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Aliphatic aldehydes are involved in many important biological processes, but detection of them at low concentrations requires expensive laboratory equipment and labor-intensive analytical methods. Typically, chromatographic and chromatograph mass spectrometric methods are used for this purpose. Therefore, developing a simple method for detecting aldehydes at low concentrations is a pressing scientific and technical challenge. We have demonstrated that a bacterial bioluminescent system can be effectively used for the semiquantitative determination of biogenic aldehydes in vitro at nanomolar concentrations. Furthermore, this system holds promise for detecting biogenic aldehydes in vivo.
CAG repeats in the first exon of the ATXN2 gene play a key role in the development of a number of neurodegenerative diseases. Understanding the mechanisms underlying CAG tract expansions and the factors influencing them could lead to the development of new methods for the prevention and treatment of these diseases. It was established that a single D/H substitution of a hydrogen bond in the CAG tract increases its stability, thereby reducing the likelihood of formation of secondary structures that interfere with the reading of genetic information from the glutamine-coding region. CAA interruptions in the CAG tract in specific locations can have a similar, but weaker, stabilizing effect.
The lipid envelope of the influenza A virus contains two major types of protein spikes formed by the transmembrane hemagglutinin trimers (HA, MW 80 kDa) and neuraminidase tetramers (NA, MW 55 kDa), in quantities of 500 and 120, respectively. The third transmembrane protein, M2 (MW 14 kDa), forms tetramers of ion channels in quantities of about 10-20 per virion. Modeling of the molecular structure using the AlphaFold software tool showed a novel model for a heterocomplex of HA0-M2 proteins, in which the M2 tetramer located inside the HA0 trimer like a "matryoshka doll." Similar models of the HA0-M2 heterocomplex were obtained for the A/Aichi/2/68 (H3N2) and A/WSN/33 (H1N1) viruses. The resulting HA0-M2 heterocomplex possessed a high structural complementarity of the macromolecular interfaces (ipTM = 0.65), had no structural clashes of atoms in the molecular interfaces (clash score = 0.0), and exhibited stable and reliable intermolecular topology with a high ranking score of 0.79. The constructed model allows to explain the phenomenon of blocking the function of M2 ion channels by the rigid conformation of the uncleaved HA0 protein and, in contrast, the activation of M2 channels after (i) specific point proteolysis of HA0 into HA1 (55 kDa) and HA2 (25 kDa) subunits and (ii) exposure to acidic pH of 4.0-5.5, leading to the disclosure of the 3D structure of the HA1/2 molecule and the opening of the M2 channel.
Genetic predisposition without doubt is one of the risk factors of cancer initiation. It is known that single nucleotide polymorphisms (SNP) of genes that maintain the genome stability, including SNP of DNA repair, may contribute to the initiation of carcinogenesis. Single-nucleotide polymorphisms of genes that support genome stability, including SNP of DNA repair genes, can contribute to cancer initiation. Polymorphism of the excision repair gene OGG1 causes interest of leading scientific groups from various countries. It is assumed that there is relationship between the rs1052133 polymorphism in the gene and predisposition to cancer initiation. The objective of this study was to establish association between rs1052133 polymorphism of base excision repair gene OGG1 and the risk of cancer initiation in people chronically exposed to ionizing radiation. Residents (888 people) of the Techa riverside settlements, chronically exposed to low or medium dose radiation from the Techa River and the East-Urals Radioactive Trace were included in the study. The study allowed researchers to establish that exposed to chronic radiation people, carriers of the rs1052133*G allele, have increased risk of malignant neoplasm initiation: OR = 1.38; 95% CI [1.05-1.83], p = 0.023. The multifactorial synergistic interactions between the dose to the red bone marrow and the rs1052133 polymorphism of the OGG1 gene was found: Testing Balanced Accuracy (TBA) = 0.56; Cross Validation Consistency (CVC) = 10/10; p = 0.01). The study found that the rs1052133 polymorphism may be considered as genetical marker of risk of cancer initiation in people chronically exposed to radiation with doses ranged from 0.74 to 3507.07 mGy (average 523.10 ± 33.89 mGy). It was found that the presence of the rs1052133*G in combination with radiation exposure can modify the risk of solid cancers initiation, as it is indicated by the synergistic relationship between the SNP and the radiation dose.
