Morphological Changes in Articular Cartilage and Free-Radical Lipid Peroxidation in Rats with Posttraumatic Osteoarthrosis.

Using the rat model of posttraumatic osteoarthrosis of the knee joint induced by surgical transection of their anterior cruciate ligaments, we showed that irreversible loss of hyaluronan by the extracellular matrix of the joint cartilage tissue against the background of oxidative stress accompanied by accumulation of intermediate LPO products in blood serum and formation of thiol system incompetence was one of the key patterns of dystrophic degeneration of the cartilage tissue. Considerable metabolic shifts were associated with structural modification of the articular hyaline cartilage: its thinning and a decrease of chondrocyte density and their abnormal spatial distribution in the matrix with predominance of solitary isolated cells with signs of karyopyknosis and karyolysis.

[The Challenges of Vaccine Development Against Betacoronaviruses: Antibody Dependent Enhancement and Sendai Virus as a Possible Vaccine Vector].

To design an effective and safe vaccine against betacoronaviruses, it is necessary to elicit a combination of strong humoral and cell-mediated immune responses as well as to minimize the risk of antibody-dependent enhancement of viral infection. This phenomenon was observed in animal trials of experimental vaccines against SARS-CoV-1 and MERS-CoV that were developed based on inactivated coronavirus or vector constructs expressing the spike protein (S) of the virion. The substitution and glycosylation of certain amino acids in the antigenic determinants of the S-protein, as well as its conformational changes, can lead to the same effect in a new experimental vaccine against SARS-CoV-2. This review outlines approaches for developing vaccines against the new SARS-CoV-2 coronavirus that are based on non-pathogenic viral vectors. For efficient prevention of infections caused by respiratory pathogens the ability of the vaccine to stimulate mucosal immunity in the respiratory tract is important. Such a vaccine can be developed using non-pathogenic Sendai virus vector, since it can be administered intranasally and induce a mucosal immune response that strengthens the antiviral barrier in the respiratory tract and provides reliable protection against infection. The mucosal immunity and the production of IgA antibodies accompanying its development reduces the likelihood of developing an antibody-dependent infection enhancement, which is usually associated only with immunopathological IgG antibodies.

Change of Antigenic Determinants of SARS-CoV-2 Virus S-Protein as a Possible Cause of Antibody-Dependent Enhancement of Virus Infection and Cytokine Storm.

A hypothesis is proposed that the cytokine storm syndrome, which complicates COVID-19 in some patients, is a consequence of antibody-dependent enhancement of virus infection, which is in turn happens due to a change in dominant antigenic determinants of SARS-CoV-2 S-protein. The antibody-dependent enhancement of virus infection is a phenomenon in which virus-specific antibodies that are not neutralizing enhance the entry of infectious virus into immune cells causing their death. Antibody-dependent enhancement has been reported for different coronaviruses. This phenomenon happens due to a decrease in the binding strength of neutralizing antibodies to the virus, which converts these antibodies into suboptimal-not neutralizing ones. According to our hypothesis, such a decrease in affinity may be associated with a change in the conformation of the viral S-protein. We believe that this conformational change is the major factor in the switching of antibodies affinity, which triggers antibody-dependent enhancement. However, other factors that contribute to antigen drift and antigenic determinant changes may also play a role.

The Challenges of Vaccine Development against Betacoronaviruses: Antibody Dependent Enhancement and Sendai Virus as a Possible Vaccine Vector.

