The methylase METTL3 is the writer enzyme of the N6‐methyladenosine (m6A) modification of RNA. Using a structure‐based drug discovery approach, we identified a METTL3 inhibitor with potency in a ...biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose‐dependent reduction in the m6A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m1A, m6Am, m7G), suggesting selectivity of the developed compound towards other RNA methyltransferases.
Writer's block: We developed and characterized a small‐molecule inhibitor of m6A writer METTL3 by protein crystallography, biochemical and cellular assays. It shows high‐nanomolar potency in the biochemical assay, good selectivity against a panel of protein methyltransferases and kinases, and it reduced m6A/A ratio in mRNAs of different cell lines. In addition, we confirmed the selectivity of our compound towards other RNA methyltransferases in living cells.
The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores (comb jellies) have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic ...predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes, and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well recognized in ctenophores, many bilaterian neuron-specific genes and genes of 'classical' neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enzymes fold into unique three-dimensional structures, which underlie their remarkable catalytic properties. The requirement to adopt a stable, folded conformation is likely to contribute to their ...relatively large size (>10,000 Da). However, much shorter peptides can achieve well-defined conformations through the formation of amyloid fibrils. To test whether short amyloid-forming peptides might in fact be capable of enzyme-like catalysis, we designed a series of seven-residue peptides that act as Zn(2+)-dependent esterases. Zn(2+) helps stabilize the fibril formation, while also acting as a cofactor to catalyse acyl ester hydrolysis. These results indicate that prion-like fibrils are able to not only catalyse their own formation, but they can also catalyse chemical reactions. Thus, they might have served as intermediates in the evolution of modern-day enzymes. These results also have implications for the design of self-assembling nanostructured catalysts including ones containing a variety of biological and non-biological metal ions.
This work is devoted to the studies of the photoluminescence of plant leaves during their temperature influence. We show new results in the decay of biological processes in green leaves. The analysis ...of obtained results allows to conclude that the main result obtained in the high-temperature treatment of green leaves in the range from 300 K to 440 K does not lead to damping of the intense red photoluminescence characteristic of green leaves. These results may be of interest not only for biology and agriculture, but also for new applications of photonics.
Three YTH-domain family proteins (YTHDF1, YTHDF2, and YTHDF3) recognize the N6-methyladenosine (m6A) modification of mRNA in cells. However, the redundancy of their cellular functions has been ...disputed. We investigate their interactions with m6A-containing RNA using X-ray crystallography and molecular dynamics (MD). The new X-ray structures and MD simulations show that the three proteins share identical interactions with the m6A-containing RNA and have similar intrinsic plasticity, thus evidencing the redundant roles of the three proteins in cellular functions.
Postoperative delirium (POD) is considered one of the most severe complications, resulting in impaired cognitive function, extended hospitalization, and higher treatment costs. The challenge of early ...POD diagnosis becomes particularly significant in cardiac surgery cases, as the incidence of this complication exceeds 50 % in certain patient categories. While it is known that neuroinflammation, neurotransmitter imbalances, disruptions in neuroendocrine regulation, and interneuronal connections contribute significantly to the development of POD, the molecular, genetic mechanisms of POD in cardiac surgery patients, along with potential metabolomic diagnostic markers, remain inadequately understood. In this study, blood plasma was collected from a group of patients over 65 years old after cardiac surgery involving artificial circulation. The collected samples were analyzed for sphingomyelin content and quantity using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS) methods. The analysis revealed four significantly different sphingomyelin contents in patients with POD compared to those who did not develop POD (control group). Employing gene network reconstruction, we perceived a set of 82 regulatory enzymes affiliated with the genetic coordination of the sphingolipid metabolism pathway. Within this set, 47 are assumed to be regulators of gene expression, governing the transcription of enzymes pivotal to the metabolic cascade. Complementing this, an additional assembly of 35 regulators are considered to be regulators of activity, degradation, and translocation dynamics of enzymes integral to the aforementioned pathway. Analysis of the overrepresentation of diseases with which these regulatory proteins are associated showed that the regulators can be categorized into two groups, associated with cardiovascular pathologies (CVP) and neuropsychiatric diseases (NPD), respectively. The regulators associated with CVP are expectedly related to the effects on myocardial tissue during surgery. It is hypothesized that dysfunction of NPD-associated regulators may specifically account for the development of POD after cardiac surgery. Thus, the identified regulatory genes may provide a basis for planning further experiments, in order to study disorders at the level of expression of these genes, as well as impaired function of proteins encoded by them in patients with POD. The identified significant sphingolipids can be considered as potential markers of POD.
For transmitting reference and heterodyne signals of active phased array antenna is developed a new design of a fiber-optic communication system. In article are considered of transmission features of ...reference and heterodyne signals in is developed by us of new design of a fiber-optic communication system. The data of experimental investigation are presented.
The article discusses the problems arising from the modernization of active phased antenna arrays (for example, an increase in the number of transceiver active elements, a decrease in the weight and ...size of the antenna system, etc.). It has been substantiated that the most rational solution of these problems is the use of fiber-optical communication systems for transmitting heterodyne signals. A new design of the transmit-receive module with a fiber-optic transmission system for an active phased antenna array has been developed. The results of experimental investigations are presented.
The unprecedented in recent history global COVID-19 pandemic urged the implementation of all existing vaccine platforms to ensure the availability of the vaccines against COVID-19 to every country in ...the world. Despite the multitude of high-quality papers describing clinical trials of different vaccine products, basic detailed data on general toxicity, reproductive toxicity, immunogenicity, protective efficacy and durability of immune response in animal models are scarce. Here, we developed a β-propiolactone-inactivated whole virion vaccine CoviVac and assessed its safety, protective efficacy, immunogenicity and stability of the immune response in rodents and non-human primates. The vaccine showed no signs of acute/chronic, reproductive, embryo- and fetotoxicity, or teratogenic effects, as well as no allergenic properties in studied animal species. The vaccine induced stable and robust humoral immune response both in form of specific anti-SARS-CoV-2 IgG and NAbs in mice, Syrian hamsters, and common marmosets. The NAb levels did not decrease significantly over the course of one year. The course of two immunizations protected Syrian hamsters from severe pneumonia upon intranasal challenge with the live virus. Robustness of the vaccine manufacturing process was demonstrated as well. These data encouraged further evaluation of CoviVac in clinical trials.
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