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Evidence for the primordial black holes (PBH) presence in the early Universe renews permanently. New limits on their mass spectrum challenge existing models of PBH formation. One of the known models is based on the closed walls collapse after the inflationary epoch. Its intrinsic feature is the multiple production of small mass PBH which might contradict observations in the nearest future. We show that the mechanism of walls collapse can be applied to produce substantially different PBH mass spectra if one takes into account the classical motion of scalar fields together with their quantum fluctuations at the inflationary stage. Analytical formulas have been developed that contain both quantum and classical contributions.

Endoplasmic reticulum-associated degradation (ERAD) is a protein quality control pathway of fundamental importance to cellular homeostasis. Although multiple ERAD pathways exist for targeting topologically distinct substrates, all pathways require substrate ubiquitination. Here, we characterize a key role for the UBE2G2 Binding Region (G2BR) of the ERAD accessory protein ancient ubiquitous protein 1 (AUP1) in ERAD pathways. This 27-amino acid (aa) region of AUP1 binds with high specificity and low nanomolar affinity to the backside of the ERAD ubiquitin-conjugating enzyme (E2) UBE2G2. The structure of the AUP1 G2BR (G2BRAUP1) in complex with UBE2G2 reveals an interface that includes a network of salt bridges, hydrogen bonds, and hydrophobic interactions essential for AUP1 function in cells. The G2BRAUP1 shares significant structural conservation with the G2BR found in the E3 ubiquitin ligase gp78 and in vitro can similarly allosterically activate ubiquitination in conjunction with ERAD E3s. In cells, AUP1 is uniquely required to maintain normal levels of UBE2G2; this is due to G2BRAUP1 binding to the E2 and preventing its rapid degradation. In addition, the G2BRAUP1 is required for both ER membrane recruitment of UBE2G2 and for its activation at the ER membrane. Thus, by binding to the backside of a critical ERAD E2, G2BRAUP1 plays multiple critical roles in ERAD.

ObjectiveA critical role in coronavirus disease 2019 (COVID-19) pathogenesis is played by immune dysregulation that leads to a generalized uncontrolled multisystem inflammatory response, caused by overproduction of proinflammatory cytokines, known as “a cytokine storm” (CS), strongly associated with a severe course of disease. The aim of this study is to identify prognostic biomarkers for CS development in COVID-19 patients and integrate them into a prognostic score for CS-associated risk applicable to routine clinical practice.Materials and MethodsThe authors performed a review of 458 medical records from COVID-19 patients (241 men and 217 women aged 60.0 ± 10.0) who received treatment in the St. Petersburg State Budgetary Institution of Healthcare City Hospital 40 (City Hospital 40, St. Petersburg), from Apr. 18, 2020 to Nov. 21, 2020. The patients were split in two groups: one group included 100 patients with moderate disease symptoms; the other group included 358 patients with progressive moderately severe, severe, and extremely severe disease. The National Early Warning Score (NEWS) score was used alongside with clinical assessment, chest computed tomographic (CT) scans, electrocardiography (ECG), and lab tests, like ferritin, C-reactive protein (CRP), interleukin (IL)-6, lactate dehydrogenase (LDH), and D-dimer.ResultsThe basic risk factors for cytokine storms in COVID-19 patients are male gender, age over 40 years, positive test result for replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, absolute lymphocyte count, dynamics in the NEWS score, as well as LDH, D-dimer, ferritin, and IL-6 levels. These clinical and instrumental findings can be also used as laboratory biomarkers for diagnosis and dynamic monitoring of cytokine storms. The suggested prognostic scale (including the NEWS score dynamics; serum IL-6 greater than 23 pg/ml; serum CRP 50 mg/L or greater; absolute lymphocyte count less than 0.72 × 109/L; positive test result for replicative coronavirus (SARS-CoV-2) RNA; age 40 years and over) is a useful tool to identify patients at a high risk for cytokine storm, requiring an early onset of anti-inflammatory therapy.

