Regulatory Mechanisms Research Articles

Addressing Internal Migration Challenges in Kazakhstan: A Systematic Approach

This research article provides a comprehensive analysis of migration processes within Kazakhstan, focusing on the challenges in internal migration. The current trends in internal migration are leading to substantial differences in the distribution of the workforce, negatively affecting both the economy of the country and regional inequalities. The authors present an economic and mathematical model that demonstrates a connection between a decrease in the appeal of migration to certain locations and a fall in the gross regional product. Furthermore, a thorough examination of the legal framework, program execution, and policy documents reveals problems in the effective use of regulatory mechanisms, particularly in relation to rural migration issues. The study presents a systematic approach and an organizational regulatory scheme to improve the scientific methodology. This scheme takes into account numerous aspects and conditions that affect internal population migration dynamics. Received: 11 July 2024 / Accepted: 31 October 2024 / Published: 05 November 2024

SlVQ15 recruits SlWRKY30IIc to link with jasmonate pathway in regulating tomato defence against root-knot nematodes.

Tomato is one of the most economically important vegetable crops in the world and has been seriously affected by the devastating agricultural pest root-knot nematodes (RKNs). Current understanding of tomato resistance to RKNs is quite limited. VQ motif-containing family proteins are plant-specific regulators; however, whether and how tomato VQs regulate resistance to RKNs is unknown. Here, we found that SlVQ15 recruited SlWRKY30IIc to coordinately control tomato defence against the RKN Meloidogyne incognita without affecting plant growth and productivity. The jasmonate (JA)-ZIM domain (JAZ) repressors of the phytohormone JAs signalling associated and interfered with the interaction of SlVQ15 and SlWRKY30IIc. In turn, SlWRKY30IIc bound to SlJAZs promoters and cooperated with SlVQ15 to repress their expression, whereas this inhibitory effect was antagonized by SlJAZ5, forming a feedback regulatory mechanism. Moreover, SlWRKY30IIc expression was directly regulated by SlMYC2, a SlJAZ-interacting negative regulator of resistance to RKNs. In conclusion, our findings revealed that a regulatory circuit of SlVQ15-SlWRKY30IIc and the JA pathway fine-tunes tomato defence against the RKN M. incognita, and provided candidate genes and clues with great potential for crop improvement.

MYB168 and WRKY20 transcription factors synergistically regulate lignin monomer synthesis during potato tuber wound healing.

Lignin is a critical component of the closing layer of the potato (Solanum tuberosum L.) tuber during healing; however, the molecular mechanism of its formation remains poorly understood. To elucidate the molecular mechanism of tuber healing, we screened the genes encoding transcription factors that regulate lignin synthesis(StMYB24/49/105/144/168, StWRKY19/20/22/23/34) and the key genes involved in lignin monomer synthesis (PHENYLALANINE AMMONIA LYASE 5 (StPAL5) and CINNAMYL ALCOHOL DEHYDROGENASE 14 (StCAD14)) for induced expression after wounding using transcriptome data. DLR, Y1H, EMSA, and ChIP-qPCR assays revealed that StMYB168 could bind directly to the StPAL5 and StCAD14 promoters to activate their expression and that StWRKY20 enhanced this regulation with a synergistic effect. Y2H, BiFC, and Co-IP assays showed that StMYB168 interacted with StWRKY20 to form a MYB-WRKY complex. Furthermore, transient overexpression of StMYB168 and StWRKY20 in Nicotiana benthamiana leaves upregulated the expression of NbPAL and NbCAD10 and promoted lignin accumulation in the leaves. In addition, overexpression of StWRKY20 and StMYB168 together resulted in higher expression levels of NbPAL and NbCAD10 and higher levels of lignin monomer and total lignin. In contrast, silencing of StMYB168 and StWRKY20 in potato significantly reduced the lignin content of wounded tubers. In conclusion, StMYB168 and StWRKY20 are important regulators of lignin biosynthesis in potato tubers during healing and can positively regulate lignin biosynthesis by forming a complex. The elucidation of this regulatory module provides information on the regulatory mechanism of lignin monomer synthesis in wounded tubers at the transcriptional level.

The Spatial-Temporal Alternative Splicing Profile Reveals the Functional Diversity of FXR1 Isoforms in Myogenesis.

