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Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI 50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus , Escherichia coli , and Pseudomonas aeruginosa . We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

One of the most probable causes of effective therapy for post-comatose disorders of consciousness is the lack of individualization of drug prescriptions. In this observational study, we analyzed 48 courses of neuromodulatory therapy in 28 patients with prolonged and chronic disorders of consciousness following severe traumatic brain injury. Comparison of 24 effective and 24 ineffective courses demonstrated higher effectiveness of pharmacotherapy through its individualization, i.e. the choice of a drug whose neuromodulatory spectrum would correspond to neurological syndromes of neurotransmitter dysfunction. In this approach, 74% of therapy courses were effective while opposite management resulted only 34% of effective courses.

The transcription factor Oct4 can rightfully be considered a pivotal element in maintaining pluripotency. In addition, its ability to function as a pioneer factor enables the reprogramming of somatic cells back into a pluripotent state. To better understand the regulation of the Oct4-encoding gene ( Pou5f1 ), the main genetic elements that regulate its expression in different states of pluripotency ought to be identified. While some elements have been well characterized for their ability to drive Pou5f1 expression, others have yet to be determined. In this work, we show that translocation of the Pou5f1 gene fragment purported to span all essential cis -elements, including the well-known distal and proximal enhancers (DE and PE), into the Rosa26 locus impairs the self-renewal of mouse embryonic stem cells (ESCs) in the naïve pluripotency state, as well as their further advancement through the formative and primed pluripotency states, inducing overall differentiation failure. These results suggest that regulatory elements located outside the previously determined Pou5f1 boundaries are critical for the proper spatiotemporal regulation of this gene during development, indicating the need for their better characterization.

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor. Synthetic derivatives of apidaecin have been developed, but structure-guided modifications have yet to be considered. In this work, we have focused on modifying key residues in the Api sequence that are responsible for the interactions that stabilize the quaternary complex. We present one of the first examples of a highly modified Api peptide that maintains its antimicrobial activity and interaction with the translation complex. These findings establish a starting point for further structure-guided optimization of Api peptides.

The β-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired β-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles. The reaction can start with 3-nitrovinylindoles themselves under two sets of conditions. The first one involves microwave irradiation of butanolic solutions of 3-nitrovinylindoles, whereas the second one consists of prior Boc protection of indolic nitrogen, where the protecting group cleanly comes off during the course of the reaction. Alternatively, the reaction can start with 3-nitrovinylindoles prepared in situ using various processes. Finally, the reaction may utilize indoles with β-nitrostyrenes, likely involving the intermediacy of spirocyclic oxazolines, which rearrange to similar heterotrienic systems undergoing cyclization to β-carbolines. As part of this study, several natural products, namely, alkaloids norharmane, harmane, and eudistomin N, were synthesized.

The Friedel-Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

During protein synthesis, the growing polypeptide threads through the ribosomal exit tunnel and modulates ribosomal activity by itself or by sensing various small molecules, such as metabolites or antibiotics, appearing in the tunnel. While arrested ribosome-nascent chain complexes (RNCCs) have been extensively studied structurally, the lack of a simple procedure for the large-scale preparation of peptidyl-tRNAs, intermediates in polypeptide synthesis that carry the growing chain, means that little attention has been given to RNCCs representing functionally active states of the ribosome. Here we report the facile synthesis of stably linked peptidyl-tRNAs through a chemoenzymatic approach based on native chemical ligation and use them to determine several structures of RNCCs in the functional pre-attack state of the peptidyl transferase centre. These structures reveal that C-terminal parts of the growing peptides adopt the same uniform β-strand conformation stabilized by an intricate network of hydrogen bonds with the universally conserved 23S rRNA nucleotides, and explain how the ribosome synthesizes growing peptides containing various sequences with comparable efficiencies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to β-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.

Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown. Here, we present a set of high-resolution X-ray crystal structures that explain why CHL is unable to inhibit peptide bond formation between the incoming glycyl-tRNA and a nascent peptide that otherwise is conducive to the drug action. Our structures reveal that fully accommodated glycine residue can co-exist in the A site with the ribosome-bound CHL. Moreover, binding of CHL to a ribosome complex carrying glycyl-tRNA does not affect the positions of the reacting substrates, leaving the peptide bond formation reaction unperturbed. These data exemplify how small-molecule inhibitors can reshape the A-site amino acid binding pocket rendering it permissive only for specific amino acid residues and rejective for the other substrates extending our detailed understanding of the modes of action of ribosomal antibiotics., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Base-assisted transformations of 2-(3-oxoindolin-2-yl)acetonitriles were investigated. Unexpectedly, attempted reactions of substrates possessing nonprotected nitrogen atoms were accompanied by unusual extrusions of 2-arylacetonitriles, followed by a 1,2-aryl shift to afford 3-hydroxyindolin-2-ones. On the other hand, the reactions for N -alkyl derivatives of oxoindolines took the expected route by only providing 1,2,3,3a,4,8b-hexahydropyrrolo[3,2- b ]indoles.