Background: Simultaneous resection of bone tumors in the fronto-naso-orbital region is a great challenge due to the need for adequate reconstruction of the facial skeleton. Pre-operative virtual planning of resection margins and the simultaneous fabrication of the cranioplasty using computer-aided design/computer-aided manufacturing (CAD/CAM) technology could allow combining the tumor resection and cosmetic restoration steps into a single procedure.Methods: We present five consecutive cases of patients with bone tumors of the fronto-naso-orbital region. The indications for surgery included: (1) the presence of a major cosmetic defect; (2) progressive tumor growth. The histological examination revealed vascular malformation, hemangioma, and fibrous dysplasia in two cases. Tumor resection was performed with the help of a drilling template in form of a tumor. The computer-designed cranioplasty formed based on the non-involved side of the skull of the patient was manufactured. In one patient, the reconstruction was performed using two separate implants.Results: The position of the implant fits in with pre-operative planning in two cases; in those cases, the additional trimming of the implant or bone defect was required. Good cosmetic outcomes were noted in all patients, and no complications occurred. No repeat surgery was necessary. The template has proved to have high application potential.Conclusion: Simultaneous resection and CAD/CAM cranioplasty in the case of bone tumors in the fronto-orbital region is a promising technique with the aim of minimizing operation time and achieving a good esthetic outcome.

Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC50 meanings and the binding energy to the assumed biological target, the p37 viral protein with R2 = 0.60.

An inexpensive and highly efficient metal-free alternative to commonly used Ru- and Ir-based catalysts was proposed. It was shown that the new 2,7-di-tert-butyl-5,10-bis(4-trifluoromethylphenyl)-5,10-dihydrophenazine outcompeted the iridium phenylpyridyl complex in photoredox activity in the alkylation of silyl enol ethers yielding aryl alkyl ketones. The reaction occurred under visible light irradiation at room temperature and was also applicable to drug derivatives (ibuprofen and naproxen). In-depth photophysical, electrochemical, and quantum chemical studies showed that the aforementioned N,N-diaryldihydrophenazine exhibited enhanced properties that were essential for the photoredox catalysis (a long-lived triplet excited state, strong reducing ability, high stability of the radical cations formed in single-electron-transfer event, and chemical inertness of the catalyst with respect to reactants). Importantly, the substituted N,N′-diaryldihydrophenazines could be obtained directly from diaryl amines; a facile, easily handled and scaled-up one-pot synthetic procedure was elaborated.

Here, we investigated the reaction of 1,3-dipolar cycloaddition of 1,3-diazido-2-nitro-2- azapropane (DANP) to propargyl alcohol over a copper-based catalyst and identified the optimum reaction conditions that enable the synthesis of 2-nitro-1,3-bis(4,4′-dihydroxymethyl)-1,2,3-triazolyl-2-azapropane (1) in more than 84% yield. The reaction between DANP, 1,5-diazido-3-nitrazapentane, and phenylacetylene produced the respective 1,2,3-triazole derivatives in 83% and 71% yields, respectively. The structures of the resultant compounds were validated by infrared and NMR spectroscopies and elemental analysis. The structure of 1 was proved by single-crystal X-ray diffraction. This study demonstrated that 1 exhibits a dose-dependent antiarrhythmic activity towards calcium-chloride-induced arrhythmia and refers to Class III: moderately hazardous substances.

A novel peptide AnmTX Sco 9a-1 with the β-hairpin fold was isolated from the swimming sea anemone Stomphia coccinea (Actinostolidae family). The peptide consists of 28 amino acid residues, including modified hydroxyproline residue, and its measured molecular mass is 2960 Da. The peptide was not toxic on mice; however, it stimulated their exploratory motivation and active search behavior, and demonstrated an anti-anxiety effect. AnmTX Sco 9a-1 at doses of 0.1 and 1 mg/kg reduced the volume of edema during 24 h better than the nonsteroidal anti-inflammatory drug, Diclofenac, at dose of 1 mg/kg in a model of acute local λ-carrageenan-induced inflammation. ELISA analysis of the animal’s blood showed that peptide at a dose of 1 mg/kg reduced the content of tumor necrosis factor-α (TNF-α), a pro-inflammatory mediator responsible in the edema development, up to the level of TNF-α in the intact group. Besides, AnmTX Sco 9a-1 demonstrated a significant analgesic effect on acute pain sensitivity in the carrageenan-induced thermal hyperalgesia model at doses of 0.1 and 1 mg/kg. Activity of AnmTX Sco 9a-1 was shown not to be associated with modulation of nociceptive ASIC channels.

