Acta Naturae最新文献

{"title":"From Dysfunction to Differentiation: A New Paradigm of T Cell Exhaustion.","authors":"V M Stepanova, A S Logvinov, E A Emelyanov, N A Katin, Yu P Rubtsov","doi":"10.32607/actanaturae.27873","DOIUrl":"https://doi.org/10.32607/actanaturae.27873","url":null,"abstract":"<p><p>CD8⁺ T cell exhaustion is the loss of certain functions typical of cytotoxic lymphocytes. CD8⁺ cytotoxic T cells originate from naive CD8⁺ T cells upon antigen exposure. Chronic or excessive antigen exposure during certain infections and cancers triggers inhibitory mechanisms that lead to functional exhaustion - a loss of the ability to secrete IFN-γ and other cytokines, as well as to produce granzyme- and perforin-containing lytic granules in response to stimulation. Functional exhaustion also affects CD4⁺ helper T cells, which further reduces CD8⁺ T cell cytotoxicity. This leads to the loss of the CD8⁺ T cell's ability to kill target cells, which negatively impacts immunity and reduces the efficacy of therapeutic T cells. Currently, T cell exhaustion is considered as a multistage, partially reversible differentiation program. Heterogeneous subsets of stem-like progenitor exhausted T cells (Tex-prog) and terminally exhausted T cells (Tex-term) have been identified. These cells differ in their degrees of dysfunction and, thus, in their potential to restore lost functions. The transcriptional exhaustion program is controlled by key transcription factors, such as TCF1, TOX, T-bet, EOMES, BATF, IRF4, etc. Understanding the dynamic changes taking place in the transcriptional profile and cellular phenotype is critical for effective immunotherapy, in particular in immune checkpoint blockade (ICB) and CAR-T cell therapy, because its success depends entirely on the T cell state. In this review, we discuss current concepts on the molecular and cellular mechanisms of T cell exhaustion, various exhaustion-associated phenotypic and functional changes, and opportunities for preventing T cell exhaustion to optimize anti-tumor immunotherapy strategies.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"4-18"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Characterization of a 12th-Century Princely Burial in St. Sophia Cathedral of Veliky Novgorod.","authors":"M V Leonova, I K Reshetova, K V Zhur, D A Vashunina, F S Sharko, N G Maksimov, M V Dobrovolskaya, N A Makarov, E B Prokhortchouk","doi":"10.32607/actanaturae.27986","DOIUrl":"https://doi.org/10.32607/actanaturae.27986","url":null,"abstract":"<p><p>The necropolis of St. Sophia Cathedral in Veliky Novgorod, Russia, as noted in chronicle sources and cathedral inventories, contains the burials of five princes from the Rurikid dynasty and two princesses from their families. To clarify the genetic ancestry of two of the buried individuals, whose remains preserved the skeletal elements required for genetic analysis, DNA extracted from the remains was sequenced. Genetic analysis has revealed that the male individual from the sarcophagus near the southern wall of the Nativity side-chapel carries the Y-chromosomal haplogroup N1a and can be identified with high probability as Mstislav Rostislavich the Brave. Analysis of DNA extracted from female skeletal remains from the reliquary shrine in the Martyrius Porch revealed no close kinship with any of the known genomes of Rurikid dynasty members. A sculptural facial reconstruction based on the skull of Prince Mstislav Rostislavich and a digital facial approximation based on the cranium of the female individual were performed.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"72-82"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening for Tumor-Specific Antibodies by Yeast Display of Native Repertoires of Tumor-Infiltrating B Cells.","authors":"Y R Vereveyko, D M Malabuiok, E A Faizullina, Yu A Mokrushina, O V Serova, S V Protsenko, N Gong, H Zheng, Yu B Kuzmin, P V Tsarapaev, I V Smirnov, N E Kushlinskii, H Zhang, A G Gabibov, S S Terekhov","doi":"10.32607/actanaturae.27909","DOIUrl":"https://doi.org/10.32607/actanaturae.27909","url":null,"abstract":"<p><p>Tumors are neoplasms that can be recognized by a patient's immune system. Recognition of tumor antigens (TAs) triggers the recruitment and proliferation of tumor-infiltrating lymphocytes. Although tumor-infiltrating T cells have long been the primary focus of research, B cells also accumulate in tumors and participate actively in TA recognition. The use of molecular display technologies for the functional profiling of tumor-infiltrating B cell (TIB) repertoires enables large-scale screening for TAs and identification of unique TIB clones that mediate selective tumor recognition. Approaches combining microfluidic technologies for reconstructing