Search Results (90)

Time delays are intrinsic to mitotic regulation, particularly within the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). These delays emerge from multi-step protein activation, molecular transport, force-dependent conformational transitions, and spatial redistribution of regulatory complexes. They span seconds to minutes and strongly influence checkpoint activation, maintenance, and silencing. Increasing evidence shows that such delayed processes shape mitotic timing, checkpoint robustness, and cell-fate decisions. While classical ordinary differential equation (ODE) models assume instantaneous biochemical responses, delay differential equations (DDEs) provide a natural framework for representing these finite timescales by explicitly incorporating system history. Recent DDE-based studies have revealed how delayed signaling contributes to bistability, oscillatory responses, prolonged mitotic arrest, and variability in checkpoint outputs. This review summarizes the biological origins of delays in SAC and SPOC, including Mad2 activation, MCC assembly and turnover, APC/C reactivation, tension maturation at kinetochores, and Bfa1–Bub2 regulation of Tem1. The article further discusses how mechanistic models with explicit delays improve our understanding of SAC–SPOC ordering, error-correction dynamics, and mitotic exit control. Finally, open challenges and future directions are outlined for integrative delay-aware modeling that unifies biochemical, mechanical, and spatial processes to better explain checkpoint function and chromosomal stability. Full article

Cervical cancer remains a significant cause of cancer-related mortality among women, particularly in low- and middle-income countries. High-throughput technologies, such as microarrays, have facilitated the comprehensive analysis of gene expression profiles in cervical cancer, enabling the identification of key differentially expressed genes (DEGs) involved in its pathogenesis. The publicly available microarray datasets, including GSE39001, GSE9750, GSE7803, GSE6791, GSE63514, and GSE52903 in combination with bioinformatics database predictions, were used to identify differential expression genes, potential biomarkers, and therapeutic targets for cervical cancer; additionally, we undertook bioinformatic analysis to determine gene ontology and possible miRNA targets related to our DEGs. Our analysis revealed several DEGs significantly associated with cervical cancer progression, such as cell death, regulation of DNA replication, protein binding processes, and transcription factors. The most relevant transcription factors (TFs) identified were SP1, ELF3, E2F1, TP53, RELA, HDAC, and FOXM1. Importantly, the DEGs with more important changes were 11 coding genes that were upregulated (KIF4A, MCM5, RFC4, PLOD2, MMP12, PRC1, TOP2A, MCM2, RAD51AP1, KIF20A, AIM2) and 14 that were downregulated (CXCL14, KRT1, KRT13, MAL, SPINK5, EMP1, CRISP3, ALOX12, CRNN, SPRR3, PPP1R3C, IVL, CFD, CRCT1), which were associated with cervical cancer. Interestingly, hub proteins KIF4A, NUSAP1, BUB1B, CEP55, DLGAP5, NCAPG, CDK1, MELK, KIF11, and KIF20A were found to be potentially regulated by several miRNAs, including miR-107, miR-124-3p, miR-147a, miR-16-5p, miR-34a-5p, miR-34c-5p, miR-126-3p, miR-10b-5p, miR-23b-3p, miR-200b-3p, miR-138-5p, miR-203a-3p, miR-214-3p, and let-7b-5p. The relationship between these genes highlights their potential as candidate biomarkers for further research in treatment, diagnosis, and prognosis. Full article

Objective: Identifying biomarkers that predict metastatic potential or guide treatment selection is critical for improving breast cancer (BC) management. Previously, we established the Mitotic Network Activity Index (MNAI) as a prognostic marker in BC. Here, we bioinformatically and experimentally evaluated MNAI as a biomarker for metastasis risk and therapeutic response. Methods: We used Kaplan–Meier and Cox proportional hazard regression analyses to assess the association between MNAI and distant metastasis-free survival (DMFS) across 14 published BC datasets. A total of 16 publicly available clinical trial datasets, including the I-SPY trials, were used to evaluate the predictive value of MNAI for treatment response. Additionally, wound-healing and transmembrane assays were conducted to determine the effects of PLK1, CHEK1, and BUB1 inhibition on BC cell migration and invasion. Results: High MNAI levels were strongly associated with shorter DMFS. Multivariate analysis further confirmed MNAI as an independent risk factor for DMFS, beyond estrogen receptor status and PAM50-based molecular subtypes. Functionally, pharmacologic disruption of the mitotic network using PLK1, CHEK1, or BUB1 inhibitors significantly reduced cell migration and invasion in MDA-MB-231 and BT-549 BC cell lines. Moreover, BC cells with high MNAI increased sensitivity to microtubule-targeting agents such as docetaxel, paclitaxel, and ixabepilone but increased resistance to tamoxifen, AKT1/2 inhibitors, and mTOR inhibitors. Consistent with these findings, analysis of 16 clinical trial cohorts revealed that patients with high MNAI achieved higher pathological complete response rates to taxane-containing and ixabepilone-based therapies. Conclusions: Our findings demonstrate the MNAI as a clinically actionable biomarker that can refine risk stratification and guide the selection of targeted or chemotherapy regimens, advancing precision medicine in BC management. Full article

