[Genetic factors in degenerative disc disease]. / Rol' geneticheskikh faktorov v razvitii degenerativno-distroficheskogo porazheniya mezhpozvonkovykh diskov.

OBJECTIVE: To analyze available literature data on the role of genetic factors in degenerative disc disease. METHODOLOGY: We reviewed the PubMed, MEDLINE, Cohrane Library, e-Library databases using the following keywords: degenerative spine lesions, intervertebral disc herniation, pathogenesis, genetic regulation. RESULTS: Searching depth was 2002-2022. We reviewed 84 references. Exclusion criteria: duplicate publications, reviews without detailed description of results, opinions. Finally, we included 43 the most significant studies. CONCLUSION: There are literature data on proinflammatory cytokines, growth factors and osteodestructive processes in pathogenesis of degenerative disc disease. However, there is only fragmentary information about the role of genetic regulation of these processes. Some factors, such as microRNA, TGF-b, VEGF, MMP are still poorly understood.

[Spatial Models of Piezo Proteins and Protein-Protein Interaction Networks in Trichoplax Animals (Placozoa)].

The marine free-living organism Trichoplax (phylum Placozoa) resembles a unicellular amoeba in shape and type of movement. Trichoplax diverged from the main evolutionary tree in the Neoproterozoic Era. Trichoplax provides one of the simplest models of multicellular animals and a strong example of how cells of an organism interact to form an ensemble during its development and movement. Two orthologs of the mouse Piezo1 protein (6B3R) were found in two Trichoplax haplotypes, H1 and H2, as a result of a search for similar sequences in the NCBI databases. Spatial models of the respective proteins XP_002112008.1 and RDD46920.1 were created via a structural alignment with 6KG7 (mouse Piezo2) template. Their domain structures were analyzed, and a limited graph of protein-protein interactions was constructed for the hypothetical mechanosensor XP_002112008.1. The possibility of signal transduction from the mechanoreceptor to membrane complexes, the cytoplasm, and the cell nucleus was shown. Trichoplax mechanoreceptors were assumed to play a role in perception of force stimuli from neighbor cells and the environment. Based on the results, the primitive Trichoplax organism was proposed as the simplest multicellular model of mechanical and morphogenetic movements.

[Spatial Reconstruction of TRPC Mechanoreceptors of the Ctenophore Mnemiopsis leidyi A. Agassiz, 1865].

The ctenophore Mnemiopsis leidyi A. Agassiz, 1865 responds to gentle mechanical stimulus with intense luminescence; however, the mechanism of this phenomenon is unknown. We searched for possible mechanosensitive receptors that initiate signal transduction resulting in photoprotein luminescence. The three orthologous genes of mouse (5z96) and drosophila (5vkq) TRPC-proteins, such as ML234550a-PA (860 a.a.), ML03701a-PA (828 a.a.), and ML038011a-PA (1395 a.a.), were found in the M. leidyi genome. The latter protein contains a long ankyrin helix consisting of 16 ANK domains. Study of the annotated domains and the network of interactions between the interactome proteins suggests that the ML234550a-PA and ML03701a-PA proteins carry out cytoplasmic transduction, but ML038011a-PA provides intranuclear transduction of mechanical signals. Spatial reconstruction of the studied proteins revealed differences in their structure, which may be related to various functions of these proteins in the cell. The question of which of these proteins is involved in the initiation of luminescence after mechanical stimulation is discussed.

Effect of monochromatic light on the behavior of the ctenophore Mnemiopsis leidyi (A. Agassiz, 1865).

