Gene Activation Research Articles

N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation.

The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila XY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of the MSL complex and are critical for the specific recruitment of the complex to the high-affinity 'entry' sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3-7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GS binds to promoters such as MSL1WT but does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.

Multiancestry Genome-Wide Association Study of Early Childhood Caries.

Early childhood caries (ECC) is the most common noncommunicable childhood disease-an important health problem with known environmental and social/behavioral influences lacking consensus genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multiancestry population of U.S. preschool-age children (N = 6,103) ages 3 to 5 y participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used International Caries Detection and Assessment System criteria to measure ECC; the primary trait was the number of primary tooth surfaces with caries experience (i.e., dmfs index). We estimated heritability and concordance rates and conducted genome-wide association analyses to estimate overall genetic effects as well as stratified by sex, household water fluoride, and dietary sugar and leveraged combined gene/gene-environment effects using 2-degree-of-freedom joint tests. Common genetic variants explained 24% of ECC phenotypic variance among unrelated individuals, while concordance rates were 0.64 (95% confidence interval [CI] = 0.42-0.79) among monozygotic twins and 0.44 (95% CI = 0.34-0.53) among first-degree relatives. Across all analyses, we identified 21 novel nonoverlapping genome-wide significant loci (P < 5 × 10-8) and 1 genome-wide significant gene (TAAR6) associated with ECC. The taste receptor activity gene set, with known roles in chemosensing, bacterial recognition, and innate immunity in the oral cavity, was strongly associated with ECC. While no locus remained significant after studywise multiple-testing correction, 3 loci were nominally significant (P < 0.05) and directionally consistent in external cohorts of 285,248 adults (rs1442369, DLGAP1 and rs74606067, RP11-856F16.2) and 18,994 children (rs71327750, SLC41A3). Meanwhile, the strongest marker known to be associated with adult caries (rs1122171, tagging the long noncoding RNA PITX1-AS1) was nominally significant (P = 0.01) and directionally consistent with ECC in our study. Taken together, the results of this study add to the genomics knowledge base for early childhood caries, offer several plausible candidates for future mechanistic studies, and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations.

New complete genome insights into Enterobacter roggenkampii FACU2: a potential player in cadmium bio-removal.

Industrial workplaces, particularly those involved in ore processing or smelting, pose a high risk of exposure to cadmium, a highly toxic metal. This study isolated and identified eight cadmium-resistant strains from industrial wastewater for their ability to resist cadmium. Enterobacter roggenkampii FACU2 demonstrated exceptional cadmium removal capabilities during our analysis, successfully eliminating 62% of the cadmium. Additionally, transmission electron microscopy (TEM) was utilized to examine the morphological change between the most and least efficient strains that responded to cadmium stress at the cellular level. Compared to the control bacteria, the treated bacteria exhibited notably higher levels of cadmium adsorption and accumulation within their cells. A complete genome analysis revealed that E. roggenkampii FACU2 has one chromosome and one plasmid with a size of 4,856,454bp and 80,926bp, respectively, in addition to harboring numerous heavy metal-resistant genes related to cadmium and other heavy metals. Moreover, the gene expression of four cadmium-resistant genes (czcA, cadA, czcC and czcD) showed that the high cadmium concentration led to a significant increase in czcA and cadA mRNA levels, thus indicating the activation of cadmium-resistant genes in the E. roggenkampii FACU2 compared to Enterobacter sp. strain FACU. Due to its ability to remove cadmium and other heavy metals, this strain holds promise as a source of genes for biological treatment methods. This application could contribute to environmental purification, ultimately benefiting human health.

Genome-wide characterization of Solanum tuberosum UGT gene family and functional analysis of StUGT178 in salt tolerance

