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Background: Ischemic stroke (IS) is an important disease causing death and disability worldwide, and further investigation of IS-related genes through genome-wide association study (GWAS) data is valuable.

Methods: The study included GWAS data from 62,100 IS patients of European origin and 1,234,808 controls in a cross-tissue transcriptome association study (TWAS). A joint analysis was first performed by the Unified Test for Molecular Markers (UTMOST) and FUSION methods. The results of the joint analysis were also validated by fine-mapping through FOCUS. Mendelian randomisation analysis was performed to determine whether the obtained genes were causally related to IS. Genome Annotated Multiple Marker Analysis (MAGMA) explored which biological functions the genes associated with IS. We used Coloc to co-localise GWAS and eQTL of the genes. We also biologically validated the results by Western blotting and immunofluorescence staining in the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model.

Results: Four TWAS methods identified only one new susceptibility gene (USP38) associated with IS risk. Mendelian randomization and colocalization analysis found that USP38 may be protective against IS development. Functional enrichment analysis indicated IS-related genes were mainly associated with the intrinsic fibrinogen activation, acute myocardial infarction, exogenous fibrinogen activation, coagulation cascade response, TNF signalling pathway and GRB2 signalling pathway. Western blotting and immunofluorescence staining demonstrated a reduction in USP38 expression in MCAO/R mice.

Conclusion: Our research indicates that USP38 is an essential gene related to IS, with its expression strongly connected with IS risk, thus providing new perspectives on the genetic framework of IS.

Background: Methyltransferase-like 3 (METTL3) regulates numerous biological processes and diverse cancers.

Objective: To explore the frequency distribution of METTL3 rs1061026, rs1139130, and rs1263801 polymorphisms, and their potential impacts on clinical outcomes and chemotherapy-induced toxicities in a cohort of Chinese pediatric patients diagnosed with primary brain tumors (PBTs).

Methods: Genotyping for three investigated SNPs was performed in 107 pediatric patients with PBTs using the Sequenom MassARRAY iPLEX platform. Serum METTL3 levels were determined by Enzyme-Linked Immunosorbent Assay. Serum methotrexate (MTX) concentrations were quantified utilizing fluorescence polarization immunoassay.

Results: The three investigated SNPs were not significantly associated with the risks of relapse and metastasis after adjusting all confounders. Compared to individuals with the rs1139130 GG genotype, GA genotype carriers exhibited a significantly higher risk of oral mucositis (adjusted OR: 7.504; 95 % CI, 1.931-29.436; P = 0.004). The rs1139130 GA (adjusted OR: 5.091; 95 % CI, 1.351-19.176; P = 0.016) and AA (adjusted OR: 9.588; 95 % CI, 1.769-51.949; P = 0.009) genotype carriers exhibited a significantly lower risk of fever than GG genotype carriers. The median dose-normalized MTX concentrations at 42 h were lower with borderline significance in children with rs1061026 GT and GG genotypes (0.004 μmol/L per g/m²) than the TT genotype carriers (0.006 μmol/L per g/m², P = 0.048). Patients with the rs1139130 GA genotype had significantly higher median serum METTL3 protein levels (59.91 ng/mL) than GG genotype carriers (44.57 ng/mL, P = 0.015).

Conclusion: This study demonstrated the association of the rs1139130 polymorphism with the development of oral mucositis and fever and the rs1061026 polymorphism with MTX exposure.

Aim: This study aims to investigate the association of the genetic variations in IGF2BP2 and CAPN10 as well as gene-environment interactions with the risk of gestational diabetes (GDM) in Chinese women.

Materials and methods: A total of 1,566 pregnant Chinese women participated in this case-control study. We employed targeted next-generation sequencing to analyze specific SNPs in IGF2BP2 (rs11927381, rs1470579, rs4402960, rs7640539) and CAPN10/rs2975760. Various genetic models were used to assess the associations of these polymorphisms with GDM risk. Gene-gene and gene-environment interactions were examined using GMDR to identify interaction models, Subsequently, logistic regression was employed to confirm the significance of these models and to evaluate their impact on GDM susceptibility.

Results: Our study identified significant associations between the C allele of IGF2BP2/rs11927381 and an increased GDM susceptibility in both dominant (P = 0.031, OR = 1.247) and heterozygote (P = 0.043, OR = 1.239) gene models. Conversely, the heterozygote TC genotype of CAPN10/rs2975760 was associated with a reduced risk of GDM (P = 0.046, OR = 0.766). Increased BMI and O₃ levels were linked to a higher GDM susceptibility. We discovered interactions between CAPN10/rs2975760 CC and IGF2BP2/rs11927381 TC genotype that exacerbated GDM risk (P = 0.022, OR = 11.337). Furthermore, interactions between IGF2BP2/rs11927381 and environmental factors were observed, indicating increased GDM risks (BMI: P = 0.004, OR = 1.011; O₃: P = 0.013, OR = 1.002; PM_2.5: P = 0.042, OR = 1.005；BC: P = 0.048, OR = 1.094; NO₃^-:P = 0.045, OR = 1.024).