Alternative splicing (AS) is a fundamental mechanism contributing to proteome diversity, yet its comprehensive landscape and regulatory dynamics during skeletal muscle development remain largely unexplored. Here, the temporal AS profiles are investigated during myogenesis in five vertebrates, conducting comprehensive profiling across 27 developmental stages in skeletal muscle and encompassing ten tissues in adult pigs. The analysis reveals a pervasive and evolutionarily conserved pattern of alternative exon usage throughout myogenic differentiation, with hundreds of skipped exons (SEs) showing developmental regulation, particularly within skeletal muscle. Notably, this study identifies a muscle-specific SE (exon 15) within the Fxr1 gene, whose AS generates two dynamically expressed isoforms with distinct functions: the isoform without exon 15 (Fxr1E15 -) regulates myoblasts proliferation, while the isoform incorporating exon 15 (Fxr1E15+) promotes myogenic differentiation and fusion. Transcriptome analysis suggests that specifically knocking-down Fxr1E15+ isoform in myoblasts modulates differentiation by influencing gene expression and splicing of specific targets. The increased inclusion of exon 15 during differentiation is mediated by the binding of Rbm24 to the intron. Furthermore, in vivo experiments indicate that the Fxr1E15+ isoform facilitates muscle regeneration. Collectively, these findings provide a comprehensive resource for AS studies in skeletal muscle development, underscoring the diverse functions and regulatory mechanisms governing distinct Fxr1 isoforms in myogenesis.

MiR-144/451: A Regulatory Role in Inflammation.

Inflammation is the natural defense mechanism of the body in response to injury, infection, or other stimuli. Excessive or persistent inflammatory responses can lead to the development of inflammatory diseases. Therefore, elucidating the regulatory mechanisms of inflammatory cells is crucial for understanding the pathogenesis of such diseases and devising novel therapeutic approaches. Moreover, miR-144/451 plays an important role in erythroid maturity and tumour development. Herein, we have reviewed the regulatory role of miR-144/451 in inflammation. Papers on miR-144, miR-451, and inflammation were retrieved from PubMed and Web of Science to be analysed and summarised. miR-144/451 plays a significant role in modulating inflammatory responses. Pro- and anti-inflammatory gene transcription is regulated by miR-144/451 binding to the 3' untranslated regions. Studies have shown that miR-451 inhibits the activation of various inflammatory cells, including macrophages, neutrophils, and T lymphocytes, thereby reducing the release of inflammatory mediators. However, miR-144 expression varies in different inflammatory diseases. miR-144 expression is downregulated in macrophages after induction by lipopolysaccharide, cysteine, or Mycobacterium tuberculosis, which promotes the secretion of inflammatory mediators; nonetheless, miR-144-3p overexpression in macrophages can aggravate atherosclerosis. Meanwhile, miR-144 overexpression prevents disruption of the lung endothelial cell barrier, whereas it exacerbates endothelial cell injury in Crohn's disease. miR-144/451 may serve as a potential target for the treatment of inflammatory diseases.

Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis

BackgroundResistance acquired after radiotherapy is directly related to the failure of various cancer treatments, including GBM. Because the mechanism for overcoming radioresistance has not yet been clearly identified, the development of diagnostic and therapeutic markers to treat radioresistance is necessary. Since increased expression of stemness- and EMT-related markers are reported to be closely correlated with radioresistance, research is underway to develop new drugs targeting these factors.MethodsTo develop an anticancer drug that overcomes radioresistance, a library of drugs already approved by the FDA was used. After treating radioresistant GBM cells with each drug, the expression of stemness- and EMT-related markers was confirmed by qRT-PCR, and as a result, Atomoxetine (ATX) was selected. It was confirmed that radioresistance-induced cell migratory, invasive, sphere formation abilities, and tumor growth using a xenograft mouse model were suppressed upon ATX treatment. Using a miRNA prediction tool, we discovered miR-520d-5p, which targets Notch2 and Hey1, key factors in radioresistance, and discovered circATIC targeting this miRNA, revealing its relationship with ATX. We demonstrated the expression regulation mechanism and signaling mechanism between circATIC, miR-520d-5p, Notch2, and Hey1 factors using a luciferase reporter assay. In addition, the results at the cellular level were clinically verified by confirming the correlation between radiation, miR-520d-5p, and circATIC using patient plasma by qRT-PCR.ResultsATX showed potential as a treatment for radioresistance by suppressing the malignant phenotype by regulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling mechanism in vitro and in vivo using radioresistant GBM cells.ConclusionsThis study revealed that ATX suppresses radioresistance through the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway. These results showed the potential of ATX as a new drug that can overcome radioresistance, a major challenge in cancer treatment, and the signaling factors identified in this mechanism suggest the possibility of use as potential targets for the diagnosis and treatment of radioresistance.