UDP-glycosyltransferases (UGTs) widely exist in plants and play essential roles in catalyzing the glycosylation reaction associated with metabolic processes. UGT gene family has been identified in many species to date. However, the comprehensive identification and systematic analysis have not been documented yet in the latest potato genome. In this study, a total of 295 UGT members (StUGT) were identified and found to be unevenly distributed on twelve chromosomes of potato. All StUGT genes were classified into 17 groups (A-P, R) and the UGT genes within the same groups have similar structural characterization. Tandem duplication was the major driving force for the StUGT gene expansion. The prediction of cis-acting elements showed that the development process, light, phytohormone, and abiotic stress-responsive elements generally existed in StUGT promoter regions. Analysis of spatial and temporal expression patterns demonstrated that StUGT genes were widely and differentially expressed in various tissues. Additionally, to investigate the salt stress-responsive genes, we analyzed the expression profiles of the StUGT genes under salt treatment. A total of 50 and 20 StUGT genes were continuously up- and down-regulated, respectively, implicating that these genes were involved in the regulation of salt tolerance. Among them, the StUGT178 gene, which was significantly induced by salt stress and contains salt-responsive element, was considered as one of the most relevant candidate genes. Transient transformation of the StUGT178 promoter in tobacco revealed that the transcriptional activation activity of the StUGT178 gene was strengthened under salt treatment. Furthermore, the heterologous expressions of the promoter and coding protein of the StUGT178 gene in Arabidopsis further demonstrated that the StUGT178 gene significantly responds to salt treatment, and enhanced salinity tolerance by regulating antioxidant enzyme activity and H2O2 accumulation. These results provide comprehensive information for a better understanding of the StUGT genes and offer a foundation for uncovering their function associated with salt stress in potato.

LINC02257 regulates malignant phenotypes of colorectal cancer via interacting with miR-1273g-3p and YB1

Colorectal cancer (CRC) is the third most common cancer diagnosed and the second leading cause of cancer-related deaths. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) are involved in the progression of various types of cancer. In this study, we aimed to identify potential causal lncRNAs in CRC through comprehensive multilevel bioinformatics analyses, coupled with functional validation. Our bioinformatics analyses identified LINC02257 as being highly expressed in CRC, and associated with poor survival and advanced tumor stages among patients with CRC. Genome-wide association analysis revealed significant associations between variants near LINC02257 and CRC, suggesting a causal role for LINC02257 in CRC. Network analysis identified LINC02257 as playing a key role in the epithelial-mesenchymal transition pathway. Single-cell RNA sequencing showed that elevated expression of LINC02257 was associated with a reduced proportion of epithelial cells. In vitro experiments showed that LINC02257 positively regulated the metastatic and proliferative potential of CRC cells. Mechanistically, LINC02257 affected CRC malignancy by functioning as a competitive endogenous RNA of microRNAs and RNA-binding proteins. LINC02257 upregulated SERPINE1 by sequestering tumor suppressive miR-1273g-3p, thereby increasing metastatic and proliferative abilities of CRC cells. Additionally, LINC02257 directly interacted with YB1 and induced its phosphorylation, thereby facilitating YB1 nuclear translocation. The transcriptional activation of YB1 target genes was associated with the oncogenic functions of LINC02257. Taken together, our results demonstrate LINC02257 as a promising therapeutic target for CRC treatment.

LAG3 immune inhibitors: a novel strategy for melanoma treatment

Melanoma, a highly aggressive skin cancer, poses significant challenges in treatment, particularly for advanced or metastatic cases. While immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1, has transformed melanoma management, many patients experience limited responses or develop resistance, highlighting the need for new therapeutic strategies. Lymphocyte activation gene 3 (LAG-3) has emerged as a promising target in cancer immunotherapy. LAG-3 inhibitors have shown potential in restoring T cell functions and enhancing anti-tumor immunity, particularly when used in combination with existing ICIs. This review discusses the latest advancements in LAG-3 inhibition for advanced melanoma, emphasizing its role in overcoming resistance and improving patient outcomes.

The Effect of Gender on the Intestinal Flora of Colorectal Cancer Under Different Stages.

This study aims to determine whether gender is a factor in the interplay between the human intestinal flora and colorectal cancer (CRC), ultimately providing new evidence for the clinical prediction and management of CRC in different genders. In this study, we included 186 untreated CRC patients, and classified them into two groups based on pathological staging: Groups Ⅰ-Ⅱ and Groups Ⅲ-Ⅳ, with male and female groups within each group. We collected preoperative fecal samples from these patients and performed 16S rRNA gene sequencing to analyze their intestinal flora. In the CRC Stages I-II cohort, the gut microbiota of the female group exhibited greater diversity and abundance compared to the male group, with a total of 13 gut microbiota demonstrating significant disparities. Notably, s__Parabacteroides gordonii, s__Bacteroides faecis, and s__Bacteroides nordii were found to be more prevalent in the female group relative to the male group. Within the CRC Stages III-IV cohort, 51 gut microbiota exhibited significant differences between the genders. In the immunocyte composition of fecal samples from patients with CRC, a higher proportion of naive B cells is observed in the male group as compared to the female group. In female CRC patients within the CRC Stages III-IV cohort, Actinomyces exhibited a significant negative correlation with activated dendritic cells, CD4+ memory T cells, and eosinophils. In male CRC patients within the CRC Stages III-IV cohort, Actinomyces demonstrated a significant positive correlation with naive B cells and a significant positive correlation with immune activation genes TNFRSF25 and TMIGD2. In female CRC patients within the CRC Stages III-IV cohort, Actinomyces showed a significant negative correlation with activated dendritic cells, CD4+ memory T cells, and eosinophils, and a significant positive correlation with immune activation genes TNFSF13B, LTA, KLRK1, and CXCL12. In the CRC Stages I-II group, the female group's intestinal flora is more diverse and richer than the male group. In the CRC Stages III-IV group, there are a total of 51 different intestinal flora in both the male and female groups. We also found that Actinomyces affects the occurrence and development of CRC in the male and female groups through different pathways. The results show that the intestinal flora differs between male and female CRC patients and is closely associated with cancer development.