The Opecoeloidea is a large group of xiphidiate digeneans parasitizing marine and freshwater fishes. According to the current taxonomic model, this superfamily contains only one family with numerous subfamilies. This study is devoted to the members of the Stenakrinae. Based on phylogenetic analysis of concatenated sequences of 18S and 28S rRNA genes of stenakrine opecoelids Caudotestis dobrovolski, C. cf. dobrovolski, Hexagrammia zhukovi, Stenakron vetustum, as well as the deep-sea xiphidiate digenean Zdzitowieckitrema incognitum, which so far has had an ambiguous phylogenetic status, we erect a new opecoeloid family, the Zdzitowieckitrematidae fam. nov. The genera Holsworthotrema and Scorpidotrema are removed from the Stenakrinae to the Scorpidotrematinae subfam. nov. within the Opecoelidae. We also remove the Stenakrinae from the Opecoelidae and recognize it as a separate family within the Opecoeloidea. The Stenakridae stat. nov. is a sister taxon to a well-supported Opecoelidae. The Zdzitowieckitrematidae occupies a sister position relative to the stenakrids and the opecoelids taken together. All three families are clearly phylogenetically distinct, however convincing morphological differences are revealed only between the Zdzitowieckitrematidae and the Stenakridae and between the Opecoelidae and the Stenakridae.

The nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels, provide cholinergic signaling, and are modulated by various venom toxins and drugs in addition to neurotransmitters. Here, four APETx-like toxins, including two new toxins, named Hmg 1b-2 Metox and Hmg 1b-5, were isolated from the sea anemone Heteractis magnifica and characterized as novel nAChR ligands and acid-sensing ion channel (ASIC) modulators. All peptides competed with radiolabeled α-bungarotoxin for binding to Torpedo californica muscle-type and human α7 nAChRs. Hmg 1b-2 potentiated acetylcholine-elicited current in human α7 receptors expressed in Xenopus laevis oocytes. Moreover, the multigene family coding APETx-like peptides library from H. magnifica was described and in silico surface electrostatic potentials of novel peptides were analyzed. To explain the 100% identity of some peptide isoforms between H. magnifica and H. crispa, 18S rRNA, COI, and ITS analysis were performed. It has been shown that the sea anemones previously identified by morphology as H. crispa belong to the species H. magnifica.

Secreted Ly6/uPAR-related protein 1 (SLURP-1) is a secreted Ly6/uPAR protein that negatively modulates the nicotinic acetylcholine receptor of α7 type (α7-nAChR), participating in control of cancer cell growth. Previously we showed, that a recombinant analogue of human SLURP-1 (rSLURP-1) diminishes the lung adenocarcinoma A549 cell proliferation and abolishes the nicotine-induced growth stimulation. Here, using multiplex immunoassay, we demonstrated a decrease in PTEN and mammalian target of rapamycin (mTOR) kinase phosphorylation in A549 cells upon the rSLURP-1 treatment pointing on down-regulation of the PI3K/AKT/mTOR signaling pathway. Decreased phosphorylation of the platelet-derived growth factor receptor type β (PDGFRβ) and arrest of the A549 cell cycle in the S and G2/M phases without apoptosis induction was also observed. Using a scratch migration assay, inhibition of A549 cell migration under the rSLURP-1 treatment was found. Affinity extraction demonstrated that rSLURP-1 in A549 cells forms a complex not only with α7-nAChR, but also with PDGFRα and epidermal growth factor receptor (EGFR), which are known to be involved in regulation of cancer cell growth and migration and are able to form a heterodimer. Knock-down of the genes encoding α7-nAChR, PDGFRα, and EGFR confirmed the involvement of these receptors in the anti-migration effect of SLURP-1. Thus, SLURP-1 can target the α7-nAChR complexes with PDGFRα and EGFR in the membrane of epithelial cells. Using chimeric proteins with grafted SLURP-1 loops we demonstrated that loop I is the principal active site responsible for the SLURP-1 interaction with α7-nAChR and its antiproliferative effect. Synthetic peptide mimicking the loop I cyclized by a disulfide bond inhibited ACh-evoked current at α7-nAChR, as well as A549 cell proliferation and migration. This synthetic peptide represents a promising prototype of new antitumor drug with the properties close to that of the native SLURP-1 protein.

