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Problem: Oxidative stress (OS) plays a key role in the pathogenesis of gestational diabetes mellitus (GDM), but it was not well understood. We aimed to investigate the biomarkers and underlying mechanisms of OS-related genes in GDM., Method of Study: The GSE103552 and GSE70493 datasets of GDM were acquired from the Gene Expression Omnibus (GEO) database. Then, oxidative stress-related differentially expressed genes (OSDEGs) were screened between GDM and normal samples from these two datasets. Further analyses were conducted by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) for these OSDEGs. Subsequently, protein-protein interaction (PPI) network analyses of these OSDEGs were carried out to screen the hub genes. Eventually, we used single-sample Gene-set enrichment analysis (ssGSEA) to compare the immune cell infiltration between GDM and normal samples., Results: We identified 26 OSDEGs. Enrichment analysis suggested that the OSDEGs enriched in OS and diabetes-related pathways. GSEA revealed that these OSDEGs enriched in sensory perception of taste and negative regulation of notch4 signaling pathways. Moreover, PPI analysis showed that 15 OSDEGs were the hub gene in GDM. A total of 14 hub genes were highly expressed in GDM and might be used as diagnosis biomarkers. Moreover, many potential agents might target 10 hub genes for GDM treatment. In addition, immune infiltrate analyses revealed that expression of 14 hub genes was positively correlated to immune infiltrates in GDM., Conclusion: OSDEGs are significant in GDM and may provide potential diagnostic biomarkers and treatment targets for GDM., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Notch1 and Notch2, transmembrane receptors belonging to the Notch family, are pivotal mediators of intercellular communication and have profound implications including cell fate determination, embryonic development, and tissue homeostasis in various cellular processes. Despite their structural homology, Notch1 and Notch2 exhibit discrete phenotypic characteristics and functional nuances that necessitate their individualized targeting in specific medical scenarios. Aberrant Notch signaling, often driven by the dysregulated activity of one receptor over the other, is implicated under various pathological conditions. Notch1 dysregulation is frequently associated with T-cell acute lymphoblastic leukemia, whereas Notch2 perturbations are linked to B-cell malignancies and solid tumors, including breast cancer. Hence, tailored therapeutic interventions that selectively inhibit the relevant Notch receptor need to be devised to disrupt the signaling pathways driving the specific disease phenotype. In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Laryngeal squamous cell carcinoma (LSCC), which represents a significant proportion of head and neck squamous cell carcinoma cases, is often diagnosed at advanced stages, underscoring the urgent need for effective biomarkers and therapeutic targets. Junctional adhesion molecule 3 ( JAM3 ) is implicated in various types of cancer; however, its role in LSCC remains unclear. Therefore, the present study aimed to investigate the epigenetic regulation and tumor‑suppressive functions and mechanisms of JAM3 in LSCC. Bioinformatics analysis and 5‑Aza‑2'‑deoxycytidine treatment, which restored JAM3 expression as confirmed by reverse transcription‑quantitative PCR and western blotting, revealed that aberrant hypermethylation of the JAM3 promoter was associated with reduced JAM3 expression and poorer clinical outcomes in patients with LSCC. In vitro experiments, including Cell Counting Kit 8, colony formation and Transwell assays, demonstrated that JAM3 overexpression inhibited LSCC cell proliferation, migration and invasion. Western blotting and immunofluorescence analysis revealed that the tumor‑suppressive function of JAM3 was mediated through activation of the Hippo pathway. By contrast, both in vitro and in vivo experiments showed that JAM3 knockdown enhanced these oncogenic behaviors by inhibiting the Hippo pathway, suggesting its critical tumor‑suppressive role. In conclusion, the results of the present study indicated that JAM3 may be epigenetically downregulated and could function as a novel tumor suppressor gene through the Hippo pathway in LSCC, offering insights into developing targeted treatments and diagnostics.

The position of cells during development is constantly subject to noise, i.e. cell-level noise. We do not yet fully understand how cell-level noise coming from processes such as cell division or movement leads to morphological noise, i.e. morphological differences between genetically identical individuals developing in the same environment. To address this question we constructed a large ensemble of random genetic networks regulating cell behaviors (contraction, adhesion, etc.) and cell signaling. We simulated them with a general computational model of development, EmbryoMaker. We identified and studied the dynamics, under cell-level noise, of those networks that lead to the development of animal-like morphologies from simple blastula-like initial conditions. We found that growth by cell division is a major contributor to morphological noise. Self-activating gene network loops also amplified cell-level noise into morphological noise while long-range signaling and epithelial stiffness tended to reduce morphological noise., Competing Interests: Declaration of competing interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Strigolactones (SLs) are plant hormones that play a crucial role in regulating various aspects of plant architecture, such as shoot and root branching. However, the knowledge of SL-responsive genes and transcription factors (TFs) that control the shaping of plant architecture remains elusive. Here, transcriptomic analysis was conducted using the SL-insensitive barley mutant hvd14.d (carried mutation in SL receptor DWARF14, HvD14) and its wild-type (WT) to unravel the differences in gene expression separately in root and shoot tissues. This approach enabled us to select more than six thousand SL-dependent genes that were exclusive to each studied organ or not tissue-specific. The data obtained, along with in silico analyses, found several TFs that exhibited changed expression between the analyzed genotypes and that recognized binding sites in promoters of other identified differentially expressed genes (DEGs). In total, 28 TFs that recognize motifs over-represented in DEG promoters were identified. Moreover, nearly half of the identified TFs were connected in a single network of known and predicted interactions, highlighting the complexity and multidimensionality of SL-related signalling in barley. Finally, the SL control on the expression of one of the identified TFs in HvD14- and dose-dependent manners was proved. Obtained results bring us closer to understanding the signalling pathways regulating SL-dependent plant development., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Soil salinization is a major factor limiting the sustainable development of the grape industry. Circular RNAs (circRNAs) are more stable than linear mRNAs and are involved in stress responses. However, the biological functions and molecular mechanisms underlying antisense circRNAs in plants remain unclear. We identified the antisense circRNA VvcircABH through high-throughput sequencing. Using genetic transformation methods and molecular biological techniques, we analyzed the effects of VvcircABH on the response to salt stress and the mechanisms underlying its effects. VvcircABH was located in the nucleus and upregulated by salt stress, while the expression level of its cognate gene VvABH (alpha/beta-hydrolase) was downregulated. VvcircABH overexpression or VvABH silencing greatly enhanced grape salt tolerance. VvcircABH could bind to the overlapping region and inhibits VvABH pre-mRNA splicing, thereby decreasing the expression level of VvABH. Additionally, VvcircABH repressed the additive effect of VvABH on the interaction between VvBRI1 (brassinosteroid-insensitive 1) and VvBKI1 (BRI1 kinase inhibitor 1), thus influencing the plant's response to BR, which plays important roles in plant salt tolerance. We conclude that VvcircABH and VvABH play distinct roles in the salt tolerance and brassinosteroid signaling response, and VvcircABH could govern the expression of VvABH by inhibiting its splicing., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