natural TIB repertoires with yeast display were used in this study to identify antibodies that recognize TAs. It has been shown that nonspecific adhesion of yeast cells to the surface of primary tumor cell cultures from patients may be a key factor hindering the isolation of tumor-specific clones. Overcoming nonspecific binding of yeast cells enables the selection of tumor-specific clones by biopanning. Clone 3.15, isolated from the TIB repertoire of a colorectal cancer (CRC) patient, recognizes TAs on the surface of a number of tumor cell lines, as well as on primary tumor cell cultures from CRC patients. We suggest that the further use of these technologies will not only expand the diversity of molecular tools for targeted immunotherapy and tumor diagnostics but will also provide a more detailed understanding of the molecular mechanisms underlying the generation and recognition of TAs.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"56-64"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Profiling of Early Pre-Ribosomal Complexes from Human Nucleolar Extracts.","authors":"K L Dobrochaeva, D K Kovaleva, A A Moraleva, R Kh Ziganshin, A S Deryabin, Yu P Rubtsov","doi":"10.32607/actanaturae.27928","DOIUrl":"https://doi.org/10.32607/actanaturae.27928","url":null,"abstract":"<p><p>The nucleolus is a key cellular compartment responsible for the major steps of ribosomal subunit biogenesis. Detailed characterization of the nucleolar proteome is essential for understanding the molecular mechanisms underlying ribosome biogenesis and may help identify novel regulators of this process. However, the nucleolar proteome, and the protein composition of early ribosomal subunit precursors in particular, remain poorly defined, largely because of the methodological inconsistencies and conflicting findings across published studies. Here, we aimed to establish a standardized approach that could be used to identify novel factors involved in the early stages of ribosome biogenesis using an optimized stepwise nucleolar extraction protocol, followed by sucrose density gradient fractionation and mass spectrometry analysis. This optimized approach allowed us to enrich for proteins directly engaged in early biogenesis steps, while depleting non-specific nucleolar \"background\" components. A total of 529 unique proteins were identified across two biological replicates. Gene Ontology (GO) analysis revealed significant enrichment of proteins annotated as ribosome biogenesis factors, including those directly involved in ribosomal subunit assembly and rRNA processing. A cross-referencing of our dataset against 188 known components of pre-ribosomal complexes represented in the PDB yielded 84 overlapping proteins. Early biogenesis factors prevailed in this group (70 out of 84), supporting the idea of the enrichment of the analyzed fraction with early pre-ribosomal complexes. The resulting protein dataset will facilitate the identification of novel factors governing the poorly understood aspects of human ribosome biogenesis.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"65-71"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and Diversity of Ly6/uPAR Proteins and Three-Finger LU Domains from the Analysis of Invertebrate Genomes.","authors":"A S Paramonov, Z O Shenkarev, E N Lyukmanova","doi":"10.32607/actanaturae.27898","DOIUrl":"https://doi.org/10.32607/actanaturae.27898","url":null,"abstract":"<p><p>The family of Three-Finger Proteins (TFPs or Ly6/uPAR) containing three-finger domains (LU domains) with a characteristic three-finger fold was initially characterized for toxins from the venom of snakes of the family Elapidae. TFPs have been described in vertebrates and some invertebrates, where they are known to participate in the regulation of membrane receptors, intercellular recognition, signal transduction, embryogenesis, and the functioning of the nervous, immune, and reproductive systems. Although a vast amount of genomic information has recently become available, the diversity and representation of TFPs in various groups of organisms, as well as the evolution of proteins belonging to this family, remain poorly understood. In this study, we employed the bioinformatics methods to analyze the annotated genomes of various metazoans available in open databases. Protein sequence analysis using hidden Markov models enabled the identification of TFPs in the genomes of the members of all the metazoan phyla, including those most evolutionarily distant from humans: ctenophores (Ctenophora), sponges (Porifera), placozoans (Placozoa), and cnidarians (Cnidaria). Further domain annotation revealed the presence of proteins with three-finger domains and a previously undescribed domain architecture in cnidarians, mollusks, and