Tag proteins, widespread among prokaryotes, are DNA glycosylases that participate in the repair of alkylated DNA excising 3-methyladenine. Among eukaryotes, Tag homologs are found only in plants, but they have not yet been characterized. Here, we report the first study of a plant Tag homolog, BvTAG1 from sugar beet (Beta vulgaris). Unlike bacterial Tags, BvTAG1 lacks activity towards alkylated DNA, which can be explained by the mutation of the critical catalytic Glu residue to Ser. At the same time, BvTAG1 exhibits a high affinity for undamaged DNA, mediated by a long N-terminal tail characteristic of all plant Tag homologs. This binding further increases in the presence of free 3-methyladenine. Our results suggest that plant Tag homologs may be required for regulating the plant response to genotoxic stress, rather than for DNA repair.
The iab-5 domain regulates transcription of the Abdominal-B (Abd-B) gene in A5 and A6 segments throughout Drosophila development. The iab-5 domain contains an initiator, which determines domain activity, and two enhancers that activate Abd-B in the A5 and A6 cuticle cells, which ensures pigmentation of these segments in adult males. In the present study, we demonstrated that deletion of the iab-5 initiator on one chromosome can negatively affect the initiator located on the homologous chromosome. This is reflected in the appearance of unpigmented spots on segment A5 in males. Isolation of the domain by an insulator and deletion of the boundary sequences that recruit Polycomb proteins enhance the effect of transvection, which inactivates initiator activity in trans. Thus, the interaction between initiators located on homologous chromosomes determines the formation of a stable activation signal for the regulatory domain throughout the development of Drosophila.
Ferroptosis is considered a promising strategy for inducing the death of tumor cells. However, the effectiveness of known ferroptosis inducers, such as erastin, is in some cases limited, which stimulates the search for new combined application strategies. In this study, the combined effect of erastin and docosahexaenoic acid (DHA) on prostate cancer cells was examined over time. It was shown that the combination of these agents is more toxic compared to their separate use for all tumor cells considered. At the same time, known ferroptosis inhibitors, ferrostatin-1 and deferoxamine, effectively prevented cell death, indicating the specificity of the mechanism of action. Transcriptomic analysis of cell lines differing in sensitivity to the combination revealed activation of antioxidant systems in more resistant cells (in particular, pronounced expression of the NQO1 and GCLM genes responsible for the reduction of quinones to hydroquinones and the synthesis of glutathione, respectively). The obtained results indicate the high synergistic potential of the erastin-DHA combination for ferroptosis induction and open new possibilities for the development of combined approaches to the therapy of resistant tumors.
to compare the efficacy and safety of different doses of colchicine (0.5 mg/day vs. 1.0 mg/day) used for the prevention of arthritis attacks in gout patients during the initiation of urate-lowering therapy. -The study included 96 patients diagnosed with gout. Patients were randomized into three groups: those receiving colchicine 0.5 mg/day, those receiving colchicine 1 mg/day, and those without anti-inflammatory therapy. All participants were prescribed febuxostat 80 mg/day. The duration of the observation period was 6 months. The frequency and severity of arthritis attacks, as well as the incidence of adverse events, were compared. -Patients who did not receive colchicine experienced arthritis attacks more frequently compared to those receiving colchicine 0.5 mg/day (p = 0.03) and 1 mg/day (p = 0.007). In the groups receiving colchicine 0.5 and 1.0 mg/day, the frequency of attacks did not differ significantly (p = 0.6), nor did the proportion of patients who did not experience arthritis attacks (18 (56%) and 22 (69%), respectively, p = 0.3). Among the patients not taking colchicine, 9 (28%) did not develop arthritis attacks (p = 0.02 compared to those taking 0.5 mg/day and p = 0.001 for 1 mg/day). The administration of colchicine 1 mg/day (but not 0.5 mg/day) was associated with lower pain intensity on the visual analog scale (VAS) during arthritis attacks compared to the non-therapy group (p = 0.04). The frequency of adverse events was comparable across the groups. -The use of colchicine 0.5 mg/day for the prevention of arthritis attacks in gout patients is justified due to the absence of differences in efficacy compared to the higher dose. However, prescribing colchicine 1 mg/day also demonstrates a good safety profile and may be considered for the prevention of arthritis attacks.