The alkyltriphenylphosphonium (TPP) group is the most widely used vector targeted to mitochondria. Previously, the length of the alkyl linker was varied as well as structural modifications in the TPP phenyl rings to obtain the optimal therapeutic effect of a pharmacophore conjugated with a lipophilic cation. In the present work, we synthesized butyltriphenylphosphonium cations halogenated and methylated in phenyl rings (C 4 TPP-X) and measured electrical current through a planar lipid bilayer in the presence of C 4 TPP-X. The permeability of C 4 TPP-X varied in the range of 6 orders of magnitude and correlates well with the previously measured translocation rate constant for dodecyltriphenylphosphonium analogues. The partition coefficient of the butyltriphenylphosphonium analogues obtained by calculating the difference in the free energy of cation solvation in water and octane using quantum chemical methods correlates well with the permeability values. Using an ion-selective electrode, a lower degree of accumulation of analogues with halogenated phenyl groups was found on isolated mitochondria of rat liver, which is in agreement with their permeability decrease. Our results indicate the translocation of the butyltriphenylphosphonium cations across the hydrophobic membrane core as rate-limiting stage in the permeability process rather than their binding/release to/from the membrane.

The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1 H -indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1 H -indole byproducts. Herein, we offer a workaround this problem that allows for effective transformation of the unwanted byproducts into acetonitrile target molecules.

Class I release factors (RFs) recognize stop codons in the sequences of mRNAs and are required for the hydrolysis of peptidyl-tRNA in the ribosomal P site during the final step of protein synthesis in bacteria, resulting in the release of a complete polypeptide chain from the ribosome. A key role in this process belongs to the highly conserved GGQ motif in RFs. Mutations in this motif can reduce the hydrolysis rate or even completely inhibit the reaction. Previously, it was hypothesized that the amino acid residues of GGQ (especially glutamine) are essential for the proper coordination of the water molecule for subsequent hydrolysis of the ester bond. However, available structures of the 70S ribosome termination complex do not allow unambiguous identification of the exact orientation of the carbonyl group in peptidyl-tRNA relative to the GGQ, as well as of the position of the catalytic water molecule in the peptidyl transferase center (PTC). This mini-review summarizes key facts and hypotheses on the role of GGQ in the catalysis of peptide release, as well as suggests and discusses future experiments aimed to produce high-quality structural data for deciphering the precise mechanism of RF-mediated catalysis.

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4 Å resolution, together with the structures of unmethylated 70S ribosome functional complexes alone or in combination with macrolides. Altogether, our structural data do not support previous models and, instead, suggest a principally new explanation of how A2058 dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4' H -spiro[indole-3,5'-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4'-alkylsubstituted derivatives hardly available by other means., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Traumatic brain injury (TBI) affects about 50 million people in the world every year. Posttraumatic epilepsy (PTE) is a significant complication of TBI of any severity. PTE occurs in 20% of patients with TBI. Treatment of patients with PTE is particularly difficult due to obvious tendency towards drug resistance. Currently, there are no validated predictive biomarkers for PTE. Development of a system of validated predictive markers would improve PTE prediction quality and therapeutic approach for these patients. This review is devoted to the current data on the most perspective predictive biomarkers of PTE for clinical practice.

