Search Results (26)

Cellular senescence, characterized by permanent cell cycle arrest, significantly influences cancer development, immune regulation, and progression. However, the precise mechanisms by which senescence contributes to colorectal cancer prognosis remain to be fully elucidated. By integrating expression profiles of senescence-related and prognostic genes in colon adenocarcinoma (COAD) patients, we formulated and confirmed a nine-gene cellular senescence-related signature (CSRS) that integrates senescence-associated and prognosis-predictive genes using data from the CellAge, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A cell senescence-related prognostic formula was developed as follows: CSRS = (CASP2 × 0.2098) + (CDKN2A × 0.1196) + (FOXD1 × 0.1472) + (ING5 × 0.3723) + (OXTR × 0.0786) + (PHGDH × 0.1408) + (SERPINE1 × 0.1127) + (SNAI1 × 0.1034) + (LIMK1 × 0.0747). In a multivariate Cox proportional hazards model, the CSRS score, age and TNM stage were all identified as significant independent indicators for overall survival, affirming their prognostic value in colorectal cancer. The CSRS-high group exhibited significantly up-regulated senescence-associated secretory phenotype (SASP) and immune cell infiltration, whereas the CSRS-low group showed an apparent better response to immune-checkpoint inhibitor therapy. Our findings suggest CSRS score and its constituent genes represent potential biomarkers for prognosis and immunotherapeutic benefit in COAD patients. Extending this nine-gene set into a broader senescence-associated panel should be a next step toward delivering truly individualized treatment plans. Full article

The large yellow croaker, or Larimichthys crocea, is highly prized for its golden color and nutritional content. The purpose of this study was to investigate the differences in body composition, mucus biochemical indices and body color in five strains of large yellow croakers (body weight: 347.01 ± 5.86 g). To conduct genetic diversity analyses of the populations, a total of 50 tailfin samples were randomly chosen from the following populations of large yellow croakers: wild (LYC1), Dai-qu population (LYC2), Yongdai 1 (LYC3), Min-yuedong population (LYC4), and Fufa 1 (LYC5). The findings demonstrated that the LYC3 group’s pigment contents, crude protein, crude lipid, and chromatic values were comparable to those of the LYC1 group (p > 0.05). There was no significant difference between the LYC1 and LYC5 groups’ mucus superoxide dismutase (SOD) and catalase (CAT) activities (p > 0.05). The alkaline phosphatases (ALP), acid phosphatases (ACP), and lysozyme (LYS) activities of the mucus in the LYC1 group were not significantly different from the LYC3 group (p > 0.05). The back skin mRNA expressions of tyrosinase (tyr), tyrosinase-related protein 1 (tyrp1), dopachrome tautomerase (dct), microphtalmia-associated transcription factor (mitf), and melanocortin 1 receptor (mc1r) were significantly up-regulated in the LYC2 and LYC4 groups compared to the LYC1, LYC3, and LYC5 groups (p < 0.05). Forkhead box d3 (foxd3), paired box 3 (pax3), purine nucleoside phosphorylase 4a (pnp4a), aristaless-like homeobox 4a (alx4a), cAMP dependent protein kinase (pka), anaplastic lymphoma kinase (alk), leukocyte receptor tyrosine kinase (ltk), and colony stimulating factor (fms) were among the mRNA expressions of the abdominal skin in the LYC1, LYC3, and LYC5 groups significantly higher than those in the LYC2 and LYC4 groups (p < 0.05). In conclusion, the LYC3 group’s crude protein, crude lipid, carotenoid, and lutein contents were most similar to those of the large yellow croaker found in the wild. Furthermore, the molecular mechanism underlying the variations in body color among the various strains of large yellow croakers was supplied for additional research. Full article

