Репозиторий Университета

© 2018 The Authors Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type of imaging probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast of imaging of human epidermal growth factor type 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result in lipophilic radiometabolites (non-residualizing labels), would provide the best imaging contrast for DARPins that internalize slowly after binding to cancer cells. The hypothesis was tested using DARPin Ec1 that binds to epithelial cell adhesion molecule (EpCAM). EpCAM is a promising therapeutic target. Ec1 was labeled with 125I using two methods to obtain the non-residualizing labels, while residualizing labels were obtained by labeling it with 99mTc. All labeled Ec1 variants preserved target specificity and picomolar binding affinity to EpCAM-expressing pancreatic adenocarcinoma BxPC-3 cells. In murine models, all the variants provided similar tumor uptake. However, 125I-PIB-H6-Ec1 had noticeably lower retention in normal tissues, which provided appreciably higher tumor-to-organ ratios. Furthermore, 125I-PIB-H6-Ec1 demonstrated the highest imaging contrast in preclinical models than any other EpCAM-imaging agent tested so far. In conclusion, DARPin Ec1 in combination with a non-residualizing label is a promising probe for imaging EpCAM expression a few hours after injection.

© 2018 The Authors Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type of imaging probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast of imaging of human epidermal growth factor type 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result in lipophilic radiometabolites (non-residualizing labels), would provide the best imaging contrast for DARPins that internalize slowly after binding to cancer cells. The hypothesis was tested using DARPin Ec1 that binds to epithelial cell adhesion molecule (EpCAM). EpCAM is a promising therapeutic target. Ec1 was labeled with 125I using two methods to obtain the non-residualizing labels, while residualizing labels were obtained by labeling it with 99mTc. All labeled Ec1 variants preserved target specificity and picomolar binding affinity to EpCAM-expressing pancreatic adenocarcinoma BxPC-3 cells. In murine models, all the variants provided similar tumor uptake. However, 125I-PIB-H6-Ec1 had noticeably lower retention in normal tissues, which provided appreciably higher tumor-to-organ ratios. Furthermore, 125I-PIB-H6-Ec1 demonstrated the highest imaging contrast in preclinical models than any other EpCAM-imaging agent tested so far. In conclusion, DARPin Ec1 in combination with a non-residualizing label is a promising probe for imaging EpCAM expression a few hours after injection.

© 2018 The Authors Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type of imaging probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast of imaging of human epidermal growth factor type 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result in lipophilic radiometabolites (non-residualizing labels), would provide the best imaging contrast for DARPins that internalize slowly after binding to cancer cells. The hypothesis was tested using DARPin Ec1 that binds to epithelial cell adhesion molecule (EpCAM). EpCAM is a promising therapeutic target. Ec1 was labeled with 125I using two methods to obtain the non-residualizing labels, while residualizing labels were obtained by labeling it with 99mTc. All labeled Ec1 variants preserved target specificity and picomolar binding affinity to EpCAM-expressing pancreatic adenocarcinoma BxPC-3 cells. In murine models, all the variants provided similar tumor uptake. However, 125I-PIB-H6-Ec1 had noticeably lower retention in normal tissues, which provided appreciably higher tumor-to-organ ratios. Furthermore, 125I-PIB-H6-Ec1 demonstrated the highest imaging contrast in preclinical models than any other EpCAM-imaging agent tested so far. In conclusion, DARPin Ec1 in combination with a non-residualizing label is a promising probe for imaging EpCAM expression a few hours after injection.

© 2018 The Authors Radionuclide-based imaging of molecular therapeutic targets might facilitate stratifying patients for specific biotherapeutics. New type of imaging probes, based on designed ankyrin repeat proteins (DARPins), have demonstrated excellent contrast of imaging of human epidermal growth factor type 2 (HER2) expression in preclinical models. We hypothesized that labeling approaches, which result in lipophilic radiometabolites (non-residualizing labels), would provide the best imaging contrast for DARPins that internalize slowly after binding to cancer cells. The hypothesis was tested using DARPin Ec1 that binds to epithelial cell adhesion molecule (EpCAM). EpCAM is a promising therapeutic target. Ec1 was labeled with 125I using two methods to obtain the non-residualizing labels, while residualizing labels were obtained by labeling it with 99mTc. All labeled Ec1 variants preserved target specificity and picomolar binding affinity to EpCAM-expressing pancreatic adenocarcinoma BxPC-3 cells. In murine models, all the variants provided similar tumor uptake. However, 125I-PIB-H6-Ec1 had noticeably lower retention in normal tissues, which provided appreciably higher tumor-to-organ ratios. Furthermore, 125I-PIB-H6-Ec1 demonstrated the highest imaging contrast in preclinical models than any other EpCAM-imaging agent tested so far. In conclusion, DARPin Ec1 in combination with a non-residualizing label is a promising probe for imaging EpCAM expression a few hours after injection.

