Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation.

Background: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation MIR 19® (siR-7-EM/KK-46) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19.

Methods: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled siR-7-EM/KK-46 (3.

Novel RyR2 Mutation (G3118R) Is Associated With Autosomal Recessive Ventricular Fibrillation and Sudden Death: Clinical, Functional, and Computational Analysis.

Background The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca from the SR during systole. The molecular mechanism underlying Ca sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations.

The Interaction of FABP with Kapα.

Gene-activating lipophilic compounds are carried into the nucleus when loaded on fatty-acid-binding proteins (FABP). Some of these proteins are recognized by the α-Karyopherin (Kapα) through its nuclear localization signal (NLS) consisting of three positive residues that are not in a continuous sequence. The Importin system can distinguish between FABP loaded with activating and non-activating compounds.

A Novel Leu92 Mutant of HIV-1 Reverse Transcriptase with a Selective Deficiency in Strand Transfer Causes a Loss of Viral Replication.

Unlabelled: The process of reverse transcription (RTN) in retroviruses is essential to the viral life cycle. This key process is catalyzed exclusively by the viral reverse transcriptase (RT) that copies the viral RNA into DNA by its DNA polymerase activity, while concomitantly removing the original RNA template by its RNase H activity. During RTN, the combination between DNA synthesis and RNA hydrolysis leads to strand transfers (or template switches) that are critical for the completion of RTN.

Tracking the interplay between bound peptide and the lid domain of DnaK, using molecular dynamics.

Hsp70 chaperones consist of two functional domains: the 44 kDa Nucleotide Binding Domain (NBD), that binds and hydrolyses ATP, and the 26 kDa Substrate Binding Domain (SBD), which binds unfolded proteins and reactivates them, utilizing energy obtained from nucleotide hydrolysis. The structure of the SBD of the bacterial Hsp70, DnaK, consists of two sub-domains: A β-sandwich part containing the hydrophobic cavity to which the hepta-peptide NRLLLTG (NR) is bound, and a segment made of 5 α-helices, called the "lid" that caps the top of the β-sandwich domain. In the present study we used the Escherichia coli Hsp70, DnaK, as a model for Hsp70 proteins, focusing on its SBD domain, examining the changes in the lid conformation.

Effect of NO inhibitors on hypovolemic shock-induced hypotension.

In vivo effect of isothiourea derivatives on NO production was studied by the method of electron paramagnetic resonance spectroscopy with a spin trap. We evaluated the influence of these compounds on hemodynamic parameters in anesthetized rats with hypovolemic shock. A correlation was found between the size of S,N-substituents in isothiourea derivatives (methyl, ethyl, and isopropyl) and NO inhibitory activity of compounds.

[NO-inhibiting activity of radioprotectors].

The effect of radioprotectors of different structure on the syntheses of nitric oxide induced by endotoxin in mice was studied. Using ESR-spectroscopy and spin trap techniques, it was shown that compounds of different chemical structure, such as aminothiols, isothiuronium derivatives, thiazolines, indolylalkylamines and others, suppressed the nitric oxide production in a whole body. The analysis of the relevant literature has confirmed the phenomenon described by the authors: radioprotectors show NO-inhibiting activity.

NO-inhibiting and vasotropic activity of some compounds with thioamidine group.

Using the method of electron paramagnetic spectroscopy we demonstrated that thiazine-thiazoline compounds and aminoethyl isothiourea containing the thioamidine group inhibit NO production in the liver of endotoxin-treated mice. Injection of these agents to anesthetized rats increased arterial pressure and enhanced respiration rate. This effect probably reflects inhibition of not only inducible, but also the constitutive synthesis of NO by compounds with thioamidine group.

Functioning of systems of the neutral amino acid transport in enterocyte brush-border membranes of rat small intestine under normal conditions and after ionising radiation.

Peculiarities of neutral amino acid (L-leucine and L-phenylalanine) transport in brush-border membranes of rat small intestine enterocytes under normal conditions and following a 1.0-Gy X-ray irradiation have been studied. The increase of the brush-border membrane permeability for ions and amino acids is considered to be the main reason of the post-irradiation disorders in the transmembrane transport of amino acids.

[Detection and treatment of lower extremity neuropathy in patients with diabetic foot].

Possibilities of diagnosis and treatment of the lower extremities neuropathy were studied in 118 patients with diabetes mellitus (DM). Neurological examination, investigation of algesic, vibratory and temperature sensibility, thermography of feet were done in each patient. Electrostimulation treatment using therapeutic-diagnostic complex "Salut 11" was applied in 47 patients.

[Effect of ionizing radiation on the structure and functional properties of the basolateral membrane of small intestine enterocytes].

The structural state and transport properties of basolateral membrane of rat small intestine enterocytes after exposure to X-ray irradiation (0.5; 1.0 and 2.

[The use of nontraditional approaches to the analysis of the effects of radiation on the system of protein phosphorylation in spleen lymphocytes].

Postradiation disturbances in functioning of Ca(2+)- and cyclic nucleotide-dependent protein kinase systems are established. Kinetic index of different protein kinases of spleen lymphocytes under irradiation with doses of 0.5 and 1 Gy are analysed using return-cards-construction and Lyapunov's-coefficient-determination methods.

[Effect of x-irradiation on the properties of cyclic AMP-dependent protein kinases from rat spleen lymphocytes].

