Synthesis of N-heterocyclic amides based on (+)-camphoric acid and study of their antiviral activity and pharmacokinetics.

Efficient conditions for the synthesis of nitrogen-containing heterocyclic derivatives of (1R,3S)(+)-camphoric acid were selected. A series of heterocyclic compounds based on (+)-camphoric acid bearing pharmacophoric fragments was synthesized using the developed methodology. The compounds were tested for their antiviral activity against SARS-CoV-2 and H1N1 influenza viruses, and efficient inhibitors were identified that are of significant interest for further studies. The stability of the compounds and pharmaco-kinetics of the leader compound were studied when administered intragastrically and intramuscularly to mice at a dose of 200 mg kg-1 using the HPLC-MS/MS method.

Gene networks for use in metabolomic data analysis of blood plasma from patients with postoperative delirium.

Postoperative delirium (POD) is considered one of the most severe complications, resulting in impaired cognitive function, extended hospitalization, and higher treatment costs. The challenge of early POD diagnosis becomes particularly significant in cardiac surgery cases, as the incidence of this complication exceeds 50 % in certain patient categories. While it is known that neuroinflammation, neurotransmitter imbalances, disruptions in neuroendocrine regulation, and interneuronal connections contribute significantly to the development of POD, the molecular, genetic mechanisms of POD in cardiac surgery patients, along with potential metabolomic diagnostic markers, remain inadequately understood. In this study, blood plasma was collected from a group of patients over 65 years old after cardiac surgery involving artificial circulation. The collected samples were analyzed for sphingomyelin content and quantity using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS) methods. The analysis revealed four significantly different sphingomyelin contents in patients with POD compared to those who did not develop POD (control group). Employing gene network reconstruction, we perceived a set of 82 regulatory enzymes affiliated with the genetic coordination of the sphingolipid metabolism pathway. Within this set, 47 are assumed to be regulators of gene expression, governing the transcription of enzymes pivotal to the metabolic cascade. Complementing this, an additional assembly of 35 regulators are considered to be regulators of activity, degradation, and translocation dynamics of enzymes integral to the aforementioned pathway. Analysis of the overrepresentation of diseases with which these regulatory proteins are associated showed that the regulators can be categorized into two groups, associated with cardiovascular pathologies (CVP) and neuropsychiatric diseases (NPD), respectively. The regulators associated with CVP are expectedly related to the effects on myocardial tissue during surgery. It is hypothesized that dysfunction of NPD-associated regulators may specifically account for the development of POD after cardiac surgery. Thus, the identified regulatory genes may provide a basis for planning further experiments, in order to study disorders at the level of expression of these genes, as well as impaired function of proteins encoded by them in patients with POD. The identified significant sphingolipids can be considered as potential markers of POD.

Plasma metabolomics and gene regulatory networks analysis reveal the role of nonstructural SARS-CoV-2 viral proteins in metabolic dysregulation in COVID-19 patients.

Metabolomic analysis of blood plasma samples from COVID-19 patients is a promising approach allowing for the evaluation of disease progression. We performed the metabolomic analysis of plasma samples of 30 COVID-19 patients and the 19 controls using the high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometric detection (LC-MS/MS). In our analysis, we identified 103 metabolites enriched in KEGG metabolic pathways such as amino acid metabolism and the biosynthesis of aminoacyl-tRNAs, which differed significantly between the COVID-19 patients and the controls. Using ANDSystem software, we performed the reconstruction of gene networks describing the potential genetic regulation of metabolic pathways perturbed in COVID-19 patients by SARS-CoV-2 proteins. The nonstructural proteins of SARS-CoV-2 (orf8 and nsp5) and structural protein E were involved in the greater number of regulatory pathways. The reconstructed gene networks suggest the hypotheses on the molecular mechanisms of virus-host interactions in COVID-19 pathology and provide a basis for the further experimental and computer studies of the regulation of metabolic pathways by SARS-CoV-2 proteins. Our metabolomic analysis suggests the need for nonstructural protein-based vaccines and the control strategy to reduce the disease progression of COVID-19.