In colorectal carcinoma (CRC), 5-fluorouracil (5-FU) remains the cornerstone of adjuvant systemic therapy, with folic acid (FA) serving as an essential adjunct. Expression of genes related to the metabolism and action of 5-FU and FA can be influenced by patient- and tumor-specific biological factors. In this study, we explore differential gene expression profiles of 180 genes representing 14 different gene sets associated with different 5-FU and FA metabolism processes, at both gene and pathway levels across clinical and molecular subgroups. In 71 patients with CRC, paired tumors and normal colonic tissues were analyzed. In CRC tissue, several gene sets (including Cell Cycle Checkpoint, Oxidative Stress Response, and Signaling Pathway, etc.) were upregulated, while three gene sets (Apoptotic, Tumor Suppressor, and Endoplasmic Reticulum Stress) were downregulated. Kirsten rat sarcoma virus (KRAS), tumor protein p53 (TP53), and microsatellite instability (MSI) status impacted gene expression across molecular subgroups. At the individual gene level, among cell cycle genes, the BUB3 mitotic checkpoint protein (BUB3) was upregulated in MSI tumors compared to MSS, whereas SMAD family member 4 (SMAD4) was downregulated in MSS tumors compared to MSI. DNA fragmentation factor alpha (DFFA) was downregulated in MSI and upregulated in MSS. Notably, thymidylate synthetase (TYMS) was more upregulated in MSI tumors (1.65-fold; 95% CI: 1.27–2.13) compared to MSS (1.19-fold; 95% CI: 1.02–1.39). Dysregulation of these genes across these factors will broaden our understanding of 5-FU-based treatment in CRC. Furthermore, targeting dysregulated pathways could form the basis for improved precision therapies tailored to CRC subtypes. Full article

To investigate the gene regulatory mechanisms underlying muscle development in Oula sheep at different growth stages, under supplementary feeding, particularly the shift in core regulatory mechanisms governing muscle development from the fetal stage to the postnatal period, we conducted transcriptomic sequencing and comparative analysis of the longissimus dorsi muscle collected during the embryonic, lamb, and adult stages. Differentially expressed genes (DEGs) potentially associated with muscle growth and development were identified across various age phases. Furthermore, Short Time-series Expression Miner (STEM) analysis was employed to decipher the temporal expression patterns of these DEGs. The results indicated that metabolic processes related to carbohydrates, energy, and amino acids were enhanced with increasing age in Oula sheep muscle. Comparative analysis between different growth stages revealed that the functional enrichment of DEGs was directly associated with changes in skeletal muscle development, with significant enrichment in biological pathways such as ECM–receptor interaction, PI3K-AKT signaling pathway, and protein digestion and absorption. Additionally, we observed that PTPRC, IL10, NDUFAB1, BUB1, BUB1B, CDK1, ITGB3, and ITGB2 may play pivotal roles in the regulation of muscle growth and development across different stages in Oula sheep. These findings provide theoretical support for the understanding of the genetic regulatory mechanisms underlying muscle development in Oula sheep. Full article

Sarcomas are heterogeneous mesenchymal tumors, and their pharmacological treatment remains challenging due to the high toxicity and poor efficacy of current therapies. This study aimed to identify common overexpressed kinases in the four most frequent sarcoma subtypes to establish novel therapeutic targets. A bioinformatics approach using patient-derived gene expression data sets identified overexpressed kinases shared across these sarcoma types. Later, BUB1 was determined as the kinase consistently overexpressed across the osteosarcoma, liposarcoma, leiomyosarcoma, and synovial sarcoma. Moreover, the role of this kinase was further validated through molecular and functional assays, including pharmacological inhibition in cell lines derived from the four sarcoma subtypes. BUB1 inhibition reduced the phosphorylation of AKT and H2A proteins, precluded cell proliferation, and inhibited colony formation in sarcoma cells. Finally, overall survival analysis highlighted a strong correlation between high BUB1 expression and poorer survival rates in sarcoma patients. Altogether, these findings underscore the potential of BUB1 as a therapeutic target and prognostic marker in sarcomas. Targeted inhibition of BUB1 may provide a novel strategy to reduce tumor growth and improve outcomes for patients with bone and soft tissue sarcomas. Full article