To clarify the contribution of charge delocalization in a lipophilic ion to the efficacy of its permeation through a lipid membrane, we compared the behavior of alkyl derivatives of triphenylphosphonium, tricyclohexylphosphonium and trihexylphosphonium both in natural and artificial membranes. Exploring accumulation of the lipophilic cations in response to inside-negative membrane potential generation in mitochondria by using an ion-selective electrode revealed similar mitochondrial uptake of butyltricyclohexylphosphonium (C 4 TCHP) and butyltriphenylphosphonium (C 4 TPP). Fluorescence correlation spectroscopy also demonstrated similar membrane potential-dependent accumulation of fluorescein derivatives of tricyclohexyldecylphosphonium and decyltriphenylphosphonium in mitochondria. The rate constant of lipophilic cation translocation across the bilayer lipid membrane (BLM), measured by the current relaxation method, moderately increased in the following sequence: trihexyltetradecylphosphonium ([P 6,6,6,14 ]) < triphenyltetradecylphosphonium (C 14 TPP) < tricyclohexyldodecylphosphonium (C 12 TCHP). In line with these results, measurements of the BLM stationary conductance indicated that membrane permeability for C 4 TCHP is 2.5 times higher than that for C 4 TPP. Values of the difference in the free energy of ion solvation in water and octane calculated using the density functional theory and the polarizable continuum solvent model were similar for methyltriphenylphosphonium, tricyclohexylmethylphosphonium and trihexylmethylphosphonium. Our results prove that both cyclic and aromatic moieties are not necessary for lipophilic ions to effectively permeate through lipid membranes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: This research is aimed to study the clinical and MRI predictors of coma duration, the intensity of critical care, and outcome of traumatic brain injury (TBI)., Material and Methods: The data from 309 patients with TBI of varying severity were included in the analysis, of whom 257 (86.7%) were treated in the intensive care unit (ICU), including 196 (63.4%) patients admitted in a comatose state lasting longer than 1 day. All patients underwent brain MRI within 21 days after the injury. MRI findings were classified according to MRI grading scale of brain damage level and localization proposed previously., Results: The proposed MRI grading significantly correlated with the Glasgow coma (GCS, r=-0.67; p<0.0001) and Glasgow outcome (0.69; p<0.001) scores in the entire group. In a subgroup of comatose patients (GCS<9) it correlated with coma duration (r=0.52; p<0.0001). Spearman correlation analysis showed a significant relationship between the MRI classification and a number of parameters: ICU length of stay (r=0.62; p<0.0001), the duration of artificial ventilation (r=0.47; p<0.0001), the rate of artificial ventilation, sedatives, analgesics, mannitol, hypertonic saline and vasopressors usage (p<0.01). These data confirm the relationship between higher grades of MRI classification (deep brain damage) and the need for the escalation of intensive care main components., Conclusion: Our results support the hypothesis that the levels and localization of brain damage, estimated by the proposed MRI grading scale, might be predictors of coma duration, intensity and duration of intensive care, and TBI outcomes. A prognosis based on clinical and neuroimaging data comparison can be valuable for planning and efficient use of the hospital beds and ICU resources, for optimizing the patient flow and timing of patient transfer to neurorehabilitation facilities.

Recently discovered reactivity of nitrostyrenes in phosphorous acid to facilitate the diastereoselective [4 + 1]-cycloaddition of indoles in combination with unusual oxazoline ring cleavage and subsequent 1,2-alkyl shift afforded stereochemically defined 2-(3-oxoindolin-2-yl)-2-arylacetonitriles as sole products.

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4' H-spiro[indole-3,5'-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Diffuse axonal injury (DAI) is one of the most severe traumatic brain injuries. The availability of neuroimaging biomarkers for monitoring expansion of traumatic brain injury in vivo is a topical issue., Purpose: To evaluate novel neuroimaging biomarkers for monitoring brain injury using diffusion kurtosis imaging (DKI) in patients with severe diffuse axonal injury., Material and Methods: DKI data of 12 patients with severe DAI (11 patients with a Glasgow Coma Scale (GCS) score of ≤ 8 and 1 patient with a GCS score of 9) and 8 healthy volunteers (control group) were compared. MRI examination was performed 5 to 19 days after injury; 7 of the 12 patients underwent repeated MRI examinations. We assessed the following parameters: mean, axial, and radial kurtosis (MK, AK, RK, respectively) and kurtosis anisotropy (KA) of the white and gray matter; fractional anisotropy (FA), axonal water fraction (AWF), axial and radial extra-axonal diffusion (AxEAD and RadEAD, respectively), and tortuosity (TORT) of the extra-axonal space) of the white matter. Regions of interest (ROIs) were set bilaterally in the centrum semiovale, genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, putamen, thalamus, midbrain, and pons., Results: A significant reduction in KA (p<0.05) in most of ROIs set on the white matter was revealed. AK was increased (p<0.05) not only in the white matter but also in the putamen and thalamus. A significant reduction in MK with time was observed when the first and second DKI data were compared. AWF was reduced in the centrum semiovale and peduncles. The TORT parameter was decreased (p<0.05) in the majority of ROIs in the white matter, with the most pronounced changes occurring in the genu and splenium of the corpus callosum., Conclusion: DKI provides novel data about microstructural injury in DAI and improves our knowledge of brain trauma pathophysiology. DKI parameters should be considered as potential biomarkers of brain injury and potential predictors of the outcome.

