport from industrial sites in the E–SE sector. The calculated mean emission ratios in urban air were CH4/benzene = 0.52–0.54 ppm/ppb, CH4/СО = 0.56–0.75 ppm/ppm, CO2/benzene = 77–93 ppm/ppb, CO2/СО = 81–131 ppm/ppm, and CO/benzene = 0.65–1.11 ppm/ppb. These ratios characterize the predominant contribution of emissions from motor transport and the heat and power equipment and can be used to refine the absolute values of emissions, including those on the basis of existing inventories of sources of anthropogenic air pollution. [ABSTRACT FROM AUTHOR]

In this work, a comparative analysis of the profile of fatty acids (FA) and volatile organic compounds (VOCs) for skimmed cow's milk fermented by four different probiotic strains of Lacticasibacillu paracasei (ABK, KF1, MA2, and MA3) was carried out. Analysis of FA and VOC profiles was performed using gas chromatography with mass spectrometric detection (GC-MS). For additional characterization of odor changes and its intensity in the fermented milk samples, the E-nose "electronic nose" odor analyzer was used. In total, the presence of 42 different FAs was detected in all samples, of which 17 were saturated, 8 monounsaturated, and 5 polyunsaturated. The strain-specific differences between the studied samples were of a complex nature and could not be explained only by the variation in the contribution of several individual FAs. The FA-nutritional indices characterizing the nutritional and biological value of the samples were different for milk fermented by different strains. Analysis of VOCs showed that the main odor-forming compounds in the studied samples were FAs and their reaction products, 2-heptanone, 2-nonanone, and 2-nonanol, which formed as a result of the following chain of transformations: β-oxidation → decarboxylation → reduction. The aroma of L. paracasei fermentation products, predicted on the basis of the odors of individual VOCs, generally coincided with their organoleptic assessment, a flavor typical of fermented milk (yogurt and curdled milk) with floral and fruity notes. [ABSTRACT FROM AUTHOR]

Being an abundant renewable source of aromatic compounds, lignin is an important component of future bio-based economy. Currently, biotechnological processing of lignin through low molecular weight compounds is one of the conceptually promising ways for its valorization. To obtain lignin fragments suitable for further inclusion into microbial metabolism, it is proposed to use a ligninolytic system of white-rot fungi, which mainly comprises laccases and peroxidases. However, laccase and peroxidase genes are almost always represented by many non-allelic copies that form multigene families within the genome of white-rot fungi, and the contributions of exact family members to the overall process of lignin degradation has not yet been determined. In this article, the response of the Trametes hirsuta LE-BIN 072 ligninolytic system to the presence of various monolignol-related phenolic compounds (veratryl alcohol, p-coumaric acid, vanillic acid, and syringic acid) in culture media was monitored at the level of gene transcription and protein secretion. By showing which isozymes contribute to the overall functioning of the ligninolytic system of the T. hirsuta LE-BIN 072, the data obtained in this study will greatly contribute to the possible application of this fungus and its ligninolytic enzymes in lignin depolymerization processes. [ABSTRACT FROM AUTHOR]

Solid-phase synthesis of aluminum–molybdenum (Al–Mo) and aluminum–nickel–molybdenum (Al–Ni–Mo) model composites as part of propylene metathesis catalysts has been conducted under mechanical activation. The structure of Al–Mo and Al–Ni–Mo model composites has been studied by X-ray diffraction analysis, high-resolution transmission electron microscopy, infrared spectroscopy, and diffuse reflectance electron spectroscopy (DRES). The DRES method has shown the presence of isolated monomeric and oligomeric molybdate compounds in the Al–Ni–Mo model composites. Granular metathesis catalysts have been synthesized by molding the Al–Mo and Al–Ni–Mo model composites with aluminum hydroxide and subsequent calcining. It has been shown that the highest activity in the propylene metathesis reaction is exhibited by an aluminum–molybdenum catalyst containing 2.6 wt % Ni, 13.0 wt % Mo, and 32.7 wt % Al. At a process temperature of 200°C, a pressure of 0.1 MPa, and a propylene feed space velocity of 1 h–1, in the presence of this catalyst, the propylene conversion achieves 33.7%; this fact makes this catalyst promising for practical applications. At the same time, the weight fraction of ethylene and butenes in the reaction product composition is 17.5 and 71.3%, respectively. [ABSTRACT FROM AUTHOR]

This work reports the detailed structure of fucoidan from Sargassum miticum (2SmF2) and its ability to potentiate the inhibitory effect of glycolysis inhibitor 2-deoxy-d-glucose (2-DG). 2SmF2 was shown to be sulfated and acetylated galactofucan containing a main chain of alternating residues of 1,3- and 1,4-linked α-l-fucopyranose, fucose fragments with monotonous 1,3- and 1,4-type linkages (DP up to 3), α-d-Gal-(1→3)-α-L-Fuc disaccharides, and 1,3,4- and 1,2,4-linked fucose branching points. The sulfate groups were found at positions 2 and 4 of fucose and galactose residues. 2SmF2 (up to 800 µg/mL) and 2-DG (up to 8 mM) were not cytotoxic against MDA-MB-231 and SK-MEL-28 as determined by MTS assay. In the soft agar-based model of cancer cell colony formation, fucoidan exhibited weak inhibitory activity at the concentration of 400 µg/mL. However, in combination with low non-cytotoxic concentrations of 2-DG (0.5 or 2 mM), 2SmF2 could effectively inhibit the colony formation of SK-MEL-28 and MDA-MB-231 cells and decreased the number of colonies by more than 50% compared to control at the concentration of 200 µg/mL. Our findings reveal the metabolically oriented effect of fucoidan in combination with a glycolysis inhibitor that may be beneficial for a therapy for aggressive cancers. [ABSTRACT FROM AUTHOR]