-Background Interleukin (IL)-6 plays an important role in the pathogenesis of comorbid rheumatoid arthritis (RA) depression. IL-6 inhibitors used to treat patients with RA may also have an antidepressant effect. - of this study is to evaluate the effectiveness of 24-week IL-6 inhibitor therapy with olokizumab (OKZ) in combination with or without psychopharmacotherapy (PPT) in patients with moderate to high RA activity. - A total of 125 patients with RA were included, 102 (81.6%) of them were women. The average age of the patients was 48.5 ± 12.6 years; the majority of the patients (86.4%) had high RA activity and had shown ineffectiveness with stable 12-week therapy using conventional synthetic disease modifying antirheumatic drugs (csDMARDs). Additionally, 34 (27.2%) patients had shown inefficiency with one or more biological DMARDs. According to the International Classification of Diseases, 10th revision (ICD-10), a psychiatrist diagnosed varying severity of depression (chronic or recurrent) in all patients during a semi-structured interview. At week 0, all patients were randomized using sequential numbers in a 2:2:1 ratio into one of three groups: in group 1, patients received csDMARDs + OKZ 64 mg subcutaneously once every 4 weeks (q4w) (n = 49); in group 2, patients received csDMARDs + OKZ 64 mg subcutaneously q4w along with PPT (n = 51); in group 3, patients received csDMARDs + PPT (n = 25). The study duration was 24 weeks. The severity of depression was assessed using the PHQ-9 (Patient Health Questionnaire 9) and MADRS (Montgomery-Asberg Depression Rating Scale) scales, and anxiety was assessed using the HAM-A (Hamilton Anxiety Rating Scale) scale. Projective experimental psychological techniques were also used. - After 12 and 24 weeks of therapy, a significant decrease in the severity of depression and anxiety was observed in all patients' groups. However, the differences between the final and initial values of the scales filled in by a psychiatrist were statistically significantly greater (p < 0.001) in the groups of patients receiving PPT: in group 2 (ΔMADRS24-0 = -20.2 ± 6.57; ΔHAM-A24-0 = -13.2 ± 5.68) and group 3 (ΔMADRS24-0 = -17.8 ± 4.73; ΔHAM-A24-0 = -13.4 ± 4.41), compared with the group 1 (ΔMADRS24-0 = -5.42 ± 7.14; ΔHAM-A24-0 = -4.58 ± 6.80). There were no significant differences between the groups according to the PHQ-9 depression questionnaire (in group 1, ΔPHQ-924-0 = -4.89 ± 4.87; in group 2, ΔPHQ-924-0 = -6.73 ± 4.97; in group 3, ΔPHQ-924-0 = -7.26 ± 5.58, respectively), despite a greater decrease in the severity of depression observed in the groups with PPT. According to a semi-structured interview with a psychiatrist and in accordance with the criteria of ICD-10 the proportion of patients without depression 24 weeks after the start of therapy was significantly higher in the groups receiving PPT: 84.3% in group 2, 100% in group 3, and 16.3% in group 1. - n patients with moderate/high RA activity and comorbid depression, OKZ without PPT can lead to a decrease in the severity of depression or, less often, to a complete regression of depressive symptoms, mainly in patients with minor depression. OKZ therapy without PPT also reduces the severity of anxiety, but does not eliminate it completely. The combination of OKZ and PPT is optimal for achieving complete regression of depression and anxiety in this category of RA patients.
Effective gene therapy depends on efficient delivery of genetic material into cells. Polyplexes, complexes of positively charged polymers and DNA, are a common non-viral delivery system. In this study, polyplexes were formed using a plasmid encoding the yellow fluorescent protein, TurboYFP, and polyethylenimine-polyethylene glycol-(TAT peptide) (PEI-PEG-TAT) block copolymers. These were used to transfect human lung adenocarcinoma A549 cells. Results showed that increasing the PEI nitrogen to DNA phosphate ratio and/or increasing the polyplex concentration significantly improved transfection efficiency, from a few percent up to 100 percent. These findings are valuable for producing specific proteins in cells, which may have applications in research and in the treatment of various diseases.
