Search Results (209)

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM. Full article

In the chicken industry, sex determination significantly affects production efficiency and raises ethical concerns in poultry farming. As a key economic species, maximizing the advantages of each sex is vital in modern intensive breeding. Therefore, understanding the mechanisms of sex determination and regulation is critical to advancing the poultry industry. Transcriptome analysis of 3.5-day-old White Leghorn chicken embryonic genital ridges (n = 30, 15 males and 15 females) was performed using sex-pooled samples (five embryos/replicate, three replicates/sex). Sequencing generated 39.6 GB of high-quality reads for inter-sex comparative analysis, revealing 283 significantly differentially expressed genes (DEGs). The DEGs were primarily enriched in pathways such as ribosome biogenesis, glycan biosynthesis and metabolism, and TGF-β signaling, which are potential candidate pathways for the differentiation of chicken embryonic gonads. Key DEGs (including SMAD2Z, FREM1, NR2F1, SEMA6A, NFIB, RNF165, SMAD7B, SMAD2W, SPIN1W, and HINTW) were validated by RT-qPCR, confirming the transcriptome sequencing results. Among the DEGs, we predict binding sites for NR2F1 and NFIB within the DMRT1 gene promoter and suggest that these factors may serve as potential upstream activators for the expression of DMRT1, and they may initiate high DMRT1 expression in the subsequent stages of male embryos and regulate testicular development. In conclusion, this study investigated DEGs in the gonads of male and female chicken embryos after 3.5 days of incubation and found that NR2F1 and NFIB may serve as potential upstream activators for the expression of DMRT1, which is involved in the early determination of chicken sex. Full article

Background: RNF114 gene encodes an E3 ubiquitin ligase involved in immune signaling and regulation of inflammation. Genetic variants, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), may interfere with protein function and cause immune diseases such as psoriasis. Although significant, the structural and functional impact of RNF114 nsSNPs is not well understood. Methods: We used comprehensive bioinformatics analyses to predict the functional impact of RNF114 nsSNPs. Deleterious variants were predicted by SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNP&GO, PANTHER, and Alpha-Missense. Protein stability was examined by I-Mutant2.0, and MUpro further contextualized variant effects. Structural modeling was performed by AlphaFold and visualized using UCSF ChimeraX 1.10.1. Additionally, we studied the Conservation using ConSurf and protein-protein interaction by STRING tools. Results: Among 252 available nsSNPs, three mutations—C49R (rs1600868749), R68C (rs745318334), and R68H (rs758000156)—were predicted to have a deleterious and destabilizing effects on the protein structure by all the tools. All three variants were located in extremely conserved residues and were predicted to significantly destabilize the protein structure. Structural modeling demonstrated disruptions in the RNF114 domain structure. STRING analysis revealed interactions of RNF114 with key immune regulators, and pathway enrichment pointed to roles in NF-κB signaling, ubiquitin-mediated proteolysis, and autoimmune disease pathways. Conclusions: In the current study, we predicted three novel, potentially pathogenic RNF114 variants with protein-destabilizing effect that could lead to immune dysregulation. Full article

Ovarian cancer (OvCa) is one of the most life-threatening female malignancies that affects 300,000 women annually worldwide. Impaired mechanisms of DNA repair are the leading cause of mutations underlying the OvCa development. microRNAs are short non-coding RNAs that regulate the expression of genes by binding to their transcripts and inducing mRNA degradation or inhibition of translation. Here, we review the miRNA-mediated dysregulation of genes involved in DNA damage response (DDR) and DNA repair pathways in OvCa. Apparently, miRNAs are capable of targeting the crucial mediators of DDR (e.g., miR-203a-3p targeting ATM (Ataxia Telangiectasia Mutated)), homologous repair (such as BRCA1 targeted by miR-9, miR-1255b, miR-193b, and miR-148b), non-homologous end joining (with RNF8 being regulated by miR-214), nucleotide excision repair (involving DDB2 targeted by miR-328-3p), or translesion DNA synthesis (involving RAD18, participating also in homologous repair and targeted by miR-379-5p). We also discuss miRNAs (such as miR-519a-3p, let-7e, miR-216b), which affect responses to OvCa therapy by targeting PARP1 (Poly(ADP-Ribose) Polymerase-1). Finally, we also discuss why, despite the identification of multiple miRNAs capable of regulating DNA repair genes, as well as those involved in the response to therapy, no miRNA-based drugs have been approved for OvCa treatment in clinics. Full article

