Acta Naturae最新文献

 significant impact on the pathogenesis of viral infections by acting as both positive and negative regulators of viral gene expression. This review summarizes the available data on lncRNAs associated with human immunodeficiency virus type 1 (HIV-1). LncRNAs can regulate both the active replication cycle and the latent phase of the HIV-1 infection, during which the integrated proviral DNA remains transcriptionally silent. Moreover, lncRNAs may serve as diagnostic markers and are potential therapeutic targets. A deeper understanding of the intricate interactions between lncRNAs and HIV-1 is essential for developing innovative treatments for the HIV infection and the associated acquired immunodeficiency syndrome (AIDS).

The Clostridioides difficile infection (CDI) is one of the most common nosocomial infections around. The key pathogenicity factors of this bacterium include the toxins A and B that cause the disease symptoms. Neutralization of these toxins is one of the promising strategies for CDI treatment. Here, we isolated a panel of single-domain antibodies to the toxin B CROPs domain. Two antibodies, TB5A7 and TB4A8, exhibiting potent neutralizing activity were modified to produce homodimeric forms. The TB5A7 and TB4A8 dimers were characterized by enhanced neutralizing activity and protected animals from a toxin B lethal challenge. The obtained antibodies may be used to develop new agents for CDI treatment.

Genital lichen sclerosus (GLS) is a chronic inflammatory dermatosis that affects the genital skin. Despite different clinical manifestations, the pathogenesis of GLS in men and women is believed to be common and is attributed to a combination of autoimmune and genetic factors. In this study, we compared the transcriptomic profiles of penile (mGLS) and vulvar lichen sclerosus (VLS), aiming to identify commonly deregulated genes. We observed a substantial heterogeneity in the transcriptomic signatures in mGLS samples, which is driven by different compositions of immune infiltrates. In mGLS, gene expression signatures strongly indicate epidermis dysfunction and overexpression of the epithelial inflammation marker Keratin 6 (KRT6) and chitinase CHIT1. No significant changes in the expression levels of known GLS markers, such as VIM, CTNNB1, LGALS7 and ECM1, were detected. However, significant changes in the expression levels of the genes associated with autoimmune diseases and the genes upregulated in squamous cell carcinoma, including TNF, CCNB1 and RUNX3, were observed. There was no enrichment in the polyU/UC insertions that were reported previously. Instead, we have identified a long non-coding RNA DRAIC with a high coding potential that is commonly upregulated in mGLS and VLS. Taken together, our results provide a comprehensive picture of the shared transcriptomic signatures, including novel biomarkers and potential therapeutic targets.

Macrophage dysfunction is a key pathogenetic mechanism in the progression of a wide range of human chronic inflammation conditions, including atherosclerosis, rheumatoid arthritis, and metabolic disorders. The CDK8 and CDK19 paralogous kinases, the subunits of the Mediator complex acting as transcription regulators, are essential modulators of the inflammatory response. This study addresses the role of CDK8/19 kinases in the macrophage inflammatory response via multiple mechanisms: activation of pro- and anti-inflammatory genes and surface markers, STAT1 pathway modulation, activation of glycolytic cascade genes, regulation of the dynamics of lipid inclusions, and phagocytic activity. Experiments have shown that CDK8 and CDK19 may exhibit functional divergence. Cdk19 knockout reveals that CDK19 plays a role in the suppression of the M1 response, as well as the regulation of lipid homeostasis and phagocytosis. Double Cdk8/19 knockout macrophages are characterized by an exacerbated anti-inflammatory response while preserving normal lipid accumulation and phagocytosis levels. Inhibition of CDK8/19 kinase activity reproduces these effects only partially, suggesting that both kinase-dependent and kinase-independent mechanisms of action exist. The identified effects reveal previously unknown regulation mechanisms of macrophage immunometabolism. Modulation of CDK8 and CDK19 activity can become a novel therapeutic target for a wide range of chronic inflammatory conditions and metabolic disorders associated with macrophage dysfunction.