© 2019 Elsevier B.V. Herein, we report on the crystal structure, magnetic and local ferroelectric properties of the Bi1−xCaxFe1−xTixO3 and Bi1−xCaxFe1−x/2Nbx/2O3 perovskites prepared by a solid state reaction method. It has been found that the Ca2+/Nb5+-containing series is characterized by a narrower concentration range (x ≤ 0.2) over which the acentric R3c structure specific to the pure BiFeO3 can be stabilized. The compositional variation in the critical concentration defining the polar/nonpolar (R3c/Pnma) phase boundary can be understood as related to the chemical modification-induced changes in the lattice spacing diminishing the stability of the a−a−a− tilting in favor of the a−b+a− one. Both the Ca2+/Ti4+ and Ca2+/Nb5+ substitutions ensure the suppression of a cycloidal antiferromagnetic order, thus leading to the formation of a weak ferromagnetic polar state. While this effect is proven to be associated with a composition-driven reduction in polar displacements, lattice defects are supposed to contribute to the instability of the cycloidal spin arrangement.

© 2019 Elsevier B.V. The formation of novel ternary cerium germanide with the chemical composition Ce33.3Ir22.2Ge44.5 (at.%) was established. As derived from powder X-ray diffraction data, the compound crystallizes with two polymorphic modifications. The high-temperature modification, established for as-cast alloy, possesses a tetragonal ThSi2-type structure and can be named as Ce(IrxGe1-x)2, x = 0.32. The low-temperature modification forms in the course of heat treatment at 1073 K, crystallizes with an orthorhombic structure of its own type and can be labeled as Ce3Ir2-xGe4+x, x = 0.02. Both structures belong to the AlB2 structural family and are closely related to each other. In both modifications, statistical mixtures of Ir and Ge atoms occupy same crystallographic sites. As found by means of magnetization measurements, the two structural variants of Ce33.3Ir22.2Ge44.5 (at.%) exhibit very similar magnetic properties. Both polymorphs are Curie-Weiss paramagnets with strong crystalline electric field features observed at low temperatures.

© 2019 International Union of Crystallography. This study of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one, C17H10N2O3, 1, and 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2H-chromen-2-one, C16H9ON3O3, 2, was performed on the assumption of the potential anticancer activity of the compounds. Three polymorphic structures for 1 and two polymorphic structures for 2 have been studied thoroughly. The strongest intermolecular interaction is stacking of the 'head-to-head' type in all the studied crystals. The polymorphic structures of 1 differ with respect to the intermolecular interactions between stacked columns. Two of the polymorphs have a columnar or double columnar type of crystal organization, while the third polymorphic structure can be classified as columnar-layered. The difference between the two structures of 2 is less pronounced. Both crystals can be considered as having very similar arrangements of neighbouring columns. The formation of polymorphic modifications is caused by a subtle balance of very weak intermolecular interactions and packing differences can be identified only using an analysis based on a study of the pairwise interaction energies.

© 2019, The Author(s). Objectives: This study was aimed to assess hemostatic disturbances in female patients with established rheumatoid arthritis (RA) in relation to menopausal status and disease activity. Method: Ninety women were included in the study, 42 patients and 48 age-matched healthy controls. There were no differences between the investigated groups regarding the presence of traditional cardiovascular risk factors. Two global hemostatic assays were employed, namely endogenous thrombin potential (ETP) and overall hemostasis potential (OHP). The parameters of the ETP assay (ETP, C-max, t-lag, t-max) and OHP assay (overall coagulation potential (OCP) and overall fibrinolytic potential (OFP)) were assessed. Moreover, the parameters of the fibrin clot (lag time, Max Abs, and slope) were measured by clot turbidity and scanning electron microscopy (SEM). Both patients and controls were divided into four subgroups according to menopause status. Results: The premenopausal controls differed significantly from all other subgroups in terms of diminished levels of ETP (p = 0.02), C-max (p = 0.01), OCP (p = 0.02), OHP (p = 0.001), and Max Abs (p = 0.008), while OFP (p = 0.0001) was increased. This tendency was not seen in the premenopausal RA patients compared with the postmenopausal RA patients. SEM images showed denser clots composed of thinner fibers in samples from RA patients. The disease activity measured by DAS28 correlated with OCP and OHP (r = 0.54; p = 0.001 and r = 0.44; p = 0.003, respectively) indicating persistent hypercoagulable condition in the whole group of RA patients. Conclusions: Our results point towards coagulation activation in premenopausal women with established RA. The patients were well characterized, which enabled assessment in a real-life setting.Key Points• Extensive assessment points towards persistent coagulation activation in premenopausal women with established rheumatoid arthritis.• Impaired thrombin generation and fibrin formation are associated with menopause in healthy women, while rheumatoid arthritis closes the gap within patients regarding menopause.• Fibrin morphology is unfavorably altered and fibrinolysis is decreased in patients with established rheumatoid arthritis.• Increased activity of thrombin activatable fibrinolysis inhibitor (TAFI) may contribute to impaired fibrinolysis in patients with rheumatoid arthritis.