Mechanisms of lipid-mediated regulation of the pore-forming activity of antimicrobial agents: studies on planar lipid bilayers

Planar lipid bilayers are unique tools designed for modeling cell membranes and electrophysiological studies of incorporated ion channels. Such model systems are designed to limit the number of components taking part in the functioning of biological membranes in order to characterize in detail the occurring processes under well-controlled experimental conditions. Planar lipid bilayers make it possible to record single events with a measured current of more than a tenth of a picoampere. The relative simplicity of the method, the ability to observe single molecular events, and the high reproducibility of the results obtained determines the unprecedented effectiveness of using planar lipid bilayers to identify key physical and chemical factors responsible for regulating the functioning of ion channels. This review represents an analysis of literature data concerning the mechanisms of lipid-associated regulation of ion channels formed by various antimicrobial agents. The examination allows us to consider the lipids as molecular chaperones that ensure the formation of pores in target membranes by antimicrobials.

Air Quality Legislation in Australia and Canada—A Review

Air pollution is a pervasive global issue affecting human health, ecosystems, and the environment. This paper reviews the evolution and implementation of air quality legislation in Australia and Canada, providing a comparative analysis of their approaches to managing air pollution. Both countries have established robust legal frameworks to address air quality issues, involving governmental policies, regulatory mechanisms, and collaborative efforts among stakeholders. Australia began its air quality regulation at the state level in the 1950s, evolving into a national framework with the National Environment Protection Measure for Ambient Air Quality in 1998. In contrast, Canada centralized its efforts with the Clean Air Act in 1971, complemented by the National Air Pollution Surveillance program. Key findings reveal that, while both nations have achieved significant improvements in air quality, challenges remain in addressing the broader impacts of air pollution, such as climate change and health-related economic burdens. Australia’s air quality standards are generally more stringent than Canada’s for particulate matter but more relaxed for sulfur dioxide, nitrogen dioxide, and ozone. Both countries employ advanced air quality monitoring and reporting systems, with Australia’s Air Quality Index and Canada’s Air Quality Health Index providing critical public health information. The study highlights the need for continuous improvement and a more integrated approach to air quality management. By examining the legislative and regulatory landscapes of Australia and Canada, this paper offers valuable insights for other countries striving to enhance their air quality governance and mitigate the adverse effects of air pollution on a global scale.

Structure and function of the proton channel OTOP1

OTOP1 belongs to the otopetrin family of membrane proteins that form proton channels in cells of diverse types. In mammals, OTOP1 is involved in sour transduction in taste cells and contributes to otoconia formation in the inner ear. From the structural point of view, otopetrins, including OTOP1, represent a quasi-tetramer consisting of four α-barrels. The exact transport pathways mediating proton flux through the OTOP1 channel and gating units modulating its activity are still a matter of debate. This review discusses current data on structural and functional features of OTOP1. Suggested proton transport pathways, regulatory mechanisms, and key amino acid residues determining functionality of the otopetrins are considered. The existing kinetic models of OTOP1 are discussed as well. Based on revealed functional properties, OTOP1 is suggested to operate as a logical XOR element that allows for proton flux only if transmembrane pH gradient exists.

Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption.

Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation-induced heart damage (RIHD) are unclear. As a novel post-translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label-free lactylation omics, protein disulfide-isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p-GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain-containing GRB2-like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1-mediated mitoROS accumulation, eventually suppressing calcium-binding and coiled-coil domain-containing protein 2 (NDP52)-induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2-mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.

IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.

Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

Regulation mechanism of nitrite degradation in Lactobacillus plantarum WU14 mediated by Fnr.

