The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves dysregulations of iron metabolism, and although the mechanism of this pathology is not yet fully ...understood, correction of iron metabolism pathways seems a promising pharmacological target. The previously observed effect of inhibiting SARS-CoV-2 infection by ferristatin II, an inducer of transferrin receptor 1 (TfR1) degradation, prompted the study of competition between Spike protein and TfR1 ligands, especially lactoferrin (Lf) and transferrin (Tf). We hypothesized molecular mimicry of Spike protein as cross-reactivity of Spike-specific antibodies with Tf and Lf. Thus, strong positive correlations (R
2
> 0.95) were found between the level of Spike-specific IgG antibodies present in serum samples of COVID-19-recovered and Sputnik V-vaccinated individuals and their Tf-binding activity assayed with peroxidase-labeled anti-Tf. In addition, we observed cross-reactivity of Lf-specific murine monoclonal antibody (mAb) towards the SARS-CoV-2 Spike protein. On the other hand, the interaction of mAbs produced to the receptor-binding domain (RBD) of the Spike protein with recombinant RBD protein was disrupted by Tf, Lf, soluble TfR1, anti-TfR1 aptamer, as well as by peptides RGD and GHAIYPRH. Furthermore, direct interaction of RBD protein with Lf, but not Tf, was observed, with affinity of binding estimated by K
D
to be 23 nM and 16 nM for apo-Lf and holo-Lf, respectively. Treatment of Vero E6 cells with apo-Lf and holo-Lf (1–4 mg/mL) significantly inhibited SARS-CoV-2 replication of both Wuhan and Delta lineages. Protective effects of Lf on different arms of SARS-CoV-2-induced pathogenesis and possible consequences of cross-reactivity of Spike-specific antibodies are discussed.
We analyze the construction of a system for processing space-time signals in a radio system that takes into account technical limitations in the measurement of the bearing. A desired efficiency can ...be achieved by using simplified processing procedures with stochastic controlled bearing interpolation. For implementation, we use processing based on truncated (low-element) managed apertures of antenna arrays and coarse (“binary”) robust signal statistics. We propose an alternative approach that involves applying the Monte Carlo method with feedback in the process of digital processing: we implement randomization and incremental stochastic control for the phase center position by sequentially activating a small number of elements during the accumulation and averaging of rough samples of the input signal. We also present quantitative results of reducing instrumental errors in bearing measurement.
Data from the NUCLEON space observatory give a strong indication of the existence of a new universal cosmic ray “knee”, which is observed in all groups of nuclei, including heavy nuclei, near a ...magnetic rigidity of about 10 TV. Universality means the same position of the knee in the magnetic rigidity scale for all groups of nuclei. The knee is observed by both methods of measurement of particles energy implemented in the NUCLEON observatory—the calorimetric method and the kinematic method Kinematic Lightweight Energy Meter. This new cosmic ray knee is probably connected with the limit of acceleration of cosmic rays by some generic or nearby source of cosmic rays.
A model of the cathode region of a plasma photoelectric converter of concentrated solar radiation in the regime of an open external circuit is considered. Plasma is analyzed in sodium vapor at a ...pressure of 104 -105 Pa. The necessary optical power is calculated for creating plasma in the state of Local Thermodynamic Equilibrium (LTE), whose temperature is in the range 4000-4500 K. This temperature provides a small internal resistance of the plasma voltage source. A large value of radiative heat conduction coefficient ensures a small temperature drop between the central part and the plasma LTE boundary near the walls of the converter. The model of a Non-LTE zone near the wall of the cathode is analyzed to specify the boundary conditions in the energy balance equation for LTE plasma. The thermal non-equilibrium plasma model resulted in the electron temperature gradient in the Non-LTE zone. The energy losses of electrons in the ionization layer near the cathode are counterbalanced by the thermal conductivity of the electron gas. The specificity of the conditions under consideration consists in the non-local nature of the balance of the electron temperature in the Non-LTE zone.
Myeloperoxidase (MPO) is a unique heme-containing peroxidase that can catalyze the formation of hypochlorous acid (HOCl). The strong interaction of MPO with low-density lipoproteins (LDL) promotes ...proatherogenic modification of LDL by HOCl. The MPO-modified LDL (Mox-LDL) accumulate in macrophages, resulting in the formation of foam cells, which is the pathognomonic symptom of atherosclerosis. A promising approach to prophylaxis and atherosclerosis therapy is searching for remedies that prevent the modification or accumulation of LDL in macrophages. Lactoferrin (LF) has several application points in obesity pathogenesis. We aimed to study LF binding to Mox-LDL and their accumulation in monocytes transformed into macrophages. Using surface plasmon resonance and ELISA techniques, we observed no LF interaction with intact LDL, whereas Mox-LDL strongly interacted with LF. The affinity of Mox-LDL to LF increased with the degree of oxidative modification of LDL. Moreover, an excess of MPO did not prevent interaction of Mox-LDL with LF. LF inhibits accumulation of cholesterol in macrophages exposed to Mox-LDL. The results obtained reinforce the notion of LF potency as a remedy against atherosclerosis.