© 2019 Elsevier B.V. The structural parameters of the Bi0.85AE0.15Fe0.85Ti0.15O3 (AE = Ca and Ba) multiferroics have been determined using variable temperature neutron powder diffraction. The compounds adopt the polar rhombohedral R3c structure near room temperature and undergo phase transitions into either the nonpolar orthorhombic Pnma (AE = Ca) or cubic Pm3-m (AE = Ba) structures on heating. In the ferroelectric phase, a temperature-driven lattice expansion is accompanied by both a diminishing of the off-center ionic displacements (thus resulting in a decrease in the spontaneous electric polarization) and a reduction in the magnitude of the antiphase oxygen octahedra tilting. Being largely different for the materials under study, the latter parameter is supposed to specify the dissimilarity in their magnetic properties.

© 2019 Wiley Periodicals, Inc. Background: Clinical measures and implant design innovation to improve primary osseointegration and reduce the bacterial contamination of the peri-implant area are intended to reduce the incidence of late inflammatory complications in dental implantation. Purpose: To study the effect of nanostructured coating and antiseptic sealant on the outcomes of dental implantation. Materials and methods: Ninety-six individuals were clinically supervised. In the first group (Screw Ti + sealant), a special antiseptic sealant matrix was used; the same sealant was used with nanocoated implants in the second group (Nanocoat + sealant), and the conventional treatment protocol was used in the control group (Screw Ti). Patients were evaluated longitudinally during treatment and rehabilitation phases with clinical examinations, radiography, periodontal pathogen detection, and patient experience surveys. Results: For patients who received a nanocoated implant and an antiseptic sealant (Nanocoat + sealant), relatively better hygienic indices were observed; there was less contamination with periodontal pathogens, bone density remained at the required level, and the overall results of treatment were better. Conclusions: Using a matrix for sealing the dental implant-abutment interface with a nanostructured surface provides reliable results regarding stable osseointegration and clinical and patient-reported outcomes of treatment success.

© 2019 Elsevier B.V. Crystal structure of the Bi1-xBaxFe1-xTixO3 ceramics across the phase boundary region between the polar rhombohedral and pseudo-cubic phases has been investigated by means of X-ray and neutron diffraction, scanning electron microscopy and differential scanning calorimetry techniques. The structural measurements have revealed a decrease in the rhombohedral distortions upon increase in the dopant content followed by the stabilization of the pseudo-cubic phase at x ≥ 0.20. While temperature increase gives rise to the similar pattern of structural changes for the lightly-doped samples, an unpredictable temperature-driven strengthening of the rhombohedral distortions has been found for the compounds belonging to the phase boundary region. The study specifies the peculiarities of the temperature-driven evolution of the crystal structure depending on the structural state of the compounds at room temperature.

© 2019 Elsevier Ltd Sandpiles are ubiquitous in nature and engineering applications but still not fully understood due to the complexity of structures and materials properties. This work presents a systematic study on the piles of Platonic solids using the discrete element method (DEM), mainly focusing on the effect of particle shape on the repose angles and bottom pressure distributions of the piles. Five Platonic particles (tetrahedron, cube, octahedron, dodecahedron, and icosahedron) were discharged to form wedge-shaped piles. It was found that the repose angle did not increase with the decrease of particle sphericity. The pile formed by the cubes had the maximum repose angle and its bottom stress dip phenomena were more significant in terms of dip width and depth than that of other particle piles. The pressure distributions at different heights of the piles were quite similar to those of the whole piles, while the shear stress distributions near the boundaries exhibited different characteristics for the cube piles. The analyses of packing structures in terms of coordination number, radial distribution function, as well as contact types inside the piles were discussed to understand the change of pressure dips. The influence of static friction on the repose angle was more significant and it enhanced the stress dip phenomenon.

The article analyzes the indicators of population reproduction on the example of the Kostroma region, presents the dynamics of the main medical and demographic indicators of the region: age structure of the population, mortality, fertility, migration, marriage and divorce rates, as well as the starting positions for overcoming reproductive and demographic disadvantages.

