[Chordoma as a neurosurgical pathology]. / Khordoma kak neirokhirurgicheskaya patologiya.

OBJECTIVE: Assess the significance of chordoma as a neurosurgical pathology, taking into account the latest edition of the WHO classification of soft tissues and bone tumors (2020). MATERIAL AND METHODS: An analysis of 28 chordomas was carried out. All chordomas were histologically verified, including using immunohistochemical markers of notochordal differentiation (S100, EMA, keratin, brachiuria protein). RESULTS: Patients with chordomas accounted for 0.25% of the total number of neurosurgical patients. The vast majority (27) of chordomas had a cranio-vertebral localization. Sacral localization (S3-S5) of the tumor was detected in 1 patient. In 4 (15%) cases, operations were performed for the recurrence of chordoma. The tumors tended to grow into the structures of the skull, overgrown the vessels and nerves, and compress the adjacent brain structures. This was manifested by pain syndrome, neurological symptoms, impaired liquorodynamics. According to histopathological criteria, 27 (96%) cases of tumors were classified as conventional (usual) chordoma type, among them 7 corresponded to the chondroid subtype of the chordoma. In 1 case (4%), a dedifferentiated chordoma was detected. CONCLUSION: Chordoma, due to its axial localization, naturally involves adjacent structures of the nervous system, has clinically significant neuropathological manifestations, and often provides direct indications for a special neurosurgical approach. This requires its consideration not only as a bone, but also as a neurosurgical oncological pathology, along with other non-meningothelial (mesenchymal) tumors of the CNS.

[Relationship between the Interhelical Packing Angles and the Length of α-Helices in Proteins].

Mutual arrangement, or packing, of α-helices in proteins depends on several factors, but, tight packing and the chemical nature of the polypeptide chain are the most important. This study shows, for the first time, that the torsion packing angles between axes of α-helices depend on their length. A database of helical pairs formed by two connected and juxtaposed α-helices has been compiled using the Protein Data Bank. These helical pairs have been subdivided into four types: (1) 10474 pairs formed by long helices; (2) 3665 pairs in which the first α-helix is long and the second is short; (3) 3648 pairs in which the first α-helix is short and the second is long; 4) 1895 pairs in which both helices are short. Analysis of the database showed that most helical pairs in which both the helices are long form α-hairpins having interhelical packing angles of Ω. ≈ 20°. Most helical pairs in which one α-helix is long and the other is short or both helices are short form αα-corners having orthogonal (Ω ≈ -70°...-90°) or slanted (Ω ≈ -50°) packing of α-helices. The possible reasons for this relationship between interhelical angles (Ω) and the length of α-helices are discussed. These results are of great importance in protein modeling and prediction since they enable the determination of the mutual arrangement of α-helices in protein molecules.

Chirality and Handedness of Protein Structures.

In proteins, the polypeptide chain forms a number of right- and left-handed helices and superhelices, right- and left-turned hairpins, and some other structures that are nonsuperimposable, although they are not mirror images of each other as the L-amino acids are not converted to the D-amino acids. This property of protein structures will be referred to here as pseudo-chirality - or handedness. It has been shown that there are two kinds of handedness in proteins - helical handedness and handedness of arrangement. Some protein structures exhibit both the kinds of handedness. Handedness is observed at all levels of protein structural organization - from α-helices, ß-strands, hairpins, ßαß-units up to complex structural motifs, superhelices, and supramolecular structures in fibrous and polymer proteins. There are several structures that have unique handedness in proteins, for example, α-helices, αα-corners, ßαß-units, abcd-units, and so on. This property of the polypeptide chain is of particular value in protein folding and protein modeling, because it drastically reduces the number of possible folds.

[Unique Combinations of ßαß-Units and Π-Like Modules in Proteins and Specific Features of Their Amino Acid Sequences].

Possible combinations of ßαß-units and Π-like modules in proteins in both right- and left-handed forms have been analyzed in detail. The correlation between the mutual arrangement of the structural elements in the polypeptide chain and their handedness has been shown. In the ßαßП combinations, which is encountered most frequently in proteins, the П-module follows the ßαß unit along the chain and both elements are right-handed. In the Пßαß combinations, where the П-module is located at the N end and the ßαß-unit follows it, the former is left-handed and the latter is right-handed. In relatively rare combinations of the left-handed ßαß-units and right-handed П-modules, the ßαß-unit follows П-module in the chain. The combinations of left-handed П-modules and the left-handed ßαß-units are unobservable in proteins. It has also been shown that the П-modules with a ß-strand-α-helix-arch-ß-strand structure are observed in proteins only in a right-handed form and half of them (51%) contains cis-prolines in their arches. These arches of nonhomologous proteins, as well as the positions of cis-prolines, nearly coincide when superimposed. The superimposed П-modules also demonstrate that their overall folds are very similar. Structural alignment of their amino acid sequences has shown that the П-modules have very similar sequence patterns of the key hydrophobic, hydrophilic, glycine, and cis-proline residues.