The SAGA complex is an important player in the regulation of eukaryotic gene transcription. The interaction of SAGA with the TREX-2 mRNA nuclear export complex makes it possible to efficiently transcribe and export mRNA at loci of actively transcribed genes near nuclear pores. However, it remains unclear whether TREX-2 is involved in anchoring the SAGA complex to the nuclear pore. In this work, we investigated the effect of knockdown of the TREX-2 complex subunits, ENY2 and Xmas-2, on the localization of the SAGA catalytic subunit, histone acetyltransferase Gcn5, in Drosophila melanogaster. The effect of knockdown on the distribution of Sgf11, a component of the SAGA deubiquitinating module, and an mRNP particle component, was also studied. We demonstrated that knockdown of ENY2 and Xmas-2 does not affect the localization of Gcn5 and Sgf11 in proximity to the nuclear pore. Therefore, TREX-2 is not required for the association of SAGA with the nuclear pore. Meanwhile, knockdown of ENY2 and Xmas-2 results in nuclear accumulation of Sgf11, suggesting that TREX-2 is involved in the localization of the SAGA-independent fraction of Sgf11 that participates in mRNA export within the mRNP particle.
For the first time, the composition and fatty acid content of Artemia spp. cysts from three hypersaline lakes in Southern Siberia were analyzed. The fatty acid composition of decapsulated Artemia cysts varied significantly between the studied water bodies. It was found that the cyst profiles from Lakes Cheder and Dus-Khol corresponded to a "marine" type, while those from Lake Tus corresponded to a "freshwater" type. An assessment of the biochemical value, including the content of eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid, the ratio of n-3/n-6 fatty acids, as well as hatching rates (hatching efficiency up to 135 thousand specimens/g, the proportion of hatched nauplii up to 85%), allowed us to recommend cysts from Lake Cheder as a promising source for the production of live feed for aquaculture.
The evolutionarily conserved transcription factor ENY2 is a component of several distinct complexes that regulate various stages of gene expression: the SAGA transcription coactivator, the THO transcription elongation complex involved in mRNA processing, and the TREX-2 complex responsible for mRNA export from the nucleus to the cytoplasm. Previous works in D. melanogaster have shown that SAGA associates with the histone locus body (HLB) biomolecular condensate, where histone mRNA transcription and processing take place, whereas TREX-2 interacts with histone mRNA and is involved in its export from the nucleus to the cytoplasm. This study demonstrates that ENY2 is a component of the HLB. ENY2 is present at the histone locus on D. melanogaster polytene chromosomes. ENY2 associates with the chromatin of the histone gene cluster as part of the SAGA coactivator complex and the THO transcription elongation complex, which also interacts with histone gene chromatin. ENY2 and subunits of the SAGA, THO, and TREX-2 complexes interact with FLASH, a specific constituent structural component of the HLB. Thus, ENY2 is present at the HLB biomolecular condensate and participates in histone gene expression as part of three functionally diverse complexes: SAGA, THO, and TREX-2.
Trans-splicing is a rare variant of the splicing process, wherein exons are joined between different pre-mRNAs. This mechanism enables the formation of a broad spectrum of mRNAs encoded by a single locus. The most prominent example in Drosophila melanogaster is the mod(mdg4) locus, where trans-splicing results in the production of more than 30 mRNAs encoding protein isoforms with distinct C-terminal domains. Previous studies have demonstrated that sequences in the 5'-region of the fourth intron of the mod(mdg4) locus play a pivotal role in initiating trans-splicing. In the present study, we show that the integration of MS2 repeats, which form a stable secondary RNA structure, into the sequence of the fourth intron completely suppressed trans-splicing. Conversely, the insertion of MS2 repeats immediately upstream of the intron only marginally reduced the efficiency of this process. Modifications of the sequences of the fourth intron that induce the formation of an additional stem loop in the pre-mRNA also negatively impacted trans-splicing. These findings underscore the significant role of RNA secondary structures in regulating trans-splicing.