This study analyzes publicly available RNA-seq data to comprehensively include the complex heterogeneity of prostate cancer (PCa) etiology. It combines prostate and prostate cancer (PCa) cell lines, representing primary PCa cells, Gleason scores, ages, and PCa of different racial origins. Additionally, some cell lines were exposed to endocrine-disrupting chemicals (EDCs). The research aims to identify hub genes and transcription factors (TFs) of the prostate carcinogenesis pathway as molecular targets for clinical investigations to elucidate EDC-induced aggressiveness and to develop potential biomarkers for their exposure risk assessments. PCa cells rely on androgen receptor (AR)-mediated signaling to survive, develop, and function. Fifteen various RNA-seq datasets were normalized for distribution, and the significance (p-value < 0.05) threshold of differentially expressed genes (DEGs) was set based on |log2FC| ≥ 2 change. Through integrated bioinformatics, we applied cBioPortal, UCSC-Xena, TIMER2.0, and TRRUST platforms, among others, to associate hub genes and their TFs based on their biologically meaningful roles in aggressive prostate carcinogenesis. Among all RNA-Seq datasets, we found 75 overlapping DEGs, with BUB1B (32%) and CCNB1 (29%) genes exhibiting the highest degree of mutation, amplification, and deletion. EDC-associated CCNB1, BUB1B, and CCNA2 in PCa cells exposed to EDCs were consistently shown to be associated with high Gleason scores (≥4 + 3) and in the >60 age group of patients. Selected TFs (E2F4, MYC, and YBX1) were also significantly associated with DEGs (NCAPG, MKI67, CCNA2, CCNB1, CDK1, CCNB2, AURKA, UBE2C, BUB1B) and influenced the overall survival (p-value < 0.05) of PCa cases. This is one of the first comprehensive studies combining 15 publicly available RNA-seq datasets to demonstrate the association of EDC-associated hub genes and their TFs aligning with the aggressive carcinogenic pathways in the higher age group (>60 years) of patients. The findings highlight the potential of these hub genes as candidates for further studies to develop molecular biomarkers for assessing the EDC-related PCa risk, diagnosing PCa aggressiveness, and identifying therapeutic targets. Full article

The conserved and essential Cdc13/CTC1-Stn1-Ten1 telomeric complex (CST) ensures chromosome stability by protecting telomere ends and regulating telomerase accessibility. In a recent study, we uncovered mutants of the S. cerevisiae CST, in which damage was sensed by the two major G2/M spindle checkpoints (one is Bub2-dependent and the other one Mad2-dependent), as well as the major G2/M DNA damage checkpoint (Mec1-dependent). In this study, we found, by fluorescence microscopy, that the stability of the mitotic tubulin spindle was profoundly affected in the best-studied of these mutants, stn1-sz2. Additional data from genetic analyses suggested the potential involvement of Stu1 and Stu2, as well as Slk19, in these defects. Throughout this study, we compared the phenotypes of stn1-sz2 with those of cdc13-1, the best-studied CST mutant, which also serves as a prototype of telomere-damage-characterized CST mutants. We propose that stn1-sz2 represents the prototype of cst mutants characterized by tubulin spindle damage. These newly described phenotypes potentially represent the basis for identifying new functions of the CST telomeric complex. These functions might consist of ensuring correct chromosome segregation through the stabilization of the mitotic spindle. Full article