arthropods. Comparison of the LU domains of early metazoans to those of humans revealed a high degree of sequence similarity (up to 69%) for some proteins. For example, the LU domains of the human activin receptors ACVR and the GPI-anchored proteins Ly6D and Lynx2 (Lypd1) appeared conserved. The function and mechanisms of action of invertebrate TFPs remain unknown. An analysis of the annotated genomes of some fungi and plants and two published genomes of choanoflagellates (Choanoflagellata), a phylum of unicellular organisms that are the most phylogenetically close to the Metazoa, revealed no presence of sequences encoding TFPs. It is hypothesized that TFPs first appeared during the evolution of protozoa, upon the transition of animals to multicellularity.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"83-93"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paradoxes of Immunity: Alternative Forms of Adaptive Immunity Discovered by Evolutionary Genomics.","authors":"E S Shilov, S A Nedospasov","doi":"10.32607/actanaturae.27905","DOIUrl":"https://doi.org/10.32607/actanaturae.27905","url":null,"abstract":"<p><p>The fundamental discoveries in immunology in the 20th century initially focused on humans and other mammals, and then they extended to other vertebrates, including birds and fishes. Significant parallels in immune system architecture and mechanisms were revealed. In all organisms, from humans to zebrafish, antibodies and B cells, CD8⁺ and CD4⁺ T cells that recognize MHC I and MHC II, respectively, were identified, along with a set of major cytokines. Advances in DNA sequencing technologies and the development of bioinformatics for genome and transcriptome analysis allowed researchers to identify unique features in immune systems in some fishes and cyclostomes in the early 21st century. Such features stood in contradiction with established concepts based on studies of the mammalian immune system. The loss of several key genes encoding critical molecular mediators of adaptive immunity (MHC II, CD4, and others) was uncovered in anglerfish, codfish, and pipefish. Simultaneously, a unique type of adaptive immune system was discovered in lampreys and hagfish which utilizes different structural scaffolds (based on LRR-rich domains) to generate adaptive immune receptors (VLRs), as well as antibodies. Moreover, most species that could be classified as immunodeficient based on the studies of the vertebrate immune system proved to retain protective functions, suggesting the existence of compensatory mechanisms.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"19-31"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Targeted Conjugate for Photodynamic Therapy of HER2-Positive Cancer.","authors":"I P Sharychev, A A Prach, E V Plotnikov, M S Larkina, P V Petunin, M V Belousov, E V Konovalova, A A Shulga, S M Deev","doi":"10.32607/actanaturae.27891","DOIUrl":"https://doi.org/10.32607/actanaturae.27891","url":null,"abstract":"<p><p>Low selectivity against cancer cells remains one of the key challenges of many modern photosensitizers. To enhance the selectivity of the action and the effectiveness of tumor therapy, a conjugate was developed comprising a photoactive compound, the water-soluble silicon phthalocyanine complex (IR700, IRDye 700DX NHS ester), and the targeted molecule DARPin G3-ABD, which is designed to target human epidermal growth factor receptor type 2 (HER2). The phototoxicity of the individual substance IR700 and the DARPin G3-ABD-IR700 conjugate was tried on tumor cell cultures with different HER2 expression levels (SKBR-3, SKOV-3, BT-474, and PC-3). The cells were irradiated using LED diodes with a wavelength of 690 nm and a luminous flux density of 0.5 W/cm². Cell viability after irradiation and following all the experimental procedures was evaluated using the standard MTT assay. The developed conjugate proved to specifically bind to HER2 receptors. The combination of high photosensitizing activity and selectivity of action against tumor cells makes the DARPin G3-ABD-IR700 conjugate a promising targeted agent for photodynamic therapy.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"109-117"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to \"Reconstruction and Paleogenetic Characterization of the Genome of Princess Maria Vsevolozha, Wife of Grand Prince Vsevolod the Big Nest\".","authors":"K V Zhur, M V Leonova, F S Sharko, E D Pankratova, A V Sirenov, D S Korobov, M V Dobrovolskaya, N A Makarov, E B Prokhortchouk","doi":"10.32607/actanaturae.28088","DOIUrl":"https://doi.org/10.32607/actanaturae.28088","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.32607/actanaturae.27916.].