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In this paper, we propose a new method for knowledge distilling based on generative adversarial networks. Discriminator CNNs is used as an adaptive knowledge distilling loss. In experiments, single shot multibox detector SSD based on MobileNet v2 and ShuffleNet v1 are used as student networks. Our tests showed AP and mAP improvement of more than 3% on PascalVOC and 1% on MS Coco datasets compared with the baseline algorithm without any architecture or dataset changes. The proposed approach is general and can be used not only with SSD but also with any type of object detection algorithms.

In this paper we combine the ideas of image matching, object detection, image retrieval and zero-shot learning for stating and solving the semantic matching problem. Semantic matcher takes two images (test and request) as input and returns detected objects (bounding boxes) on test image corresponding to semantic class represented by request (sample) image. We implement our single-shot semantic matcher CNN architecture based on GoogleNet and YOLO/DetectNet architectures. We propose the detection-by-request training and testing protocols for semantic matching algorithms. We train and test our CNN on the ILSVRC 2014 with 200 seen and 90 unseen classes and provide the real-time object detection with mAP 23 for seen and mAP 21 for unseen classes.

Background. Prior to the introduction of new agents — immune checkpoint inhibitors — for inoperable and/or metastatic melanoma (IMM), chemotherapy outcomes were generally poor. The median (Me) overall survival (OS) in IMM was no more than 6-9 months, and the Me of progression-free survival (PFS) was about 2 months. The introduction of immune checkpoint inhibitors and targeted therapy changed the prognosis for the life of IMM patients dramatically. The development, studies, and approval of a new original PD-1 inhibitor, prolgolimab, in Russia in 2020 prompted the professional community to conduct a prospective observational study in the Russian Federation to assess its real-world efficacy and safety. Aim To evaluate the real-world efficacy and safety of prolgolimab in patients with IMM. Materials and methods. From October 2020 to October 2022, 700 patients with IMM receiving prolgolimab in real clinical settings in oncological institutions of various levels in the Russian Federation were included in the study. The main inclusion criteria were: pathology-confirmed diagnosis of melanoma; metastatic and/or inoperable type; use of prolgolimab outside of clinical trials; and signed informed consent. Objective response rate in the general population and the Intention-to-treat and Per Protocol populations was considered the main criterion for evaluating the efficacy of therapy, and the safety criterion was the incidence of grade 3-4 adverse events (AEs). PFS and OS rates were also assessed. Statistical analysis was performed using the SPSS 25.0 software package. Results. The objective response rate for the Per Protocol population (with radiographic assessment available) was 42% (n=235/559). Disease progression was reported in 26.7% (n=149) of patients, stabilization in 31.3% (n=175), and disease control in 73.3% of patients with IMM, regardless of the line of therapy. At the follow-up Me of 12 months (0-36), PFS for all patients regardless of the line of therapy was 8 months (95% confidence interval [Cl] 6.537-9.463), 6-month PFS was 55%, and 12-month PFS was 41%. OS Me for all included patients was 32 months, 6-month OS was 82%, and 12-month OS was 69%. Depending on the line of therapy, the OS Me was: line 1 - not reached, line 2-30 months (95% Cl 16.007-43.993), line 3 and subsequent- 22 months (95% Cl 14.264-29.736); p=0.736. According to the CTCAE 5.0 general terminology criteria for AEs, a total of 136/693 (19.6%) AEs of varying degrees were reported, in particular: grade 1-2 - 105/693 (15.2%), grade 3-4 - 25/693 (3.6%), unknown grade - 5/693 (0.7%), as well as one fatal case (0.1%) due to thromboembolism in the vascular center with an unclear (according to the investigator's assessment) relation with prolgolimab. Conclusion The results obtained at 12 months of follow-up confirm the high efficacy and satisfactory tolerability of prolgolimab in patients with IMM in real-world practice, regardless of the line of therapy and other characteristics.