The analysis of protein evolutionary relationships is of both theoretical and practical significance. Identifying and characterizing evolutionary relationships between the components of protein complexes and metabolic enzymes fosters a deeper understanding of their evolutionary history and molecular evolution. The existence of related enzymes makes the annotation of new sequences complicated, since this process relies heavily on accurately determining the protein family classification of the sequence being analyzed. Clusters of Orthologous Groups (COGs) are widely used for the classification of prokaryotic proteins. COGs are constructed based on the occurrence of the respective protein-coding genes within complete genomes. Previously, we introduced COGcollator, a tool designed to visualize the relatedness between COGs by analyzing the hits of their profile HMMs (Hidden Markov Models). This paper presents an update of the COGcollator web service. It is based on the latest version of the COG database and features a completely new interface and additional functionalities. To demonstrate the capabilities of our tool and the validity of the data, we present the COGcollator results for the subunits of NADH:quinone oxidoreductase type 1 (NDH-1), a homologue of the mitochondrial complex I, as the evolutionary relationships of NDH-1 with other protein complexes have been extensively documented in the literature. The web service is available free of charge without registration at https://boabio.belozersky.msu.ru/en/COGcollator. Through the web service interface, users can access pre-calculated COGcollator results for 4,972 COGs and download their respective profile HMMs.

Genetic variation in the genes involved in the maintenance of cellular homeostasis may influence susceptibility to type 2 diabetes (T2D). However, the nature of the interplay among these loci and their prognostic value remains unclear. In this study, we analyzed variants in the FOXO3A, FOXO3, FOXO1, HMOX1, and SIRT1 genes. The HMOX1 rs2071746*T/T genotype was associated with an increased risk of T2D (OR = 1.36, PFDR = 0.030), whereas the FOXO1 rs9549240 (OR = 0.52, PFDR = 0.002) and SIRT1 rs3758391 (OR = 0.80, PFDR = 0.015) genotypes exhibited a protective effect. We detected nonlinear interactions, including FOXO1 rs9549240*G + SIRT1 rs3758391*T + SIRT1 rs7895833*A and HMOX1 rs2071746*A + SIRT1 rs3758391*T + SIRT1 rs7895833*A, with significant synergistic effects (SF = 3.19 and 2.56, P < 0.03). Models incorporating these interactions achieved an AUC of 69.8%, which increased to 86.2% when combined with age, sex, and the body mass index. These findings suggest that interactions between the pathways regulating oxidative stress and metabolism may contribute to the genetic predisposition to T2D.

Cancer remains a critical public health challenge, and developing novel approaches to cancer therapy is highly relevant. Targeted tumor therapy using antibody-drug conjugates (ADCs) has already demonstrated its efficacy in multiple tumors. Ganglioside GD2 is a promising target for ADC development. However, its functional properties, which are important for the cytotoxicity of ADCs, remain poorly understood. This study focuses on the mechanisms of receptor-mediated endocytosis for the conjugate formed between the anti-GD2 antibody ch14.18 and monomethyl auristatin E (MMAE), as well as the approaches for modulating this process using endocytosis inhibitors. Our findings demonstrate that anti-GD2 ADCs are efficiently internalized into tumor cells through various endocytic pathways, including the clathrin- and caveolin-mediated pathways, as well as macropinocytosis. The efficiency of ADC accumulation directly correlates with the level of GD2 expression on the tumor cell surface and is determined by the properties of the parental antibody, independent of the cytotoxic payload. Endocytosis inhibitors can modulate the functional properties of anti-GD2 ADCs, either decreasing or increasing the cytotoxic effects of the conjugates in GD2-positive cells. Nystatin, a specific inhibitor of caveolin-mediated endocytosis, increased ADC accumulation in cells and reduced the IC₅₀ 1.5- to 2.5-fold depending on the cell line. Although administration of nystatin together with anti-GD2 ADCs did not enhance tumor growth inhibition compared to ADC monotherapy in the GD2- positive mouse tumor model, further optimization of combination therapy conditions aimed at enhancing receptor-mediated endocytosis is a promising strategy for potentiating the antitumor effects of anti-GD2 ADCs.