Gene-Activating Framework Nucleic Acid-Targeted Upregulating Sirtuin-1 to Modulate Osteoimmune Microenvironment for Diabetic Osteoporosis Therapeutics.

Diabetic osteoporosis, a prevalent chronic complication of diabetes, is marked by reduced bone mass, increased bone fragility, and susceptibility to fractures. A significant cause of this condition is the disruption of osteoblastic homeostasis due to prolonged hyperglycemia, which impedes bone regeneration and remodeling. Despite its prevalence, no effective treatments specifically target diabetic osteoporosis. Recently, small-activating RNA (saRNA) therapy has attracted attention for its targeting capacity, high efficacy, and minimal side effects. However, RNA's inherent properties, such as structural instability, susceptibility to degradation, and poor penetration, limit its applications. To address these limitations, a gene-activating tetrahedral framework nucleic acid (tFNA) with sirtuin-1 (SIRT1) gene activation function is developed, termed Tsa. Tsa exhibits an RNA-protecting effect and can effectively penetrate cell membranes to upregulate SIRT1 gene expression. At the histological level, Tsa treatment alleviates diabetic osteoporosis by increasing bone trabecular density and promoting new bone formation. At the cellular level, it switches macrophage polarization toward the anti-inflammatory M2 phenotype while inhibiting the inflammatory M1 phenotype, creating a favorable bone immune microenvironment for osteoblasts. At the genetic level, Tsa activates SIRT1 expression, which deacetylates Acetyl-p65 to block the NF-κB pathway and restore the osteoimmune environment. Overall, this research demonstrates a nanodrug "Tsa", capable of activating SIRT1 and modulating the bone immune environment, thereby showcasing its immense potential for diabetic osteoporosis treatment.

Co-Inhibition of tGLI1 and GP130 Using FDA-Approved Ketoconazole and Bazedoxifene Is Synergistic Against the Growth and Metastasis of HER2-Enriched and Triple-Negative Breast Cancers

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and GP130 are co-overexpressed in the majority of HER2-enriched breast cancers and TNBCs at 53.8% and 44.4%, respectively. tGLI1+IL-6/IL-6R/GP130 signaling is frequently co-enriched and co-activated in HER2-enriched breast cancer and TNBC when compared to luminal subtypes. tGLI1+GP130 co-overexpression strongly promotes CSCs of HER2-enriched breast cancer and TNBC. FDA-approved tGLI1 inhibitor Ketoconazole and GP130 inhibitor Bazedoxifene synergize against breast cancer proliferation and CSC phenotypes in vitro and reduce TNBC tumor growth and metastatic burden in vivo. Our study demonstrates, for the first time, that co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways is synergistic against HER2-enriched breast cancer and TNBC, warranting future clinical investigations.

The Molecular Mechanism of Dicofol as an Agonist of the Human Estrogen Receptor: Insights from Molecular Docking and MM-GBSA Studies

The risk to human health has increased worldwide due to the widespread use of organochlorine pesticides. Dicofol (DCF), an organochlorine pesticide, is one of the most contentious endocrine disruptors; it can interact with nuclear receptors and interfere with their regular function. A member of the steroid hormone receptor family, the estrogen receptor (ER) is found in many bodily tissues. It binds to androgens and controls the activity of genes that are responsive to androgens. There is a chance that DCF will disrupt the estrogen receptor. In light of these specifics, we tested the ER disruption and related mechanisms of DCF using Molecular Docking, Generalized Born, and Surface Area Continuum Salvation (MM GBSA) in Molecular Mechanics. Dicofol may bind to the ER with efficiency, according to the docking results that were obtained. The MMGBSA results demonstrated that lipophilic interactions were the primary driver of the stable binding process. The current study supports the structural evidence that DCF is an endocrine disruptor and provides crucial guidance for finding safer alternatives.