Fumarate and nitrate reduction regulatory protein (Fnr)-a global transcriptional regulator-can directly or indirectly regulate many genes in different metabolic pathways at the top of the bacterial transcription regulation network. The present study explored the regulatory mechanism of Fnr-mediated nitrite degradation in Lactobacillus plantarum WU14 through gene transcription and expression analysis of oxygen sensing and nir operon expression regulation by Fnr. The interaction and the mechanism of transcriptional regulation between Fnr and GlnR were also examined under nitrite stress. After Fnr and GlnR purification by glutathione S-transferase tags, they were successfully expressed in Escherichia coli by constructing an expression vector. The results of electrophoresis mobility shift assay and qRT-PCR indicated that Fnr specifically bound to the PglnR and Pnir promoters and regulated the expression of nitrite reductase (Nir) and GlnR. After 6-12h of culture, the expressions of fnr and nir under anaerobic conditions were higher than under aerobic conditions; the expression of these two genes increased with sodium nitrite (NaNO2) addition during aerobic culture. Overall, the present study indicated that Fnr not only directly participated in the expression of Nir and GlnR but also indirectly regulated the expression of Nir through GlnR regulation.

The dynamic N1-methyladenosine RNA methylation provides insights into the tomato fruit ripening.

N1-methyladenosine (m1A) methylation is an essential mechanism of gene regulation known to impact several biological processes in living organisms. However, little is known about the abundance, distribution, and functional significance of mRNA m1A modification during fruit ripening of tomato the main model species for fleshy fruits. Our study shows that m1A modifications are prevalent in tomato mRNA and are detected in lncRNA and circRNA. The distribution of m1A peaks in mRNA segments indicates that m1A is mainly enriched at the start codon and CDS regions. Assessing changes in global RNA methylation during fruit ripening in wild-type tomatoes and in the ripening-impaired Nr mutant affected in the ethylene receptor gene (SlETR3) revealed a decrease in the overall methylation levels from mature green (MG) stage to 6 days postbreaker (Br + 6). Nr mutant fruits show significantly lower methylation levels than Ailsa Craig (AC) fruits. Notably, differences in m1A methylation are well correlated to the expression levels of a number of key ripening-related genes. The integration of RNA-seq and MeRIP-seq data suggests a potential positive impact of m1A modifications on gene expression. In comparison to the AC fruits, the hypomethylation and reduced expression of ethylene-related genes, ACO3, EBF1, and ERF.D6, in the Nr mutants likely underpin the distinct phenotypic traits observed between the two fruit genotypes at the Br6 stage. Overall, our study brings further arguments supporting the potential significance of m1A methylation modifications in fruit ripening, a developmental process that is instrumental to plant reproduction and to fruit sensory and nutritional qualities.

Critical role of ROCK1 in AD pathogenesis via controlling lysosomal biogenesis and acidification

BackgroundLysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer’s disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood.MethodsROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1–TFEB axis on lysosomes in APP/PS1 transgenic mice.ResultsROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevation resulted in abundant extracellular Aβ deposition which in turn bound to Aβ receptors and activated RhoA/ROCK1, thus forming a vicious circle of AD pathogenesis. Genetically downregulating ROCK1 lowered its interference with TFEB, promoted TFEB nuclear distribution, lysosomal biogenesis and lysosome-mediated Aβ clearance, and eventually prevented pathological traits and cognitive deficits in APP/PS1 mice.ConclusionIn summary, our results provide a mechanistic insight into the critical role of ROCK1 in lysosomal regulation and Aβ clearance in AD by acting as a novel upstream serine kinase of TFEB.

Carnosine Synthase (TsATPGD) Alleviates Lipid Peroxidation Under Transcriptional Control by an Nfe2-like Gene in Tridacna Squamosa

As an important mollusk in reef ecosystems, Tridacna squamosa forms pro-survival symbiotic relationships that hinge on an exquisite redox equilibrium between the host and the photosynthetic symbiont, zooxanthellae. The exact regulatory mechanisms thereof remain poorly understood. In this study, a novel Nfe2-like transcription factor in T. squamosa was identified and characterized with respect to its antioxidant and cytoprotective roles. Gene structure and phylogenetic analysis reveal that T. squamosa possesses a single transcription factor TsNfe2l in contrast to mammalian Nfe2l1 (Nrf1) and Nfe2l2 (Nrf2), belonging to protein members of the bZIP-NFE2 subfamily and functionally resembling the mammalian Nfe2l1. A conserved bZIP domain permits its binding to the antioxidant response element (ARE) in vitro and in HEK293T cells. Further analyses such as promoter prediction suggest that TsNfe2l target genes engage mainly in the regulation of multiple enzymes involved in antioxidation and allied pathways. Notably, TsNfe2l transcriptionally upregulates carnosine synthase (TsATPGD), which subsequently produces L-carnosine abundantly to shield cells from oxidative damage. Moreover, the blockage of TsNfe2l nucleic acid binding reduced the expression of TsATPGD and L-carnosine content in the gill, resulting in elevated lipid peroxidation. Collectively, our findings establish novel molecular insight into TsNfe2l as a critical regulator of redox homeostasis in T. squamosa through carnosine synthesis.