[Structure and Features of Amino Acid Sequences of L-Modules in SH3-Like Folds].

A novel L-shaped repeat module whose structure can be represented as ß-strand-loop-ß-strand has been identified in a stereochemical analysis of nonhomologous SH3-like folds. ß-Strands of the L-module are positioned at a ~90° angle to each other in different orthogonally packed ß-layers. Together with a crossover loop, they form a half-turn of a right-handed superhelix. A database of 60 nonhomologous SH3-like domains has been compiled using the Protein Data Bank to study structural similarities and differences of L-modules. Occurrence frequencies of L-modules have been determined depending on the length of their loops. It has been shown that L-modules with ßmαααßn- and ßmαααßαßn-conformations, where m and n are numbers of ß-residues in the first and second ß-strands, occur most often (57 and 8%, respectively). Spatial structures of L-modules of the same type are very similar, demonstrated through superimposing them using computer programs. Structural alignment of the amino acid sequences encoding L-modules has been performed, making it possible to identify key positions for hydrophobic, hydrophilic, and proline residues.

THE MAYAK WORKER DOSIMETRY SYTEM (MWDS-2013): DETERMINATION OF THE INDIVIDUAL SCENARIO OF INHALED PLUTONIUM INTAKE IN THE MAYAK WORKERS.

In order to estimate doses of workers exposed to plutonium, it is necessary to make assumptions about both the route and the time course of intake. The objective of this study was to determine a time course for the inhalation rate for plutonium (intake regime) useful for biokinetic modeling. Records from workplace air sampling, personnel biophysical examinations and autopsy data from former Mayak Production Association (MPA) workers were used. Plutonium accumulation strongly correlated with the volumetric activity of plutonium in workplace air. Using data from activity in air at MPA workplaces over time, a three-step function of intake was adopted. The adequacy of this three-step function was tested by comparing predicted doses using more complicated intake regimes. Uncertainties on the three-step function were also characterized based on air sampling data. The three-step function was assumed to be common to all workers, but an individual intake regime for each worker was calculated by convoluting it with the worker's actual employment history.

[Relationship between structure and amino acid sequence of strongly twisted and coiled ß-hairpins in globular proteins].

ß-Hairpins are widespread in proteins, and it is possible to find them both within ß-sheets and separately. In this work, a comparative analysis of amino acid sequences of ß-strands within strongly twisted ß-hairpins from different structural protein subclasses has been conducted. Strongly twisted and coiled ß-hairpin generates in the space a right double helix out of ß-strands that are connected by a loop region (connections). The frequencies of amino acid residues on the internal (concave) and external (convex) surfaces of strongly twisted ß-hairpins have been determined (220 ß-hairpins from nonhomologous proteins were studied). The concave surface of these ß-hairpins is mainly generated by hydrophobic residues, while the convex surface by hydrophilic residues; accordingly, the alternation of hydrophobic internal and hydrophilic external residues is observed in their amino acid sequences. Amino acid residues of glycine and alanine (especially in places of the largest twisting of the strands) were anomalously frequently found in internal positions of strongly twisted and coiled ß-hairpins. It was established that internal positions never contain the proline residues, while external positions in the twisting region contain them in a relatively large amount. It was demonstrated that at least one amino acid residue in αL- or ε-conformation is required for generation of relatively short (up to 7 amino acid residues) connection. As a rule, these positions are occupied by glycines. Thus, not only the alternation of hydrophobic and hydrophilic amino acid residues, but also the presence of one or two glycine residues in the connection region and the excess of glycines and alanines in the places of the largest strand twisting on the concave surface, as well as the presence of prolines on the convex surface, are required to generate a strongly twisted and coiled ß-hairpin.

Dynamics of body burdens and doses due to internal irradiation from intakes of long-lived radionuclides by residents of Ozyorsk situated near Mayak PA.