Conclusion: GDM is significantly associated with IGF2BP2/rs11927381 and CAPN10/rs2975760 polymorphisms as well as exposure to O₃. Furthermore, the interaction between the CAPN10/rs2975760 CC genotype and IGF2BP2/rs11927381 TC genotype, as well as environmental factors (O₃, PM_2.5, BMI), significantly increases the risk of GDM in Chinese women.

Bird contour feathers exhibit a complex hierarchical structure composed of a rachis, barbs, and barbules, with barbules playing a crucial role in maintaining feather structure and function. Understanding the molecular mechanisms underlying barbule formation is essential for advancing our knowledge of avian biology and evolution. In this study, we identified a novel gene, pennaceous barbule cell factor (PBCF), using microarray analysis, RT-PCR, and in situ hybridization. PBCF is expressed in barbule cells adjacent to the ramus during pennaceous barbule formation, where these cells fuse with the ramus to establish the feather's branching structure. PBCF expression occurs transiently after melanin pigmentation of the barbule plates but before the expression of barbule-specific keratin 1 (BlSK1). Orthologues of PBCF, predicted to be secreted proteins, are conserved across avian species, with potential homologues detected in reptiles, suggesting an evolutionary lineage-specific adaptation. Additionally, PBCF is expressed in non-vacuolated notochord cells and the extra-embryonic ectoderm of the yolk sac, hinting at its broader developmental significance. The PBCF gene produces two mRNA isoforms via alternative splicing, encoding a secreted protein and a glycophosphatidylinositol (GPI)-anchored membrane-bound protein, indicating functional versatility. These findings suggest that PBCF may be involved as an avian-specific extracellular matrix component in cell adhesion and/or communication, potentially contributing to both feather development and embryogenesis. Further investigation of PBCF's role in feather evolution and its potential functions in other vertebrates could provide new insights into the interplay between development and evolution.

Object: N6-methyladenosine (m⁶A), is well known as the most abundant epigenetic modification in messenger RNA, but its influence on laryngeal squamous cell carcinoma (LSCC) remains largely unexplored and poorly understood. This study was designed to explore the effects of m⁶A on WISP1-mediated epithelial-mesenchymal transition (EMT) and tumorigenesis in LSCC.

Methods: m⁶A methylated and expression levels of WISP1 in LSCC tumor tissues and cells were measured by MeRIP-qPCR, qRT-PCR, and western blotting. The regulatory mechanism of m⁶A modification of WISP1 in LSCC was determined using MeRIP-qPCR, RIP, dual luciferase reporter assay, and RNA stability assay. Cell viability was assessed utilizing MTT method. The invasion and migration ability of LSCC cells were determined by transwell and wound healing method, respectively. Tumor xenograft models were used for the in vivo experiments.

Results: The m⁶A methylation level of WISP1 was significantly enhanced in LSCC patients and LSCC cell lines. Overexpression of the m⁶A methyltransferase METTL3 significantly upregulated WISP1 expression by promoting its m⁶A methylation level, whereas METTL3 inhibition exhibited the opposite effect in LSCC cells. Functionally, we found that METTL3 accelerated the viability, invasion, migration, and EMT of LSCC cells by upregulating WISP1. Additionally, overexpression of METTL3 increased WISP1 expression and tumorigenesis were verified in in vivo experiments. Mechanistically, m⁶A-modified WISP1 was recognized by IGF2BP1, which enhanced the stability of WISP1 mRNA.

Conclusion: Our findings indicate that the m⁶A modification of WISP1 promotes EMT in LSCC by enhancing WISP1 mRNA stability via an IGF2BP1-dependent manner, which may highlight an m⁶A methylation-based approach for LSCC diagnosis and therapy.

The oncoprotein c-Myc is expressed in all breast cancer subtypes, but its expression is higher in triple-negative breast cancer (TNBC) compared to estrogen receptor (ER+), progesterone receptor (PR+), or human epidermal growth factor receptor 2 (HER2+) positive tumors. The c-Myc gene is crucial for tumor progression and therapy resistance, impacting cell proliferation, differentiation, senescence, angiogenesis, immune evasion, metabolism, invasion, autophagy, apoptosis, chromosomal instability, and protein biosynthesis. Targeting c-Myc has emerged as a potential therapeutic strategy for TNBC, a highly aggressive and deadly breast cancer form. This review highlights c-Myc as a pharmacological target, discussing antitumor compounds in preclinical and clinical trials. Notably, the c-Myc inhibitor OMO-103 has shown promise in a Phase II clinical trial for advanced cancer patients. Further research is needed to develop new drugs targeting this gene, protein, or its pathways, and additional studies on cancer patients are encouraged.