Age Classification in Forensic Medicine Using Machine Learning Techniques.

The aim of the study was to assess the capabilities of age determination (age group) at death using classification techniques by histomorphometric characteristics of osseous and cartilaginous tissue aging. Materials and Methods: The study material was a database containing the findings of morphometric researches of osseous and cartilaginous tissue histologic specimens from 294 categorized male corpses aged 10-93 years. For data analysis and classification we used modern machine learning methods: k-NN, SVM, logistic regression, CatBoost, SGD, naive Bayes, random forest, nonlinear dimensionality reduction methods (t-SNE and uMAP), and recursive feature elimination for feature selection. Results: The used techniques (algorithms) provided effective representation of a complex data set (76 histomorphometric features), allowing to reveal the cluster structure inside the low dimensional feature space, thus fitting the classifier becomes even more reasonable. During feature selection, we estimated their importance for age group classification and studied the relationship between classification quality and the number of features inside the feature space. Data pre-processing made it possible to get rid of noise and keep most informative features, thereby accelerating a learning process and improving the classification quality. Data projection showed more well-defined cluster structure in the space of selected features. The accuracy of establishing certain groups was equal to 90%. It proves high efficiency of machine learning techniques used for forensic age diagnostics based on histomorphometric findings.

Study on osteoinductive activity of biotin film by low-energy electron beam deposition.

Biotin film was prepared by low-energy electron beam deposition (LEBD). The molecular structure, chemical composition and micromorphology of the biotin film were investigated by 1HNMR, FTIR, XPS, AFM and SEM. The results showed the molecular structure of a monolayer of biotin film is fully consistent with the molecular structure of the initial biotin powders. The contact angle test showed that the biotin film exhibit good hydrophilicity. The release kinetics of biotin film was tested by UV-Vis method. It was found that the film was almost completely released in about two weeks. The cell viability of MC3T3-E1 cells on the surface of the biotin film was attaining 100.54 ± 1.7% (P < 0.05), showing excellent biocompatibility and biosafety. Titanium implant with surface of biotin film was implanted into the femoral head of rabbits as experimental group. The animals were euthanized after four weeks. Compared with the control group, mature lamellar bone formation was observed with dense trabecular bone, and the expression of Coll-I, Runx2 and BMP-2 was better. The results showed that the repair effect of bone defect in the experimental group was excellent.

Osteogenic potential evaluation of biotin combined with magnesium-doped hydroxyapatite sustained-release film.

Biotin is one of the water-soluble B-complex group of vitamins. Recent studies have found that the relative protein expression of BMP2, BSP and OPG in MC3T3-E1 cells is prominent after 14 days of co-culture with biotin film, especially for BMP2. It is also found that the rapid degradation of biotin film in vivo limits its application value. In this work, magnesium-doped hydroxyapatite (MgHA) film can form a porous network structure as a biological sustained-release film. Therefore, the multilayer (MgHA|biotin|MgHA|biotin) film was prepared by pulsed laser assisted electron beam deposition technique. The morphology, structure and properties of biotin film and multilayer film were analyzed and characterized. Also, the osteogenic effect of biotin film and multilayer film was evaluated after implantation into the femoral bone marrow cavity of SD rats. The results of micro-CT scan and 3D reconstruction showed that there were a large number of trabecular bones around the multilayer film, which was superior to biotin film in osteogenesis. Hematoxylin-eosin staining showed cancellous bone structure and intact bone marrow structure around the multilayer film, and the newly formed bone became lamellar. Masson-trichromatic staining revealed abundant osteoid and braided bone formation around the multilayer film. In conclusion, MgHA sustained release film can realize the continuous release of bioactive drugs, which provides a new route to accelerate the repair of bone defects.

Permeation of Nanoparticles into Pulmonary Surfactant Monolayer: In Situ X-ray Standing Wave Studies.