A novel trend in anticancer therapy is based on the combination of cytotoxic and metabolic drugs. Bach1 is a transcription factor activating glycolysis and increasing proliferation and metastatic potential in cancer cells. The cytotoxic effect was evaluated for a combination of rotenone, an inhibitor of mitochondrial respiration, and two different inhibitors of Bach1 transcription factor in the prostate cancer cell lines (PC3 and Du145) and colorectal cancer (HT-29 and HCT-116) in a kinetic mode. An enhancement of the cytotoxic action of the combination therapy was observed only for the prostate cancer cell lines PC3 and Du145. No enhancement of cytotoxicity of zinc porphyrin in the presence of rotenone was observed for the НСТ-116 line. The HT-29 line was not sensitive to either inhibitor or their combination with rotenone at 24 h incubation. According to the PCR results, HT-29 was the only line showing an extremely high activation of heme oxygenase 1 (HMOX1) in the presence of the Bach1 inhibitor, pointing to the highest level of the antioxidant defense in this cell line. The sensitivity of the prostate cancer cell lines to the combination therapy points to the significant differences in the metabolism between the prostate and colorectal cell lines.
of the study is to evaluate the efficacy, safety, and immunogenicity of divozilimab (DIV), anti-CD20 monoclonal antibody, in patients with systemic sclerosis (SS). . Patients with SS according to ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) 2013 criteria with modified Rodnan skin score (mRSS) ≥10 and ≤20 and forced vital capacity (FVC) ≥40% from the due took part in the study. Infusions of DIV 250 mg were administered on weeks 0 and 2, and DIV 500 mg on week 24 with the subsequent use in open mode, starting from week 48. This publication presents data obtained for 48 weeks of trial (before the DIV infusion at week 48). Primary endpoint was the change in the mRSS from baseline to week 48. The dynamic of FVC was estimated as the secondary endpoint. The safety evaluation included the frequency and profile of adverse events and adverse reactions (ARs). Immunogenicity was assessed by detection of binding and neutralizing anti-drug antibodies on weeks 2, 24, and 48. : The patients (151) were randomized into two groups: DIV (n = 76) and placebo (n = 75). The most were female; the median duration of the disease was about 3-4 years. The initial value of the mRSS was 14 and 13 points in DIV and Placebo groups, respectively. The change of mRSS from baseline to week 48 was -5.8 ± 1.1 points in DIV group and -2.7 ± 1.0 points in placebo group (adjusted mean difference (AMD) with 95% confidence interval -3.1 (-4.5; -1.7); p < 0.0001). The lung function was stable in patients treated with DIV. A comparable safety profile of DIV and placebo was demonstrated. The most frequent ARs were infusion reactions and a decrease in the number of lymphocytes. There were no severe and serious ARs in DIV group. All infusion reactions were mild and moderate. 5.3% (4/76) patients in DIV group had binding antibodies without neutralizing activity. : Divozilimab has demonstrated a significant decrease in severity of skin fibrosis, a positive effect on the respiratory function, and a favorable safety profile, which allows it to be considered as a promising therapeutic option for SS.
To develop a unified diagnostic algorithm for axial psoriatic arthritis (axPsA). MATERIALS AND METHODS. : A total of 122 patients with psoriatic arthritis (PsA), duration less than 10 years, were included in the study according to CASPAR criteria, provided that they also had axial involvement. Axial involvement was detected in case of radiographic sacroiliitis [(rSI); bilateral grade ≥2 or unilateral grade ≥ 3] or active MRI SI (MRI-SI), or ≥ 1 syndesmophyte(s) of the cervical and/or lumbar spine (CS/LS), or facet joints ankyloses of the CS. Patients were evaluated for the presence of inflammatory back pain (IBP) by ASAS criteria. Back pain lasting over 3 months, that did not meet ASAS criteria was considered chronic back pain (chrBP). HLA-B27 antigen status was observed. RESULTS AND DISCUSSION. : IBP was identified in 87 (71.3%), chrBP-in 35 (28.7%) patients, 49 (40.2%) patients had older age (>40 years) at back pain onset; 120 (98.4%) patients had peripheral arthritis, 75 (61.5%)-dactylitis, 69 (56.6%)-enthesitis, 122 (100%)-psoriasis, 90 (73.8%)-nail psoriasis. Isolated axial disease without peripheral arthritis was found in 2 (1.6%) patients. rSI was detected in 85 (69.7%) patients, in 28 of 85 (32.9%) patients rSI developed without IBP. Spinal lesions of the LS and CS were found in 100 (82.0%) patients, chunky "non-marginal" syndesmophytes-in 60 (49.2%), asymmetrical syndesmophytes of the LS-in 22 of 72 (30.6%), paravertebral ossification-in 5 (4.1%) patients. Isolated spinal lesions without rSI were found in 37 (30.3%), isolated spinal lesions without rSI or MRI-SI-in 21 (17.2%) patients. HLA-B27 was observed in 27 of 86 (31.4%) examined patients. Diagnostic algorithm for axPsA was developed. All PsA patients, regardless whether they experienced IBP/chrBP or not, must undergo diagnostic imaging: pelvis, LS and CS X-ray. In patients without rSI, MRI of the sacroiliac joints should be performed. AxPsA diagnosis must be confirmed by imaging. Axial involvement is detected in case of rSI or MRI-SI, or ≥1 syndesmophyte(s) of the CS/LS, or facet joints ankyloses of the CS.