The piggyBac+TET-on transposon induction system has a high efficiency in integrating exogenous genes in multiple cell types, can precisely integrate to reduce genomic damage, has a flexible gene expression regulation, and a strong genetic stability. When used in conjunction with somatic cell nuclear transfer experiments, it can precisely and effectively reveal the intrinsic mechanisms of early biological development. This study successfully reprogrammed black-boned sheep fibroblasts (SFs) into induced pluripotent stem cells (iPSCs) using the piggyBac+TET-on transposon system and investigated their impact on early embryonic development. Seven exogenous reprogramming factors (bovine OCT4, SOX2, KLF4, cMyc, porcine NANOG, Lin-28, and SV40 Large T) were delivered into SFs, successfully inducing iPSCs. A growth performance analysis revealed that iPSC clones exhibited a raised or flat morphology with clear edges, positive alkaline phosphatase staining, and normal karyotypes. The transcriptome analysis indicated a significant enrichment of iPSCs in oxidative phosphorylation and cell proliferation pathways, with an up-regulated expression of the ATP5B, SDHB, Bcl-2, CDK1, and Cyclin D1 genes and a down-regulated expression of BAX (p < 0.05). Somatic cell nuclear transfer experiments demonstrated that the cleavage rate (85% ± 2.12) and blastocyst rate (52% ± 2.11) of the iPSCs were significantly higher than those of the SFs (p < 0.05). The detection of trilineage marker genes confirmed that the expression levels of endoderm (DCN, NANOS3, FOXA2, FOXD3, SOX17), mesoderm (KDR, CD34, NFH), and ectoderm (NEUROD) markers in iPSCs were significantly higher than in SFs (p < 0.01). The findings demonstrate that black-boned sheep iPSCs possess pluripotency and the potential to differentiate into all three germ layers, revealing the mechanisms by which reprogrammed iPSCs influence early embryonic development and providing a critical foundation for research on sheep pluripotent stem cells. Full article

Type 2 diabetes (T2D) is a prevalent chronic disease in the Korean population, influenced by lifestyle, dietary habits, and genetics. This study aimed to identify the effects of food intake and genetic factors on T2D progression in Korean adults using a multi-state illness-death model. We analyzed three transition models: normal glucose tolerance (NGT) to prediabetes (PD), NGT to T2D, and PD to T2D. We first identified dietary patterns significantly associated with each transition, using multivariate Cox proportional hazards models. Then, we assessed the impact of single-nucleotide polymorphisms (SNPs) on each transition, incorporating these dietary patterns as covariates. Our analysis revealed significant associations between the identified dietary patterns and the risk of PD and T2D incidence among individuals with NGT. We also identified novel genetic variants associated with disease progression: two SNPs (rs4607517 in Glucokinase [GCK] and rs758982 in Calcium/Calmodulin-Dependent Protein Kinase II Beta [CAMK2B]) in the NGT to PD model, and eight SNPs in the NGT to T2D model, including variants in the Zinc Finger Protein 106 (ZNF106), PTOV1 Extended AT-Hook Containing Adaptor Protein (PTOV1), Proprotein Convertase Subtilisin/Kexin Type 2 (PCSK2), Forkhead Box D2 (FOXD2), Solute Carrier Family 38 Member 7 (SLC38A7), and Neuronal Growth Regulator 1 (NEGR1) genes. Functional annotation analysis using ANNOVAR revealed that rs4607517 (GCK) and rs59595912 (PTOV1) exhibited high Combined Annotation-Dependent Depletion (CADD) and Deleterious Annotation of Genetic Variants using Neural Networks (DANN) scores, suggesting potential pathogenicity and providing a functional basis for their association with T2D progression. Integrating dietary and genetic factors with a multi-state model, this comprehensive approach offers valuable insights into T2D development and highlights potential targets for prevention and personalized interventions. Full article

Methamphetamine (METH) is a potent psychostimulant that disrupts cognitive and neurobiological functions in brain regions such as the prefrontal cortex (PFC) and hippocampus. Chronic METH use leads to altered synaptic plasticity, neuroinflammation, and mitochondrial dysfunction, contributing to methamphetamine use disorder (MUD). This study investigates gene expression changes following long-access intravenous METH self-administration in a rodent model. RNA sequencing (RNA-Seq) was conducted on PFC and hippocampal tissue to identify differentially expressed genes (DEGs) between METH-treated and control groups. We identified 41 DEGs in the PFC and 32 in the hippocampus, many involved in synaptic plasticity, immune response, and energy metabolism. Key findings included downregulation of mitochondrial function genes and upregulation of genes related to neural development and extracellular matrix organization, highlighting the profound transcriptional effects of METH. As a proof-of-concept, we explored individual gene expression variability in relation to economic demand for METH. Rats exhibiting higher demand showed distinct molecular profiles, including upregulation of genes linked to neural signaling and transcription regulation, such as Foxd1 and Cdh1. This preliminary analysis demonstrates that individual differences in drug-seeking correlate with unique gene expression patterns. These findings suggest that both group-level and individual molecular changes contribute to the neurobiological mechanisms of METH use. A better understanding of these individual differences could potentially inform the development of personalized therapeutic approaches for MUD. Full article