High-resolution X-ray techniques were applied to examine the effects of gold nanoparticles (size <5 nm) on natural pulmonary surfactant and pure DPPC monolayers preliminarily formed on water subphase in a Langmuir trough. Hydrophobic and hydrophilic nanoparticles were delivered from nanoaerosol using electrodeposition method. Grazing incidence diffraction, X-ray reflectivity, and X-ray standing wave measurements allow to monitor the changes in molecular organization of lipid monolayer and to locate the position of gold nanoparticles. X-ray experiments were performed over a period of 9-14 h. The obtained results evidenced that, on a long time scale, the deposition of nanoparticles, even at low doses, can induce pronounced alterations in lipid monolayer. The presented data can help to elucidate the mechanism of pulmonary translocation of inhaled nanoparticles that is of special interest for biomedical investigations of potential risk of nanoaerosols for human health.

Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients.

This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data were analyzed using robust linear regression with Huber's M-estimates, and a number of metabolites with correlated content in plasma and CSF was identified. The statistical analysis shows a significant correlation of metabolite content in plasma and CSF samples for the majority of metabolites. Several metabolites were shown to have high correlation in the control samples, but not in the glioma patients. This can be due to the specific metabolic processes in the glioma patients or to the damaged integrity of blood-brain barrier. The results of our study may be useful for the understanding of molecular mechanisms underlying the development of gliomas, as well as for the search of potential biomarkers for the minimally invasive diagnostic procedures of gliomas.

Molecular Dynamics Studies in Nanojoining: Self-Propagating Reaction in Ni/Al Nanocomposites.

Reactive joining with Ni/Al nanocomposites is an innovative technology that provides an alternative to more common bonding techniques. This work focuses on a class of energetic material, produced by high energy ball milling and cold rolling. The initial microstructure is more complex than that of reactive multilayer nanofoils, produced by magnetron sputtering, in which the bilayer thickness is constant. Typical samples are composed of reactive nanocomposite particles that are numerically modelized by randomly distributed layered grains. The self-propagating reaction was studied by means of molecular dynamics simulations. We determined the front characteristics and investigated the elemental mechanics that trigger propagation. Both dissolution of Ni in amorphous Al and sustained crystallization of the B2-NiAl intermetallic compound were found to contribute to the heat delivered during the process.

Features of electron beam deposition of polymer coatings with the prolonged release of the drug component.

The first part of the paper provides a comprehensive analysis of the features of electron beam formation of polymer coatings with the prolonged release of the drug compound using ciprofloxacin and clotrimazole as an example. The influence features of the low-energy electron beam on the molecular structure of medicinal chemical preparations have been established. The impossibility of producing the coatings based on medicinal compounds with a complex molecular structure (vancomycin, micafungin, etc.) by a low-energy electron beam has been justified. The second part of the paper introduces a fundamentally new vacuum method for the formation of the composite coatings based on antibiotics and antifungal drugs, accompanied by the prolonged release of the drug component. This method allows the formation of composite coatings based on medicinal compounds with a complex molecular structure. It is effective for modifying implants to prevent the risk of implant-associated infectious complications which are the result of the occurrence of mixed biofilms. The method can be used to form composite layers based on topical antitumor drugs for cancer control.

High-resolution structural insights into the heliorhodopsin family.

Rhodopsins are the most abundant light-harvesting proteins. A new family of rhodopsins, heliorhodopsins (HeRs), has recently been discovered. Unlike in the known rhodopsins, in HeRs the N termini face the cytoplasm. The function of HeRs remains unknown. We present the structures of the bacterial HeR-48C12 in two states at the resolution of 1.5 Å, which highlight its remarkable difference from all known rhodopsins. The interior of HeR's extracellular part is completely hydrophobic, while the cytoplasmic part comprises a cavity (Schiff base cavity [SBC]) surrounded by charged amino acids and containing a cluster of water molecules, presumably being a primary proton acceptor from the Schiff base. At acidic pH, a planar triangular molecule (acetate) is present in the SBC. Structure-based bioinformatic analysis identified 10 subfamilies of HeRs, suggesting their diverse biological functions. The structures and available data suggest an enzymatic activity of HeR-48C12 subfamily and their possible involvement in fundamental redox biological processes.