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited effective treatments available, including targeted therapies, often leading to poor prognosis. Mitotic checkpoint kinase BUB1 is frequently overexpressed in TNBC and correlates with poor survival outcomes suggesting its potential as a therapeutic target. This study explores the cytotoxicity of TNBC cells to BUB1 inhibition, alone or in combination with radiation and demonstrates that ferroptosis, an iron-dependent form of programmed cell death, has a role. Methods: TNBC cell lines (SUM159, MDA-MB-231, and BT-549) were treated with a BUB1 inhibitor BAY1816032 (BUB1i) alone or in combination with the ferroptosis activator RSL3 with or without 4 Gy irradiation. Cell viability assays were conducted to assess treatment effects, qPCR analyses measured expression of key ferroptosis markers including ACSL4, GPX4, PTGS2, SLC7A11, NCOA4, IREB2, NFS1, and TFRC expression, and TBARS assay measured the lipid peroxidation levels. Ferroptosis specificity was confirmed through co-treatment with the ferroptosis inhibitor Ferrostatin-1 (F-1). Results: In all TNBC cell lines studied, BUB1 inhibition significantly induced ferroptosis, marked by increased expression of ACSL4 and PTGS2, decreased expression of GPX4 and SLC7A11, and increased lipid peroxidation levels. The combination of BUB1i with RSL3 further amplified these ferroptotic markers, suggesting at least an additive effect, which was not present with the combination of BUB1i and radiation. Co-treatment with Ferrostatin-1 reversed the expression of ferroptosis markers, suggesting that BUB1i-mediated cell death may involve ferroptotic signaling in TNBC cell lines. Conclusions: This study demonstrates that BUB1 inhibition may independently induce ferroptosis in TNBC cell lines, which is enhanced when combined with a ferroptosis activator. Further research is warranted to delineate the molecular mechanism of BUB1-mediated ferroptosis in TNBC. Full article

BUB1B, a member of the spindle assembly checkpoint family known as BUB1 mitotic checkpoint serine/threonine kinase B, has been associated with the promotion of tumor progression. Nevertheless, its specific contributions to tumorigenesis remain largely unexplored. This study seeks to offer a systematic and comprehensive analysis of the role of BUB1B in the progression of various cancers, with a particular focus on lung adenocarcinoma, utilizing a range of databases. We investigated BUB1B’s role in pan-cancer using TCGA data, analyzing it with platforms like HPA, TIMER, TISIDB, GEPIA, cBioPortal, GDC, LinkedOmics, and CancerSEA. Additionally, we assessed BUB1B’s impact on lung adenocarcinoma proliferation and migration through CCK-8, wound healing, transwell assays and Western blot analysis. This study found that BUB1B was upregulated in most cancers and was significantly linked to patient prognosis. Its expression correlated with immune cell infiltration and genetic markers of immunomodulators across different cancers. BUB1B was involved in the acute inflammatory response and IgA production pathways but negatively correlated with inflammation in lung adenocarcinoma. Moreover, the siRNA-mediated knockdown of BUB1B resulted in the inhibition of proliferation and migration of lung cancer cells in vitro. This study underscores the potential of BUB1B as a biomarker and a promising therapeutic target for patients with lung adenocarcinoma. Full article

The tomato leafminer, Tuta absoluta, is an invasive pest that poses a significant threat to Solanaceae crops, including tomatoes, potatoes, and eggplants. Its ability to adapt to various environmental conditions, especially cold stress, allows it to survive in regions with fluctuating temperatures. In this study, the molecular response of T. absoluta adults to rapid cold hardening (RCH) under gradually decreasing non-lethal temperatures was investigated. Using RNA-seq, 197 upregulated genes and 626 downregulated genes were identified in response to cold hardening. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that upregulated genes were primarily associated with the cell cycle and cell division, including key genes such as CDC25A, BUB1, ORC2, and PlK1, as well as metal ion transporters like unc-93. Downregulated genes were found to be involved in metabolism and oxidative phosphorylation, including COX4, ATPase_I, and ATP-synt_ab. Weighted gene coexpression network analysis (WGCNA) indicated a positive correlation between cell cycle-related genes and RCH, while metabolic processes, including fatty acid metabolism, were negatively correlated with cold hardening. These findings provide new insights into the transcriptional mechanisms of insect responses to cold stress, and highlight potential targets for environmentally sustainable pest management strategies. Full article

Endometrial cancer (EC) presents a substantial health challenge, with increasing incidence and mortality rates. Despite advances in diagnosis and treatment, understanding the molecular underpinnings of EC progression remains unknown. In this study, we conducted a comprehensive investigation utilizing The Cancer Genome Atlas (TCGA-UCEC n = 588) data to analyze gene co-expression patterns, elucidate biological process pathways, and identify potential prognostic and diagnostic biomarkers for EC, using weighted gene co-expression network analysis (WGCNA), differential gene expression, survival analysis, and functional analysis, respectively. We determined that the Green module (M5) was significantly correlated with patient survival. Functional analysis of the genes in module M5 indicates involvement in cell cycle regulation, mitotic spindle assembly, and intercellular signaling. TPX2, BUB1, and ESPL1 were among the top differentially expressed genes in the Green module, suggesting their involvement in critical pathways that contribute to disease progression and patient survival outcomes. The biological and clinical assessments of our findings provide an understanding of the molecular landscape of EC and identified several potential prognostic markers for patient risk stratification and treatment selection. Full article

