Vol 88, No 1 (2023)

B lymphocytes play an important role in the regulation of immune response in both normal and pathological conditions. Traditionally, the main functions of B cells were considered to be antibody production and antigen presentation, but in recent decades there have been discovered several subpopulations of regulatory B lymphocytes (Bregs) which maintain immunological tolerance and prevent overactivation of the immune system. Memory (mBregs, CD19⁺CD24^hiCD27⁺) and transitional (tBregs, CD19⁺CD24^hiCD38^hi) subpopulations of Bregs are usually considered in the context of studying the role of these B cells in various human pathologies. However, the mechanisms by which these Breg subpopulations exert their immunosuppressive activity remain poorly understood. In this work, we used bioinformatic analysis of open-source RNA sequencing data to propose potential mechanisms of B cell immunosuppression. Analysis of differential gene expression before and after activation of these subpopulations allowed us to identify six candidate molecules that may determine the functionality of mBregs and tBregs. IL4I1-, SIRPA-, and SLAMF7-dependent mechanisms of immunosuppression may be characteristic of both Breg subsets, while NID1-, CST7-, and ADORA2B-dependent mechanisms may be predominantly characteristic of tBregs. An in-depth understanding of the molecular mechanisms of anti-inflammatory immune response of B lymphocytes is an important task for both basic science and applied medicine and can facilitate the introduction of new approaches to the therapy of complex diseases.

In 1994 a new class of prokaryotic compartments was discovered, collectively called “encapsulins” or “nanocompartments”. Encapsulin shell protomer proteins self-assemble to form icosahedral structures of various diameters (24-42 nm). Inside of nanocompartments shells, one or several cargo proteins, diverse in their functions, can be encapsulated. In addition, non-native cargo proteins can be loaded into nanocompartments, and shell surfaces can be modified via various compounds, which makes it possible to create targeted drug delivery systems, labels for optical and MRI imaging, and to use encapsulins as bioreactors. This review describes a number of approaches to the application of encapsulins in various fields of science, including biomedicine and nanobiotechnologies.

The amino acid sequences of coat proteins (CPs) of potexviruses such as potato virus X (PVX) and alternanthera mosaic virus (AltMV) share about 40% sequence identity. However, the N-terminal CP domains of these virions differ both in length (the N-terminal CP domain of PVX is longer by 28 residues, ∆N = 28), and in amino acid sequence. In this work, we determined the effect of the N-terminal CP domain on the structure and physicochemical properties of the entire PVX and AltMV virions. It was shown that the melting point of PVX samples is 10-12°C higher than that of AltMV preparations; the circular dichroism spectra of these viruses also differ significantly. Spatial alignment of the existing high-resolution potexvirus CP structures showed that the RMSD value between C_α-atoms was the largest for the N-terminal domains of the two compared models. From computer simulations the ∆N-terminal CP domain of PVX is completely disordered. According to synchrotron small-angle X-ray scattering (SAXS) data, the structure of CP of PVX and AltMV virions differs, in particular, CP PVX has a larger size of crystallinity regions and, therefore, is more ordered. Using SAXS, virion diameters and helix parameters in solution are calculated. The influence of the conformation and localization of the N-terminal domain of PVX CP relative to the surface of the virion on its structure was revealed. Presumably, the increased thermal stability of PVX virions compared to AltMV is provided by the elongated N-terminal domains (ΔN = 28), which ensures additional contact between the adjacent CP subunits in the PVX virion.

Inhibition of the biosynthetic pathways of compounds essential for T. cruzi is considered by researchers as one of the possible mechanisms of action of potential drugs against Chagas disease. As one of these mechanisms, we consider inhibition of galactonolactone oxidase from T. cruzi (TcGAL), which catalyzes the final step in the synthesis of vitamin C, an antioxidant that T. cruzi is unable to assimilate from outside and must synthesize itself. In this work, for the first time, a class of effective inhibitors of TcGAL was found - allylbenzenes from plant sources. A non-competitive mechanism of action of apiol has been established and it has been found that natural allylpolyalkoxybenzenes (APAB) - apiol, dillapiol, etc. are effective inhibitors of TcGAL with IC50 = 20-130 µM. It was found that the conjugation of APAB with triphenylphosphonium, which ensures the selective delivery of biologically active substances to mitochondria, makes it possible to increase the efficiency and/or the maximum percentage of inhibition compared to unmodified APAB.

Inorganic polyphosphates (polyP), according to literature data, are involved in the regulatory processes of molecular complex of the Saccharomyces cerevisiae cell wall (CW). The aim of the work was to reveal relationship between polyP, acid phosphatase Pho3p, and the major CW protein, glucanosyl transglycosylase Bgl2p, which is the main glucan-remodelling enzyme with amyloid properties. It has been shown that the yeast cells with deletion of the PHO3 gene contain more high molecular alkali-soluble polyP and are also more resistant to exposure to alkali and manganese ions compared to the wild type strain. This suggests that Pho3p is responsible for hydrolysis of the high molecular polyP on the surface of yeast cells, and these polyP belong to the stress resistance factors. The S. cerevisiae strain with deletion of the BGL2 gene is similar to the Δpho3 strain both in the level of high molecular alkali-soluble polyP and in the increased resistance to alkali and manganese. Comparative analysis of the CW proteins demonstrated correlation between the extractability of the acid phosphatase and Bgl2p, and also revealed a change in the mode of Bgl2p attachment to the CW of the strain lacking Pho3p. It has been suggested that Bgl2p and Pho3p are able to form a metabolon or its parts that connects biogenesis of the main structural polymer of the CW, glucan, and catabolism of an important regulatory polymer, polyphosphates.

Organism adaptation to metabolic challenges requires coupling of metabolism to gene expression. In this regard, acylations of histones and metabolic proteins acquire significant interest. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, is mediated by changes in the protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetyl(methyl)phosphinate (AcMeP) or acetylphosphonate methyl ester (AcPMe), followed by the assessment of physiological parameters, brain protein acylation, and expression/phosphorylation of PDHA subunit. At the same dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins with apparent molecular masses of 15-20 kDa. Regarding the proteins of 30-50 kDa, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. The unchanged succinylation of the 30-50 kDa proteins after the administration of AcMeP coincides with the upregulation of desuccinylase SIRT5. No significant differences between the levels of brain PDHA expression, PDHA phosphorylation, parameters of behavior or ECG are observed in the studied animal groups. The data indicate that the short-term inhibition of brain PDH affects acetylation and/or succinylation of the brain proteins, that depends on the inhibitor potency, protein molecular mass, and acylation type. The homeostatic nature of these changes is implied by the stability of physiological parameters after the PDH inhibition.

В статье «Исторические тренды видовой продолжительности жизни человека и актуарной скорости старения» Л.А. Гаврилова и Н.С. Гавриловой проверяется выполнение компенсаторного эффекта смертности (CEM), заключающегося в увеличении скорости старения с уменьшением начальной смертности, в современной популяции людей. При исследовании использовались поперечные данные из базы данных HMDB, а в качестве инструментария количественной оценки CEM - математические модели Гомпертца, Гомпертца-Мэйкхема, проводилось сравнение с зависимостью, называемой «корреляция Стрелера-Милдвана». Корреляция Стрелера-Милдвана вытекает из общей теории «General theory of mortality and aging», опирающейся на понятия жизненной силы организма (vitality) и устойчивости организма к внешнему негативному воздействию. Её развитие содержится в работе Yashin et al. Важно отметить, что теоретически все три подхода описывают старение одного организма, а не группы или популяции. В статье Гавриловых это обстоятельство игнорируется и обсуждается в настоящем комментарии.