Unusual features of the c-ring of F1FO ATP synthases.

Membrane integral ATP synthases produce adenosine triphosphate, the universal "energy currency" of most organisms. However, important details of proton driven energy conversion are still unknown. We present the first high-resolution structure (2.3 Å) of the in meso crystallized c-ring of 14 subunits from spinach chloroplasts. The structure reveals molecular mechanisms of intersubunit contacts in the c14-ring, and it shows additional electron densities inside the c-ring which form circles parallel to the membrane plane. Similar densities were found in all known high-resolution structures of c-rings of F1FO ATP synthases from archaea and bacteria to eukaryotes. The densities might originate from isoprenoid quinones (such as coenzyme Q in mitochondria and plastoquinone in chloroplasts) that is consistent with differential UV-Vis spectroscopy of the c-ring samples, unusually large distance between polar/apolar interfaces inside the c-ring and universality among different species. Although additional experiments are required to verify this hypothesis, coenzyme Q and its analogues known as electron carriers of bioenergetic chains may be universal cofactors of ATP synthases, stabilizing c-ring and prevent ion leakage through it.

The Enhancement of Metal-Binding Properties in Hemoglobin: The Role of Mild Damaging Factors.

X-ray studies revealed the considerable enhancement of metal-binding properties in human hemoglobin under exposure to mild damaging factors (in the presence of 0.09 M urea or upon heating for 30 min at 50 °C). Changes in the element composition of the hemoglobin monolayer, formed on the water subphase in the Langmuir trough, have been monitored in real time by the total external reflection X-ray fluorescence measurements. X-ray absorption spectroscopy has been applied to study the local environment of zinc ions bound on hemoglobin molecules. According to these data, each zinc ion is coordinated by four ligands, two of which are cysteine and histidine. The oxidative stress has been found to accelerate extensively the enhancement of metal-binding ability in protein. A two-stage mechanism has been proposed as a possible explanation of the observed phenomenon: First, in the presence of the mild damaging agents, protein molecules can undergo a transition from the native conformation to a more labile intermediate state that increases the accessibility of amino acid residues (in particular cysteine). At the second stage, oxidation of cysteine and the subsequent activation of cysteine SH groups can affect markedly the protein-metal interaction. The presented investigations provide a deeper insight into the pathogenesis of metabolic disorders that excessive concentrations of the endogenic toxicants might trigger in an organism.

Grazing-incidence small-angle X-ray scattering study of correlated lateral density fluctuations in W/Si multilayers.

A structural characterization of W/Si multilayers using X-ray reflectivity (XRR), scanning transmission electron microscopy (STEM) and grazing-incidence small-angle X-ray scattering (GISAXS) is presented. STEM images revealed lateral, periodic density fluctuations in the Si layers, which were further analysed using GISAXS. Characteristic parameters of the fluctuations such as average distance between neighbouring fluctuations, average size and lateral distribution of their position were obtained by fitting numerical simulations to the measured scattering images, and these parameters are in good agreement with the STEM observations. For the numerical simulations the density fluctuations were approximated as a set of spheroids distributed inside the Si layers as a 3D paracrystal (a lattice of spheroids with short-range ordering but lacking any long-range order). From GISAXS, the density of the material inside the density fluctuations is calculated to be 2.07 g cm-3 which is 89% of the bulk value of the deposited layer (2.33 g cm-3).

Relationship of study conditions and health state of high education students.