Ctenophores are invertebrate, gelatinous predators that perform complex movements due to their numerous ciliary comb plates. We investigated the behavioral responses of the ctenophore Mnemiopsis leidyi A. Agassiz, 1865 to red, green, and blue lights of different powers and fluxes emitted by LEDs or lasers. White LEDs were used to mimic natural sunlight. When laser light was directed to the aboral organ, the animals tended to leave the illumination zone. The blue-light reaction was six times faster than the red-light reaction. The behavioral strategy of the animals changed significantly when their freedom of maneuvering was restricted. Typical locomotions were ranked according to the laser beam avoidance time from the beginning of exposure to going into darkness. The minimum reaction time was required for turning and moving the ctenophore, while moving along the laser beam and turning around required more time. Typical patterns of behavior of M. leidyi in the light flux were established using cluster analysis. Three preferential behavioral strategies were identified for avoiding laser irradiation: 1) body rotation; 2) shifting sideways; and 3) movement with deviation from the beam. The elementary ability of ctenophores to make decisions in situative conditions has been demonstrated.

[Etiopathogenetic substantiation of surgical treatment of neurogenic pain syndromes]. / Etiopatogeneticheskoe obosnovanie khirurgicheskogo lecheniya neirogennykh bolevykh sindromov.

The purpose of the study was to improve classification of neurogenic (neuropathic) pain syndromes. This will make it possible to define the indications for appropriate analgesic surgery for each type of drug-resistant neurogenic pain syndrome. Incorrect management of neurogenic pain syndromes is usually associated with underestimation of pathogenetic prerequisites for its occurrence. Differentiation of compression, deafferentation and mixed neurogenic pain syndromes makes it possible to determine appropriate surgery and avoid tactical errors. Moreover, this approach allows you to save patients from unreasonable long-standing suffering. Patients with chronic pain syndromes often become disabled, sometimes in the prime of life, and isolated from society and family. Therefore, treatment of chronic pain is currently an urgent problem.

[Mortality in acute appendicitis in Russia]. / Letal'nost' pri ostrom appenditsite v Rossii.

OBJECTIVE: To analyze the causes of mortality in patients with acute appendicitis in Russia. MATERIAL AND METHODS: We retrospectively studied mortality in patients with acute appendicitis in the Russian Federation in 2020. We surveyed the hospitals with mortality reported in the electronic database of annual reports to the chief surgeon of the Ministry of Health of the Russian Federation. RESULTS: There were 259 deaths among 150.393 patients with acute appendicitis aged ≥18 years (in-hospital mortality 0.17%). We obtained data about 95.8% (n=248) of lethal cases including 86.3% (n=214) complicated and 13.7% (n=34) uncomplicated forms of disease. Two patients died without surgery (0.8%). Among the deceased, 58.2% (n=145) were men and 41.8% (n=103) were women. Mean patient age was 66.2 years [0.95% CI 64.2-68.1]. The main cause of death in complicated appendicitis was late presentation (after 4.9 days [0.95% CI 4.3-5.4]) that resulted peritonitis and sepsis in 71.5% (n=153) of patients. Cardiovascular diseases were noted in 23.4% (n=50) of cases. A new coronavirus infection was detected in 7.0% (n=15) of patients. However, COVID-19 as a direct cause of death was recognized in 2.8% (n=6) of cases. Other reasons accounted for 2.3% (n=5). In uncomplicated appendicitis, cardiovascular diseases were the main cause of mortality (73.5%, n=25). Peritonitis and sepsis were found in 11.8% (n=4) of cases, COVID-19 - in 5.9% (n=2). Other causes accounted for 8.8% (n=3). Diagnostic, tactical, technical problems and their combination were revealed in 54.4% of lethal outcomes. CONCLUSION: Mortality from acute appendicitis in the Russian Federation is low, comparable with international data, and mainly associated with delayed treatment and complicated course of disease. However, the impact of diagnostic, tactical and technical errors on the outcome of acute appendicitis is significant.

[Surgical treatment of thoracic spine fracture in a patient with ankylosing spondylitis: case report and literature review]. / Khirurgicheskoe lechenie pereloma grudnogo otdela pozvonochnika na fone ankiloziruyushchego spondilita: klinicheskii sluchai i obzor literatury.