It was shown, that in conditions of acute radiation affection in doze 0.5 and 1 Gy, there was a decrease of 32 and 55% in activity of cyclic AMP-dependent protein kinases, isolated from cytosol of lymphocytes. The analysis of cAMP-dependent protein kinases properties has shown, that disturbance in the interaction of the enzyme with protein substrate of phosphotransferase reaction and main modulater enzymes activity--cAMP proceeds of the ionising radiation effect.

[Endonucleolysis of chromatin in rat thymus and spleen lymphocytes after irradiation].

The level of soluble DNA fragments (polydesoxynucleotides) in thymus and spleen lymphocytes is enhanced 12 h after the whole-body X-ray irradiation in dose of 0.5 and 1 Gy. The level of Ca2+, Mg(2+)-DNAase activity in lysed cells extracts, measured with calf spleen DNA, was enhanced in the region of 0.

[Post-radiation disturbances in the cyclic nucleotide system in rat spleen and thymus lymphocytes].

The changes in cAMP and cGMP content in rat spleen and thymus lymphocytes after irradiation in doses of 0.5 and 1 Gy, are determined, indicating to significant disturbances in the system of cyclic nucleotides. Radiation affected the functioning of enzymes both of synthesis and hydrolysis of cAMP and cGMP in spleen lymphocytes.

[Release of arachidonate from rat spleen lymphocytes after irradiation].

After spleen lymphocytes incubation with 14C-arachidonic acid 14C label was found associated predominantly with phosphatidylethanolamine (PE) and phosphatidylcholine (PC). Addition of 0.5 mkM a 23187 to the incubation media with 2 mM CaCl2 caused a 4-fold increase in release of labeled free arachidonate in lymphocytes of the control animals.

[Phospholipase A2 in the biochemical mechanisms of spleen lymphocyte reaction to x-ray irradiation of animals].

Preincubation of rat splenic lymphocytes with nonspecific mitogens and calcium ionophore A23187 led to the activity of phospholipase A2 which hydrolyzed arachidonoyl phospholipids and to increased cellular levels of free arachidonic acid. The effect of some substances was decreased as follows: A23187 > > lipopolysaccharide > phytohemagglutinin > concanavalin A. Dose-dependent activation of phospholipid hydrolysis and arachidonic acid release were observed within 6-12 hrs after X-ray irradiation of animals in doses of 0.

[Second messenger systems and protein kinase activity in rat thymus and liver in the early stages of radiation injury].

The effect of ionizing radiation (7, 76 Gr) on the content of cyclic nucleotides and Ca2+ ions from rat thymus and liver has been established: it was increased 15, 30 min and 4.6 h and decreased 2, 12 h and 24 h after the irradiation. Changes in activity of cyclic nucleotide-dependent protein kinases and Ca2+, phospholipid-dependent protein kinase correlated with the contents of secondary messengers in the irradiated rats (30 min and 4 h after irradiation) are shown.

[Effects of irradiation on fatty acid structure of membrane lipids of the sarcoplasmic reticulum].

It has been shown that single local X-irradiation (0.21 C/kg) of the rabbit hind limb in the early period of acute radiation injury (1 and 14 h) causes a decrease in saturation of sarcoplasmic reticulum membrane lipids. It is mainly connected with a decreased saturation of the total fraction of phosphatidyl serine, phosphatidyl inositol and phosphatidyl choline.

[Phospholipase A2 from rat spleen lymphocytes hydrolyzing arachidonoyl-phospholipids].

Phospholipase A2 activity in the postnuclear supernatant of lymphocytes has been studied by measuring 14C arachidonate released from labelled phosphatidyl ethanolamine (PE) and phosphatidyl choline (PC) as exogenous substrates. The pH optimum was 7.5-9.

[The content of cyclic nucleotides, free cytoplasmic Ca2+ and malondialdehyde in the splenic lymphocytes and thymocytes of rats under the action of moderate doses of radiation].

It has been shown that the malonic dialdehyde (MDA) content in spleen lymphocytes of rats increases after whole-body X irradiation with a dose of 0.5 Gy to reach the maximum level in 24 h. Simultaneously, the concentration of cGMP and free cytosol Ca2+ increases.

[Lipid peroxidation of rat spleen and thymus lymphocytes treated with x-rays (0-5-1.0 Gy)].

It is established, that low doses of X-ray irradiation have affected activation of lipid peroxidation (LPO) in immunocompetent cells of the spleen and thymus. The amount of malonic dialdehyde (MDA) in lymphocytes of spleen and thymocytes increases 2 times twenty-four hours after animals' irradiation by X-rays in a dose of 0.5 Gy; when a dose grows to 1.

[Structural changes in the sarcoplasmic reticulum membrane of skeletal muscles at the early stage of x-ray irradiation].

A single X-ray irradiation of the rabbit hindlimbs in a dose of 0.24 C/kg evokes a decrease in fluorescence of the ANS probe bound with membranes of the sarcoplasmatic reticulum as a result of the decrease of binding sites, binding constant as well as the quantum output of the probe. A decrease in fluorescence of tryptophan residues of Ca-ATPase localized in membranes and attenuation of interaction of its SH-group with dithionitrobenzoic acid has been also observed at early postradiation terms (1 and 24 h).