Cyclosporin is an 11-amino acid cyclic peptide with pharmacologically valuable properties which has a variety of actual and potential applications. Its activity relies on the cell membrane ...permeability which, in turn, depends on the structure of cyclosporine and its ability to change the conformation. In this work, conformational exchange processes occurring in cyclosporin C were studied using one- and two-dimensional nuclear magnetic resonance spectroscopy. The free energy barrier separating two major conformers observed in polar solution (acetonitrile) was found to be 77 ± 2 kJ/mol. Less populated conformation states are also present in the solution, which agrees with the ease of formation of multiple forms revealed by MD simulations of cyclosporin C.
•Cyclosporin variant C in a polar solvent (acetonitrile) was studied by NMR.•Two distinct conformers were found to prevail in the solution.•Parameters of the chemical exchange between two main conformers were obtained.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cyclosporins B, C, D, and E were characterized by NMR spectroscopy, and backbone flexibility was studied by molecular dynamics simulation. Structures of the molecules were characterized by nuclear ...Overhauser effect spectroscopy, which revealed that the studied peptides have many common features. Molecular dynamics simulation showed that the backbone of cyclosporin E is relatively more rigid than in other peptides. Calcium-dependent swelling of liver mitochondria under the influence of four considered compounds was also investigated. Three of them were found to have the activity similar to cyclosporin A, inhibiting opening of the mitochondrial pore at concentrations within 100–300 nM. However, cyclosporin E did not show any biological effect at concentrations up to 1 μM. Results of this study agree with the idea on the correlation between the peptide chain flexibility and its bioavailability.
•Four cyclosporin variants (B, C, D, E) were studied by NMR and biophysical methods.•Structures of the molecules in chloroform and in complex with micelles are similar.•Backbone dynamics on the nanosecond time scale is restricted in CsE.•CsE does not inhibit opening of calcium-dependent MPT pore in rat liver mitochondria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peptides play a critical role in the life of organisms, performing completely different functions. The biological activity of some peptides, such as cyclosporins, can be determined by the degree of ...membrane permeability. Thus, it becomes important to study how the molecule interacts with lipid bilayers. Cyclosporins C, E, H and L were characterised molecular dynamics simulation; NMR spectroscopy studies were also carried out for cyclosporins C and E. The comparison of one- and two-dimensional spectra revealed certain similarities between spatial structures of the studied cyclosporin variants. Upon dissolving in water containing DPC micelles, which serve as model membranes, subtle changes in the NMR spectra appear, but in a different way for different cyclosporins. In order to understand whether observed changes are related to any structural modifications, simulation of the interaction of the peptide with the phospholipid micelle was performed. The onset of the interaction was observed, when the peptide is trapped to the surface of the micelle. Simulations of this kind are also of interest in the light of the well-known membrane permeability of cyclosporin, which is important for its biological action.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A finite element algorithm in a mixed formulation has been developed to find stresses and displacements occurring in a shell of revolution. The finite discretization element has been taken in the ...form of a curvilinear quadrangle of the middle shell surface. As the nodal unknowns in the mixed formulation, forces and moments inherent in the middle surface with a bilinear approximation have been used, as have the displacements and their first derivatives in two approximation variants of the sought kinematic quantities in scalar and vector form. By the example of calculations, the efficiency has been shown for the approximation of the sought kinematic quantities as vector fields, and it has been noted that the determination of stresses occurring in shells of revolution made of incompressible materials is quite possible.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The paper formulates a new vision of the reasons for the formation of the modern structural-geological appearance of the Northern Black Sea and the offshore area of the Azov Sea. The catastrophic ...events in the Northern Black Sea, during the Permian-Triassic period, about 250 million years ago, allegedly occurred. Giant asteroid exploded (or just collapsed) when it entered the dense layers of the atmosphere, and its multifarious debris formed numerous circular structures on the Northern Black Sea during the fall. It has suggested that this space catastrophe is the forerunner of the famous Permian extinction of the terrestrial biota.
Graphically and descriptively, it has been proved that approximately along the Bataisk-Krasnoperekopsk-Izmail line, according to the RSD, 3 large circular structures and up to 20 small ones are decoded. It is proved – the line corresponds to the Northern suture zone, which separates the East-European platform from the Scythian epiorogenic zone. The suture area has been active for approximately 250 million years.
It has been theoretically proved that it is the invasive effect of the cosmic body that is the root cause of the fault zone, which in Cimmeria evolved into the Northern suture zone.