Trans-splicing, the process where exons from two different pre-mRNA molecules are joined, is an efficient mechanism for generating diverse isoforms encoded by a single locus. This process has been most thoroughly studied in the mod(mdg4) locus of Drosophila. This locus comprises one gene encoding the constant N-terminal part of the Mod(mdg4) protein and five genes that encode over thirty 3'-exons clustered together, determining the diversity of C-terminal domains. In this study, transgenic lines were obtained where a strong polyadenylation signal from the SV40 virus was inserted into two 3'-exon clusters with the aim of halting transcription and, consequently, reducing the frequency of trans-splicing between the constant exons of the mod(mdg4) gene and the 3'-exons of the modified clusters. Unexpectedly, it was found that SV40 polyadenylation signals had no effect on either the transcription level of the clusters or the efficiency of trans-splicing. The results indicate the ability of RNA polymerase II, transcribing the 3'-exons of the mod(mdg4) locus, to overcome even strong polyadenylation signals from SV40.
Aging is a key challenge for modern society. In particular, brain aging is accompanied by chronic inflammation, depletion of energy potential, and an increased level of oxidative stress, with changes in blood composition playing a special role in this process. Recent studies also show that aging progresses non-linearly throughout life. Primates are genetically and anthropometrically the closest laboratory animals to humans, thus representing the most accurate model for research. This study establishes baseline values for biochemical parameters (including the state of the body's antioxidant system), cellular-hematological, and genomic indicators in aging primates of various species, sexes, and ages from the Kurchatov Complex of Medical Primatology. In aging males, the concentration of lipid peroxidation products was lower than in females of the same age and species. Analysis of antioxidant defense parameters indicates a more stable redox balance in old cynomolgus macaques of both sexes, which may be associated with their lower aggressiveness and high adaptability. The biochemical profile analysis in aging rhesus macaques revealed that females exhibit elevated levels of all measured parameters. In aging cynomolgus macaques, there are fewer sex-related differences in blood composition characteristics compared to rhesus macaques. It can be noted that under the housing conditions of the primates at the nursery of the Kurchatov Complex of Medical Primatology, several types of aging based on blood parameters can be observed within the same age category across different species and sexes.
Boron Neutron Capture Therapy (BNCT) is one of the innovative methods for treating oncological diseases. Its selectivity is based on the targeted delivery of the boron-10 isotope to tumor cells, followed by neutron irradiation, the 10B(n, α)7Li reaction occurs with a local release of 2.79 MeV of energy. Budding boron delivery agents are nanoscale systems. This study evaluated in vitro cytotoxicity, accumulation, and retention of elemental boron nanoparticles, synthesized by laser ablation and laser fragmentation, in U87 and BT474 tumor cells and BJ-5ta fibroblasts. It was shown that both types of nanoparticles exhibit low cytotoxicity at therapeutically relevant concentrations. Boron accumulation was maximal after 24 h of incubation and was significantly higher in tumor cells, especially in the BT474 cell line, compared to fibroblasts. The obtained data indicate the promise of these nanoparticles as boron delivery agents for BNCT.