The article presents results of study concerning relationship of educational conditions and health state of high education students in 3 institutes of Voronezh city. Subjective self-assessment of health covered first 3 years students of Voronezh State Medical university (VSMU), Voronezh State university of engineering technologies (VSUET) and Voronezh State Construction university (VSCU). Health worsening was seen in 50,2% of VSMU students, in 28,7% of VSUET students and in 23,9% of VSCU examinees since beginning of the high education, and revealed breach of legislation concerning requirements of high education conditions are nearly identical.

Superconductor-insulator transition in long MoGe nanowires.

The properties of one-dimensional superconducting wires depend on physical processes with different characteristic lengths. To identify the process dominant in the critical regime we have studied the transport properties of very narrow (9-20 nm) MoGe wires fabricated by advanced electron-beam lithography in a wide range of lengths, 1-25 µm. We observed that the wires undergo a superconductor-insulator transition (SIT) that is controlled by cross sectional area of a wire and possibly also by the width-to-thickness ratio. The mean-field critical temperature decreases exponentially with the inverse of the wire cross section. We observed that a qualitatively similar superconductor-insulator transition can be induced by an external magnetic field. Our results are not consistent with any currently known theory of the SIT. Some long superconducting MoGe nanowires can be identified as localized superconductors; namely, in these wires the one-electron localization length is much smaller than the length of a wire.

Dynamical and statistical properties of high-temperature self-propagating fronts: an experimental study.

We present a detailed experimental study of high-temperature self-propagating fronts using image processing techniques. The intrinsic features of the wave propagation are investigated as a function of the combustion temperature TC for a model system made of titanium and silicon powders. Different front behavior is realized by changing the molar ratio x of the mixture Ti+xSi. Outside the range x=[0.3,1.5], no thermal front is propagating while inside, three regimes are observed: steady-state combustion which is characterized by a flat front propagating at constant velocity and two unsteady regimes. The combustion temperature (or the corresponding ratio x) is thus playing the role of bifurcation parameter leading from stationary state to complex behavior. In the titanium-rich mixture, the position of the front oscillates and hot spots propagate along the external border of the sample. At lower amounts of Ti, localized bright regions appear randomly and deform the front profile. The associated dynamical behavior is a relay-race mechanism which becomes more pronounced close to the combustion limit. Methods are developed to characterize the structural and dynamical properties of thermal waves near instabilities, with a special emphasis on the statistical aspects. It is clearly demonstrated that the mesoscopic scale phenomena interfere significantly with the macroscopic behavior. The experiments reveal front behaviors that cannot be described using the usual macroscopic theories.

Determination of the superconductor-insulator phase diagram for one-dimensional wires.

We establish the superconductor-insulator phase diagram for quasi-one-dimensional wires by measuring a large set of MoGe nanowires. This diagram is roughly consistent with the Chakravarty-Schmid-Bulgadaev phase boundary, namely, with the critical resistance being equal to RQ=h/4e2. Deviations from this boundary for a small fraction of the samples prompt us to suggest an alternative phase diagram, which matches the data exactly. Transport properties of wires in the superconducting phase are dominated by phase slips, whereas insulating nanowires exhibit a weak Coulomb blockade behavior.

[Biocompatible antibacterial polymer coatings with ciprofloxacin extended release].

A procedure for application of thin composite coats based on polymers (polyurethane or polyethylene) and ciprofloxacin in active gaseous phase generated by electron beam dispersion under vacuum was developed. The coats were shown to be highly dispersed systems whose components preserved the initial molecular structure and had antibacterial activity. The composite coats based on polyurethane were more stable to ciprofloxacin leaching in isotonic sodium chloride solution.

Magnetic-field enhancement of superconductivity in ultranarrow wires.

We study the effect of an applied magnetic field on sub-10-nm wide MoGe and Nb superconducting wires. We find that magnetic fields can enhance the critical supercurrent at low temperatures, and do so more strongly for narrower wires. We conjecture that magnetic moments are present, but their pair-breaking effect, active at lower magnetic fields, is suppressed by higher fields. The corresponding microscopic theory, which we have developed, quantitatively explains all experimental observations, and suggests that magnetic moments have formed on the wire surfaces.