Rehabilitation of patients with severe traumatic brain injury (sTBI) is a topical medical and social issue because this pathology is one of the main causes of mortality and disability in the young working age population [1]. The most common sTBI consequences include motor and cognitive impairment as well as depression of consciousness [2, 3]. Despite significant progress in treatment of the consequences of severe traumatic brain injury, there are no treatment and rehabilitation standards for these patients, and the used rehabilitation measures are not always effective. These circumstances substantiate the need for the development of additional methods of neurotherapy. Over the past decade, transcranial electrical and magnetic stimulation (TMS) has been increasingly used as neuromodulatory treatment in clinical practice [4-12]. The accumulated experience has shown that transcranial neurostimulation methods require a more individualized approach in terms of both careful selection of patients and choice of exposure parameters. This review is based on an analysis of the most significant publications and recommendations recognized in the scientific community, as well as on reports of domestic and foreign authors presented at dedicated congresses in comparison with experience of our own research on transcranial stimulation. The paper discusses the main problems of using this method in medical practice of sTMI and their possible solutions.

The development of post-traumatic hydrocephalus (PTH) after severe traumatic brain injury can cause, in some cases, severe impairment of consciousness and prevent rehabilitation of patients. The influence of cerebrospinal fluid (CSF) circulation disorders on processes of consciousness recovery is a fundamental problem that requires in-depth research. The issues of differential diagnosis, results of surgical treatment of PTH, and its complications in patients in the vegetative status (VS) and minimally conscious state (MCS) remain poorly covered., Material and Methods: We performed a retrospective analysis of the long-term outcomes of surgical treatment in 82 PTH patients in the VS (38 cases) and MCS (44 cases)., Results: A significant clinical improvement occurred in 60.6% of VS patients and in 65.9% of MCS patients. The rate of shunt infection was high and amounted to 21.05% in the group of VS patients and 20.4% in the group of MCS patients. The rate of shunt system dysfunction was 26.05% in the first group and 20.4% in the second group. Postoperative mortality (associated directly with treatment complications) was 3.6%. Total mortality was 10.9%., Discussion: The positive effect of shunting surgery in patients with gross impairment of consciousness was associated with transition to higher levels of consciousness. The high rate of complications, especially infections, was due to a serious condition of patients and comorbidities, in particular chronic infection foci. Shunt system dysfunction was not a factor of the adverse outcome of surgical treatment because rarely led to irreversible consequences, but required repeated surgery. Mortality after shunting surgery was significantly higher in patients with gross impairment of consciousness than in other groups of patients. We found a correlation between deaths in VS patients and shunt infection in the postoperative period., Conclusion: CSF shunting surgery is an important step in surgical rehabilitation of PTH patients. To assess the contribution of various risk factors to the development of shunt infection and to develop measures reducing its rate, further prospective studies are needed.

The study purpose was to develop a technique for intravital visualization of the brainstem reticular formation fibers in healthy volunteers using magnetic resonance imaging (MRI)., Material and Methods: The study included 21 subjects (13 males and 8 females) aged 21 to 62 years. The study was performed on a magnetic resonance imaging scanner with a magnetic field strength of 3 T in T1, T2, T2-FLAIR, DWI, and SWI modes. A CSD-HARDI algorithm was used to identify thin intersecting fibers of the reticular formatio., Results: We developed a technique for reconstructing the reticular formation pathways, tested it in healthy volunteers, and obtained standard quantitative indicators (fractional anisotropy (FA), apparent diffusion coefficient (ACD), fiber length and density, and axial and radial diffusion). We performed a comparative analysis of these indicators in males and females. There was no difference between these groups and between indicators for the right and left brainstem. Our findings will enable comparative analysis of examination results in patients with brain pathology accompanied by brainstem injury, which may help predict the outcome. This work was supported by a grant of the Russian Foundation for Basic Research (#16-04-01472).