Engineering Nicotiana benthamiana for chrysoeriol production using synthetic biology approaches

Flavonoids are prevalent plant secondary metabolites with a broad range of biological activities. Their antioxidant, anti-inflammatory, and anti-cancer activities make flavonoids widely useful in a variety of industries, including the pharmaceutical and health food industries. However, many flavonoids occur at only low concentrations in plants, and they are difficult to synthesize chemically due to their structural complexity. To address these difficulties, new technologies have been employed to enhance the production of flavonoids in vivo. In this study, we used synthetic biology techniques to produce the methylated flavone chrysoeriol in Nicotiana benthamiana leaves. The chrysoeriol biosynthetic pathway consists of eight catalytic steps. However, using an Agrobacterium-mediated transient expression assay to examine the in planta activities of genes of interest, we shortened this pathway to four steps catalyzed by five enzymes. Co-expression of these five enzymes in N. benthamiana leaves resulted in de novo chrysoeriol production. Chrysoeriol production was unaffected by the Agrobacterium cell density used for agroinfiltration and increased over time, peaking at 10 days after infiltration. Chrysoeriol accumulation in agroinfiltrated N. benthamiana leaves was associated with increased antioxidant activity, a typical property of flavones. Taken together, our results demonstrate that synthetic biology represents a practical method for engineering plants to produce substantial amounts of flavonoids and flavonoid derivatives without the need for exogenous substrates.

Ratio of l-(+)- and d-(−)-Lactic Acids Produced by Enterococcus faecalis Changes Depending on the Culture pH

Enterococcus faecalis (E. faecalis) has been associated with the specific production of l-(+)-lactic acid. However, in this study, d-(−)-lactic acid production by E. faecalis was observed under specific pH conditions. E. faecalis PR31 exhibited a significant amount of d-(−)-lactic acid under a stirring culture in MRS broth at pH 4.5, 5.8, and 6.0, and the contents of d-(−)-lactic acid were 45.1, 35.9, and 36.2%, respectively. When the cell suspension prepared at a pH of 6.0 was reacted with l-(+)- or d-(−)-lactic acid, d-(−)- or l-(+)-lactic acid was produced, respectively, in a time- and dose-dependent manner. Therefore, this phenomenon of d-(−)-lactic acid production in PR31 was suggested to be due to the activation of the larA gene encoding lactate racemase that is present in PR31. However, even in the E. faecalis-type strain NBRC 100480, which contains neither larA nor vanH, encoding d-(−)-lactate dehydrogenase VanH, d-(−)-lactic acid was also produced at specific pH values. Therefore, the production of d-(−)-lactic acid in NBRC 100480 was thought to occur not via the activation of larA. The biological significance of d-(−)-lactic acid production in E. faecalis depending on the pH and the detailed underlying mechanism, including whether it is the same in PR31 and NBRC 100480, remain to be elucidated in future studies.

Multiomics Analyses Reveal that Fatty Acid Metabolism and TCA Cycle Contribute to the Achievement of Functional Cure in Chronic Hepatitis B.

Peg-IFNα is one of the current therapeutic strategies for Hepatitis B virus (HBV) seroclearance. Nevertheless, the underlying mechanisms are not yet adequately understood. The objective of this study was to explore the potential mechanisms using multiomics approach. For the first time, we revealed the transcriptomic, proteomic, and metabolomic characterizations of Peg-IFNα-induced HBsAg seroclearance. We found that Peg-IFNα caused significant changes during the treatment. Patients who achieved HBsAg seroclearance were characterized as having decreased transcriptional activity of genes involved in fatty acid metabolism and the glycolysis/gluconeogenesis pathway, with up-regulated expression of fatty acid degradation-related proteins. Consistently, mitochondrial TCA cycle metabolites, including citric, isocitric, and malic acids, were significantly elevated in patients who achieved HBsAg seroclearance. We also observed up-regulated transcriptional activity of NK cell-mediated cytotoxicity, positive regulation of B cell activation, immunoglobulin production, and T cell receptor complex in functional-cured patients. Conversely, the metabolites associated with unsaturated fatty acid biosynthesis were increased in HBsAg persistent patients, and the transcriptional activity of immunoglobulin production and T cell receptor complex was down-regulated after 48 weeks of Peg-IFNα treatment. Our findings provided valuable resources to better understand the process of HBsAg seroclearance and shed new light on the pathways to facilitate higher functional cure rates for CHB.