The paper describes value chains as new forms of economic interaction in-between the market and hierarchical structures. The main reasons for their emergence are discussed from managerial, neoclassical and institutional approaches. The patterns of value added distribution between members of value chains as well as factors influencing this distribution are analysed. Special emphasis is placed on changes in configuration of value chains brought about by digital technologies. The authors explain that reasons for creation of value chains (such as uncertainty reduction, transaction cost savings, protection of investments in specific assets as well as distribution of implicit knowledge) are similar to those for vertical integration within a company or a corporate group. That is to say, value chains can be regarded as sets of neoclassical and relational contracts. The analysis of real data leads to the conclusion that integrators and companies located on endpoints of value chains (the so-called smiling curve) do not always have an advantage in distribution of value added. Quite often the suppliers of key components are the ones who tend to have this advantage. The ways digital transformation influences membership of value chains as well as distribution of power and value added within them are revealed. The authors explain the increasing role of digital platforms as integrators of economic interaction as well as owners of information about suppliers and consumers of products. The transfer of power from producers of material goods to creators of digital prototypes of these goods is discussed.

Objective. To assess inter-expert agreement among spine surgeons having different levels of clinical experience when working with the AOSpine classification (TLCS, 2013). Materials and Methods. The study involved nine surgeons divided into three equal groups depending on work experience. All respondents were asked to classify the MSCT data of 50 patients with acute injuries to the thoracic and lumbar spine pursuant to TLCS (2013) classification. To evaluate inter-expert agreement, a Kappa coefficient interpreted according to Landis – Koch criteria was used. Results. The overall coefficient of inter-expert agreement for all observations among all groups of respondents was 0.43, which reflects a moderate level of agreement. Moderate inter-expert agreement was revealed for injury types A (0.45) and C (0.56), and satisfactory – for type B (0.34). The highest levels of agreement were obtained for subtypes A1 (0.67) and A4 (0.80) in the group of advanced specialists and for type C (0.70) in the group of specialists with a basic level of experience. Conclusion. The study demonstrated predominantly moderate level of inter-expert agreement when working with the AOSpine classification (TLCS, 2013). The accuracy of its use increases with a gain in practical experience of a surgeon.

Introduction. Ethnosociological monitoring in a polyethnic region is conducted not only due to the need for an assessment of the public policy regulation in this field, but also due to the increase in the heuristic potential for preventing various kinds of social conflicts. The objective of the paper is to identify the dynamics of the development of interethnic relations in the Republic of Mordovia and the influence of various stratification processes on the development of ethnic relations, based on a comparative analysis of scientific studies. Materials and Methods. Regular sociological measurements carried out by the Research Institute of Regionology under Ogarev Mordovia State University and by the Scientific Center for Social and Economic Monitoring in 1990–2010 were used as the research materials. The interpretation of the results was carried out using the institutional, comparative and natural historical methods. Results. The main trends in the development of mass consciousness of the population of a polyethnic region in the context of various socio-political periods of the development of Russia have been revealed: from the ‘parade of sovereignties’ that followed the collapse of the Soviet Union to the reactualization of the ideology of a strong multiethnic Russian state. It has been emphasized that over the years, the main reasons exerting a negative impact on the nature of interethnic relations have mainly been not the interethnic conflicts, but the politically or economically marked factors (the economic crisis, inflation, appointment to managerial posts based on the ethnicity of a person, income inequality between representatives of different ethnic origins, etc.). Discussion and Conclusion. Although interethnic relations in the Republic of Mordovia has almost never achieved an increased level of conflict, the republic’s leadership was able to build an effective system for regulating them, which made it possible to minimize the degree of social and ethnic tension in society. The article may be useful to scientists and practitioners in the field of the development of interethnic relations and to all those interested in the issues of ethnosociology.

Introduction. The article tries to consider everyday sociocultural practices implemented by the population of a multi-ethnic region, ranging from hostility towards people of a different nationality at the place of work to nationalist propaganda in the media. Materials and Methods. The empirical basis consists of the results of the sociological study “Ethnic and Confessional Situation in the Republic of Mordovia”, carried out by the researchers of Research Center for Social and Economic Monitoring in May 2019. Results and Discussion. The results indicate that, regardless of nationality, the residents of the region demonstrate a rather high level of tolerance, which is manifested both in declarative assessments of the level of interethnic tension and a low frequency of dissimilative sociocultural practices. Conclusion. The use of the adjusted scale of social distance (or the scale of assessment of loyalty) allows the authors to state that the factor of nationality is not decisive in the situation of kinship, while belonging to a different religion in some cases can negatively affect ethnic stability.