OBJECTIVE: To describe the features of diagnosis and surgical treatment of thoracic spine fracture in a patient with ankylosing spondylitis. MATERIAL AND METHODS: We present a patient with ankylosing spondylitis, blunt thoracic spine trauma and Th10-Th11 fracture, spinal cord compression and contusion and moderate lower extremity paresis. Preoperative and postoperative CT and MRI (after 8 months) were performed for control of decompression. RESULTS: The authors identified the main factors affecting the quality of life of patients with spine fractures following ankylosing spondylitis and formulated treatment algorithm. CONCLUSION: Active strategy is advisable for spine fractures following ankylosing spondylitis: spinal cord decompression, creation of anatomical compliance in the damaged vertebral segment and its fixation by transpedicular system. A similar surgical treatment of spine fractures following ankylosing spondylitis makes it possible to achieve early activation of patients and reduce rehabilitation period.

Postpartum Involution of Mouse Myometrium in Acute CCl4-Induced Hepatosis and Its Correction with Immobilized Hyaluronidase.

We studied structural rearrangement of the myometrium of C57BL/6 mice during the postpartum period under conditions of acute toxic hepatosis induced by CCl4 injection and its correction with immobilized hyaluronidase. In contrast to physiological pregnancy, involution of the myometrium in mice under conditions of acute toxic hepatosis were not completed by the 10th day of the postpartum period. When toxic hepatosis was corrected with immobilized hyaluronidase, the main mechanism of postpartum involution of the mouse myometrium was clasmacytosis, the process of postpartum involution was significantly accelerated, but not completed by the 10th day, probably due to reduced vascularization of the myometrium.

Broad temperature range ferrielectric liquid crystal as a highly sensitive quadratic electro-optical material.

A chiral smectic liquid crystal in which a ferrielectric phase with a helix pitch p0 less than 125 nm exists over a temperature range of at least from -3°C to +36°C has been developed. Such a wide temperature range (including room temperatures) of the ferrielectric phase with a subwavelength helix pitch has been achieved for the first time, to the best of our knowledge, which creates opportunities for the practical use of ferrielectric liquid crystals. A quadratic electro-optical effect caused by deformations of the helix in an electric field is observed in the ferrielectric phase, and the Kerr coefficient, which reaches almost 200 nm/V2, is significantly higher than the same coefficient for the blue phase and for the smectic C* phase, which means a higher sensitivity of the developed ferrielectric liquid crystal to the electric field. The electro-optical response time does not exceed 300 µs at room temperatures for this ferrielectric liquid crystal.

Motility disorders and disintegration into separate cells of Trichoplax sp. H2 in the presence of Zn2+ ions and L-cysteine molecules: A systems approach.

Placozoa remain an ancient multicellular system with a dynamic body structure where calcium ions carry out a primary role in maintaining the integrity of the entire animal. Zinc ions can compete with calcium ions adsorption. We studied the effect of zinc ions and l-cysteine molecules on the interaction of Trichoplax sp. H2 cells. The regularity of formless motion was diminished in the presence of 20-25 µM of Zn2+ ions leading to the formation of branching animal forms. Locomotor ciliated cells moved chaotically and independently of each other leaving the Trichoplax body and opening a network of fiber cells. Application of 100 µM cysteine resulted in dissociation of the plate into separate cells. The combined chemical treatment shifted the effect in a random sample of animals toward disintegration, i.e. initially leading to disorder of collective cell movement and then to total body fragmentation. Two dissociation patterns of Trichoplax plate as "expanding ring" and "bicycle wheel" were revealed. Analysis of the interaction of Ca2+ and Zn2+ ions with cadherin showed that more than half (54%) of the amino acid residues with which Ca2+ and Zn2+ ions bind are common. The contact interaction of cells covered by the cadherin molecules is important for the coordinated movements of Trichoplax organism, while zinc ions are capable to break junctions between the cells. The involvement of other players, for example, l-cysteine in the regulation of Ca2+-dependent adhesion may be critical leading to the typical dissociation of Trichoplax body like in a calcium-free environment. A hypothesis about the essential role of calcium ions in the emergence of Metazoa ancestor is proposed.