We present the results of Auroral Kilometric Radiation (AKR) measurements near the plasmapause on the ERG (Arase) satellite. The apogee of the satellite's orbit is located near the ecliptic plane, at latitudes ±30°. According to the generally accepted point of view, AKR observation is impossible in this region since it is shielded by the plasmasphere. Simultaneous measurements of AKR and local plasma density made it possible to determine that AKR in near-equatorial regions occur in plasma channels — density inhomogeneities elongated along magnetic field lines. AKR from sources located in the auroral magnetosphere is transferred by these channels to the equatorial region. This work analyzes the conditions for the capture and propagation of AKR in low plasma density channels. In the geometrical optics approximation, we have simulated the conditions for the radiation capture and propagation. The calculation results show that the proposed scheme for AKR capture into plasma channels can explain the measurement results — the radiation transfer from the auroral region to the near-equatorial region.

This article discusses the urgent aspects of online learning didactics. They are comprised of, for instance, organization and methods of organized learning, main principles of actions aimed at practical orientation; their objective is combination of the methods of distance learning, formation of efficient skills of students with social mediation, analysis of reasons of errors and their correction, pursuance of success in relevant areas. Organized online learning also provides opportunity for students to use all advantages of digital technologies: flexibility, individual distribution of learning duration, compatibility with other forms of occupation. In addition to digital know-how, organization of learning and independent work of distant students can develop self-discipline, sustainability of acquired skills. Students can use various digital sources of information available under various conditions in addition to that organized under the management of distance learning teacher.

ABSTRACTThe main approach to preventing tick-borne encephalitis (TBE) is vaccination. Formaldehyde-inactivated TBE vaccines have a proven record of safety and efficiency but have never been characterized structurally with atomic resolution. We report a cryoelectron microscopy (cryo-EM) structure of the formaldehyde-inactivated TBE virus (TBEV) of Sofjin-Chumakov strain representing the Far-Eastern subtype. A 3.8 Å resolution reconstruction reveals the structural integrity of the envelope E proteins, specifically the E protein ectodomains. The comparative study shows a high structural similarity to the previously published structures of the TBEV European subtype strains Hypr and Kuutsalo-14. A fraction of inactivated virions exhibits asymmetric features including the deformations of the membrane profile. We propose that the heterogeneity is caused by inactivation and perform a local variability analysis on the small parts of the envelope protein shell to reveal membrane curvature features possibly induced by the inactivation. The results of this study will have implications for the design of novel vaccines against diseases caused by flaviviruses.

NEXT is an experiment dedicated to neutrinoless double beta decay searches in xenon. The detector is a TPC, holding 100 kg of high-pressure xenon enriched in the 136Xe isotope. It is under construction in the Laboratorio Subterráneo de Canfranc in Spain, and it will begin operations in 2015. The NEXT detector concept provides an energy resolutionbetter than 1% FWHM and a topological signal that can be used to reduce the background. Furthermore, the NEXT technology can be extrapolated to a 1 ton-scale experiment.

Genomic profiling, or molecular profiling of the tumor, is becoming a key component of therapeutic decision making in clinical oncology, and is typically carried out via next generation sequencing. However, the interpretation of the results and evaluation of rationale for targeting the uncovered alterations is challenging and requires a deep understanding of cancer biology, genetics, genomics and oncology. Multidisciplinary molecular tumor boards represent a promising strategy in the facilitation of molecularly-informed therapeutic decisions, and usually consist of specialists with various fields of expertise. To effectively communicate the biological and clinical significance of genomic findings, as well as to make molecular tumor board discussions more productive, we developed and implemented evidence blocks into case discussions in our center. We found that this approach facilitated clinicians’ understanding of the results of genomic profiling, and resulted in shorter yet more efficient case discussions within the molecular tumor board. Here, we discuss our experience with evidence blocks and how their implementation influenced the molecular tumor board practice.