To design an effective and safe vaccine against betacoronaviruses, it is necessary to use their evolutionarily conservative antigenic determinants that will elicit the combination of strong humoral and cell-mediated immune responses. Targeting such determinants minimizes the risk of antibody-dependent enhancement of viral infection. This phenomenon was observed in animal trials of experimental vaccines against SARS-CoV-1 and MERS-CoV that were developed based on inactivated coronavirus or vector constructs expressing the spike protein (S) of the virion. The substitution and glycosylation of certain amino acids in the antigenic determinants of the S-protein, as well as its conformational changes, can lead to the same effect in a new experimental vaccine against SARS-CoV-2. Using more conservative structural and accessory viral proteins for the vaccine antigenic determinants will help to avoid this problem. This review outlines approaches for developing vaccines against the new SARS-CoV-2 coronavirus that are based on non-pathogenic viral vectors. For efficient prevention of infections caused by respiratory pathogens the ability of the vaccine to stimulate mucosal immunity in the respiratory tract is important. Such a vaccine can be developed using non-pathogenic Sendai virus vector, since it can be administered intranasally and induce a mucosal immune response that strengthens the antiviral barrier in the respiratory tract and provides reliable protection against infection.

Two-dimensional Ising model for microarray hybridization: cooperative interactions between bound target molecules.

The Langmuir adsorption model is widely used for description and quantification of microarray oligo-target hybridization. According to the model, the binding centers for adsorption of target molecules from solution are represented by oligo-probes. However, the Langmuir model does not consider the interactions between the targets adsorbed at the neighboring binding centers, which are possible due to high-density of array-bound probes. We have shown that the two-dimensional Ising model, which takes into account the nearest neighboring target molecules interactions, better describes the experimental data of oligo-target hybridization in comparison with the Langmuir model. Thus, we found an evidence for existence of positive cooperative interactions between adsorbed target molecules: so, binding of the first target molecules facilitates the binding of subsequent ones to the neighboring probes. Communicated by Ramaswamy H. Sarma.

[Oncolytic Paramyxoviruses: Mechanism of Action, Preclinical and Clinical Studies].

Preclinical studies demonstrate that a broad spectrum of human and animal malignant cells can be killed by oncolytic paramyxoviruses, which includes cells of ecto-, endo- and mesodermal origin. In clinical trials, significant reduction or even complete elimination of primary tumors and established metastases has been reported. Different routes of virus administration (intratumoral, intravenous, intradermal, intraperito-neal, or intrapleural) and single- vs. multiple-dose administration schemes have been explored. The reported side effects were grades 1 and 2, with the most common among them being mild fever. There are certain advantages in using paramyxoviruses as oncolytic agents compared to members of other virus families exist. Thanks to cytoplasmic replication, paramyxoviruses do not integrate the host genome or engage in recombination, which makes them safer and more attractive candidates for widely used therapeutic oncolysis than ret-roviruses or some DNA viruses. The list of oncolytic Paramyxoviridae members includes the attenuated measles virus, mumps virus, low pathogenic Newcastle disease, and Sendai viruses. Metastatic cancer cells frequently overexpress certain surface molecules that can serve as receptors for oncolytic paramyxoviruses. This promotes specific viral attachment to these malignant cells. Paramyxoviruses are capable of inducing efficient syncytium-mediated lysis of cancer cells and elicit strong immune stimulation, which dramatically enforces anticancer immune surveillance. In general, preclinical studies and phases I-III of clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches.

[Diagnostic errors in patients with giant-cell tumor, bone cyst and osteosarcoma].

The article contains diagnostic error analysis of 439 patients with giant-cell tumor (176), bone cyst (158) and osteosarcoma (105) aged 4-75 for theperiod of 1990-2015. Morphological investigation of surgical material taken from the pathological focus sowed that diagnostic errors in clinical and X-ray examinations comprised up to 40.6% in giant -cell cases, 37.2% in bone cyst cases and 34.2% (p<0.05) in osteosarcoma cases.

[IN VIVO EVALUATION OF POLYCAPROLACTONE-HYDROXYAPATITE SCAFFOLD BIOCOMPATIBILITY].