Immune Checkpoint Inhibitor Myopathy: The Double-Edged Sword of Cancer Immunotherapy.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

Chromatin topology dynamics in gene activation.

Chromatin topology dynamics in gene activation.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

Lung cancer has emerged as a highly aggressive malignancy posing a significant global health hazard, with a particular concern for the rising incidence and mortality of gene-altered non-small cell lung cancer (NSCLC). As the prevalence of NSCLC rises, the investigation and selection of tumor treatment techniques are gaining significance. The treatment of individuals with genetic mutations in advanced NSCLC has emphasized the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Early and subsequent generations of EGFR-TKIs have demonstrated clinical efficacy in NSCLC patients carrying select genetic alterations. Osimertinib, a third-generation EGFR-TKI, has been sanctioned as the standard first-line therapy and is also utilized as a second-line option for individuals who develop the T790M resistance mutation following prior EGFR-TKI treatment. Approximately 10 to 30 percent of patients diagnosed with NSCLC exhibit EGFR mutations. This leads to abnormal activation of cancer genes and inactivation of tumor suppressor genes, resulting in poor prognosis for patients. This paper aims to analyze the development and resistance processes of EGFR inhibitors, thereby enhancing the comprehension of the resistance pathways to EGFR-TKIs.

Cbf11 and Mga2 function together to activate transcription of lipid metabolism genes and promote mitotic fidelity in fission yeast.

Within a eukaryotic cell, both lipid homeostasis and faithful cell cycle progression are meticulously orchestrated. The fission yeast Schizosaccharomyces pombe provides a powerful platform to study the intricate regulatory mechanisms governing these fundamental processes. In S. pombe, the Cbf11 and Mga2 proteins are transcriptional activators of non-sterol lipid metabolism genes, with Cbf11 also known as a cell cycle regulator. Despite sharing a common set of target genes, little was known about their functional relationship. This study reveals that Cbf11 and Mga2 function together in the same regulatory pathway, critical for both lipid metabolism and mitotic fidelity. Deletion of either gene results in a similar array of defects, including slow growth, dysregulated lipid homeostasis, impaired cell cycle progression (cut phenotype), abnormal cell morphology, perturbed transcriptomic and proteomic profiles, and compromised response to the stressors camptothecin and thiabendazole. Remarkably, the double deletion mutant does not exhibit a more severe phenotype compared to the single mutants. In addition, ChIP-nexus analysis reveals that both Cbf11 and Mga2 bind to nearly identical positions within the promoter regions of target genes. Interestingly, Mga2 binding appears to be dependent on the presence of Cbf11 and Cbf11 likely acts as a tether to DNA, while Mga2 is needed to activate the target genes. In addition, the study explores the distribution of Cbf11 and Mga2 homologs across fungi. The presence of both Cbf11 and Mga2 homologs in Basidiomycota contrasts with Ascomycota, which mostly lack Cbf11 but retain Mga2. This suggests an evolutionary rewiring of the regulatory circuitry governing lipid metabolism and mitotic fidelity. In conclusion, this study offers compelling support for Cbf11 and Mga2 functioning jointly to regulate lipid metabolism and mitotic fidelity in fission yeast.

Molecular mechanisms of action of curaxin CBL0137 on breast cancer cells in vitro