The abscisic acid (ABA) signalling pathway plays a crucial role in plants' response to drought stress. In this study, we aimed to characterize the impact of an ABA signalling module, which consisted of TaPYL9 and its downstream partners in Triticum aestivum, on plant drought adaptation. Our results showed that TaPYL9 protein contains conserved motifs and targets plasma membrane and nucleus after being sorted by the endoplasmic reticulum. In addition, TaPYL9 transcripts in both roots and leaves were significantly upregulated in response to drought stress. We conducted glucuronidase (GUS) histochemical staining analysis for transgenic plants carrying a truncated TaPYL9 promoter, which suggested that cis-elements associate with ABA and drought response, such as ABRE, DRE and recognition sites MYB and MYC, regulating the gene transcription under drought conditions. Using protein interaction assays (i.e., yeast two-hybrid, bimolecular fluorescence complementation (BiFC), co-immunoprecipitation (Co-IP) and in vitro pull-down), we demonstrated interactions between the intermediate segment of TaPYL9, the intermediate segment of TaPP2C6, the N-terminus of TaSnRK2.8 and the C-terminus of the transcription factor TabZIP1 in wheat, indicating the involvement of TaPYL9 in the constitution of an ABA signalling module, namely TaPYL9/TaPP2C6/TaSnRK2.8/TabZIP1. Transgene analysis revealed that TaPYL9, TaSnRK2.8 and TabZIP1 positively regulated drought response, while TaPP2C6 negatively regulated it, and that these genes were closely associated with the regulation of stomata movement, osmolyte accumulation and ROS homeostasis. Electrophoretic mobility shift (EMSA) and transcriptioal activation assays indicated that TabZIP1 interacted promoters of TaP5CS2, TaSLAC1-1 and TaCAT2 and activated transcription of these genes, which regulated proline biosynthesis, stomata movement and ROS scavenging upon drought signalling, respectively. Furthermore, we found that the transcripts of TaPYL9 and stress-responsive genes were positively correlated with yields in wheat cultivars under field drought conditions. Altogether, our findings suggest that the TaPYL9-involved signalling pathway significantly regulates drought response by modulating osmotic stress-associated physiological processes in T. aestivum., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Objective: We aimed to elucidate the potential contributions of the toll-like receptor (TLR) signalling pathway and identify promising candidates for new-onset microscopic polyangiitis (MPA) using integrated bioinformatics analysis., Methods: A PCR array was used to determine the expression profiles of TLR signalling-related genes in CD4 + T lymphocytes of individuals with new-onset MPA and healthy controls. Four genes were selected for validation through real-time quantitative polymerase chain reaction (RT-qPCR). Followed by functional enrichment and pathway analysis, we identified the hub genes with cytoHubba. The differentially expressed miRNAs of the target genes were subsequently predicted and visualized via Cytoscape. Finally, these candidates were validated and evaluated at the expression level and for diagnostic value in public databases., Results: Nineteen differentially expressed genes were screened, and the levels of the validated genes detected using RT‒qPCR were consistent with the findings obtained through the PCR array. The significantly enriched signalling pathways involved were TLR signalling pathway, IL-17 signalling pathway, and NF-κB signalling pathway. Nine hub genes and nine key miRNAs were identified. Furthermore, analysis of three distinct gene expression datasets validated several key genes (TLR4, MYD88, IRF1, CXCL10, CXCL8, and CSF2), showing significant differences between groups and strong diagnostic value, especially TLR4, MYD88, and IRF1. Interestingly, in contrast to the validation results, our results showed that CXCL10 and CXCL8 expression levels were markedly lower, but CSF2 was highly expressed in patients with MPA compared to controls., Conclusion: Aberrant expression of TLRs may occur in CD4 + T lymphocytes of patients with new-onset MPA, offering insights into the pathogenesis as well as potential biomarkers and novel therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study investigates the molecular responses to heatstroke in young and old patients by comparing whole-genome transcriptomes between age groups. We analyzed transcriptomic profiles from patients categorized into two age-defined cohorts: young (mean age = 44.9 ± 6 yr) and old (mean age = 66.1 ± 4 yr). Control subjects, exposed to similar environmental heat conditions but without developing heatstroke, were also included in the analysis to provide a baseline for comparison. Despite uniform heatstroke severity at admission, as indicated by core body temperature, consciousness level, and organ damage markers, notable gene expression differences emerged. Old patients showed 37% fewer differentially expressed genes compared with young patients at admission, with a shift toward gene upregulation, deviating from the usual downregulation seen in heat stress responses. Both age groups exhibited increased heat shock protein gene expression, activated the heat stress, and unfolded protein responses indicating comparable proteotoxic stress. Nonetheless, age-specific differences were evident in critical regulatory pathways like Sirtuin, mTOR, and p53 signaling, along with key pathways related to proteostasis, energy metabolism, oxidative stress, and immune responses. Following cooling, older adults exhibited a decline in the heat stress response and a cessation of the unfolded protein response, in contrast to the sustained responses seen in younger individuals. This pattern suggests an age-related adaptability or a diminished protective response capacity with aging. These findings provide insights into the biological mechanisms that may contribute to age-specific vulnerabilities to heat. NEW & NOTEWORTHY Our study reveals distinct molecular responses to heatstroke across age groups, with older adults showing fewer differentially expressed genes and an atypical pattern of gene upregulation, contrasting with the downregulation in usual heat stress responses. It also uncovers a reduced heat stress response and an abbreviated unfolded protein response in older adults, likely impairing their cellular repair mechanisms. This contributes to increased vulnerability during severe heat waves, underscoring the urgent need for age-specific interventions.

Flooding is a widespread natural disaster that causes tremendous yield losses of global food production. Rice is the only cereal capable of growing in aquatic environments. Direct seeding by which seedlings grow underwater is an important cultivation method for reducing rice production cost. Hypoxic germination tolerance and root growth in waterlogged soil are key traits for rice adaptability to flooded environments. Alternative oxidase (AOX) is a non-ATP-producing terminal oxidase in the plant mitochondrial electron transport chain, but its role in hypoxia tolerance had been unclear. We have discovered that AOX1a is necessary and sufficient to promote germination/coleoptile elongation and root development in rice under flooding/hypoxia. Hypoxia enhances endogenous H 2 O 2 accumulation, and H 2 O 2 in turn activates an ensemble of regulatory genes including AOX1a to facilitate the conversion of deleterious reactive oxygen species to H 2 O 2 in rice under hypoxia. We show that AOX1a and H 2 O 2 act interdependently to coordinate three key downstream events, that is, glycolysis/fermentation for minimal ATP production, root aerenchyma development and lateral root emergence under hypoxia. Moreover, we reveal that ectopic AOX1a expression promotes vigorous root and plant growth, and increases grain yield under regular irrigation conditions. Our discoveries provide new insights into a unique sensor-second messenger pair in which AOX1a acts as the sensor perceiving low oxygen tension, while H 2 O 2 accumulation serves as the second messenger triggering downstream root development in rice against hypoxia stress. This work also reveals AOX1a genetic manipulation and H 2 O 2 pretreatment as potential targets for improving flooding tolerance in rice and other crops., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

SWI/SNF protein complexes are evolutionarily conserved epigenetic regulators described in all eukaryotes. In metameric animals, the complexes are involved in all processes occurring in the nervous system, from neurogenesis to higher brain functions. On the one hand, the range of roles is wide because the SWI/SNF complexes act universally by mobilizing the nucleosomes in a chromatin template at multiple loci throughout the genome. On the other hand, the complexes mediate the action of multiple signaling pathways that control most aspects of neural tissue development and function. The issues are discussed to provide insight into the molecular basis of the multifaceted role of SWI/SNFs in cell cycle regulation, DNA repair, activation of immediate-early genes, neurogenesis, and brain and connectome formation. An overview is additionally provided for the molecular basis of nervous system pathologies associated with the SWI/SNF complexes and their contribution to neuroinflammation and neurodegeneration. Finally, we discuss the idea that SWI/SNFs act as an integration platform to connect multiple signaling and genetic programs., Competing Interests: Declarations. Ethics Approval: No ethical approval is required for this study. Consent to Participate: Not applicable. Consent for Publication: The authors give consent for the publication of this review article. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Seed dormancy is an important adaptive trait in plants. Proper seed dormancy enables the avoidance of preharvest sprouting in the undesirable conditions like rainfall frequently. In this study, qPSR8, a major QTL for preharvest sprouting, was isolated, and a previously reported heading-date gene, CCT30, was verified as the candidate gene. The CCT30 knockout mutants (CCT30-CR) enhanced seed dormancy and ABA sensitivity as compared with the wild-type ZH11. Conversely, CCT30 overexpressing plants had opposite phenotype changes and had a decreased ABA content. The expression of ABA synthesis genes such as OsNCEDs and ABA signalling genes such as ABI3 and ABI5 were upregulated and sugar metabolism-related genes such as amylase genes were downregulated in CCT30-CR. Correspondingly, fewer free sugars, such as monosaccharides and oligosaccharides, accumulated in CCT30-CR. The freshly harvested seeds from CCT30-CR had no ability to transmit sugar signals when treated with 1% exogenous glucose. In addition, CCT30 interacted with the transcription factor OsbZIP37, which negatively regulates seed dormancy. Overall, CCT30 promotes preharvest sprouting by enhancing sugar signals that inhibit the ABA-mediated pathway, and CCT30 is a good gene for breeding rice varieties resistant to preharvest sprouting., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