Biocompatibility is one of the main and very important properties for scaffolds. The aim of the present study was to investigate cells population dynamics in vivo in the process of original polycaprolactone-hydroxyapatite scaffold colonization, as well as tissue reactions to the implantation to assess the biocompatibility of the matrix. It has been found that tissue reactive changes in white rats subside completely up to the 21st day after subcutaneous polycaprolactone-hydroxyapatite scaffold implantation. Matrix was actively colonized by connective tissue cells in the period from the 7th to the 21st day of the experiment. However, intensive scaffold vascularization started from the 14th day after implantation. These findings suggest a high degree of the polycaprolactone-hydroxyapatite scaffold biocompatiblilitye.

Mechanisms of Oncolysis by Paramyxovirus Sendai.

Some viral strains of the Paramyxoviridae family may be used as anti-tumor agents. Oncolytic paramyxoviruses include attenuated strains of the measles virus, Newcastle disease virus, and Sendai virus. These viral strains, and the Sendai virus in particular, can preferentially induce the death of malignant, rather than normal, cells. The death of cancer cells results from both direct killing by the virus and through virus-induced activation of anticancer immunity. Sialic-acid-containing glycoproteins that are overexpressed in cancer cells serve as receptors for some oncolytic paramyxoviruses and ensure preferential interaction of paramyxoviruses with malignant cells. Frequent genetic defects in interferon and apoptotic response systems that are common to cancer cells ensure better susceptibility of malignant cells to viruses. The Sendai virus as a Paramyxovirus is capable of inducing the formation of syncytia, multinuclear cell structures which promote viral infection spread within a tumor without virus exposure to host neutralizing antibodies. As a result, the Sendai virus can cause mass killing of malignant cells and tumor destruction. Oncolytic paramyxoviruses can also promote the immune-mediated elimination of malignant cells. In particular, they are powerful inducers of interferon and other cytokynes promoting antitumor activity of various cell components of the immune response, such as dendritic and natural killer cells, as well as cytotoxic T lymphocytes. Taken together these mechanisms explain the impressive oncolytic activity of paramyxoviruses that hold promise as future, efficient anticancer therapeutics.

[Structural and functional characteristics of bone tissue and blood cytokines in health and disease of the joints].

Change of structural and functional state of bone in patients with primary osteoarthrosis of the hip joint compared to healthy individuals is characterized by decreased bone formation with a relative predominance of resorption. Osteopenic syndrome develops in the background of evident imbalance of a blood cytokine profile with increasing the level of proinflammatory and the variability of the level of anti-inflammatory cytokines.

[Analysis of binding of oligonucleotides on microarrays: hybridization energy isotherms].

The study reports a thermodynamic model describing microarray oligo-target hybridization. The relationship between hybridization signal intensity and Gibbs free energy change for oligo-target duplex formation was our function of interest. The behavior of this function that we called energetical hybridization isotherm in response to target concentration change was modeled considering different ratios of oligo-probes/target concentrations. The results of modeling were compared with the relevant and currently available from literature microarray adsorption experiment.

[Reparative regeneration of rat soft tissues is affected by a wound-healing composite].

We researched influence of original wound-healing composite, including chitosan and nanoparticles of copper and zinc, on specific of reparative regeneration of an experimental soft tissue full layer rat's wounds, which were conditionally aseptic and infected. The composite stimulation of reparative regeneration is related both to its antibacterial effect, and to the influence on the state of structural biopolymers of the connecting tissue.

[Analysis of DNA-ligand binding in solution and on biochips].

Ligand binding to DNA, as well as to microarrays, requires a system approach to description and analysis. This type of approach implies a fixed sequence of operations. Firstly, it is necessary to make a description of a binding scheme that realizes ligand and polymer in common spatial way. Secondly, a physical model of binding is required. Thirdly, a mathematical binding model should be constructed on the basis of the binding scheme and the physical model of binding. Every analysis of experimental data needs this preliminary work. A mathematical apparatus and classification of binding models have to follow on. Classification of different binding isotherms by different binding models is the direct problem. The inverse problem is a reconstruction of parameters of a binding model by experimental binding isotherm curves. The inverse problem can only be solved after solving the direct problem. An example of classification of binding models by oligonucleotides or proteins binding cooperativity and polymer properties like homo- or heteropolymer is presented.