Introduction: Increasingly, identification of BRAF mutation in colorectal cancer is used to guide management and predict cancer behaviour. There is, however, still significant diversity within this cohort of patients, both in terms of clinical phenotype and treatment outcomes. This may be explained, at least in part, by differences between classes of BRAF mutations and the presence of concomitant mutations. Methods: We present a retrospective cohort study of sequential patients diagnosed with BRAF-mutated (V600 and non-V600) colorectal cancer between 2014 and 2022. Information regarding presentation, treatment outcomes and molecular subtype was identified using the electronic medical record. Results: This study included 406 patients with BRAF-mutated colorectal cancer, 253 (228 ^V600BRAF) of whom had localised disease and 153 (137 ^V600BRAF) with metastatic disease at the time of diagnosis. In patients with localised disease at diagnosis, the ^V600BRAF mutation was associated with older median age (73 vs. 63 years, p = 0.04) and a higher prevalence of right-sided primary (73% vs. 40%, p < 0.01), mismatch repair deficiency (56% vs. 8%, p < 0.01), and faster time to disease relapse (p = 0.006). In the metastatic setting, ^non-V600BRAF mutation was associated with a higher prevalence of KRAS mutation (27% vs. 1%, p < 0.01), NRAS mutation (14% vs. 3%, p = 0.04) and PIK3CA mutation (33% vs. 8%, p = 0.02). Mismatch repair deficiency was more common in patients with ^V600BRAF mutations than in those with ^non-V600BRAF mutations (20% vs. 0%, p = 0.01). The median survival of patients with the ^V600BRAF mutation was 14 months, and 34 months in those with ^non-V600BRAF mutations. Concomitant RNF43 mutation in metastatic disease, was associated with a significantly higher incidence of disease control from combined BRAF and EGFR inhibition, when compared to those without an RNF43 mutation (100% vs. 54%, p = 0.02). Conclusions: Presentation and outcomes of BRAF-mutated colorectal cancer are heterogenous. The type of BRAF mutation, and the presence of concomitant RNF43 mutation, may explain some of the differences in cancer behaviour. Routine reporting of RNF43 mutations would assist clinicians to give more personalised treatment recommendations. Full article