The Masculinizer (Masc) gene plays a crucial role in masculinization during insect embryonic gonadal development. Nevertheless, the Masc expression pattern and function in crabs remain largely unknown. In the present study, we screened and validated the Masc gene from transcriptome data of mud crab S. paramamosain. The Masc relative transcript level in the testis was significantly higher than that of ovaries and other tissues, as measured by quantitative real-time PCR. In situ hybridization showed that Masc exhibited a significant signal throughout all stages of testicular development. The phylogenetic analysis revealed conservation in the evolution of crustaceans, potentially indicating its functional importance. Masc RNA interference showed that the expression of testis bias-related genes decreased significantly while the ovary bias-related genes increased significantly. Transcriptome data suggested that Masc regulates several signaling pathways, including the mTOR, Wnt, insulin, and other sex-related pathways. These results indicate that Masc may play a role in mud crab male development with possible application in sex control in aquaculture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present a Case with combined AGS and Cornelia de Lange Syndrome (CdLS)-a cohesinopathy-with comprehensive analysis of the immune and genomic abnormalities., Case and Methods: A 20-year old man presented with chilblain lesions and resorption of distal phalanges of fingers and toes, somatic and psychomotor retardation, microcephaly, synophrys, hearing losing and other aberrancies consistent with the phenotype of CdLS. We used whole exome sequencing to genetically map the associated mutations and performed transcriptome profiling and enrichment analysis in CD14 + monocytes of the patient and immune phenotyping by mass cytometry (CyToF), comparing to healthy individuals and lupus patients as disease controls. DNA damage response was assayed by confocal microscopy in the peripheral blood of this patient., Results: Next generation exome sequencing confirmed a homozygous SAMHD1 gene mutation and a hemizygous non-synonymous mutation on SMC1A gene, responsible for the AGS and CdLS, respectively. Transcriptome profiling of CD14 + monocytes of the patient showed enrichment of type I IFN signaling and enhanced DNA damage response pathway. Broad immune phenotype of the peripheral blood of the patient revealed absence of activated T cell populations, increased frequency of NK cells and plasmablasts and enhanced granulocytic lineage. Further analysis suggested activation of the ATM branch of DNA damage response and increased apoptosis in the periphery of the patient., Conclusions: A rare case of a patient bearing two genetic lesions (responsible for AGS/CdLS syndromes) exhibits distinctive features of genomic damage and interferon responses. Immune phenotype revealed granulocytic skewing and absence of activated T cells compatible with chronic antigenic stimulation and/or homing of these cells at sites of inflammation., Competing Interests: Declarations. Ethics approval and consent to participate: The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Attikon University Hospital, (Athens, Greece, protocol 10|22-6-2017). Written informed consent was obtained from all participants or their guardians. Consent for publication: Patients or guardian of patients gave informed consent for publishing the research results or images after anonymization. Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. The authors have no relevant financial or non‑financial interests to disclose., (© 2025. The Author(s).)

Background: Glioblastoma (GBM) is a highly aggressive brain tumor associated with a poor patient prognosis. The survival rate remains low despite standard therapies, highlighting the urgent need for novel treatment strategies. Advanced imaging techniques, particularly magnetic resonance imaging (MRI), are crucial in assessing GBM. Disruptions in various oncogenic signaling pathways, such as Receptor Tyrosine Kinase (RTK)-Ras-Extracellular signal-regulated kinase (ERK) signaling, Phosphoinositide 3- Kinases (PI3Ks), tumor protein p53 (TP53), and Neurogenic locus notch homolog protein (NOTCH), contribute to the development of different tumor types, each exhibiting distinct morphological and phenotypic features that can be observed at a microscopic level. However, identifying genetic abnormalities for targeted therapy often requires invasive procedures, prompting exploration into non-invasive approaches like radiogenomics. This study explores the utility of radiogenomics and machine learning (ML) in predicting these oncogenic signaling pathways in GBM patients., Methods: We collected post-operative MRI scans (T1w, T1c, FLAIR, T2w) from the BRATS-19 dataset, including scans from patients with both GBM and LGG, linked to genetic and clinical data via TCGA and CPTAC. Signaling pathway data was manually extracted from cBioPortal. Radiomic features were extracted from four MRI modalities using PyRadiomics. Dimensionality reduction and feature selection were applied and Data imbalance was addressed with SMOTE. Five ML models were trained to predict signaling pathways, with Grid Search optimizing hyperparameters and 5-fold cross-validation ensuring unbiased performance. Each model's performance was evaluated using various metrics on test data., Results: Our results showed a positive association between most signaling pathways and the radiomic features derived from MRI scans. The best models achieved high AUC scores, namely 0.7 for RTK-RAS, 0.8 for PI3K, 0.75 for TP53, and 0.4 for NOTCH, and therefore, demonstrated the potential of ML models in accurately predicting oncogenic signaling pathways from radiomic features, thereby informing personalized therapeutic approaches and improving patient outcomes., Conclusion: We present a novel approach for the non-invasive prediction of deregulation in oncogenic signaling pathways in glioblastoma (GBM) by integrating radiogenomic data with machine learning models. This research contributes to advancing precision medicine in GBM management, highlighting the importance of integrating radiomics with genomic data to understand tumor behavior and treatment response better., Competing Interests: Declarations. Ethical approval and consent to participate: Not Applicable. Consent for publication: Not Applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

The role of human epidermal growth factor 2 (HER2) in male breast cancer (MBC) is poorly defined. A comprehensive description of HER2 status was conducted. A total of 6,015 MBC patients from 45 studies and 135 MBC patients with sequencing data were identified. HER2 positive rates and hazard ratios (HR) for overall survival (OS) were combined using Metaprop. The prevalence of HER2 + MBC was 10.0% (95% CI: 8.0-13.0%). Subgroup analyses showed that 7% (95% CI: 2.0-14.0%) had HER2 + protein overexpression. 10% of MBC patients had HER2 + overexpression and/or gene amplification. Asian MBC patients had the highest HER2 + incidence of 17% (95% CI: 12.0-22.0%). The prevalence of HER2 positive MBC fluctuated widely from 2001 to 2015 and then stabilized at 10%. HER2 positivity was significantly correlated with worse OS than negative ones (HR = 1.92, 1.47-2.51). The proportion of HER2 + MBC was inconsistent with the results for the intrinsic HER2-enriched subtype. Altered genes in HER2 + MBC, such as ERBB2, AGO2, RECQL4, and CLTC, were not detected in HER2-MBC. Genomic analysis revealed differences between the patients with HER2 + MBC and those with HER2 + FBC. The percentage of HER2 + MBC was slightly lower than that of women. Multiple approaches may be needed to jointly assess HER2 status in MBC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Disclosure: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interests in the subject matter or materials discussed in this manuscript. Ethics approval: Not applicable., (© 2025. The Author(s).)