Alternative splicing is coupled to gene expression in a subset of variably expressed genes

Numerous factors regulate alternative splicing of human genes at a co-transcriptional level. However, how alternative splicing depends on the regulation of gene expression is poorly understood. We leveraged data from the Genotype-Tissue Expression (GTEx) project to show a significant association of gene expression and splicing for 6874 (4.9%) of 141,043 exons in 1106 (13.3%) of 8314 genes with substantially variable expression in nine GTEx tissues. About half of these exons demonstrate higher inclusion with higher gene expression, and half demonstrate higher exclusion, with the observed direction of coupling being highly consistent across different tissues and in external datasets. The exons differ with respect to multiple characteristics and are enriched for hundreds of isoform-specific Gene Ontology annotations suggesting an important regulatory mechanism. Notably, splicing-expression coupling of exons with roles in JUN and MAP kinase signalling could play an important role during cell division.

Comprehensive Analysis and Verification of the Prognostic Significance of Cuproptosis-Related Genes in Colon Adenocarcinoma

Colon adenocarcinoma (COAD) is a frequently occurring and lethal cancer. Cuproptosis is an emerging type of cell death, and the underlying pathways involved in this process in COAD remain poorly understood. Transcriptomic and clinical data for COAD patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We investigated alterations in DNA and chromatin of cuproptosis-related genes (CRGs) in COAD. In order to identify predictive differentially expressed genes (DEGs) and various molecular subtypes, we used consensus cluster analysis. Through univariate, multivariate, and Lasso Cox regression analyses, four CRGs were identified. A risk prognostic model for cuproptosis characteristics was constructed based on four CRGs. This study also examined the association between the risk score and the tumor microenvironment (TME), the immune landscape, and drug sensitivity. We distinguished two unique molecular subtypes using consensus clustering analysis. We discovered that the clinical characteristics, prognosis, and TME cell infiltration characteristics of patients with multilayer CRG subtypes were all connected. The internal and external evaluations of the predicted accuracy of the prognostic model built using data derived from a cuproptosis risk score were completed at the same time. A nomogram and a clinical pathological analysis make it more useful in the field of medicine. A significant rise in immunosuppressive cells was observed in the high cuproptosis risk score group, with a correlation identified between the cuproptosis risk score and immune cell infiltration. Despite generally poor prognoses, the patients with a high cuproptosis risk but low tumor mutation burden (TMB), cancer stem cell (CSC) index, or microsatellite instability (MSI) may still benefit from immunotherapy. Furthermore, the cuproptosis risk score positively correlated with immune checkpoint gene expression. Analyzing the potential sensitivity to medications could aid in the development of clinical chemotherapy regimens and decision-making. CRGs are the subject of our in-depth study, which exposed an array of regulatory mechanisms impacting TME. In addition, we performed additional data mining into clinical features, prognosis effectiveness, and possible treatment medications. COAD’s molecular pathways will be better understood, leading to more precise treatment options.

Morphological and molecular mechanisms of floral nectary development in Chinese Jujube

BackgroundChinese jujube (Ziziphus jujuba Mill.), also called Chinese date, is one of the oldest and widely cultivated fruit trees with great economic values, which, at least, can be attributed to the melliferous flower with highly developed nectary that can secret huge amount of nectar in a rather tiny floral size. However, the morphological nature, metabolic products, developmental process, as well as molecular and regulatory mechanisms of jujube nectary remain largely unknown.ResultsHere, we selected Z. jujuba ‘Dongzao’ as a system to address these questions. We uncovered that the jujube nectary is an annular or donut-shaped secretory protrusion that surrounds the base of the carpels, along with emerald and glistening hues, which can produce a bulk honey with many metabolic compounds (e.g. saccharides and flavonoids) that has a high nutritional value and benefit for human health. The development of jujube nectary is a dynamic process of earlier cell division followed by later cell expansion. We also identified putative genes associated with the nectary development and found that the CRABS CLAW (CRC) ortholog (ZjCRC) is the key to nectary development: the gene is highly expressed in nectary; ectopic expression of it in the Arabidopsis crc-1 mutant rescued the lost nectary (also the carpel and silique defects). We also demonstrated that a MADS-box transcription factor ZjAGAMOUS1 (ZjAG1) is required for the direct activation of ZjCRC expression.ConclusionsTaken together, our results not only provide a comprehensive portrait of the jujube nectary, but also pave the way to effective utilization of jujube and other woody crops.