Autoregulation of cerebral blood flow (ACBF) is a system of mechanisms for maintaining stable adequate perfusion of the brain despite changes in systemic arterial pressure. In recent years, new data on the numerous metabolic and systemic mechanisms of cerebral blood flow regulation have been obtained, but the role of neurogenic regulation has not yet been fully understood and, therefore, not considered in clinical practice., Aim: The study aim was to assess the effect of anatomical injuries to deep brain structures on the extent and duration of ACBF abnormalities in a model of severe diffuse axonal injury (DAI)., Results: The study demonstrated that brain injury in the projection of a dopaminergic structure (substantia nigra) and a cholinergic structure (nucleus basalis of Meynert region) was more common in patients with impaired ACBF and was associated with a longer duration of the impairment., Conclusion: The obtained data may indicate the presence of central (neurogenic) pathways of cerebral vessel tone regulation; traumatic injury of the pathways leads to a more severe and prolonged period of impaired ACBF. Probably, injury to these regulatory structures in some patients has an indirect effect on the course of intracranial hypertension. Further experimental and clinical studies in this direction are needed to elucidate all elements of neurogenic regulation of cerebral vessel tone and ACBF mechanisms.

Aim: To determine indicators of homeostasis, inflammation and homocysteine in the young-aged patients with ischemic stroke (IS) of different genesis in the subacute and chronic stages., Material and Methods: Out of 218 patients with IS (mean age 34.7±8.7 years), 55 had stroke due to dissection of the inner carotid or the spinal artery, 28 due to cardioembolia, 38 due to antiphospholipid syndrome (APS), 16 due to cerebral arteritis; 85 patients were classified as having cryptogenic stroke, including 23 with noncerebral thrombosis (coagulopathy of unknown etiology) and 62 with no thrombosis. The control group included 28 healthy people matched for age and sex., Results: There were 1) an increase in von Willebrand factor and coagulation factor VIII as well as a decrease in plasminogen and an increase in plasmin-inhibitor in IS caused by thrombosis (APS, cardioembolia, coagulopathy of unknown etiology); 2) alterations in erythrocyte aggregation and deformity in cryptogenic stroke; 3) mild or moderate hyperhomocysteinemia, with the exception of patients with APS and arteritis. Linear regression analysis confirmed these relationships. Discriminant analysis identified the clusters of parameters characteristic of APS (an increase in (aPTT), plasminogen, blood sedimentation rate, C-reactive protein) and cardioembolia (decreased protein C and increased hematocrit)., Conclusion: The laboratory markers associated with cerebral thrombosis can be used for identification of a prothrombotic state as a cause of IS in the young age. Moderate hyperhomocysteinemia is a risk factor but not a cause of IS. The increase of inflammatory markers in APS suggests a role of infection in its development.

When preparing the review, we analyzed publications available at the Medline database; a total of 1,083 publications related to the review's subject were analyzed. After more careful analysis, we selected 117 publications devoted to the development of neuronavigation in craniocerebral surgery, historical prerequisites of neuronavigation emergence, current trends, and future perspectives of the technique.

Aim: To explore neurotransmitter system dysfunctions involved in maintaining of consciousness and motor functions in patients with severe traumatic brain injury (TBI) and to assess their severity and predictive value., Material and Methods: Authors examined 100 patients (34 women and 66 men), aged 32.0 ± 13.0 years, with severe TBI. Eighty-eight patients (31 women and 57 men) were studied in the acute stage (1-15 days, mean 5.8 ± 3.7 days) and 70 patients (24 women and 46 men) in the subacute stage (18-70 days, mean 30.4 ± 12.7 days). Inclusion criteria were: severe TBI with depression of consciousness (≤ 7 scores on the Glasgow Coma Scale), admission to the hospital in acute and subacute stages. Outcome of TBI was evaluated using the Glasgow Outcome Scale., Results and Conclusion: The following clinical syndromes of neurotransmitter system dysfunction were singled out: excess or insufficiency of glutamate, cholinergic deficit, excess or insufficiency of dopamine. Their transformation during disease was identified. Predictive value of neurotransmitter dysfunctions for TBI is emphasized.

It was only 40 years ago that the first PC appeared. Over this period, rather short in historical terms, we have witnessed the revolutionary changes in lives of individuals and the entire society. Computer technologies are tightly connected with any field, either directly or indirectly. We can currently claim that computers are manifold superior to a human mind in terms of a number of parameters; however, machines lack the key feature: they are incapable of independent thinking (like a human). However, the key to successful development of humankind is collaboration between the brain and the computer rather than competition. Such collaboration when a computer broadens, supplements, or replaces some brain functions is known as the brain-computer interface. Our review focuses on real-life implementation of this collaboration.