Ischemic stroke is caused by blockage of blood vessels in brain, affecting normal function. The roles of Signal Transformer and Activator of Transcription 1 (STAT1), CASP8, and MYD88 in ischemic stroke and its care are unclear. The ischemic stroke datasets GSE16561 and GSE180470 were found from the Gene Expression Omnibus database. Batch effect removal, finding differentially expressed genes (DEGs), weighted gene co-expression network analysis, protein-protein interaction analysis, functional enrichment analysis, immune infiltration analysis, comparative toxicogenomics database analysis were carried out. Gene expression heat maps were drawn, and miRNAs were found that regulate core DEGs. A total of 1183 DEGs were obtained, which were mainly concentrated in immune effector processes, cell activation, and protein serine/threonine kinase activity, the NOD-like receptor signaling pathway, NF-kappa B signaling pathway, C-type lectin receptor signaling pathway, and P53 signaling pathway. Four core genes were identified. Heatmap revealed high expression of (CASP8, MYD88, and STAT1) in whole blood samples of ischemic stroke. Comparative toxicogenomics database analysis demonstrated (CASP8, MYD88, and STAT1) are related to cerebral hemorrhage, reperfusion injury, hypertension, and inflammation. In ischemic stroke, expression of STAT1, CASP8, and MYD88 is higher and leads to poorer prognosis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Osteosarcoma (OS) is the most commonly diagnosed primary malignant bone tumor in children and adolescents. Despite significant advancements in therapeutic strategies against OS over the past few decades, the prognosis for this disease remains poor, largely due to its high invasiveness and challenges associated with its treatment. N6-methyladenosine (m6A) modification is one of the most abundant epigenetic modifications of RNAs, and many studies have highlighted its crucial role in OS. This article provides a comprehensive summary and introduction to m6A regulators, including methyltransferases, demethylases, and binding proteins. The article emphasizes how regulated m6A modifications can either promote or inhibit OS. It also delves into the mechanisms by which m6A-modified messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs) participate in signaling pathways such as the Wnt/β-catenin, PI3K/AKT, and STAT3 pathways, and discusses these mechanisms in detail. Given the abnormal expression of m6A regulators in OS, the article also explores their potential applications as biomarkers or therapeutic targets in clinical settings. It is anticipated that this review will provide new insights into the diagnosis and treatment of OS., Competing Interests: Declarations. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent to publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder affecting women of childbearing age, and we aimed to reveal its underlying molecular mechanisms. Gene expression profiles from GSE138518 and GSE155489, and single-cell RNA sequencing (scRNA-seq) data from PRJNA600740 were collected and subjected to bioinformatics analysis to identify the complex molecular mechanisms of PCOS. The expression of genes was detected by RT-qPCR. Through differential analysis, we identified 230 common differentially expressed genes (DEGs) in GSE138518 and GSE155489. GSEA results showed significant enrichment of purine metabolism and oocyte meiosis in the control group, while GSVA results indicated significant activation of ECM receptor interaction, and antigen processing and presentation in PCOS. Weighted gene co-expression network analysis revealed 7 co-expression modules, with the bisque4 module showing the highest positive correlation with PCOS. Enrichment analysis revealed that genes in the bisque4 module were mainly involved in the PI3K-Akt signaling pathway, calcium signaling pathway, and Ras signaling pathway. Pseudotime trajectory analysis of cell subpopulations revealed the potential developmental trajectory of PCOS. The gene expression consistent with the potential developmental trajectory was validated by RT-qPCR. Our study, by analyzing multiple datasets, has revealed the complex molecular network of PCOS, offering new insights into understanding its pathophysiological basis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: To elucidate the genetic and molecular mechanisms underlying psoriasis by employing an integrative multi-omics approach, using summary-data-based Mendelian randomization (SMR) to infer causal relationships among DNA methylation, gene expression, and protein levels in relation to psoriasis risk., Methods: We conducted SMR analyses integrating genome-wide association study (GWAS) summary statistics with methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data. Publicly available datasets were utilized, including psoriasis GWAS data from the European Molecular Biology Laboratory-European Bioinformatics Institute and the UK Biobank. Heterogeneity in dependent instruments (HEIDI) test and colocalization analyses were performed to identify shared causal variants, and multi-omics integration was employed to construct potential regulatory pathways., Results: Our analyses identified significant causal associations between DNA methylation, gene expression, protein abundance, and psoriasis risk. We discovered two pathways involving the long non-coding RNA RP11-977G19.11 and apolipoprotein F (APOF). Methylation at sites cg26804944 and cg02705573 was negatively associated with RP11-977G19.11 expression. Reduced expression of RP11-977G19.11 was linked to increased APOF levels, which were positively associated with a higher risk of psoriasis. Methylation at sites cg00172967, cg00294382, and cg24773560 was positively associated with RP11-977G19.11 expression. Elevated expression of RP11-977G19.11 was associated with decreased APOF levels, reducing the risk of psoriasis. Colocalization analysis highlighted APOF as a key protein in psoriasis pathogenesis. Validation using skin tissue, EBV-transformed lymphocytes data and inflammation-related protein panels confirmed the associations of RP11-977G19.11 and APOF with psoriasis., Conclusions: Our multi-omics analysis provides preliminary evidence for potential molecular mechanisms in psoriasis pathogenesis. Through the integration of GWAS and molecular QTL data, we identify candidate pathways that may be relevant to disease biology. While these findings require extensive experimental validation, they offer a framework for future investigations into the molecular basis of psoriasis., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: We have no potential conflicts of interest to disclose., (© 2025. The Author(s).)

Age-related hearing loss (ARHL) is the most prevalent sensory impairment in the elderly. However, the pathogenesis of ARHL remains unclear. This study was aimed to explore the potential inflammation-related genes of ARHL and suggest novel therapeutic targets for this condition. Initially, a total of 105 Inflammatory related differentially expressed genes (IRDEGs) were obtained by overlapping the differentially expressed genes from the GSE49522 and GSE49543 datasets with Inflammatory related genes. The IRDEGs were mainly enriched in MAPK, PI3K-Akt, Hippo and JAK-STAT pathways by analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. We then identified 10 key IRDEGs including Alox5ap, Chil1, Clec7a, Dysf, Fcgr3, etc. using Least absolute shrinkage and selection operator regression analysis and converted them into human genes. The ROC curve indicated that Alox5ap expression presented a high accuracy in distinguishing between different groups. By CIBERSORT algorithm, 8 humanized key IRDEGs were correlated with the infiltration abundance of 3 immune cells. Finally, it showed that the Alox5ap expression was significantly more effective compared to other variables in the diagnostic model of ARHL. This study suggests that inflammation might play a role in the development of ARHL, providing a deeper understanding of the underlying causes of this disease., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD., Methods: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data., Results: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes., Conclusions: Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Cancer hypoxia, a crucial characteristic of malignancy, ranging from practically non-hypoxic to severe, impacts gene expression, metabolism and mechanisms associated with tumor formation serves as a key obstacle in cancer therapy. It triggers a complex network of cell signaling pathways, such as the NF-κB, PI3K, mTOR/AKT,MAPK, HIF and their associated genes regulating the effects of the same. The onset and advancement of cancer are attributed to genetic and epigenetic modifications which are intrinsically related. Off late, it has been observed that in disease progression, the epigenetic modifications lead to gene mutations that in turn alter the epigenome, presenting a major hurdle in fabricating treatment strategies. However, theprogress in science and technology has led to the emergence of various surfacing omics and multi-view clustering algorithms, which offer unparalleled prospects for further subtyping cancers, enhancing the prognosis and treatment results of these subtypes, and comprehending crucial pathophysiological mechanisms across diverse molecular strata. Multi-omics has allowed scientists to gain a more comprehensive understanding of the various ways that cellular malfunction can lead to cancer. So, it becomes of utmost importance to firstly understand the epigenetic changes taking place in tumor hypoxia at gene level. This review sheds light on the role of HIF gene in hypoxic milieu and its relationship with mechanisms of cancer epigenetics. It further glances as to how omics approach can be used to study the oncogenic cellular changes and how bioinformatic tools aid in identification of complex gene networks involved in disease progression. Lastly, it glimpses through the benefits and shortcomings of the existing epi drug therapy and how it can be used in developing novel treatment options., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n = 4) from those without (n = 7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and healthy control (HC) groups, with virus defense and interferon (IFN) signaling being the key pathways identified as enriched in SLE as expected. We next conducted a comparative analysis of genes differentially expressed in SLE-CMD and SLE-non-CMD relative to HC samples. Our analysis highlighted differences in IFN signaling, RNA sensing and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD. This is the first study to investigate possible gene signatures associating with CMD in SLE, and our data strongly suggests that distinct molecular mechanisms underly vascular changes in CMD and non-CMD involvement in SLE., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The experiments were approved by the institutional review board at Cedars-Sinai Medical Center, which oversees the approval of experiments, specifically in the realm of medical ethics. We confirm that all experiments were conducted in accordance with relevant guidelines and regulations, including the Principles of Human Experimentation Ethics and Good Clinical Practice., (© 2025. The Author(s).)

Background: Casein kinase I protein Hrr25 plays important roles in many cellular processes, including autophagy, vesicular trafficking, ribosome biogenesis, mitochondrial biogenesis, and the DNA damage response in Saccharomyces cerevisiae . Pin4 is a multi-phosphorylated protein that has been reported to be involved in the cell wall integrity (CWI) pathway and DNA damage response. Pin4 was reported to interact with Hrr25 in yeast two-hybrid and large-scale pulldown assays., Methods/objectives: Co-immunoprecipitation and yeast two-hybrid assays were utilized to confirm whether Pin4 and Hrr25 interact and to determine how they interact. Genetic interaction analysis was conducted to examine whether hrr25 mutations form synthetic growth defects with mutations in genes involved in CWI signaling. Immunoblotting was used to determine whether Hrr25 phosphorylates Pin4., Results: We show that Hrr25 interacts with Pin4 and is required for Pin4 phosphorylation. pin4 mutations result in synthetic slow-growth phenotypes with mutations in genes encoding Bck1 and Slt2, two of the protein kinases in the MAP kinase cascade that regulates CWI in the budding yeast. We show that hrr25 mutations result in similar phenotypes to pin4 mutations. Hrr25 consists of an N-terminal kinase domain, a middle region, and a C-terminal proline/glutamine-rich domain. The function of the C-terminal P/Q-rich domain of Hrr25 has been elusive. We found that the C-terminal region of Hrr25 is required both for Pin4 interaction and CWI., Conclusions: Our data suggest that Hrr25 is implicated in cell wall integrity signaling via its association with Pin4.