United Kingdom Anti-crisis Alternative.

The article deals with the factors that ensure the sustainability of the reproduction of the British socio-economic model in the long term. Some features of the conceptual role of the UK in the formation of the global world order were studied. The impact of the COVID-19 on the economy of the United Kingdom was shown and the reasons for the deepest decline in production in the history of the country were summarized. The factors of chronic decline in productivity on the British labor market and strategic approaches to solving this problem were presented. Some provisions of the Trade and Cooperation Agreement between the UK and the European Union are discussed. The concept of sovereign money is analyzed as a possible response of British economic experts to the challenges of modern crises.

Direct Investment from Russia Abroad: Changes since 2018.

The article considers the specifics of Russian foreign direct investment outflows in 2018-the first half of 2020. Three main reasons for the new stagnation of Russian foreign investment expansion are identified: 1) the strengthening of "sanctions war" with the West after the election of Vladimir Putin for the 4th presidential term; 2) the slowdown in the global economy in 2018-2019 against the background of relatively low prices for hydrocarbons and other raw materials exported from Russia; and 3) the crisis caused by the coronavirus pandemic in 2020. These factors resulted in a reduction of both outward foreign direct investment stocks by Russian MNEs (partially due to revaluation of their assets after the collapse of the ruble rate), and a decrease in investments of wealthy Russians in foreign real estate as well as pseudo-foreign investment because of the regular attempts to conduct de-offshorization. Based on a study conducted at INION within the framework of the international program for studying MNEs from emerging markets, a list of leading Russian non-financial MNEs by the end of 2019 is presented. Further prospects of Russian direct investment are shown at the end of the article.

Modelling transport and mean age of dense core vesicles in large axonal arbours.

A model simulating the transport of dense core vesicles (DCVs) in type II axonal terminals of Drosophila motoneurons has been developed. The morphology of type II terminals is characterized by the large number of en passant boutons. The lack of both scaled-up DCV transport and scaled-down DCV capture in boutons results in a less efficient supply of DCVs to distal boutons. Furthermore, the large number of boutons that DCVs pass as they move anterogradely until they reach the most distal bouton may lead to the capture of a majority of DCVs before they turn around in the most distal bouton to move in the retrograde direction. This may lead to a reduced retrograde flux of DCVs and a lack of DCV circulation in type II terminals. The developed model simulates DCV concentrations in boutons, DCV fluxes between the boutons, age density distributions of DCVs and the mean age of DCVs in various boutons. Unlike published experimental observations, our model predicts DCV circulation in type II terminals after these terminals are filled to saturation. This disagreement is likely because experimentally observed terminals were not at steady state, but rather were accumulating DCVs for later release. Our estimates show that the number of DCVs in the transiting state is much smaller than that in the resident state. DCVs travelling in the axon, rather than DCVs transiting in the terminal, may provide a reserve of DCVs for replenishing boutons after a release. The techniques for modelling transport of DCVs developed in our paper can be used to model the transport of other organelles in axons.

A Numerical Study of Sensitivity Coefficients for a Model of Amyloid Precursor Protein and Tubulin-Associated Unit Protein Transport and Agglomeration in Neurons at the Onset of Alzheimer's Disease.

Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters, we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the influence of model parameters on the total concentrations of amyloid precursor protein (APP) and tubulin-associated unit (tau) protein in the axon is reciprocal to the influence of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-ß and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early damage in AD may be reversible.

How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study.