Introduction. Breast cancer (BC) represents a group of malignant neoplasms with various molecular profiles, which are characterized by aberrations in the mechanisms of epigenetic transcription regulation. One of these disruptions associated with a worse prognosis is the overexpression of the BET protein family, responsible for the interaction of transcription factors with histone-rich acetylated regions. Previously, for the multitargeted epigenetically active agent curaxin CBL0137 (CBL), we have shown the ability to inhibit the expression of BRD2, BRD3, BRD4 proteins in HeLa TI cells and BRD3, BRD4 proteins in BC cells.Aim. To analyze the molecular mechanisms of CBL0137 action on BC cells in vitro, including: 1) assessment of cytotoxicity, 2) analysis of the effect on the cell cycle, 3) assessment of the ability to trigger apoptosis, 4) cause DNA damage, and 5) analyze the effect on the expression of genes involved in proliferation, apoptosis and repair processes.Materials and methods. The cytotoxicity of CBL on BC cells (MCF7, MDA-MB-231, SKBR3) was assessed using the MTT assay. The effect of the agent on the cell cycle and activation of apoptosis was analyzed by flow cytometry. Analysis of DNA damage under the action of CBL was performed using the comet assay. Changes in the expression of genes associated with proliferation, repair and apoptosis were evaluated using real-time polymerase chain reaction.Results. The half maximal inhibitory concentration (IC50) on BC cells under the action of CBL0137 were 1 μM at 72-hour exposure, 14–25 μM at 24-hour. Curaxin CBL (0.5 and 1 μM) caused G2/M cell cycle arrest, and also triggered apoptosis in all cell lines. Under the action of 1 μM CBL, an increase in the degree of DNA damage in MCF7 and SKBR3 cells was recorded, and under the action of both concentrations in MDA-MB-231 cells. The gene expression profile involved in proliferation also corresponded to the arrest in the G2/M phase of the cell cycle. Also, under the action of CBL, the activation of p53-dependent repair genes occurred. An increase in the expression of pro-apoptotic and a decrease in anti-apoptotic genes was shown.Conclusion. Curaxin CBL0137 showed differential effects on molecular processes in BC cells. We have identified a cytostatic effect of the compound, confirmed at various molecular levels. The data obtained indicate the ability of CBL0137 to inhibit tumor processes in BC cells, which makes it a potentially interesting agent for combination therapy.

Comparative liver transcriptome analysis in hamsters infected with food-borne trematodes Opisthorchis felineus, Opisthorchis viverrini, or Clonorchis sinensis.

Epidemiologically important food-borne trematodes Opisthorchis viverrini and Clonorchis sinensis are recognized as biological carcinogens of Group 1A, while Opisthorchis felineus is in Group 3 as noncarcinogenic to humans. Mechanisms of the biological carcinogenesis are still elusive. Some studies highlight chronic inflammation as a key factor and common pathway for cancer initiation and progression. Nonetheless, the chronic inflammation alone does not explain why these three species differ in carcinogenicity. We focused this study on genome-wide landscapes of liver gene expression and activation of cellular pathways in Mesocricetus auratus golden hamsters infected with C. sinensis (South Korea), O. viverrini (Thailand), or O. felineus (Russia) at 1 and 3 months after infection initiation. Liver transcriptomes of golden hamsters (HiSeq Illumina, 2X150 bp) were sequenced at 1 and 3 months postinfection. Data processing was carried out using the following bioinformatic and experimental approaches: analysis of differential gene expression, estimates of proportions of affected liver cell types, liver histopathology, and examination of weighted gene coexpression networks. All infections caused enrichment with inflammatory response signaling pathways, fibrogenesis and cell proliferation, and IL2-STAT5, TNF-NF-κB, TGF-β, Hippo, MAPK, and PI3K-Akt signaling pathways. Nevertheless, species-specific responses to each infection were noted too. We also identified species-specific responses of liver cell types, differentially expressed gene clusters, and cellular pathways associated with structural liver damage (such as periductal fibrosis, epithelial neoplasia, and inflammation). This is the first comparative analysis of gene expression landscapes in the liver of experimental animals infected with O. viverrini, O. felineus, or C. sinensis. The trematodes have species-specific effects on the hepatobiliary system by triggering signaling pathways, thereby leading to differences in the severity of hepatobiliary structural lesions and contributing to the pathogenicity of closely related foodborne trematodes.

Advancing public understanding of epigenetics: the EPIBOOST project’s video science outreach

ABSTRACT The public’s growing interest in epigenetics, particularly its applications in human health, underscores the significance of epigenetic mechanisms in regulating gene activity and promoting phenotypic diversity without altering DNA sequences. Within the framework of the Extended Evolutionary Synthesis, epigenetics is regarded as a non-genetic contributor to evolution. The EPIBOOST project, “BOOSting excellence in environmental EPIgenetics,” investigates epigenetic changes induced by contaminants in aquatic organisms and aims to enhance public understanding of epigenetics through science outreach videos. A multidisciplinary team comprising Biology, Education, and Design researchers produced the video “What is Epigenetics?” using a design-based research methodology and a design thinking approach. This process involved storyboard design, audio recording, image production, video editing, testing, refinement, and public dissemination. The interactive development of the storyboard and script aimed to efficiently communicate the significance of epigenetics, fostering public understanding of this emerging research area through an effective science communication strategy. This paper focuses on the development process for the first video, which aims to promote public awareness of epigenetics using the AEIOU framework (Awareness, Enjoyment, Interest, Opinions, and Understanding) to elucidate epigenetic concepts such as DNA methylation, gene expression, and phenotype, and their integration in environmental assessment frameworks.