Insomnia is increasingly common and poses significant health risks. The aims of this study are to identify apoptosis-related genes and potential biomarkers for insomnia and to find new therapeutic targets. Insomnia gene expression profiles were downloaded from the Gene Expression Omnibus database, and differentially expressed genes in normal and insomnia samples were identified by limma rapid differential analysis, and then the major modular genes with clinical relevance to insomnia were analyzed using the Weighted Gene Co-Expression Network Analysis, and intersections were obtained with the differentially expressed genes as well as with apoptotic gene databases. We validated apoptosis-related differentially expressed genes, enriched and analyzed the specific biological process of insomnia and related signaling pathways. In addition, we constructed a protein-protein interaction network and obtained Top10 hub genes using Cytoscape. We selected 3 of them as hub genes and compared their expression in normal hippocampal neuronal cells and hippocampal neuronal cells of the model group exposed to corticosterone induction by Western Blot and qRT-PCR experiments. A total of 190 differentially expressed apoptosis-related genes were identified in insomnia, and BCL2, SOCS3, and IL7R were identified as important hub genes. Enrichment analysis showed that the occurrence of apoptosis in insomnia was mainly related to "PI3K-Akt signaling pathway," "JAK-STAT signaling pathway," "P53 signaling pathway" and so on. GO analysis showed that apoptosis in insomnia was mainly related to "immune response," "T cell differentiation in thymus," and "positive regulation of MAPK cascade." Western Blot and qRT-PCR experiments showed that BCL2, SOCS3, IL7R antiapoptotic indexes were under-expressed in modeled hippocampal neuronal cells compared to normal hippocampal neuronal cells. This study emphasizes the role of apoptosis-related genes in insomnia and preliminarily predicts that the occurrence of insomnia is closely related to apoptosis. Compared to the normal group, the antiapoptotic ability of hippocampal neurons in the model group is reduced. Although BCL2 has been studied in the context of sleep deprivation, SOCS3 and IL7R have not yet been explored in insomnia. Insomnia and sleep deprivation involve similar pathways, but due to different mechanisms and types of insomnia, gene expression may vary., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Psoriasis is a complex inflammatory skin disease characterized by reversible albeit relapsing red scaly plaques in the skin of a patient. In addition to the genetic predisposition, involvement of epigenetic and non-coding RNAs have also been liked with the disease. Nevertheless, any comprehensive study involving transcriptomic, small-RNA and DNA methylation at the genomic level from same patients is lacking. To investigate the complex regulation of molecular pathways in psoriasis, we carried out multi-omics integrative analysis of RNA-sequencing, small RNA-sequencing and DNA methylation profiling from the psoriatic and adjacent normal skin tissues. Our multi-omics analysis identified the genes and biological processes regulated either independently or in combination by DNA methylation and microRNAs. We identified miRNAs that specifically regulated keratinocyte hyper-proliferation, and cell cycle progression and checkpoint signaling in psoriasis. On contrary, DNA methylation was found to be more predominant in regulating immune and inflammatory responses, another causative factor in psoriasis pathogenesis. Many characteristic pathways in psoriasis e.g., Th17 cell differentiation and JAK-STAT signaling, were found to be regulated by both miRNAs and DNA methylation. We carried out functional characterization of a downregulated miRNA hsa-let-7c-5p, predicted to target upregulated genes in psoriasis involved in cell cycle processes, Th17 cell differentiation and JAK-STAT signaling pathways. Overexpression of hsa-let-7c-5p in keratinocytes caused the downregulation of its target genes, resulting in reduced cell proliferation and migration rates, demonstrating potential of miRNAs in regulating psoriasis pathogenesis. In conclusion, our findings identified distinct and shared gene-networks regulated by DNA methylation and miRNAs of a complex disease with reversible phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic heart failure (CHF) combined with hyperuricemia (HUA) is a comorbidity that is hard to diagnose by a single biomarker. Exosomal miRNAs are differentially expressed in cardiovascular diseases and are closely associated with regulating most biological functions. This study aimed to provide evidence for miRNA as a new molecular marker for precise diagnosis of the comorbidity of CHF with HUA and further analyze the potential targets of differentially expressed miRNA. This controlled study included 30 CHF patients combined with HUA (Group T) and 30 healthy volunteers (Group C). 6 peripheral blood samples from Group T and Group C were analyzed for exosomal miRNAs by high-throughput sequencing and then validated in the remaining 24 peripheral blood samples from Group T and Group C by applying real-time PCR (RT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using R software to predict the differential miRNAs' action targets. 42 differentially expressed miRNAs were detected (18 upregulated and 24 downregulated), in which miR-27a-5p was significantly upregulated (P<0.01), and miR-139-3p was significantly downregulated (P<0.01) in Group T. The combination of miR-27a-5p and miR-139-3p predicted the development of CHF combined with HUA with a maximum area under the curve (AUC) of 0.899 (95 % CI: 0.812-0.987, SEN=79.2 %, SPE=91.7 %, J value = 0.709). GO and KEGG enrichment analysis revealed that the differentially expressed miRNAs had a role in activating the AMPK-mTOR signaling pathway to activate the autophagic response. Collectively, our findings suggest that upregulated exosomal miR-27a-5p combined with downregulated exosomal miR-139-3p can be used as a novel molecular marker for precise diagnosis of CHF combined with HUA and enhanced autophagy by AMPK-mTOR signaling pathway may be one pathogenesis of the differentially expressed miRNAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Colon cancer is the leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) are key regulators of gene expression, often dysregulated in colon cancer. This study aims to elucidate the therapeutic role of miR-134-5p as a tumor suppressor miRNA in colon cancer cells. We analyzed miRNA expression profiles in primary and metastatic colon cancer cells. The clinical significance of miR-134-5p was evaluated using the TCGA database. Bioinformatics tools (HADDOCK) predicted miRNA-mRNA interactions and the molecular docking of miRNA-mRNA-AGO2 complexes. Luciferase reporter assays, cell proliferation, immunofluorescence, colony forming unit assays, and qRT-PCR analysis assessed miR-134-5p effects on KRAS, PIK3CA, and downstream signaling pathways in primary and metastatic colon cancer cells. miR-134-5p was downregulated in colon cancer cells. Bioinformatics analysis suggested KRAS, PIK3CA, EGFR, and HDAC5 as potential targets. HADDOCK analysis revealed strong binding affinity and structural stability between KRAS, PIK3CA, miR-134-5p, and AGO2. Gene-reporter assays confirmed miR-134-5p-mediated degradation of KRAS and PIK3CA. miR-134-5p transfection reduced KRAS and PI3K protein levels, suppressed EGFR/RTK signaling and its downstream targets, and inhibited HDAC expression, ultimately reducing colon cancer cell proliferation. The results of this study confirm that miR-134-5p acts as a potential tumor suppressor miRNA in colon cancer cells by inhibiting KRAS and PI3K expression through AGO2-mediated gene silencing. It deregulates downstream EGFR signaling and HDACs, thereby reducing colon cancer cell proliferation. These findings highlight miR-134-5p as a promising therapeutic target for miRNA-mediated anticancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024. Published by Elsevier Inc.)

Programmed cell death (PCD) pathways play pivotal roles in the development and progression of peripheral nerve injury (PNI). PANoptosis, as a novel form of PCD pathway with key features of pyroptosis, apoptosis and necroptosis, is implicated in the pathogenesis of multiple neurologic diseases. This study aimed to identify PANoptosis-related biomarkers and characterize their molecular roles and immune landscape in PNI. PANoptosis-related genes (PRGs) were retrieved from Reactome pathway database and previous literatures. Differentially expressed PANoptosis-related genes (DEPRGs) were identified based on a time-series transcriptome sequencing dataset. DEPRGs were predicted to be enriched in inflammatory response, inflammatory complex, PCD and NOD-like receptor signaling pathway through GO, KEGG, Reactome and GSEA analysis. Hub genes, including Ripk3, Pycard and Il18, were then recognized through PPI network and multiple algorithms. The molecular regulatory mechanisms of hub genes were elucidated by transcription factor network and competing endogenous RNA network. Moreover, the immune cell landscape of hub genes was analyzed. Eventually, the expression levels of hub genes were verified through external dataset and animal model. Ripk3, Pycard and Il18 were remarkably upregulated in PNI samples, which were in consistent with the results of bioinformatic analysis. This study uncovered the molecular characterization of PANoptosis-related genes in PNI and illustrated the novel PANoptosis biomarkers for PNI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite the progress made in the development of targeted therapies, breast cancer (BC) continues to pose a significant threat to the health of women. Transcriptomics has emerged due to the advancements in high-throughput sequencing technology. This provides crucial information about the role of non-coding RNAs (ncRNAs) in human cells, particularly long ncRNAs (lncRNAs), in disease development and function. When the control of these ncRNAs is disrupted, various illnesses emerge, including cancer. Numerous studies have produced empirical data on the function of lncRNAs in tumorigenesis and disease development. However, the roles and mechanisms of numerous lncRNAs remain unidentified at the molecular level because their regulatory role and the functional implications of abnormalities in cancer biology have yet to be thoroughly defined. The review gives an itemized summary of the most current developments in the role of lncRNA in BC, focusing on three main pathways, PI3K, MAPK, NF-kB, and hypoxia, and their resistance mechanisms., Competing Interests: Declaration of competing interest There is no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors., Competing Interests: Competing interests: J.R.B.P. and E.J.G. are employees/shareholders of Insmed. J.R.B.P. also receives research funding from GSK and consultancy fees from WW International. Y.Z. is a UK University worker at GSK. S.O. has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, AstraZeneca, NorthSea Therapeutics and Courage Therapeutics. V.S., V.T., T.O., G.T., and K.S. are employees of deCODE genetics, a subsidiary of Amgen. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Bruton's tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin homology and tec homology (PH-TH) domains of BTK are required for signaling. Dimerization of the PH-TH module strongly stimulates the kinase activity of BTK in vitro. Here, we investigated whether BTK dimerizes in cells using the PH-TH module and whether this dimerization is necessary for signaling. To address this question, we developed high-throughput mutagenesis assays for BTK function in Ramos B cells and Jurkat T cells. We measured the fitness costs for thousands of point mutations in the PH-TH module and kinase domain to assess whether dimerization of the PH-TH module and BTK kinase activity were necessary for function. In Ramos cells, we found that neither PH-TH dimerization nor kinase activity was required for BTK signaling. Instead, in Ramos cells, BTK signaling was enhanced by PH-TH module mutations that increased membrane adsorption, even at the cost of reduced PH-TH dimerization. In contrast, in Jurkat cells, we found that BTK signaling depended on both PH-TH dimerization and kinase activity. Evolutionary analysis indicated that BTK proteins in organisms that evolved before the divergence of ray-finned fishes lacked PH-TH dimerization but had active kinase domains, similar to other Tec family kinases. Thus, PH-TH dimerization is a distinct feature of BTK that evolved to exert stricter regulatory control on kinase activity as adaptive immune systems gained increased complexity.