Natural selection and artificial breeding are crucial methods for developing new animal groups. The Baiyu black goats and Chuanzhong black goats are indigenous goat breeds from distinct ecological regions in Sichuan Province, with dramatically different growth and reproductivity. This study aimed to systematically elucidate the differences in production performance and genetic traits between Baiyu black goats and Chuanzhong black goats. We quantified growth and reproductive attributes for both breeds. Furthermore, we conducted a comprehensive analysis of genetic diversity, population structure, and selection signatures using whole-genome resequencing data. This dataset included 30 individuals from the Baiyu black goat breed, 41 from the Chuanzhong black goat breed, and an additional 59 individuals representing Chengdu grey goats, Tibetan cashmere goats, and Jianchang black goats, totaling 130 individuals across five goat breeds. The comparative analysis of production performance revealed that the weight and body size of Chuanzhong black goats were significantly higher than those of Baiyu black goats (p < 0.01). At the same time, the average kidding rate and kid-weaning survival rate of Chuanzhong black goats were also notably superior to those of Baiyu black goats (p < 0.01). The Baiyu black goats exhibited a more abundant genetic diversity and distinct genetic differences compared to the Chuanzhong black goat, according to an analysis grounded on genomic variation. The Baiyu black goats are more closely related to Tibetan cashmere goats, whereas Chuanzhong black goats share a closer genetic relationship with Chengdu grey goats. Additionally, we employed the π, Fst, and XP-EHH methodologies to identify genes related to immunity (TRIM10, TRIM15, TRIM26, and TRIM5), neurodevelopment (FOXD4L1, PCDHB14, PCDHB4, PCDHB5, PCDHB6, and PCDHB7), reproduction (BTNL2 and GABBR1), body size (NCAPG, IBSP, and MKNK1), and meat quality traits (SUCLG2 and PGM5). These results provide a theoretical basis for further resource conservation and breeding improvement of the Baiyu black goat and Chuanzhong black goat. Full article

Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often result in high rates of false positives and low precision. Here, we introduce an advanced computational tool, DeepIMAGER, for inferring cell-specific GRNs through deep learning and data integration. DeepIMAGER employs a supervised approach that transforms the co-expression patterns of gene pairs into image-like representations and leverages transcription factor (TF) binding information for model training. It is trained using comprehensive datasets that encompass scRNA-seq profiles and ChIP-seq data, capturing TF-gene pair information across various cell types. Comprehensive validations on six cell lines show DeepIMAGER exhibits superior performance in ten popular GRN inference tools and has remarkable robustness against dropout-zero events. DeepIMAGER was applied to scRNA-seq datasets of multiple myeloma (MM) and detected potential GRNs for TFs of RORC, MITF, and FOXD2 in MM dendritic cells. This technical innovation, combined with its capability to accurately decode GRNs from scRNA-seq, establishes DeepIMAGER as a valuable tool for unraveling complex regulatory networks in various cell types. Full article

Spermatogenesis is critical for insect reproduction and is regulated by many different genes. In this study, we found that Forkhead transcription factor Fd59a functions as a key factor in the spermatogenesis of Drosophila melanogaster. Fd59a contains a conversed Forkhead domain, and it is clustered to the FoxD subfamily with other FoxD members from some insect and vertebrate species. Mutations in Fd59a caused swelling in the apical region of the testis. More importantly, fewer mature sperm were present in the seminal vesicle of Fd59a mutant flies compared to the control flies, and the fertility of Fd59a^2/2 mutant males was significantly lower than that of the control flies. Immunofluorescence staining showed that the homeostasis of the testis stem cell niche in Fd59a^2/2 mutant and Fd59a RNAi flies was disrupted and the apoptosis of sperm bundles was increased. Furthermore, results from RNA sequencing and qRT-PCR suggested that Fd59a can regulate the expression of genes related to reproductive process and cell death. Taken together, our results indicated that Fd59a plays a key role in the spermatogenesis of Drosophila. Full article

It has been reported that forkhead box D1 (FOXD1) plays an established role in human early embryonic development and is broadly involved in various malignancies. However, there is limited information regarding FOXD1 expression in head and neck squamous cell carcinoma (HNSCC). This present study aimed to explore the clinical significance of FOXD1 in patients with HNSCC. Tissue microarrays of 334 primary HNSCC patients who underwent surgery between 2008 and 2010 at Sun Yat-sen University Cancer Center were investigated by immunohistochemistry regarding FOXD1 expression. χ² test was used to estimate the relationship of FOXD1 expression with clinicopathologic characteristics. Univariate and multivariate analyses were performed to identify FOXD1 expression as an independent prognostic indicator of overall survival (OS) and disease-free survival (DFS). FOXD1 expression is closely associated with postoperative recurrence. HNSCC patients with high FOXD1 expression have poorer prognoses than the low-expression group (p < 0.05). According to multivariate analysis, FOXD1 was an independent prognostic factor for OS and DFS. The results revealed that FOXD1 could be a prognostic factor for HNSCC and might serve as a potential target for novel therapies. Full article