This paper presents and discusses new autopsy results and other historic data from earlier autopsies and environmental monitoring linked to releases from the Mayak PA facilities in the Chelyabinsk oblast in the southern Urals. The focus is on residents of the town of Ozyorsk located near to Mayak PA and the dynamics of body burdens and radiation doses from inhalation of plutonium alpha and americium-241, and ingestion of strontium-90 and caesium-137. It is demonstrated that accumulation and exposure from these radionuclides was mainly due to unplanned releases in the 1950s and 60s. The mean content of plutonium alpha at the time of autopsy of people commencing residence in Ozyorsk from 1949 to 1959 was about 3.5 Bq, falling to 0.2 Bq in those arriving after 1990. A reducing trend was also seen for (241)Am. The highest (90)Sr content in Ozyorsk residents was measured in 1967. The (137)Cs body content of residents arriving in Ozyorsk at any time was in almost all cases below the limit of detection. The committed effective dose from internal exposure to these long-lived radionuclides which would have been accumulated in Ozyorsk residents if present from 1949 to 2013 is estimated to be 13 mSv. This dose is primarily attributed to intakes during 1949 to 1959 when the annual effective dose rate was approximately 1 mSv y(-1). The current value is about 0.1 mSv y(-1). This dose is about 20 times higher than the dose from global man-made fallout, which is about 0.005 mSv y(-1) at present, but much lower than that from natural background radiation, i.e. about 2 mSv y(-1). The experience gained from this work and continuing activities can contribute to the development of improved international guidance in legacy situations, particularly as regards the provision and use of monitoring data to test and thereby build confidence in prognostic models for radiation conditions and potential future exposures. The scope includes evidence for the rate of reduction in radionuclide concentrations in environmental media and in their bioavailability, resuspension of long-lived alpha radionuclides, uptake of (90)Sr and (137)Cs in the food-chain, and confirmation of cumulative uptake via autopsy and whole body counting measurements. Continuing investigations will thus support decisions on future planned releases and contribute to planning of remediation of other areas affected by historic releases.

[Two mechanisms of protein folding: theoretical analysis].

In the present study, two possible mechanisms of protein folding are analized. One of them is based on the hypothesis that at the first step of protein folding a nucleus is formed and then the remaining part of the molecule or domain is folded around it. For example, ß-proteins containing 3ß-corners can fold in this way. According to the other mechanism, the three-dimensional structure of proteins is formed as a result of interactions between "ready-made" building blocks. Analysis of structural features of the 3ß-corners and features of their amino asid sequences enable us to conclude that the 3ß-corner can fold into its unique structure per se and can act as a nucleus or "ready-made" building block in protein folding. The larger protein structures can be obtained by stepwise addition of ß-strands to the 3ß-corner in accordance with a restricted set of rules as shown in the corresponding structural tree, which is available at http://strees.protres.ru/. On the other hand, complementary interactions of the two 3ß-corners can result in formation of the fold that is observed in the serine protease domain and similar proteins.

Structures closed into cycles in globular proteins.

Different types of structures closed into cycles are widespread at all the levels of structural organization of proteins. ß-Hairpins, triple-stranded ß-sheets, and ßαß-units represent simple structural motifs closed into cycles by systems of hydrogen bonds. Secondary closing of these simple motifs into larger cycles by means of different superhelices, split ß-hairpins, or SS-bridges results in formation of complex structural motifs such as abcd-units, φ-motifs, five- and seven-segment α/ß-motifs, etc. At the level of tertiary structure many proteins and domains fold into structures closed into cylinders. Apparently, closing the motifs and domains into cycles and cylinders results in formation of more cooperative and stable structures as compared with open ones, and this may be the reason for high frequencies of occurrence of the motifs in proteins.

Structures closed into cycles in proteins containing 3ß-corners.

In the present study, pathways of growth of protein structures represented in the structural tree for ß-proteins containing 3ß-corners are analyzed. It is shown that the frequency of occurrence of the completed structures of known proteins within branches of the tree is quite different. This means that allowed pathways of growth of protein structures are not equal and their usage is quite different. In most cases, addition of one or two ß-strands nearest along the chain to the root 3ß-corner (67%) or addition of three ß-strands to the 3ß-corner results in the formation of structures closed into cycles or barrels. Therefore, the pathways that result in closed structures are used most often in the first steps of growth of the root 3ß-corner. Amino acid sequences coding for left-handed superhelices that close into cycles the 3ß-corners are also analyzed. It is demonstrated that most crossover sites where the polypeptide chain passes from one ß-layer to the other have one or two residues in sterically constrained α(L)- or ε-conformations, which should be glycines or residues with flexible side chains in order to reduce the steric constraints.

[Structiure of beta-beta-hairpins closed into cycles by S-S-bridges].

In the present study, a stereochemical analysis of proteins containing beta-beta-hairpins closed into cycles by S-S-bridges has been performed. A database of these proteins has been compiled from the Protein Data Bank (total 428 PDB entries). 390 beta-beta-hairpins closed into cycles by S-S-bridges have been found in non-homologous proteins included into the database. Analysis showed that 118 hairpins contain S-S-bridges formed by cysteins located opposite to each other in the neighboring beta-strands. Among them, 110 hairpins are left-turned and 8 beta-hairpins are right -turned when viewed from the same side where S-S-bridges are located. In the other group of 272 beta-hairpins, the S-S-bridge is formed by two cysteins one of which is located in the beta-strand and the other in the loop juxtaposed to the beta-hairpin at the N- (84%) or C-terminus (16%). As shown, in most cases the loop-hairpin region closed into a cycle by the S-S-bridge formes a turn of a left-handed superhelix.