We develop a mathematical model that enables us to investigate possible mechanisms by which two primary markers of Alzheimer's disease (AD), extracellular amyloid plaques and intracellular tangles, may be related. Our model investigates the possibility that the decay of anterograde axonal transport of amyloid precursor protein (APP), caused by toxic tau aggregates, leads to decreased APP transport towards the synapse and APP accumulation in the soma. The developed model thus couples three processes: (i) slow axonal transport of tau, (ii) tau misfolding and agglomeration, which we simulated by using the Finke-Watzky model and (iii) fast axonal transport of APP. Because the timescale for tau agglomeration is much larger than that for tau transport, we suggest using the quasi-steady-state approximation for formulating and solving the governing equations for these three processes. Our results suggest that misfolded tau most likely accumulates in the beginning of the axon. The analysis of APP transport suggests that APP will also likely accumulate in the beginning of the axon, causing an increased APP concentration in this region, which could be interpreted as a 'traffic jam'. The APP flux towards the synapse is significantly reduced by tau misfolding, but not due to the APP traffic jam, which can be viewed as a symptom, but rather due to the reduced affinity of kinesin-1 motors to APP-transporting vesicles.

Simulating the effect of formation of amyloid plaques on aggregation of tau protein.

In this paper, we develop a mathematical model that enables the investigation of the production and intracellular transport of amyloid precursor protein (APP) and tau protein in a neuron. We also investigate the aggregation of APP fragments into amyloid-ß (Aß) as well as tau aggregation into tau oligomers and neurofibrillary tangles. Using the developed model, we investigate how Aß aggregation can influence tau transport and aggregation in both the soma and the axon. We couple the Aß and tau agglomeration processes by assuming that the value of the kinetic constant that describes the autocatalytic growth (self-replication) reaction step of tau aggregation is proportional to the Aß concentration. The model predicts that APP and tau are distributed differently in the axon. While APP has a uniform distribution along the axon, tau's concentration first decreases and then increases towards the synapse. Aß is uniformly produced along the axon while misfolded tau protein is mostly produced in the proximal axon. The number of Aß and tau polymers originating from the axon is much smaller than the number of Aß and tau polymers originating from the soma. The rate of production of misfolded tau polymers depends on how strongly their production is facilitated by Aß.

Simulating Reversibility of Dense Core Vesicles Capture in En Passant Boutons: Using Mathematical Modeling to Understand the Fate of Dense Core Vesicles in En Passant Boutons.

The goal of this paper is to use mathematical modeling to investigate the fate of dense core vesicles (DCVs) captured in en passant boutons located in nerve terminals. One possibility is that all DCVs captured in boutons are destroyed, another possibility is that captured DCVs can escape and reenter the pool of transiting DCVs that move through the boutons, and a third possibility is that some DCVs are destroyed in boutons, while some reenter the transiting pool. We developed a model by applying the conservation of DCVs in various compartments composing the terminal, to predict different scenarios that emerge from the above assumptions about the fate of DCVs captured in boutons. We simulated DCV transport in type Ib and type III terminals. The simulations demonstrate that, if no DCV destruction in boutons is assumed and all captured DCVs reenter the transiting pool, the DCV fluxes evolve to a uniform circulation in a type Ib terminal at steady-state and the DCV flux remains constant from bouton to bouton. Because at steady-state the amount of captured DCVs is equal to the amount of DCVs that reenter the transiting pool, no decay of DCV fluxes occurs. In a type III terminal at steady-state, the anterograde DCV fluxes decay from bouton to bouton, while retrograde fluxes increase. This is explained by a larger capture efficiency of anterogradely moving DCVs than of retrogradely moving DCVs in type III boutons, while the captured DCVs that reenter the transiting pool are assumed to be equally split between anterogradely and retrogradely moving components. At steady-state, the physiologically reasonable assumption of no DCV destruction in boutons results in the same number of DCVs entering and leaving a nerve terminal. Because published experimental results indicate no DCV circulation in type III terminals, modeling results suggest that DCV transport in these type III terminals may not be at steady-state. To better understand the kinetics of DCV capture and release, future experiments in type III terminals at different times after DCV release (molting) may be proposed.