Using modern RSD made it possible to identify large circular structures of the Northern Black Sea Region. These are Azov, Bataisk and Kalamitska.
Major research interest in the segments of the Azov astrobleme in the context of the oil and gas exploration work is determined. It is proved by retrospective geological information that the identifying structures have a significant depth of occurrence and here the earth’s crust should be saturated with a significant number of supply channels (decompression zones) favorable for hydrocarbon migration.
The Compressed Baryonic Matter (CBM) experiment at FAIR aims to study the area of the QCD phase diagram at high net baryon densities and moderate temperatures using heavy-ion collisions. The FAIR ...accelerator will provide high-intensity heavy-ion beams up to Au ions in the beam momentum range 3.5A-12A GeV/c per nucleon. In order to achieve it's physics goals and to perform multi-differential measurements of rare probes such as multistrange hadrons or hypernuclei, CBM plans to operate at unprecedented peak interaction rates of up to 10 MHz.
Following an introduction into the physics program of the CBM, recent developments related to the preparation of the experiment, physics performance studies, and detector components tests within the so-called FAIR PHASE-0 program are discussed. In particular, the status of the mCBM project at GSI, which operated with high-intensity beams for the first time last year and combines various CBM detector subsystems with a common data acquisition system (DAQ), are presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The discourse on the nature and boundaries of royal sovereignty, which unfolded with the coming to power of George III in Great Britain, is considered. The key features and changes in ...the constitutional views of the Tories that took shape in the 60—90s of the 18
th
century are examined in the article. The relevance of the study lies in determining the nature and role of the discourse under study in the formation of a new Tory identity, concentrating on the integral role of the monarch. The novelty of the research lies in the emphasis on the religious component of this discourse, as well as in the use of church sermons as a special kind of source. At the same time, some excerpts of sermons are introduced into scientific circulation for the first time. It is emphasized that during the period under study, the Tory party did not have a political ideology, and the current policy was influenced by fears about the stability of the English constitution associated with the events in the North American colonies. The validity of the cautious approaches of the supporters of the critical direction in modern British historiography to the assessment of Tory identity in the last third of the 18
th
century is shown. The author’s assessment of how Toryism of the 60—90s of the 18
th
century reinterprets the experience of the “old Tories”, combining traditional respect for the royal prerogative with the recognition of the rights and privileges of parliament.
Comparative analysis of the use of the defining equations of plasticity theories obtained at the loading step in three ways is performed. In the first method, the relations between strains increments ...and stresses increments are obtained by differentiating the governing equations of the small elastic-plastic deformations theory between full stresses and strains. In the second method, the authors based on the proportionality hypothesis between the component deviators of strains increments and the component deviators of stresses increments without separating the incremental strain into elastic and plastic parts obtain the determining equations at the loading step. In the third method, the relations between the incremental strain and the stresses increment of the plastic flow theory are used on the basis of the hypothesis about the proportionality of the plastic deformations increments to the components of the stress deviator. Based on the analysis of algorithms for obtaining the constitutive relations and the analysis of the numerical results of the calculation example, preference is given to the second method of obtaining expressions between stress increments and strain increments without separating the latter into elastic and plastic parts.
The displacement vector components vector (invariant) approximation implementation and the initial inclination angles by the hypothesis of S. P. Tymoshenko in obtaining the thin shell quadrangular ...finite element nodal forces stiffness matrix and the column is shown.
Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins reduce the amount of low-density lipoprotein (LDL) cholesterol, which is known as a well-established risk factor for ...atherosclerosis. Despite the fact that statins have a common pharmacologic target essential to sterol biosynthesis, their efficacy, safety, and potential non-LDL actions vary significantly for different statins. There is a hypothesis that pharmacological features of statins depend on their location in cell membrane, but to the present day there is a lack of information in literature on interactions of statins with the surface of the cell membrane in liquid media. The results of NMR experiments showed that all studied statins form intermolecular complexes with models of cell membranes (dodecylphosphocholine micelles) in water solution. Locations of pravastatin, simvastatin, fluvastatin and cerivastatin on model membranes were established by NOESY NMR data. Distinctions in their positions can explain differences in pharmacological properties of studied compounds.
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•NMR study showed that statins form molecular complexes with model membranes.•Pravastatin, simvastatin, fluvastatin, cerivastatin have different locations in DPC micelles.•Location of statins in model membranes can explain their pharmacological differences.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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