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA and ICGC cohorts related to renal clear cell carcinoma were included. GO and KEGG analyses were conducted to determine the biological significance of differentially expressed cuproptosis-related LncRNAs (CRLRs). Machine learning (LASSO), Kaplan–Meier, and Cox analyses were conducted to determine the prognostic genes. The tumor microenvironment and tumor mutation load were further studied. TIDE and IC50 were used to evaluate the response to immunotherapy, a risk model of LncRNAs related to the cuproptosis genes was established, and the ability of this model was verified in an external independent ICGC cohort. LncRNAs were identified in normal HK-2 cells and verified in four renal cell lines via qPCR. (3) Results: We obtained 280 CRLRs and identified 66 LncRNAs included in the TCGA-KIRC cohort. Then, three hub LncRNAs (AC026401.3, FOXD2−AS1, and LASTR), which were over-expressed in the four ccRCC cell lines compared with the human renal cortex proximal tubule epithelial cell line HK-2, were identified. In the ICGC database, the expression of FOXD2-AS1 and LASTR was consistent with the qPCR and TCGA-KIRC. The results also indicated that patients with low-risk ccRCC—stratified by tumor-node metastasis stage, sex, and tumor grade—had significantly better overall survival than those with high-risk ccRCC. The predictive algorithm showed that, according to the three CRLR models, the low-risk group was more sensitive to nine target drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706, ATRA, AP.24534, axitinib, and AZ628), based on the estimated half-maximal inhibitory concentrations. In contrast, the high-risk group was more sensitive to ABT.263 and AKT inhibitors VIII and AS601245. Using the CRLR models, the correlation between the tumor immune microenvironment and cancer immunotherapy response revealed that high-risk patients are more likely to respond to immunotherapy than low-risk patients. In terms of immune marker levels, there were significant differences between the high- and low-risk groups. A high TMB score in the high-risk CRLR group was associated with worse survival, which could be a prognostic factor for KIRC. (4) Conclusions: This study elucidates the core cuproptosis-related LncRNAs, FOXD2−AS1, AC026401.3, and LASTR, in terms of potential predictive value, immunotherapeutic strategy, and outcome of ccRCC. Full article

Evolutionary mechanisms have shaped the genomic architecture of Colombian Creole cattle breeds. The mating and selection processes have impacted several traits, promoting differences within and between populations. Studies of population structure and selection signatures in Colombian Creole breeds are scarce, and need more attention to better understand genetic differentiation, gene flow, and genetic distance. This study aimed to analyze the population structure and identify selection imprints in the Criollo Caqueteño (CAQ) population. It used 127 CAQ animals genotyped with Chip HD 777,000 SNPs. The population structure analyses used discriminant principal component analysis (DAPC), integrated haplotype scoring (iHS), and index-fixing (Fst) methodologies to detect selection signals. We can highlight SNP regions on the genes TMPRSS15, PGAM2, and EGFR, identified by the Fst method. Additionally, the iHS regions for cluster 1 identified candidate genes on BTA 3 (CMPK1 and FOXD2), BTA 11 (RCAN1), and BTA 22 (ARPP21). In group 2, we can highlight the genes on BTA 4 (SLC13A4, BRAF), BTA 9 (ULBP), BTA 14 (CSMD3) and BTA 19 (KRTAP9-2). These candidate genes have been associated with fertility traits, precocity, growth, and environmental and disease resistance, indicating a genetic potential in CAQ animals. All this promotes a better understanding of the diversity and genetic structure in the CAQ population. Based on that, our study can significantly assist the sustainable development and conservation of the breed in the Colombian Amazon. Full article