Simulating tubulin-associated unit transport in an axon: using bootstrapping for estimating confidence intervals of best-fit parameter values obtained from indirect experimental data.

In this paper, we first develop a model of axonal transport of tubulin-associated unit (tau) protein. We determine the minimum number of parameters necessary to reproduce published experimental results, reducing the number of parameters from 18 in the full model to eight in the simplified model. We then address the following questions: Is it possible to estimate parameter values for this model using the very limited amount of published experimental data? Furthermore, is it possible to estimate confidence intervals for the determined parameters? The idea that is explored in this paper is based on using bootstrapping. Model parameters were estimated by minimizing the objective function that simulates the discrepancy between the model predictions and experimental data. Residuals were then identified by calculating the differences between the experimental data and model predictions. New, surrogate 'experimental' data were generated by randomly resampling residuals. By finding sets of best-fit parameters for a large number of surrogate data the histograms for the model parameters were produced. These histograms were then used to estimate confidence intervals for the model parameters, by using the percentile bootstrap. Once the model was calibrated, we applied it to analysing some features of tau transport that are not accessible to current experimental techniques.

Utilization of the bootstrap method for determining confidence intervals of parameters for a model of MAP1B protein transport in axons.

This paper develops a model of axonal transport of MAP1B protein. The problem of determining parameter values for the proposed model utilizing limited available experimental data is addressed. We used a global minimum search algorithm to find parameter values that minimize the discrepancy between model predictions and published experimental results. By analyzing the best fit parameter values it was established that some processes can be dropped from the model without losing accuracy, thus a simplified version of the model was formulated. In particular, our analysis suggests that reversals in MAP1B transport are infrequent and can be neglected. The detachment of anterogradely-biased MAP1B from microtubules (MTs) and the attachment of retrogradely-biased MAP1B to MTs can also be neglected. An analytical solution for the simplified model was obtained. Confidence intervals for the determined parameters were found by bootstrapping model residuals. The resultant analysis heavily constrained the values of some parameters while showing that some could vary without significantly impacting model error. For example, our analysis suggests that, above a certain threshold value, the kinetic constant determining the rate of MAP1B transition from the retrograde pausing state to the off-track state has little impact on model error. On the contrary, the kinetic constant describing MAP1B transition from a pausing to a running state has great impact on model error.

What mechanisms of tau protein transport could be responsible for the inverted tau concentration gradient in degenerating axons?

In tauopathies, such as Alzheimer's disease (AD), microtubule (MT)-associated protein tau detaches from MTs and aggregates, eventually forming insoluble neurofibrillary tangles. In a healthy axon, the tau concentration increases toward the axon terminal, but in a degenerating axon, the tau concentration gradient is inverted and the highest tau concentration is in the soma. In this article, we developed a mathematical model of tau transport in axons. We calibrated and tested the model by using published distributions of tau concentration and tau average velocity in a healthy axon. According to published research, the inverted tau concentration gradient may be one of the reasons leading to AD. We therefore used the model to investigate what modifications in tau transport can lead to the inverted tau concentration gradient. We investigated whether tau detachment from MTs due to tau hyperphosphorylation can cause the inverted tau concentration gradient. We found that the assumption that most tau molecules are detached from MTs does not consistently predict the inverted tau concentration gradient; the predicted tau distribution becomes more uniform if the axon length is increased. We then hypothesized that in degenerating axons some tau remains bound to MTs and participates in the component 'a' of slow axonal transport but that the rate of tau reversals from anterograde to retrograde motion increases. We demonstrated that this hypothesis results in a tau distribution where the tau concentration has its maximum value at the axon hillock and its minimum value at the axon terminal, in agreement with what is observed in AD. Our results thus suggest that defects in active transport of tau may be a contributing factor to the onset of neural degeneration.