© 2018 MDPI AG. All rights reserved. Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus Niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

© 2018 Wiley Periodicals, Inc. A new approach to making a photopolymeric composition was first elaborated in this work based on the use of poly-N,N′-(m-phenylene)isophtalamide as the heterochain polymer matrix together with 4,4′-diphenyl oxide diacrylamide as the crosslinking agent. Reproducible three-dimensional (3D) objects have been formed using a laser stereolithograph completed with a laser with wavelength of 405 nm. According to the thermogravimetric analysis, the thermal stability of the formed objects could be changed through a control from 260 to 405 °C. Moreover, it was proven that the tensile strength of samples of the crosslinked films reached 90.1 ± 3.2 MPa at the elongation at break of 12.4 ± 2.3%, depending on the forming parameters of such samples. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46463.

© 2018 Elsevier B.V. Development of efficient biodegradable, environmentally responsive, biocompatible and non-toxic delivery system is needed for efficient gene delivery. As well known, properties of the vehicle are determined by the structure of carrier components. The aim of the current study was to estimate in vitro transfection efficacy of aliphatic di-, tri- and tetrapeptide-based cationic lipoplexes loaded with siRNA in function of a number of cationic groups using 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Physicochemical properties and cytotoxicity of the liposomes were found to be dependent upon a number of amino acid derivatives in an amphiphilic polar head. Uptake of liposomes loaded with nucleic acid (lipoplexes) and their localization in HEK293T cells was studied by confocal microscopy. The liposomes based on lipotripeptides had the highest transfection efficiency which was 20-fold higher than those fabricated from lipotetrapeptides.

© 2018, University of Kragujevac, Faculty of Science. All rights reserved. Two sets of reactants for modelling neurogenesis (SRMN) were developed based on the designed and tested genetic structures of lentiviral vectors. SRMN-1 contains the genetic construct LVV-GFAP-GCaMP3 and is intended for cellspecific transduction in astroglia cells. SRMN-2 contains the genetic construct LVV-PRSx8-TN-XXL and is intended for the phenotype-specific transduction in neurons. The present study examined SRMN-1 and SRMN-2 samples and assessed their efficiency in vitro and in vivo in Norvegicus rats. Specificity to particular cell types for all SRMN samples exceeded 97%. The number of induced signalling cascades was determined via activation of intracellular ingsignalling cascades in neurons and astrocytes (purinergic receptors and β-adrenoceptors). The results demonstrated dynamic recording of fluorescent signals and a two-fold increase in intensity after addition of the activator in all samples. The experimental SRMN samples revealed successful and stable transfection of catecholaminergic neurons and astrocytes, data on transfection efficiency, specificity of the developed genetic structures of SRMN, and calcium dynamics in transfected neurons and astrocytes.

© 2018 by the authors. Composite fibers and films based on cellulose and betulin were spun for the first time from solutions in N-methylmorpholine-N-oxide using the dry-wet jet method. The rheological properties of the composite solutions did not reveal any fundamental difference from those of the cellulose solutions. Introduction of betulin into the cellulose matrix (up to 10%) led to a decrease in the mechanical properties of the obtained fibers. The structure of the composite fibers was analyzed using SEM and X-ray diffraction methods. It was shown that the introduction of an additive into the cellulose matrix led to a decrease in the structural ordering of the cellulose. Comparative studies of the antibacterial activity of the composite films on Escherichia coli (E. coli) were carried out. The antifungal activity of the composite films was estimated using the strain of the O-97 Trichoderma viride Pers ex Fr (Gause Institute of New Antibiotics, Moscow, Russia).

© 2018 Wiley-VCH Verlag GmbH  &  Co. KGaA, Weinheim The rational design of broad-spectrum antivirals requires data on antiviral activity of compounds against multiple viruses, which are often not available. We have developed a panel of (+)ssRNA viruses composed of Enterovirus and Flavivirus genera members allowing to study these activity spectra. Antiviral activity profiling of a set of nucleoside analogues revealed N4-hydroxycytidine as an efficient inhibitor of replication of coxsackieviruses and other enteroviruses, but ineffective against tick-borne encephalitis virus. Furano[2, 3-d]pyrimidine nucleosides with n-pentyl or n-hexyl tails showed selective inhibition of Enterovirus A representatives. 5-(Tetradec-1-yn-1-yl)-uridine showed selective inhibition of tick-borne encephalitis virus at the micromolar level.

© 2018 Astro Ltd. This paper describes a new approach to the fabrication of superconducting nanowire single-photon detectors from ultrathin NbN films on SiO2 substrates. The technology is based on nonlinear femtosecond optical lithography and includes direct formation of the sensitive element of the detector (the meander) through femtosecond laser exposure of the polymethyl methacrylate resist at a wavelength of 525 nm and subsequent removal of NbN using plasma-chemical etching. The nonlinear femtosecond optical lithography method allows the formation of planar structures with a spatial resolution of ∼50 nm. These structures were used to fabricate single-photon superconducting detectors with quantum efficiency no worse than 8% at a wavelength of 1310 nm and dark count rate of 10 s-1 at liquid helium temperature.