Cancer, a complicated disease characterized by aberrant cellular metabolism, has emerged as a formidable global health challenge. Since the discovery of abnormal aldolase A (ALDOA) expression in liver cancer for the first time, its overexpression has been identified in numerous cancers, including colorectal cancer (CRC), breast cancer (BC), cervical adenocarcinoma (CAC), non-small cell lung cancer (NSCLC), gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic cancer adenocarcinoma (PDAC), and clear cell renal cell carcinoma (ccRCC). Moreover, ALDOA overexpression promotes cancer cell proliferation, invasion, migration, and drug resistance, and is closely related to poor prognosis of patients with cancer. Although originally discovered to promote cancer initiation and progression by accelerating glycolysis, recent studies have revealed its atypical roles in cancer, e.g., adjusting cytoskeleton, regulating mRNA translation, cell signaling pathways, and DNA repair. These aforementioned findings challenge our traditional understanding of ALDOA function and prompt deep exploration of its novel roles in tumor biology. The present review summarizes the latest insights into ALDOA as a potential cancer biomarker and therapeutic target., Competing Interests: Declarations. Conflicts of interests: The authors declare that they have no competing interests., (© 2025. The Author(s) under exclusive licence to Japan Human Cell Society.)

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxic environments at the cellular level and is an independent risk factor for the development of cardiovascular disease. Endothelial cell (EC) dysfunction precedes the development of cardiovascular disease; however, the mechanisms by which ECs respond to these intermittent hypoxic events are poorly understood. To better understand EC responses to hypoxia, we examined the effects of sustained hypoxia (SH) and intermittent hypoxia (IH) on the activation of HIF-1α in ECs. While SH stabilized HIF-1α and led to its nuclear localization, IH did not activate HIF-1α and the expression of its target genes. Using RNA-sequencing, we evaluated transcriptional responses of ECs to hypoxia. SH induced the expression of HIF-1α and hypoxia response genes, while IH affected cell-cycle regulation genes. A cytoscape protein-protein interaction network for EC response to hypoxia was created with differentially expressed genes. The network comprises cell-cycle regulation, inflammatory signaling via NF-κB and response to VEGF stimulus subnetworks on which SH and IH had distinct activities. As OSA is associated with elevated catecholamines, we investigated the effect of epinephrine on the EC response to SH and IH. Transcriptomic responses under IH and epinephrine revealed protein-protein interaction networks emphasizing distinct subnetworks, including cytokine-mediated TNFα signaling via NF-κB, Wnt/LRP/DKK signaling and cell cycle regulation. This study reveals differential transcriptomic responses under SH and IH characterised by HIF-1α transcriptional response induced only by SH, but not by IH. The study also features the potential molecular events that may occur at the vascular level in OSA.

Several microRNAs (miRNAs) emerged as powerful regulators of fibrotic processes, "fibromiRs", and can also influence the expression of genes responsible for the generation of reactive oxygen species, "redoximiRs". We aimed to investigate whether plasma exosomes from hypertensive and diabetes patients are enriched in fibromiRs and redoximiRs using deep sequencing technology and their association with relevant signalling pathways implicated in oxidative stress and fibrogenesis by GO terms and KEGG pathways. RNA-Seq analysis from P-EXO identified 31 differentially expressed (DE) miRNAs in patients compared to controls, of which 77% are biofluid specific. The majority of the exosomal DE miRNAs were identified as fibromiRs (55%) or redoximiRs (26%). One of the most representative miRNAs identified was miR-21-5p, of which levels in P-EXO were increased by 3.83-fold change ( p < 0.0001) in hypertensive patients with albuminuria and were highly associated (r Spearman = 0.64, p < 0.0001). In addition, P-EXO miR-21-5p had a high accuracy in discriminating renal damage (AUC = 0.82, p < 0.0001). Bioinformatic analysis revealed that miR-21-5p regulates key pathways in the context of organ fibrosis, such as chemokine, Ras, and MAPK signalling. Additionally, in vitro studies showed an increase in P-EXO miR-21-5p levels after TGF-β1 damage and oxidative stress. This novel study found an enrichment of fibromiRs and redoximiRs in P-EXO from hypertensive/diabetic patients with renal dysfunction. miR-21-5p, such as a RedoxifibromiR, has a significant accuracy for discriminating renal damage and is closely related with relevant signalling pathways implicated in fibrogenesis in podocytes.

Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying its potential downstream targets and their correlation with clinical outcomes. Methods : RNA-seq transcriptome and pathway enrichment analyses were conducted on the TSPX-overexpressing NSCLC cell lines, A549 and SK-MES-1, originating from lung adenocarcinoma and squamous cell carcinoma subtypes, respectively. In addition, comparative analyses were performed using the data from clinical NSCLC specimens (515 lung adenocarcinomas and 502 lung squamous cell carcinomas) in the Cancer Genome Atlas (TCGA) database. Results : TCGA data analysis revealed significant downregulation of TSPX in NSCLC tumors compared to adjacent non-cancerous tissues (Wilcoxon matched pairs signed rank test p < 0.0001). Notably, the TSPX expression levels were inversely correlated with the cancer stage, and higher TSPX levels were associated with better clinical outcomes and improved survival in lung adenocarcinoma, a subtype of NSCLC (median survival extended by 510 days; log-rank test, p = 0.0025). RNA-seq analysis of the TSPX-overexpressing NSCLC cell lines revealed that TSPX regulates various genes involved in the cancer-related signaling pathways and cell viability, consistent with the suppression of cell proliferation in cell culture assays. Notably, various potential downstream targets of TSPX that correlated with patient survival (log-rank test, p = 0.016 to 4.3 × 10 -10 ) were identified, including EGFR pathway-related genes AREG , EREG , FOSL1 , and MYC , which were downregulated. Conclusions : Our results suggest that TSPX plays a critical role in suppressing NSCLC progression by downregulating pro-oncogenic genes, particularly those in the EGFR signaling pathway, and upregulating the tumor suppressors, especially in lung adenocarcinoma. These findings suggest that TSPX is a potential biomarker and therapeutic target for NSCLC management.