Einstein’s 1919 distinction between “principle theories” and ”constructive theories” has been applied by Jeffrey Bub to classify the Copenhagen interpretation of quantum mechanics (QM) as a principle theory agree with this classification. Additionally, I argue that Bohm’s interpretation of QM fits Einstein’s concept of a constructive theory. Principle theories include empirically established laws or principles, such as the first and second laws of thermodynamics or the principles of special relativity, including the Born Rule of QM. According to Einstein, principle theories offer ”security in their foundations and logical perfection”. However, ultimate understanding requires constructive theories, which build complex phenomena from simpler models. Constructive theories provide intelligible models of physical phenomena. Bohm’s QM, with its added microstructure, presents such a model. In this framework, quantum phenomena appear from statistical ensembles of microparticles in motion, with deterministic particle trajectories guided by the wave function. This reveals how Bohm’s account offers a constructive model for understanding quantum phenomena. Full article

Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the subcutaneous adipose tissue (SAT) of 1-day and 21-day old Laiwu piglets. The results showed that the SAT of Laiwu piglets significantly increased from 1-day to 21-day, and transcriptome analysis showed that there were 2352 and 2596 differentially expressed genes (DEGs) between 1-day and 21-day SAT in male and female piglets, respectively. Expression of genes in glycolysis, gluconeogenesis, and glycogen metabolism such as pyruvate kinase M1/2 (PKM), phosphoenolpyruvate carboxy kinase 1 (PCK1) and amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) were significantly different between 1-day and 21-day SAT. Genes in lipid uptake, synthesis and lipolysis such as lipase E (LIPE), acetyl-CoA carboxylase alpha (ACACA), Stearoyl-CoA desaturase (SCD), and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were also differentially expressed. Functional analysis showed enrichment of DEGs in transcriptional regulation, protein metabolism and cellular signal transduction. The protein–protein interaction (PPI) networks of these DEGs were analyzed and potential hub genes in these pathways were identified, such as transcriptional factors forkhead box O4 (FOXO4), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein delta (CEBPD), signal kinases BUB1 mitotic checkpoint serine/threonine kinase (BUB1) and cyclin-dependent kinase 1 (CDK1), and proteostasis-related factors ubiquitin conjugating enzyme E2 C (UBE2C) and cathepsin D (CTSD). Moreover, we further analyzed the transcriptomes of SAT between genders and the results showed that there were 54 and 72 DEGs in 1-day and 21-day old SAT, respectively. Genes such as KDM5D and KDM6C showed gender-specific expression in 1-day and 21-day SAT. These results showed the significant changes in SAT between 1-day and 21-day in male and female Laiwu pigs, which would provide information to comprehensively understand the programming of adipose tissue early development and to regulate adipose tissue function. Full article

Background: Despite advances in targeted therapies and immunotherapies, traditional treatments like microtubule stabilizers (paclitaxel, docetaxel), DNA-intercalating platinum drugs (cisplatin), and radiation therapy remain essential for managing locally advanced and metastatic lung cancer. Identifying novel molecular targets could enhance the efficacy of these treatments. Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is overexpressed in lung cancers and its inhibition will sensitize lung cancers to chemoradiation. Methods: BUB1 inhibitor (BAY1816032) was combined with cisplatin, paclitaxel, a PARP inhibitor olaparib, and radiation in cell proliferation and radiation-sensitization assays. Biochemical and molecular assays evaluated the impact on DNA damage signaling and cell death. Results: Immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) compared to normal tissues. In NSCLC, BUB1 overexpression correlated directly with the expression of TP53 mutations and poorer overall survival in NSCLC and SCLC patients. BAY1816032 synergistically sensitized lung cancer cell lines to paclitaxel and olaparib and enhanced cell killing by radiation in both NSCLC and SCLC. Molecular analysis indicated a shift towards pro-apoptotic and anti-proliferative states, evidenced by altered BAX, BCL2, PCNA, and Caspases-9 and -3 expressions. Conclusions: Elevated BUB1 expression is associated with poorer survival in lung cancer. Inhibiting BUB1 sensitizes NSCLC and SCLC to chemotherapies (cisplatin, paclitaxel), targeted therapy (olaparib), and radiation. Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies. Full article