</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"118"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Antibiotic and Antimycotic Compositions for the Eradication of Microorganisms from Cell Cultures.","authors":"Y A Prokopenko, E A Faizullina, O V Serova, S V Protsenko, Yu A Mokrushina, N Gong, H Zheng, Yu B Kuzmin, P V Tsarapaev, D M Malabuiok, Y R Vereveyko, I V Smirnov, N E Kushlinskii, H Zhang, A G Gabibov, S S Terekhov","doi":"10.32607/actanaturae.27907","DOIUrl":"https://doi.org/10.32607/actanaturae.27907","url":null,"abstract":"<p><p>Cell cultures underlie the vast majority of <i>in vitro</i> research. Despite strict sterility requirements and the availability of high-tech equipment to prevent contamination, laboratory practice remains associated with a significant risk of contamination of mammalian cell cultures with bacterial and fungal agents. According to the American Type Culture Collection (ATCC), 15-35% of cell lines are contaminated with mycoplasma, posing a high risk of cross-contamination and leading to significant distortions of the experimental data obtained using such cultures. Furthermore, microbial contamination is a major risk factor when working with cell cultures isolated from patient surgical biospecimens. Despite the availability of ready-made solutions for eradicating microorganisms and preventing cell culture contamination, the problem of antibiotic resistance is particularly relevant for such contamination, and commercially available agents are often ineffective. In this study, combinations of antimicrobial agents were selected to address two of the most common practical challenges in cell culture: (i) complete elimination of mycoplasma infection and (ii) preventing contamination of primary cell cultures with bacteria and fungi that are components of the patient microbiome. A combination of tylosin, tetracycline, ciprofloxacin, erythromycin, and chloramphenicol was shown to completely eradicate mycoplasma from infected cell cultures. A combination of levofloxacin, polymyxin B, vancomycin, meropenem, and the antifungals micafungin and voriconazole completely eliminated the risk of microbial contamination during primary culture isolation, including from complex specimens such as surgical resections from colorectal cancer patients. The selected compositions successfully combine low cytotoxicity with a broad spectrum of antimicrobial activity, allowing for their effective use in laboratory practice. Nonetheless, the principle of minimizing the use of antimicrobial agents should be strictly adhered to in order to control the spread of antibiotic resistance.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"94-101"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconstruction of a Self-sustaining System of Oscillating Glycolytic Reactions in Artificial Microreactors.","authors":"O M Alekhina, P V Bashkirov, A S Silantyev, S P Dudik, D S Matyushkina, O V Shcherbakova, V M Govorun","doi":"10.32607/actanaturae.27965","DOIUrl":"https://doi.org/10.32607/actanaturae.27965","url":null,"abstract":"<p><p>Synthetic cell design is one of the daunting challenges of modern biology. While the genome synthesis problem has already been solved technologically, the understanding of the molecular composition of the intracellular environment required for initiating artificial life still remains elusive. One of the mechanisms of self-organization in prebiotic systems is the oscillatory processes (oscillations) arising from feedback regulation. Such dynamics are inherent to glycolysis as the metabolic core of the cell. The objective of this study was to reconstruct the oscillatory glycolytic chain and investigate its behavior upon confinement to microcompartments and upon interaction with nucleic acids. We used the <i>Saccharomyces cerevisiae</i> extract as a model and demonstrated the presence of fluctuations in the concentrations of glycolytic metabolites: ATP, NADH, hexose-6-phosphates, glyceraldehyde-3-phosphate, 3-phosphoglycerate, and phosphoenolpyruvate (PEP). Moreover, the PEP and pyruvate concentrations had a dramatic effect on the stability of oscillations. We also demonstrated that the reduction of the system volume accompanying the encapsulation into a microchip leads to a more rapid onset of oscillations. Furthermore, synthetic mRNA and DNA were found to reduce the amplitude and period of oscillations in a translation-independent manner. Hence, this study demonstrates the feasibility of reconstructing metabolic oscillations in microvolumes and reveals the effect of nucleic acids on the glycolytic dynamics, which is important for the development of protocellular systems.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"18 3","pages":"32-41"},"PeriodicalIF":1.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}