[Differential diagnosis of thyrotoxicosis in subjects with post-immunization reaction].

An increasingly greater fraction of the general population is getting involved in the immunization program. However, conditions of individual subjects are not always properly evaluated prior to immunization. The clinical case reported below demonstrates the difficulty of diagnostic examination of patients with Graves disease (toxic goiter), endocrine ophthalmopathy, and post-immunization reaction.

A novel structural motif and structural trees for proteins containing it.

In the present study, a novel structural motif that can be represented as a combination of the known betaalphabeta-unit and psi-motif is described and analyzed. In theory, there are four possible combinations of the motifs since each of them can exist in two forms, left-handed and right-handed. For this study, we have selected 140 nonhomologous proteins in which 158 combinations of such types have been found. The combination of the right-handed psi-motif and the right-handed betaalphabeta-unit has been shown to occur most often (87 cases out of 158) and the combination of the left-handed betaalphabeta-unit and the left-handed psi-motif does not occur at all. Three novel structural trees in which the commonly occurring combinations are taken as the root structures have been constructed.

[Novel structural tree for (alpha + beta)-proteins containing abCd-units].

A database of 926 (alpha + beta)-proteins and (alpha + beta)-domains containing abCd-units (among them 401 are nonhomologous) has been compiled from the Protein Data Bank (total 2636 PDB entries). A novel structural tree for this structural class of proteins that is composed of 286 possible polypeptide chain folds has been constructed. The structural classification of (alpha + beta)-proteins containing abCd-unit based on the structural tree has been developed. Both the database and the structural tree are accessible at the web-site (http://strees.protres.ru/).

[Novel structural tree for beta-proteins containing abcd-units].

A database of 528 beta-proteins and beta-domains containing abcd-units (among them 244 are nonhomologous) has been compiled from the Protein Data Bank (total 1511 PDB entries). A novel structural tree for this structural class of proteins that is composed of 153 possible polypeptide chain folds has been constructed. The structural classification of beta-proteins containing abcd-unit based on the structural tree has been developed. Both the database and the structural tree are accessible at the web-site (http://strees.protres.ru/).

Structural trees for proteins containing phi-motifs.

In the present study, a novel structural motif of proteins referred to as the phi-motif is considered, and two novel structural trees in which the phi-motif is taken as the root structure have been constructed. The simplest phi-motif is formed by three adjacent beta-strands connected by loops and packed in one beta-sheet so that its overall fold resembles the Greek letter phi. Construction of the structural trees and modeling of folding pathways have shown that all structures of the protein superfamilies can be obtained by stepwise addition of alpha-helices and/or beta-strands to the root phi-motif taking into account a restricted set of rules inferred from known principles of protein structure. The structural trees are a good tool for structure comparison, structural classification of proteins, as well as for searching for all possible protein folds and folding pathways.

[Modified model of potato virus X coat protein structure].

We propose the modified model of the structure of coat protein (CP) subunits in filamentous virions of potato virus X (PVX). The model is similar to the one proposed by us in 2001 for the CP of another helical plant virus (potato virus A) belonging to other (potyvirus) group. In this model the PVX CP molecule consist of two main domains--a bundle of four alpha-helices located close to the virion long axis and a so-called RNP-fold (or abCd-fold) located near the virion surface. Basing on this model we suggest possible mechanism of described by J.G. Atabekov and colleagues structural transition ("remodeling") of the PVX virions resulting from their interaction with virus-specific TGB-1 protein.

[Role of the structural context in selection of hydrophobic side-chain rotamers in a- and d-positions of alpha-helices].

The study shows that in coiled-coil proteins the distribution of hydrophobic side-chain rotamers in a- and d-positions of alpha-helices is strongly dependent on the mutual arrangement of the a-helices. In coiled-coil dimers, where a-helices are packed "face-to-face", most side chains occupying a-positions adopt t-rotamers, and those in d-positions adopt g- -rotamers. In tetramers, where alpha-helices are packed "side-by-side", most side chains in a-positions adopt g- -rotamers and those in d-positions adopt t-rotamers. These features can be used for prediction of side-chain rotamers in protein modeling and design.

Mechanism of selection of side-chain rotamers in alpha-helices.

In this study, a possible mechanism of selection of side-chain rotamers based on the rotamer distributions in known coiled-coil proteins is suggested. According to this mechanism, interhelical hydrophobic, polar, and packing interactions bring alpha-helices closer to each other and this effect squeezes side chains out of the helix-helix interface. As a result, in dimeric coiled coils and long alpha-alpha-hairpins where alpha-helices are packed in a face-to-face manner, most side chains occupying the a-positions have t-rotamers and those in the d-positions g(-)-rotamers. In tetramers, where alpha-helices are packed side-by-side, most side chains in the a-positions adopt g(-)-rotamers and those in the d-positions t-rotamers.