[Properties of hybridization isotherms upon binding of ligands on microchips].

A simple thermodynamic model describing the microarray oligo-target hybridization has been constructed. The relationship between the hybridization signal intensity and Gibbs free energy for oligo-target duplex formation has been considered. The behavior of this function, which we called energetical hybridization isotherm, in response to target concentration change was modeled at different ratios of oligo-probes/target concentrations. The results of modeling were compared with the relevant and currently available data from microarray adsorption experiments.

[Compression neuropathy of upper limbs in miners].

The authors analyzed prevalence of individual types of upper limb compression neuropathy in miners of coal and iron-ore mines. Medical examination covered main mining occupations exposed to suchhazards as local vibration, cooling microclimate, functional overstrain. Some types of compression neuropathies appeared to depend on duration of exposure to the hazards and on the occupation hands disease stage.

[Prevalence of vertebrogenic diseases].

The authors studied prevalence of bone congenital malformations including congenital vertebral canal stenosis, of acquired vertebral canal stenosis due to intervertebral disc prolapse, yellow ligament hypertrophy, and combinations of those two in patients with occupational and general vertebral diseases.

[Some aspects of occupational spinal diseases]. / Nekotorye aspekty professional'noi vertebrogennoi patologii.

Prevalence of neurologic cervical and lumbar disorders among workers does not depend upon hardness of work conditions. First diagnosed occupational vertebral syndromes were clinically divided into reflectory and compression ones. Length of service, age and X-ray signs appeared not to differ significantly between the groups.

Thermodynamic criteria for high hit rate antisense oligonucleotide design.

Antisense oligonucleotides are used for therapeutic applications and in functional genomic studies. In practice, however, many of the oligonucleotides complementary to an mRNA have little or no antisense activity. Theoretical strategies to improve the 'hit rate' in antisense screens will reduce the cost of discovery and may lead to identification of antisense oligonucleotides with increased potency. Statistical analysis performed on data collected from more than 1000 experiments with phosphorothioate-modified oligonucleotides revealed that the oligo-probes, which form stable duplexes with RNA (DeltaG(o)37 < or = -30 kcal/mol) and have small self-interaction potential, are more frequently efficient than molecules that form less stable oligonucleotide-RNA hybrids or more stable self-structures. To achieve optimal statistical preference, the values for self-interaction should be (DeltaG(o)37) > or = -8 kcal/mol for inter-oligonucleotide pairing and (DeltaG(o)37) > or = -1.1 kcal/mol for intra-molecular pairing. Selection of oligonucleotides with these thermodynamic values in the analyzed experiments would have increased the 'hit rate' by as much as 6-fold.

Thermodynamic calculations and statistical correlations for oligo-probes design.

Optimization of probe design for array-based experiments requires improved predictability of oligonucleotide hybridization behavior. Currently, designing oligonucleotides capable of interacting efficiently and specifically with the relevant target is not a routine procedure. Multiple examples demonstrate that oligonucleotides targeting different regions of the same RNA differ in their hybridization ability. The present work shows how thermodynamic evaluations of oligo-target duplex or oligo self-structure stabilities can facilitate probe design. Statistical analysis of large sets of hybridization data reveals that thermodynamic evaluation of oligonucleotide properties can be used to avoid poor RNA binders. Thermodynamic criteria for the selection of 20 and 21mers, which, with high probability, interact efficiently and specifically with their targets, are suggested. The design of longer oligonucleotides can also be facilitated by the same calculations of DeltaG(o) (T) values for oligo-target duplex or oligo self-structure stabilities and similar selection schemes.

[Occupation-related compression neuropathies of the lower limbs]. / Professional'no obuslovlennye kompressionnye nevropatii nizhnikh konechnostei.

Occupational medical examinations and hospital studies considered prevalence and clinical features of compression neuropathies of lower limbs in workers subjected to static and dynamic overload of legs. Findings are locomotory and vascular disorders causing compression of peripheral nerves.