Long non-coding RNAs (lncRNAs) are a collection of non-coding RNA molecules that consist of more than 200 nucleotides. In human malignancies, these lncRNAs exhibit abnormal expression patterns and play a significant role in either suppressing or promoting tumor growth. They achieve this by modulating various functions and mechanisms within cancer cells, including proliferation, invasion, metastasis, apoptosis, and resistance to different therapeutic approaches. The downregulation of long non-coding RNA growth arrest‑specific transcript 5 (GAS5) has been observed in multiple tumor types, indicating its role as a tumor suppressor in cancer. GAS5 exhibits interactions with various proteins, DNA, and microRNAs (miRNAs), leading to the upregulation of several mRNAs encoding suppressor proteins like PTEN. Consequently, this upregulation inhibits tumor growth. In this review, we have examined the existing literature concerning the expression of GAS5 and its diagnostic significance in female tissue-specific cancers, including breast, cervical, ovarian, and endometrial cancers. Additionally, we have explored its interactions with different miRNAs and its impact on cancer progression and resistance to therapy in these malignancies.

Cold stress during the booting stage of rice (Oryza sativa) significantly reduces yields, particularly in temperate and high-altitude regions. This study investigates the Ctb1 gene, critical for booting-stage cold tolerance, to improve breeding of resilient rice varieties. Re-sequencing the Ctb1 promoter in 202 accessions identified six Insertions and/or deletions (InDels) and four Single nucleotide polymorphisms (SNPs), with an InDel at -1,302 bp significantly boosting Ctb1 expression and cold tolerance. Accessions carrying this InDel (Haplotype I) exhibited the highest tolerance. Near-isogenic lines (NIL-Ctb1^HapI) introduced Haplotype I into the cold-sensitive Huazhan (HZ) variety, resulting in a 5.9-fold increase in Ctb1 expression, higher seedling survival, improved pollen fertility, a 64.2 % increase in seed setting rate, and a 12 g per plant yield boost under cold stress. These findings confirm the critical role of the -1,302 InDel in cold tolerance and establish NIL-Ctb1^HapI as a valuable breeding tool for cold-resilient rice.

Introduction: Overweight and obesity are chronic and multifactorial diseases with a strong genetic component contributing to weight gain across all age groups. This study aimed to conduct a Genome-wide Association Study (GWAS) on a cohort of 1,004 Brazilian children (5-11 years old) to identify specific DNA regions associated with susceptibility to overweight.

Methods: The GWAS was performed on children participating in the SCAALA (Asthma and Allergy Social Changes in Latin America) program, with participants classified as either overweight or non-overweight. Genotyping was carried out using the Illumina 2.5 Human Omni bead chip. Using ELISA, cytokine levels (IL-5, IL-13, IL-10, and IFN) were measured in the blood culture supernatant. Furthermore, pathway analyses were conducted utilizing the Gene Ontology tool.

Results: Our analysis revealed eight significant signals distributed across the genome. The most prominent single nucleotide variant (SNV) was identified in the IL1R1 gene, followed by three variants in the LOC105377841 region (located between the ADH5P4 and EYS genes), as well as variants in the KNTC1, RAPTOR, and DSCAM genes. Among the identified variants, three (IL1R1, RAPTOR, and DSCAM) are associated with immune mechanisms, one (ST18) is linked to the death pathway, and one (KNTC1) is associated with mitotic spindle assembly. The genetic risk score analysis demonstrated that having one or more variants among the six analyzed significantly increased the risk of being overweight by eightfold.

Conclusions: Our study uncovered genetic loci within pathways with strong biological plausibility, including identifying a novel region (LOC105377841) not previously associated with overweight. Understanding the genetic variants involved in overweight and obesity is crucial for advancing our knowledge of these diseases, particularly within mixed populations such as the Brazilian population.

Background: T cell senescence affects non-small cell lung cancer (NSCLC) by compromising the anti-tumor immune response. However, the prognostic significance of T cell senescence-related genes in NSCLC remains unclear.

Methods: The scRNA-seq data from normal lung and NSCLC tissues, along with co-incubation experiments involving NSCLC cells and T cells, were utilized to identify T cell senescence characteristics. The TCGA-NSCLC dataset was used for training, and 8 independent NSCLC cohorts from GEO were combined for validation. Various machine learning algorithms were employed for feature selection, with multivariate Cox regression used to construct the risk model. Two NSCLC cohorts receiving anti-PD1/PDL1 treatment from GEO were employed to validate the risk model's predictive capability for immunotherapeutic response. Additionally, 10 pairs of paracarcinoma and NSCLC tissues from a local hospital and transfection assays on T cells were used for validation.

Results: T cells in the NSCLC microenvironment displayed increased senescent features (all P < 0.05). SLC2A1, TNS4, and GGTLC1 were integrated into the risk model, which proved to be a significant prognostic predictor in both training (P < 0.001) and validation (P < 0.05) cohorts. The risk signature also demonstrated strong predictive power for immunotherapeutic sensitivity (both AUC > 0.8). Higher CD3⁺SLC2A1⁺ and CD3⁺TNS4⁺ T cell infiltration, along with lower CD3⁺GGTLC1⁺ T cell levels, were observed in NSCLC (all P < 0.05). Moreover, GGTLC1 overexpression suppressed T cell senescence (all P < 0.05).

Conclusion: A T cell senescence-related gene signature has been established to predict prognosis and immunotherapeutic response in NSCLC.