The article aims to reveal the main features of the Bolshevik project to build the Kingdom of Reason in the USSR, associated with the radical reformatting of the relationship between the rational and irrational in the establishment of the socialist society. Theoretical sources include the works of Karl Marx and Friedrich Engels, linking the construction of a new communist society to the demystification of social relations and the elimination of alienation and reification; the writings of Vladimir Lenin and other prominent figures of the Soviet state, devoted to the organization of planned economy and the widespread implementation of rational management methods; and the works of the outstanding educator Anton Makarenko, aimed at developing and implementing the idea of educating a new Soviet person. The article posits Bolshevism (Leninism) as the Russian version of socialist transformation, inheriting its fundamental ideas from the French Enlightenment, including the concept of the Kingdom of Reason, manifested in the system of rationally organized planning, accounting, and control. However, in practice, the development of this system, taken to its extreme forms, gave rise to a number of utopian projects that became embodiments of irrational thinking. Thus, the original idea to build the Kingdom of Reason underwent a transformation into its opposite. Nevertheless, the authors of the article believe that the Soviet model of a rationally organized social structure can be considered, if not fully realized, then overall a fairly successful project of building the Kingdom of Reason in a socialist state and methodologically correct sociopedagogical system for shaping a new person.

The inherent contradictions of the modern world order prompt researchers to seek interpretations for some of their manifestations beyond traditional discourses. The article proposes to examine the concept of international integration through the lens of the conformity discourse, since it is possible to describe such a complex process of today’s integration of sovereign states only within the interdisciplinary approach. The theory of axiological ontologism plays a crucial role in unfolding the conformity discourse within the realm of the sociology of international relations. Guided by this theory, researchers have the opportunity to transpose the concept of conformity from social psychology into the subject area of the sociology of international relations. This transposition leads to a shift in the semantics of the concept: conformity might be interpreted as the inclination of a nation state to reshape its values and change a behavioral strategy on the world stage under the pressure of the “international community”. However, it is essential to take into account that different theories of international relations make it possible to appeal to various conformity discourses. According to the author, the normative conformity aligns more with neorealism, since this theory considers actors of world politics to be engaged in integration processes based on the political environment, without being prone to sacrificing their interests for the sake of symbolic “unity”. The discourse of informational conformity is advisable to be developed from the standpoint of neoliberalism, which regards actors of world politics as assimilating values of the “international community” and accepting them through repetitive integrational practices.

Background. In an era of breakthroughs in cancer immunotherapy, CheckMate 067 studies declared the combination of PD-1 and CTLA-4 inhibitors a new standard of care for patients with metastatic melanoma (MM). A significant limitation of the widespread use of the combination of ipilimumab and nivolumab in routine clinical practice is the high risk of severe immune-mediated adverse events. Prolgolimab and nurulimab are a combination of fixed doses of original monoclonal antibodies (manufactured by JSC "BIOCAD," Russia) to the PD-1 receptor (prolgolimab) and the CTLA-4 receptor (nurulimab) (3:1 ratio). This paper presents the results of an international, multicenter, double-blind, placebo-controlled, comparative, randomized, phase II OBERTON clinical study to investigate the efficacy and safety of nurulimab + prolgolimab combination therapy with continued prolgolimab therapy compared to prolgolimab alone as first-line therapy in patients with unresectable melanoma (uRM) or MM (NCT03913923). Materials and methods. The study included patients with uRM or MM who were not previously treated for metastatic disease. The patients were randomized into two groups (1:1). Patients in group 1 were treated with a nurulimab (1 mg/kg) and prolgolimab (3 mg/kg) combination at a dose of 0.2 mL/kg (equivalent to 1 mg/kg of nurulimab and 3 mg/kg of prolgolimab) once every 3 weeks during the first 4 blinded infusions. Patients in group 2 received prolgolimab monotherapy at a dose of 3 mg/kg once every 3 weeks during the first 4 blinded infusions. Starting from infusion 5, patients in both groups received open prolgolimab 1 mg/kg once every 2 weeks. The primary endpoint of the study was progression-free survival (PFS). The study is registered on ClinicalTrials.gov under the number NCT05732805 and is currently ongoing, but recruitment of new patients has been completed. Results. One hundred seventeen patients were randomized and received at least one dose of the study therapy. At a median follow-up of 16.79 months, the median PFS was 12.2 (4.9; not achieved) months in the nurulimab + prolgolimab group and 2.8 (1.5; 4.7) months in the prolgolimab monotherapy group (95% confidence interval 0.36-0.90, hazard ratio 0.57). PFS at 24 months was 41% in the nurulimab + prolgolimab group and 25.4% in the prolgolimab monotherapy group. In both groups, the therapy was well tolerated. Grade 3-4 immune-mediated adverse events were reported in 15.5% of patients who received nurulimab + prolgolimab, compared with 1.7% of those who received prolgolimab alone. The most frequent grade 3-4 treatment-related adverse events in both treatment groups were increased alanine aminotransferase and aspartate aminotransferase and asthenia. Overall, the safety profile was favorable, as expected for the class of immune checkpoint inhibitors, anti-CTLA-4, and anti-PD-1 monoclonal antibodies. Discussion. The results demonstrate a favorable safety profile in both the nurulimab + prolgolimab combination and prolgolimab monotherapy groups as the first-line treatment for uRM or MM. The assessment of the primary endpoint, PFS, showed the benefit of combination immunotherapy followed by switching to prolgolimab compared to prolgolimab alone. Conclusion. Combination immunotherapy with the CTLA-4 inhibitor nurulimab and the PD-1 inhibitor prolgolimab, available as a combination of solutions of two drugs in a single vial, with a further switch to monotherapy with prolgolimab, can fill an important niche in the treatment of patients with uRM or MM. Confirmation of the obtained data on the efficacy and safety of the combined regimen of nurulimab + prolgolimab in comparison with PD-1 inhibitor monotherapy is expected from the ongoing phase III BCD-217-2 OCTAVA study (NCT05732805).