Grand Prince of Vladimir Vsevolod the Big Nest and his wife Maria Vsevolozha (Shvarnovna) had twelve children, eight of whom were sons; Grand Prince Alexander Yaroslavich Nevsky was their grandson. Two competing hypotheses exist regarding the origin of Maria Vsevolozha, attributing it to either Ossetian or Czech nobility. Maria Shvarnovna was buried in the Knyaginin Monastery in Vladimir, Russia. Although her remains were reinterred several times, they were never moved from the original burial location. During the 2015 restoration works, skeletal remains, presumably belonging to Maria Shvarnovna, were sampled for paleogenetic analysis in order to determine their origin. More than 144,000 single nucleotide polymorphisms (SNPs) were identified. Their analysis demonstrated that the remains belong to a female carrying mitochondrial haplogroup U4b1a4 and unambiguously confirmed a third-degree biological relationship (great-grandmother-great-grandson) with Prince Dmitry Alexandrovich, the son of Grand Prince Alexander Yaroslavich Nevsky. This result fully corresponds to the genealogical relationships described in medieval chronicles. A multivariate statistical analysis of the genome revealed the two most probable proximal genetic sources of her origin: an Alan component, understood here in a broad cultural-historical sense encompassing populations of the Early and High Middle Ages, and an East Eurasian component. Among medieval populations, the genome of Maria Shvarnovna shows the closest genetic affinity to individuals associated with the SaltovoMayaki archaeological culture, characteristic of the Don forest-steppe region and resulting from the migration of Alan tribes, as well as to individuals from the Kara-Zhygach necropolis (14^th century), whose genomes also consist of a dominant Alan and a minor East Eurasian component. Not only do the findings support the Alan hypothesis and reject the Czech origin of Maria Shvarnovna, but they also allow one to confidently assert the reliable genetic identification of early representatives of the Rurikid princely dynasty due to the confirmed biological relationship with her great-grandson Dmitry Alexandrovich.

The nonsense-mediated mRNA decay (NMD) pathway is a mRNA quality control mechanism which not only degrades deleterious transcripts but also orchestrates a large number of post-transcriptional regulatory programs through unproductive splicing. We have developed a robust metric derived from splicing quantification in the RNA-seq data to measure NMD efficiency at a sample level. We demonstrate that NMD efficiency varies substantially both between and within tissues, with the magnitude of the variation comparable to that observed upon knockdown of the core NMD factor UPF1. By analyzing TCGA cancer cohorts, we further show that, in many tumors, unproductive splicing events undergo coordinated changes towards either collective suppression or collective activation of NMD isoforms, which is indicative of global deregulation of the activity of the NMD pathway. Consistently, we observed a striking divergence of NMD efficiency in cancers from the tissue-specific baseline level, suggesting that tumors partially erase the NMD signature of their tissue of origin. The application of the developed metric to RNA-binding protein knockdowns made it possible to identify several novel potential regulators of NMD efficiency. In sum, this study provides a solid framework for quantifying NMD efficiency, describes its biological and clinical relevance, and opens new avenues for dissecting mechanisms of post-transcriptional gene expression regulation by the NMD pathway.

Pancreatic adenocarcinoma is one of the most aggressive cancers. Its treatment relies on conventional chemotherapy agents; particularly gemcitabine. Chemotherapy is known to induce cell cycle arrest and the development of a senescent phenotype in tumor cells. The accumulation of senescent cells limits tumor proliferation, followed by the secretion of factors of the senescence-associated secretory phenotype promoting malignancy in the tumor microenvironment and metastasis. This makes the search for drugs suitable for senolytic therapy highly relevant. This study explored the senolytic properties of a DR5 receptor-selective mutant variant of the antitumor cytokine TRAIL DR5-B in human pancreatic cancer cell lines, after prolonged co-incubation with gemcitabine or doxorubicin. In the MIA PaCa-2 and PANC-1 cell lines, both drugs significantly increased β-galactosidase activity and the expression of senescence markers, such as the cell cycle inhibitors p21 and p27; DR5-B effectively suppressed cell viability after chemotherapy treatment. In the BxPC-3 cell line, the drugs did not induce senescence and DR5-B cytotoxicity was virtually unchanged. Some features of senescence were observed in AsPC-1 cells; however, these cells remained resistant to DR5-B, presumably due to cFLIP overexpression. Hence, the DR5-B protein shows promise as a senolytic agent for the treatment of certain types of pancreatic adenocarcinoma.