Bone is a multifaceted tissue requiring orchestrated interplays of diverse cells within specialized microenvironments. Although significant progress has been made in understanding cellular and molecular mechanisms of component cells of bone, revealing their spatial organization and interactions in native bone tissue microenvironment is crucial for advancing precision medicine, as they govern fundamental signaling pathways and functional dependencies among various bone cells. In this study, we present the first integrative high-resolution map of human bone and bone marrow, using spatial and single-cell transcriptomics profiling from femoral tissue. This multi-modal approach discovered a novel bone formation-specialized niche enriched with osteoblastic lineage cells and fibroblasts and unveiled critical cell-cell communications and co-localization patterns between osteoblastic lineage cells and other cells. Furthermore, we discovered a novel spatial gradient of cellular composition, gene expression and signaling pathway activities radiating from the trabecular bone. This comprehensive atlas delineates the intricate bone cellular architecture and illuminates key molecular processes and dependencies among cells that coordinate bone metabolism. In sum, our study provides an essential reference for the field of bone biology and lays the foundation for advanced mechanistic studies and precision medicine approaches in bone-related disorders., (© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Ferroptosis and immune responses are critical pathological events in spinal cord injury (SCI), whereas relative molecular and cellular mechanisms remain unclear., Methods: Micro-array datasets (GSE45006, GSE69334), RNA sequencing (RNA-seq) dataset (GSE151371), spatial transcriptome datasets (GSE214349, GSE184369), and single cell RNA sequencing (scRNA-seq) datasets (GSE162610, GSE226286) were available from the Gene Expression Omnibus (GEO) database. Through weighted gene co-expression network analysis and differential expression analysis in GSE45006, we identified differentially expressed time- and immune-related genes (DETIRGs) associated with chronic SCI and differentially expressed ferroptosis- and immune-related genes (DEFIRGs), which were validated in GSE151371. Protein-protein interaction and microRNA-mRNA-transcription factor regulatory networks were constructed based on Search Tool for the Retrieval of Interacting Genes (STRING) and NetworkAnalyst, respectively, which were validated by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Cell subclusters and unique features of microglia in SCI were identified by single-cell transcriptomic analysis, which were validated in GSE226286. Spatial expression patterns of DETIRGs and DEFIRGs were validated in brain injury (GSE214349) and SCI (GSE184369). Potential mechanisms underlying neuronal regeneration by neurotrophin-3 (NT3)-chitosan were revealed by transcriptomic analyses in GSE69334. Immune- and ferroptosis-related mechanisms of nanolayered double hydroxide loaded with NT3 (LDH-NT3) were investigated in vivo and in vitro., Results: GBP2, TEC, UNC93B1, PLXNC1, NFATC1, IL10RB, and TLR8 were DETIRGs represented chronic SCI-specific genes and peripheral blood biomarkers. NFKB1 may regulate expression of CYBB and HMOX1 in a unique subcluster of M1 microglia within the middle SCI lesion, establishing links between microglial ferroptosis and neuroinflammation. Reduced inflammatory responses and microglial ferroptosis were potential effects of NT3-chitosan or LDH-NT3 on neuronal regeneration., Conclusions: A novel subcluster of microglia exhibiting M1 polarization and ferroptosis phenotype was involved in SCI. These microglia may trigger neuroinflammation and induce neuronal degeneration within the middle site of SCI, which might be inhibited by NT3-chitosan or LDH-NT3., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with institutional recommendations. The procedures were approved by the Animal Welfare Committees of Tongji University in Shanghai, China. Consent to for publication: Not applicable. Competing interests: The authors declare no competing of interest., (© 2025. The Author(s).)

Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 (gdf6Y) in Nothobranchius furzeri, an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele (gdf6X). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3, the mRNA decay activator zfp36l2 as a new GDF6 signaling target., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The fibrosis of pathologic scar (PS) is formed by the excessive deposition of extracellular matrix, resulting in an abnormal scar. Recent clinical tests have indicated that the regulation of PS fibroblast cells (PSF cells) proliferation can serve as an intervention measure for PS. Our work aimed to elucidate the specific mechanism of action of TCF4 on the progression of PS fibrosis., Methods: Our study used qRT-PCR and Western blot to search for the expression of key proteins in PS clinical samples and cells. Transwell, CCK-8, and wound scratch assays were employed to analyze the proliferation and migration of PSF cells. CHIP, dual-luciferase reporter experiments, and bio-informatics analysis were used to analyze the interactions between molecules., Results: The analysis of PS clinical samples confirmed a positive correlation between TCF4 and miR-494-3p. This regulatory mechanism was related to the progression of PS. We verified that the overexpression of miR-494-3p or the knockdown of THBS1 both suppressed the proliferation and migration of PSF cells. Furthermore, we also confirmed the binding relationships between TCF4, miR-494-3p, and THBS1. Simultaneously, we verified the existence of the TCF4/miR-494-3p/THBS1 regulatory network in PS. This regulatory process affects the development of PS fibrosis., Conclusion: Our study results indicate that TCF4, miR-494-3p, and THBS1 are abnormally expressed in PS. TCF4 increases the proliferation and migration ability of PSF cells through the miR-494-3p/THBS1 signaling pathway, which promotes the fibrosis of PS., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite the recent advances in vaccination and treatment strategies, cervical cancer continues to claim numerous lives every year. Owing to the fact that non-coding RNAs (ncRNAs) such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) interact with coding transcripts, and effectuate key roles in the tumorigenesis and metastasis of cervical cancer, there has been extensive research in recent years to explore their potential as biomarkers for early detection, or as therapeutic targets. Through this review, we aim to provide a comprehensive overview of the recent advancements in discoveries about cervical cancer-associated lncRNA-miRNA-mRNA axes, their dysregulation, and their roles in various signaling pathways associated with the growth, survival, invasion, and metastasis of cervical cancer cells. We further discuss the potential therapeutic strategies to utilize the dysregulated lncRNAs as diagnostic and prognostic biomarkers, and as therapeutic targets to ameliorate the prognosis of cervical cancer., Competing Interests: Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Plants have colonized lands 450 million years ago. This terrestrialization was facilitated by developmental and functional innovations. Recent evo-devo approaches have demonstrated that one of these innovations was the mutualistic arbuscular mycorrhizal symbiosis (AMS). The genetic pathways that have been involved in the establishment and functioning of AMS since its evolution remain poorly described. Here, we found that intracellular colonization by AM fungi induces a transcriptional reporter of the common symbiosis pathway, well-described in angiosperms, in the liverwort Marchantia paleacea . Mutants of either of the three main genes of this pathway, SYMRK , CCaMK, and CYCLOPS, disrupt the ability of M. paleacea to associate with AM fungi. Finally, overexpressing gain-of-function CCaMK or CYCLOPS leads to convergent transcriptomic signatures that partially overlap with AMS. Altogether, our data indicate that plants have maintained three genes of the common symbiotic pathway to support symbiotic interactions since their most recent common ancestor., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: In the soy sauce fermentation industry, Aspergillus oryzae (A. oryzae) plays an essential role and is frequently subjected to high salinity levels, which pose a significant osmotic stress. This environmental challenge necessitates the activation of stress response mechanisms within the fungus. The Zn(II) 2 Cys 6 family of transcription factors, known for their zinc binuclear cluster-containing proteins, are key regulators in fungi, modulating various cellular functions such as stress adaptation and metabolic pathways., Results: Overexpression of AozC decreased growth rates in the presence of salt, while its knockdown enhanced growth, the number of spores, and biomass, particularly under conditions of 15% salt concentration, doubling these metrics compared to the wild type. Conversely, the knockdown of AozC via RNA interference significantly enhanced spore density and dry biomass, particularly under 15% salt stress, where these parameters were markedly improved over the wild type strain. Moreover, the overexpression of AozC led to a downregulation of the FAD2 gene, a pivotal enzyme in the biosynthesis of unsaturated fatty acids (UFAs), which are essential for preserving cell membrane fluidity and integrity under saline conditions. Transcriptome profiling further exposed the influence of AozC on the regulation of UFA biosynthesis and the modulation of critical stress response pathways. Notably, the regulatory role of AozC in the mitogen-activated protein kinase (MAPK) signaling and ABC transporters pathways was highlighted, underscoring its significance in cellular osmotic balance and endoplasmic reticulum homeostasis. These findings collectively indicate that AozC functions as a negative regulator of salt tolerance in A. oryzae., Conclusion: This research suggest that AozC acts as a negative regulator in salt tolerance and modulates fatty acid biosynthesis in response to osmotic stress. These results provide insights into the regulatory mechanisms of stress adaptation in A. oryzae., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Despite the emergence of the first human papillomavirus vaccine, the incidence of cervical cancer is still responsible for more than 350,000 deaths yearly. Over the past decade, ecto-5'-nucleotidase (CD73/5'-NT) and extracellular adenosine (ADO) signalling has been the subject of many investigations to target cancer progression. In general, the adenosinergic axis has been linked to tumourigenic effects. However, CD73 can play contradictory effects, probably dependent on the tumour type, tumour microenvironment and tumour stage, thus being in some circumstances, inversely related to tumour progression. We herein reviewed the pathophysiological function of CD73 in cervical cancer and performed in silico analysis of the main components of the adenosinergic signalling in human tissues of cervical cancer compared to non-tumour cervix tissue. Our data showed that the NT5E gene, that encoded CD73, is hypermethylated, leading to a decreased CD73 expression in cervical cancer cells compared to normal cells. Consequently, the high availability of ADO cytoplasmatic/extracellular leads to its conversion to AMP by ADK, culminating in global hypermethylation. Therefore, epigenetic modulation may reveal a new role for CD73 in cervical cancer.