Exploration of common pathogenesis and candidate hub genes between HIV and monkeypox co-infection using bioinformatics and machine learning

This study explored the pathogenesis of human immunodeficiency virus (HIV) and monkeypox co-infection, identifying candidate hub genes and potential drugs using bioinformatics and machine learning. Datasets for HIV (GSE 37250) and monkeypox (GSE 24125) were obtained from the GEO database. Common differentially expressed genes (DEGs) in co-infection were identified by intersecting DEGs from monkeypox datasets with genes from key HIV modules screened using Weighted Gene Co-Expression Network Analysis (WGCNA). After gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and construction of protein-protein interaction (PPI) network, candidate hub genes were further screened based on machine learning algorithms. Transcriptional factors (TFs) and miRNA-candidate hub gene networks were constructed to understand regulatory mechanisms and protein-drug interactions to identify potential therapeutic drugs. Seven candidate hub genes—MX2, ADAR, POLR2H, RPL5, IFI16, IFIT2, and RPS5—were identified. TFs and miRNAs associated with these hub genes, playing a key role in regulating viral infection and inflammation due to the activation of antiviral innate immunity, were also identified through network analysis. Potential therapeutic drugs were screened based on these hub genes: AZT, a nucleotide reverse transcriptase inhibitor, suppressed viral replication in HIV and monkeypox co-infection, while mefloquine inhibited inflammation due to the activation of antiviral innate immunity. In conclusion, the study identified candidate hub genes, their transcriptional regulation, signaling pathways, and small-molecule drugs in HIV and monkeypox co-infection, contributing to understanding the pathogenesis of HIV and monkeypox co-infection and informing precise therapeutic strategies.

Концептуальні рамки управління борговим фінансуванням публічних бюджетів

Introduction. Overcoming the consequences of the COVID-19 pandemic and full-scale Russian aggression against Ukraine caused the destruction of a stable system of managing financial flows not only in our country, but also in many states. Market and regulatory mechanisms for mobilization and the use of financial resources were undermined. Fiscal consolidation measures were changed in favor of expansion. The need to increase the resource base on the basis of state debt has intensified. The use of standardized approaches in the field of fiscal policy did not make it possible to limit risks under new conditions. The task of implementing new conceptual approaches to the management of public budget financing based on the use of debt instruments has arisen. Problem Statement. An increase in debt financing of public budgets helps to expand the volume of resources for the implementation of state plans. At the same time, the pressure on the financial system is growing, which requires making significant changes to the formation of the structure of debt instruments, their placement on domestic and foreign financial markets, attraction of resources on preferential terms from foreign partners, fulfillment of repayment and servicing obligations, refinancing and restructuring of loans. Determining rational management decisions on these issues involves the development of a conceptual framework for public debt financing. The purpose is to study the formation of a conceptual framework for managing debt financing of public budgets and their use in the practice of public administration. Methods. Research methods are used: historical, logical, abstraction, description, generalization, comparison, grouping, analysis and synthesis. Results. The adoption of the debt framework guides the definition of debt strategy, debt management goals, indicators of its volume and structure, debt management tasks, as well as mechanisms and tools for their implementation. The debt strategy reflects the orientation of the debt policy, the goals of public debt management for long and medium-term periods, its indicators, the use of tools and mechanisms for achieving the adopted goals, the formation of the debt portfolio for the specified terms, the classification of risks of government debt management taking into account their impact on the performance of state budget, the application of refinancing and restructuring mechanisms for state liabilities. Conclusions. The conceptual framework for managing debt financing of public budget is an important guiding document aimed at taking into account the conditions for placing debt obligations among investors (state institutions, non-state depositors, non-residents), access to international financial markets, cooperation with international organizations and financial institutions, acceptance of debt portfolio (the structure of state budget financing), built according to types of debt instruments, sources of financing, currencies of loan repayment and servicing, repayment terms, loan servicing rates and debt refinancing. The development and implementation of the conceptual framework for the management of public debt transactions is important for Ukraine. In the conditions of overcoming the consequences of the war and post-war reconstruction, it is necessary to apply a comprehensive approach to the formation, distribution and use of resources raised on the basis of the use of public debt instruments.