Fluorescent diagnosis was first proposed in the early XX century and has been used in neurosurgery for about 15 years. The method relies on selective accumulation of strongly fluorescent protoporphyrin IX in tumor cells. Over the past years, the method of intraoperative fluorescence diagnosis has occupied its niche in many neurosurgical clinics around the world and is now used for fast intraoperative diagnosis in brain tumor surgery. However, the efficiency of fluorescent intraoperative diagnosis using 5-aminolevulinic acid is 80-90% and 58.8% for surgery of Grade III-IV and I-II gliomas, respectively. One of the methods to improve the efficiency of fluorescent diagnosis is to use vector systems for delivering fluorescent drugs into the tumor. This paper reports the results of an experimental study of systems for delivering fluorescent agents (protoporphyrin IX, Alexa 488, Alexa 660) using connexin-43 antibodies in rats with transplanted C6 glioma.

It is now becoming increasingly clear that the course and outcome of craniocerebral injury (CCI) are determined not only by its biomechanism, severity, patient's age, presence of premorbid factors, etc., but also by individual features of the genome of each patient, which puts traumatic brain injury among multifactorial diseases. The genome determines the presence or absence of«genetic predilection to the development of various complications and sequelae of CCI, which generally determines the progression of traumatic brain injury disease. The first part of the review by Potapov et al. (201 0) [2] was devoted to the role of apolipoprotein E (apoE) gene polymorphism in CCI, the second one [3]- to the role of inflammation and immune response genes in the course and outcome of CCI. The present (third) part will provide a review of modern data on the effect of genes underlying intracellular processes of oxidative stress, apoptosis, regeneration, and synthesis of neurotransmitters and their receptors.

This paper reviews research articles published in the former USSR and post-soviet countries on the consolidation of powder materials using electric current that passes through the powder sample and/or a conductive die-punch set-up. Having been published in Russian, many of the reviewed papers are not included in the mainstream electronic databases of the scientific articles and thus are not known to the scientific community. The present review is aimed at filling this information gap. In the paper, the electric current-assisted sintering techniques based on high- and low-voltage approaches are presented. The main results of the theoretical modeling of the processes of electromagnetic field-assisted consolidation of powder materials are discussed. Sintering experiments and related equipment are described and the major experimental results are analyzed. Sintering conditions required to achieve the desired properties of the sintered materials are provided for selected material systems. Tooling materials used in the electric current-assisted consolidation set-ups are also described.

Changes in plasma noradrenalin (NA) and dopamine (DA) levels were evaluated in the stages of consciousness recovery in patients with severe traumatic brain injury with and without deep brain structure damage. Forty-eight patients (36 men and 12 women), aged from 12 to 56 (31,9±10,9) yeas, were enrolled in the study. Two variants of catecholamine (CA) changes were found: 1) a CA-dissociation that was oppositely directed to NA and DA changes was observed in unconsciousness; 2) a CA-dissociation (unidirectional NA and DA changes) that was observed after the restoration of consciousness. In patients with the damage of two frontal lobes and deep brain structures, CA-association periods were seen in the stage of mental confusion with psychomotor agitation or when the brain stem was damaged. The duration of CA-association was negatively correlated with the velocity, quality of consciousness recovery and outcomes evaluated by the Glasgow scale.

This article covers evaluation of work conditions and health state in workers engaged into open-cast extraction of refractories and of building quartz sand in moderate climate of Voronezh region.

Lymphotoxin was found to be present in supernatants from 22 human lymphocytes cultures stimulated with phytohemagglutinin in a dose of 5 and 10 microgram/ml. The lymphocytes were obtained from the peripheral blood of 6 apparently healthy persons. Lymphotoxin activity was determined by simple and objective method, i.e. by staining the target cells (mouse L-cells) monolayer with crystal violet, with the following determination of optic densities of the L-cells lysates at 570 nm in the spectrophotometer. As revealed, 1 : 5 dilutions of the supernatants from the lymphocyte cultures incubated for 48 hours inhibited the L-cells growth by from 40 to 60%. With further incubation of the cultures (up to 72 and 96 hours) the cytotoxicity of their supernatants for the target cells showed no increase, whereas the blasttransformation index reaches the maximal value by 72nd incubation hour. Supernatants from unstimulated lymphocyte cultures failed to produce any cytotoxic effect on L-cells.