The efficiency has been compared of the optimized acylation processes of 7-aminocephalosporanic acid (7-ACA) and its С3 derivatives ...(7-amino-3-2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (TDA), and 1-methyl-5-mercapto-1,2,3,4-tetrazolyl-7-aminocephalosporanic acid (7-TMCA)) by methyl esters of 1(H)-terazolylacetic and
D
-mandelic acids (METzAA and MEMA). These processes are catalyzed by immobilized cephalosporin-acid synthetase (IECASA) and are the biocatalytic stages of two different chemical-biocatalytic pathways for the synthesis of cefazolin (CEZ) and cefamandole (CFM). Biocatalytic acylation of 7-ACA resulting in the formation of semi-products of the synthesis of antibiotics proceeded more efficiently than acylation of the corresponding C3 derivatives of 7-ACA, leading to the formation of CEZ and CFM, in terms of both the achieved product yield and the possibility of obtaining compounds in high concentration in the reaction mixture. At the same time, the synthetase ability of IECASA is highest in the acylation of 7-ACA using METzAA. It was shown that the chemical-biocatalytic synthesis of CEZ and CFM by direct biocatalytic acylation of 7-ACA followed by chemical modification of the semi-product at the C3 position of the β-lactam nucleus is a promising alternative to the traditional pathway using the biocatalytic acylation of 7-ACA derivatives with a substituted 3-acetoxy group.
Acylation of 1-methyl-5-mercapto-1,2,3,4-tetrazolyl-7-aminocephalosporanic acid, which is the β-lactam nucleus of antibiotics such as Cefamandole, Cefazaflur, Cefotetan, and Cefoperazone, has been ...carried out using immobilized cephalosporin-acid synthetase as a biocatalyst. Methyl esters of
D
-mandelic acid, 1(H)-tetrazolylacetic acid, cyanomethylthioacetic acid, thienylacetic acid,
D
-phenylglycine, and
D
-
p
-hydroxyphenylglycine were used as acylating agents. Cefamandole and six
chimeric
compounds composed of the C3-modified β-lactam nucleus and the acyl parts of various known antibiotics were obtained by the method of kinetically controlled synthesis. Potentially, it is possible to test the antimicrobial activity of the synthesized new
chimeric
cephalosporins under mild conditions without isolation, directly in the aqueous medium of reaction mixtures after biocatalytic synthesis. The high efficiency of cephalosporin-acid synthetase in the acylation of 1-methyl-5-mercapto-1,2,3,4-tetrazolyl-7-aminocephalosporanic acid with methyl esters of 1(H)-tetrazolylacetic acid and cyanomethylthioacetic acid was demonstrated.
Myeloperoxidase (MPO), an oxidant-producing enzyme of neutrophils, has been shown to prime platelet activity promoting immunothrombosis. Native MPO is a homodimer, consisting of two identical ...protomers (monomer) connected by a single disulfide bond. But in inflammatory foci, MPO can be found both in the form of a monomer and in the form of a dimer. Beside MPO can also be in complexes with other molecules and be modified by oxidants, which ultimately affect its physicochemical properties and functions. Here we compared the effects of various forms of MPO as well as MPO in complex with ceruloplasmin (CP), a physiological inhibitor of MPO, on the platelet activity. Monomeric MPO (hemi-MPO) was obtained by treating the dimeric MPO by reductive alkylation. MPO was modified with HOCl in a molar ratio of 1:100 (MPO-HOCl). Using surface-enhanced Raman scattering (SERS) spectroscopy we showed that peaks at about 510 and 526 cm−1 corresponded to disulfide bond was recognizable in the SERS-spectra of dimeric MPO, absent in the spectrum of hemi-MPO and less intense in the spectra of MPO-HOCl, which indicates the partial decomposition of dimeric MPO with a disulfide bond cleavage under the HOCl modification. It was shown hemi-MPO to a lesser extent than dimeric MPO bound to platelets and enhanced their agonist-induced aggregation and platelet-neutrophil aggregate formation. MPO modified by HOCl and MPO in complex with CP did not bind to platelets and have no effect on platelet activity. Thus, the modification of MPO by HOCl, its presence in monomeric form as well as in complex with CP reduces MPO effect on platelet function and consequently decreases the risk of thrombosis in inflammatory foci.
Type 2 diabetes mellitus (T2DM) is accompanied by halogenative stress resulting from the excessive activation of neutrophils and neutrophilic myeloperoxidase (MPO) generating highly reactive ...hypochlorous acid (HOCl). HOCl in blood plasma modifies serum albumin (Cl-HSA). We studied the formation of neutrophil extracellular traps (NETs) in the whole blood and by isolated neutrophils under the action of Cl-HSA. It was found that Cl-HSA induces neutrophil priming and NETosis. MPO-containing as well as MPO-free NETs were found. These NETs with different composition can be a product of NETosis of one and the same neutrophil. NET formation in neutrophils with vacuolated cytoplasm was detected. In the presence of Cl-HSA, acceleration of NET degradation was observed. Accelerated NET degradation and neutrophil priming can be the factors contributing to the development of complications in T2DM.
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