Abstract The T5 family of viruses are tailed bacteriophages characterized by a long non-contractile tail. The bacteriophage DT57C is closely related to the paradigmal T5 phage, though it recognizes a different receptor (BtuB) and features highly divergent lateral tail fibers (LTF). Considerable portions of T5-like phages remain structurally uncharacterized. Here, we present the structure of DT57C determined by cryo-EM, and an atomic model of the virus, which was further explored using all-atom molecular dynamics simulations. The structure revealed a unique way of LTF attachment assisted by a dodecameric collar protein LtfC, and an unusual composition of the phage neck constructed of three protein rings. The tape measure protein (TMP) is organized within the tail tube in a three-stranded parallel α-helical coiled coil which makes direct contact with the genomic DNA. The presence of the C-terminal fragment of the TMP that remains within the tail tip suggests that the tail tip complex returns to its original state after DNA ejection. Our results provide a complete atomic structure of a T5-like phage, provide insights into the process of DNA ejection as well as a structural basis for the design of engineered phages and future mechanistic studies.

Extracellular vesicles (EVs) are of growing interest in the context of screening for highly informative cancer markers. We have previously shown that uterine aspirate EVs (UA EVs) are a promising source of ovarian cancer (OC) diagnostic markers. In this study, we first conducted an integrative analysis of EV-miRNA profiles from UA, malignant ascitic fluid (AF), and a conditioned medium of cultured ascites cells (ACs). Using three software packages, we identified 79 differentially expressed miRNAs (DE-miRNAs) in UA EVs from OC patients and healthy individuals. To narrow down this panel and select miRNAs most involved in OC pathogenesis, we aligned these molecules with the DE-miRNA sets obtained by comparing the EV-miRNA profiles from OC-related biofluids with the same control. We found that 76% of the DE-miRNAs from the identified panel are similarly altered (differentially co-expressed) in AF EVs, as are 58% in AC EVs. Interestingly, the set of miRNAs differentially co-expressed in AF and AC EVs strongly overlaps (40 out of 44 miRNAs). Finally, the application of more rigorous criteria for DE assessment, combined with the selection of miRNAs that are differentially co-expressed in all biofluids, resulted in the identification of a panel of 29 miRNAs for ovarian cancer screening.