Most cases of Stickler syndrome are due to autosomal-dominant COL2A1 gene mutations leading to abnormal type II collagen. Ocular findings include axial eye lengthening with vitreal degeneration and early-onset glaucoma, which can result in vision loss. Although COL2A1 is a major player in cartilage and bone formation, its specific role in eye development remains elusive. We investigated the role of Col2a1a in neural crest migration and differentiation during early zebrafish eye development. In situ hybridization, immunofluorescence, live imaging, exogenous treatments [10 μM diethylaminobenzaldehyde (DEAB), 100 nM all-trans retinoic acid (RA) and 1–3% ethanol (ETOH)] and morpholino oligonucleotide (MO) injections were used to analyze wildtype Casper (roy−/−;nacre−/−), TgBAC(col2a1a::EGFP), Tg(sox10::EGFP) and Tg(foxd3::EGFP) embryos. Col2a1a colocalized with Foxd3- and Sox10-positive cells in the anterior segment and neural crest-derived jaw. Col2a1a expression was regulated by RA and inhibited by 3% ETOH. Furthermore, MO knockdown of Col2a1a delayed jaw formation and disrupted the ocular anterior segment neural crest migration of Sox10-positive cells. Interestingly, human COL2A1 protein rescued the MO effects. Altogether, these results suggest that Col2a1a is a downstream target of RA in the cranial neural crest and is required for both craniofacial and eye development. Full article

Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle transition. We hypothesized that the identification of pathways downstream of FOXD1 may define candidates for pharmacological modulation to suppress the G2/M transition in ccRCC. We developed an analysis pipeline that utilizes RNA sequencing, transcription factor binding site analysis, and phenotype validation to identify candidate effectors downstream from FOXD1. Compounds that modulate candidate pathways were tested for their ability to cause growth delay at G2/M. Three targets were identified: FOXM1, PME1, and TMEM167A, which were targeted by compounds FDI-6, AMZ-30, and silibinin, respectively. A 3D ccRCC tumor replica model was used to investigate the effects of these compounds on the growth of primary cells from five patients. While silibinin reduced 3D growth in a subset of tumor replicas, FDI-6 reduced growth in all. This study identifies tractable pathways to target G2/M transition and inhibit ccRCC growth, demonstrates the applicability of these strategies across patient tumor replicas, and provides a platform for individualized patient testing of compounds that inhibit tumor growth. Full article

Uveal melanoma (UM) is a deadly ocular malignancy, originating from uveal melanocytes. Although much is known regarding prognostication in UM, the exact mechanism of metastasis is mostly unknown. Metastatic tumor cells are known to express a more stem-like RNA profile which is seen often in cell-specific embryonic development to induce tumor progression. Here, we identified novel transcription regulators by reanalyzing publicly available single cell RNA sequencing experiments. We identified five transcription regulators of interest: ELL2, KDM5B, REXO4, RBFOX2 and FOXD1. Our most significant finding is FOXD1, as this gene is nearly exclusively expressed in high-risk UM and its expression is associated with a poor prognosis. Even within the BAP1-mutated UM, the expression of FOXD1 is correlated with poor survival. FOXD1 is a novel factor which could potentially be involved in the metastatic capacity of high-risk UM. Elucidating the function of FOXD1 in UM could provide insight into the malignant transformation of uveal melanocytes, especially in high-risk UM. Full article

Analysis of microRNA (miRNA) expression signatures in head and neck squamous cell carcinoma (HNSCC) has revealed that the miR-30 family is frequently downregulated in cancer tissues. The Cancer Genome Atlas (TCGA) database confirms that all members of the miR-30 family (except miR-30c-5p) are downregulated in HNSCC tissues. Moreover, low expression of miR-30e-5p and miR-30c-1-3p significantly predicts shorter survival of HNSCC patients (p = 0.0081 and p = 0.0224, respectively). In this study, we focused on miR-30e-5p to investigate its tumor-suppressive roles and its control of oncogenic genes in HNSCC cells. Transient expression of miR-30e-5p significantly attenuated cancer cell migration and invasive abilities in HNSCC cells. Nine genes (DDIT4, FOXD1, FXR1, FZD2, HMGB3, MINPP1, PAWR, PFN2, and RTN4R) were identified as putative targets of miR-30e-5p control. Their expression levels significantly predicted shorter survival of HNSCC patients (p < 0.05). Among those targets, FOXD1 expression appeared to be an independent factor predicting patient survival according to multivariate Cox regression analysis (p = 0.049). Knockdown assays using siRNAs corresponding to FOXD1 showed that malignant phenotypes (e.g., cell proliferation, migration, and invasive abilities) of HNSCC cells were significantly suppressed. Overexpression of FOXD1 was confirmed by immunostaining of HNSCC clinical specimens. Our miRNA-based approach is an effective strategy for the identification of prognostic markers and therapeutic target molecules in HNSCC. Moreover, these findings led to insights into the molecular pathogenesis of HNSCC. Full article