Background: Karyotype 46, XY female disorders of sex development (46, XY female DSD) are congenital conditions due to irregular gonadal development or androgen synthesis or function issues. Genes significantly influence DSD; however, the underlying mechanisms remain unclear. This study identified a Chinese family with 46, XY female DSD due to the CUL4B gene., Methods: The proband medical history and pedigree were investigated. Whole-exome sequencing was performed to analyze different variations. Transiently transfected testicular teratoma (NT2/D1), KGN ovarian cells with either mutant or wild-type CUL4B gene, and knock-in Cul4b mouse models were confirmed. The expression levels of sex-related genes were analyzed., Results: A 9.5-year-old girl was diagnosed with 46, XY DSD. A hemizygous variant c.838 T > A of the CUL4B gene was detected. The mRNA and protein levels of WNT4 and FOXL2 genes were higher than those in the wild-type group; however, CTNNB1, SOX9, and DMRT1 were lower in the wild-type group in NT2/D1 cells. In KGN ovarian cells of the mutant group, the mRNA and protein levels for WNT4 and CTNNB1 were elevated. Damaged testicular vasculature and underdeveloped seminal vesicles were observed in Cul4b L337M mice., Conclusions: A missense CUL4B variant c.838 T > A associated with 46, XY female DSD was identified, and may activate the Wnt4/β-catenin pathway. Our findings provide novel insights into the molecular mechanisms of 46, XY female DSD., Competing Interests: Declarations. Ethics approval and consent to participate: A review and approval of the study were obtained from the Ethics Committee of the First Affiliated Hospital at Zhejiang University School of Medicine, China (approval number 2023–0898). The study was conducted in accordance with the Declaration of Helsinki Principles. The parents of the proband provided written informed consent. The ARRIVE guidelines and the Basel Declaration were followed during animal studies. Consent for publication: Not applicable. Competing interests: The authors declare no conflict of interest., (© 2025. The Author(s).)

Background: Renal osteodystrophy (ROD) is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder (CKD-MBD) that is characterized by aberrant bone mineralization and remodeling. ROD increases the risk of fracture and mortality in CKD patients. The underlying mechanisms of ROD remain elusive, partially due to the absence of an appropriate animal model. To address this gap, we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing (RNA-seq)., Methods: Eight-week-old male C57BL/6J mice were randomly allocated into three groups: control group ( n = 5), adenine and high-phosphate (HP) diet group ( n = 20), and the optimized adenine-containing diet group ( n = 20) for 12 weeks. We assessed the skeletal characteristics of model mice through blood biochemistry, microcomputed tomography (micro-CT), and bone histomorphometry. RNA-seq was utilized to profile gene expression changes of ROD. We elucidated the functions of differentially expressed genes (DEGs) using gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). DEGs were validated via quantitative real-time polymerase chain reaction (qRT-PCR)., Results: By the fifth week, adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group, precluding further model development. Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels, accompanied by pronounced hyperparathyroidism and hyperphosphatemia. The femur bone mineral density (BMD) of the model mice was lower than that of control mice, with substantial bone loss and cortical porosity. ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers. Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice. Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway. The significant upregulation of alkaline ceramidase 1 ( Acer1 ), alkaline ceramidase 2 ( Acer2 ), prosaposin-like 1 ( Psapl1 ), adenosine A1 receptor ( Adora1 ), and sphingosine-1-phosphate receptor 5 ( S1pr5 ) were successfully validated in mouse femurs by qRT-PCR., Conclusions: Optimized adenine diet mouse model may be a valuable proxy for studying ROD. RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis, thereby providing new avenues for therapeutic intervention., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Imatinib resistance is a major obstacle to the successful treatment of gastrointestinal stromal tumors (GIST). Long non-coding RNAs (LncRNAs) have been identified as important regulatory factors in chemotherapy resistance. This study aimed to identify key lncRNAs involved in imatinib resistance of GISTs. First, MSC-AS1 was found to be upregulated in imatinib-resistant GIST tissues and imatinib-resistant GIST cells. Cellular experiments demonstrated that MSC-AS1 overexpression decreased imatinib sensitivity of GIST cells, evidenced by increased cell survival, colony formation, migration, and invasion. Moreover, suppression of MSC-AS1 improved the imatinib resistance of imatinib-resistant GIST cells. Furthermore, MSC-AS1 upregulated the expression of FNDC1 and Anillin via sponging miR-200b-3p, activated the phosphatidylinositol-3-kinase-AKT signaling pathway, and thereby driving imatinib resistance in vitro and in vivo. Overall, this study elucidates the crucial role and mechanism of MSC-AS1 in the imatinib resistance of GIST, providing the potential therapeutic strategy for overcoming the imatinib resistance of GIST., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All clinical experiments were approved by the Ethics Committee at China-Japan Union Hospital of Jilin University (2023-KYYS-023) and operated following the Declaration of Helsinki. Informed consent: Informed consent was obtained from all participants. Human or animal rights: All animal experiments were conducted in accordance with institutional guidelines and were approved by the Institutional Animal Care and Use Committee of Yishengyuan Gene Technology Co., LTD (No. 20240107)., (© 2025. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: The study aimed to was to investigate the relationship between miR-2861, miR-5011-5p, and colorectal carcinogenesis., Method: In the present study, it was isolated RNA from both the tumor and non-tumor tissue of a total of 80 CRC patients and after synthesizing the cDNA, it was performed qRT-PCR to determine the expression levels of miR‑2861 and miR‑5011-5p. In addition, it was predicted that dysregulated miRNAs targets, pathways and functional gene annotations that may be important in colorectal carcinogenesis using KEGG pathway and GO analysis., Results: The resulting data revealed that both expression levels of miR-2861 and miR-5011-5p were significantly decreased in tumor tissues compared with non-tumor tissues of CRC patients. The GO and KEGG pathway analysis showed that miR-2861 and miR-5011-5p may participate in multiple the biological process, cellular components, and molecular function subcategories such as mitotic cell cycle, regulation of small GTPase mediated signal transduction, cell death, and acid binding transcription factor activity. It was also revealed that target genes of miRNAs can be found in signaling pathways such as TGF-beta, Rap1, Ras, cAMP, Wnt, mTOR and, PI3K-Akt signaling pathways., Conclusion: These findings imply that miR-2861 and miR-5011-5p might function as tumor suppressors in the development of CRC., Competing Interests: Declarations. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the local ethics committee of Gaziantep University, Turkey (approval numbers: 2021/179). Informed consent was obtained from all individuals included in this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

cGAS plays an important role in regulating both tumor immune responses and DNA damage repair. Nevertheless, there was little research that comprehensively analyzed the correlation between cGAS and the tumor microenvironment, immune cell infiltration, and DNA damage repair in different cancers. In this study, The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) data were used to analyze the mRNA expression and genomic alterations of cGAS in pan-cancer. The HPA database was used to explore the protein levels of cGAS in normal tissues and cancers. Correlation analysis were performed to explore the role of cGAS in interferon expression, immune cell infiltrations, DNA damage repair, and predictive immune markers. The prognostic value of cGAS was analyzed using survival data from the TCGA, Kaplan-Meier plotter database, and PrognoScan database. Lastly, the role of cGAS in DNA damage repair signaling and interferon signaling was validated in NSCLC cell lines. The results showed that cGAS was widely expressed in human normal tissues and various cancers, and the expression of cGAS was significantly upregulated in almost all of the solid cancers. Genomic analysis indicated that the expression of cGAS was positively correlated with copy number levels, while negatively correlated with the methylation levels of cGAS promoter. In addition, the level of cGAS was positively correlated with type I interferons expression, infiltration levels of most immune cell types, TMB and MSI levels, stromal and immune scores, and DNA damage repair gene sets including nonhomologous end joining and homologous recombination pathway. Survival analysis indicated that cGAS levels were associated with patient prognosis in several cancers. Lastly, in vitro study showed knockdown of cGAS expression inhibits the DNA damage repair signaling pathway and interferon signaling in NSCLC. In conclusions, cGAS is wildly activated in human cancers, which might participate in regulating cancer immunity and DNA damage repair. cGAS could be used as an effective target for cancer treatment and might be a potential predictive immune marker., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)