Chronic obstructive pulmonary disease (COPD) involves persistent inflammation and dysregulated lipid metabolism, with foamy macrophages playing a central role in disease progression. Exosomes—vesicles transporting microRNAs (miRNAs)—mediate intercellular communication, but their contribution to foamy macrophage-driven COPD remains unclear. This study investigates the role of exosomal miRNAs, particularly let-7, in modulating lipid metabolism and inflammation in foamy macrophages. Bone marrow-derived macrophages (BMDMs) were treated with oxidized low-density lipoprotein (oxLDL) and lipopolysaccharide (LPS) to induce foamy macrophage formation. Exosomal miRNA profiles were analyzed, and the function of let-7c-3p was assessed via transfection. Foamy macrophages released significantly more exosomes (392.7 × 10⁷ particles) than controls (284.9–302.5 × 10⁷), without differences in exosome size or molecular content. The miRNA sequencing and qRT-PCR confirmed downregulation of exosomal let-7c-3p in foamy macrophages, correlating with increased RNF8 and decreased RXR expression—markers of disrupted PPAR/RXR signaling. Pathway analysis implicated let-7c-3p in regulating PPAR/RXR, WNT/β-catenin, and pulmonary fibrosis pathways. Transfection with let-7 mimics reduced lipid accumulation (52% to 19%), suppressed RNF8, restored RXR, and lowered IL-6 and TNF-α levels, indicating strong anti-inflammatory and lipid-modulating effects. Loss of exosomal let-7c-3p aggravates lipid dysregulation and inflammation in COPD by impairing PPAR/RXR signaling. Restoring let-7 expression reverses these effects, highlighting its potential as a diagnostic biomarker and therapeutic target. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, is rising rapidly and disproportionately affects Hispanic/Latino (H/L) populations. While FOLFOX is a standard first-line chemotherapy, its impact on tumor genomics in EOCRC remains poorly understood. Given the central role of WNT signaling in colorectal cancer (CRC), we aimed to characterize WNT pathway alterations in EOCRC across diverse populations and assess their associations with FOLFOX treatment and clinical outcomes. Methods: Somatic mutation data from 2515 CRC patients (266 H/L, 2249 Non-Hispanic White [NHW]) were analyzed. Patients were stratified by age (EOCRC vs. late-onset colorectal cancer), ancestry (H/L vs. NHW), and FOLFOX treatment status. Mutation frequencies in WNT pathway genes were compared, and Kaplan–Meier analysis evaluated overall survival. Results: WNT pathway alterations were pervasive across groups, with APC mutations dominating. Notably, non-canonical WNT mutations (e.g., CTNNB1, RNF43) were significantly less frequent in FOLFOX-treated H/L EOCRC patients compared to untreated individuals, suggesting potential chemotherapy-driven selection. In NHW patients, FOLFOX treatment was associated with reduced mutation frequencies across multiple WNT regulators, which correlated with improved overall survival. Conclusions: Our findings reveal that WNT pathway dysregulation in EOCRC is shaped by ancestry, treatment status, and age. FOLFOX appears to reduce specific WNT alterations in H/L patients and broader WNT disruptions in NHW patients, with survival benefits observed primarily in the latter. These results underscore ancestry-specific molecular responses to chemotherapy and the need for precision oncology strategies tailored to high-risk populations. Full article

This work presents an image processing algorithm for the segmentation of the personalized mapping of retinal nerve fiber layer (RNFL) bundle trajectories in the human retina. To segment RNFL bundles, preprocessing steps were used for noise reduction and illumination correction. Blood vessels were removed. The image was fed to a maximum–minimum modulation algorithm to isolate retinal nerve fiber (RNF) segments. A modified Garway-Heath map categorizes RNF orientation, assuming designated sets of orientation angles for aligning RNFs direction. Bezier curves fit RNFs from the center of the optic disk (OD) to their corresponding end. Fundus images from five different databases (n = 300) were tested, with 277 healthy normal subjects and 33 classified as diabetic without any sign of diabetic retinopathy. The algorithm successfully traced fiber trajectories per fundus across all regions identified by the Garway-Heath map. The resulting trace images were compared to the Jansonius map, reaching an average efficiency of 97.44% and working well with those of low resolution. The average mean difference in orientation angles of the included images was 11.01 ± 1.25 and the average RMSE was 13.82 ± 1.55. A 24-2 visual field (VF) grid pattern was overlaid onto the fundus to relate the VF test points to the intersection of RNFL bundles and their entry angles into the OD. The mean standard deviation (95% limit) obtained 13.5° (median 14.01°), ranging from less than 1° to 28.4° for 50 out of 52 VF locations. The influence of optic parameters was explored using multiple linear regression. Average angle trajectories in the papillomacular region were significantly influenced (p < 0.00001) by the latitudinal optic disk position and disk–fovea angle. Given the basic biometric ground truth data (only fovea and OD centers) that is publicly accessible, the algorithm can be customized to individual eyes and distinguish fibers with accuracy by considering unique anatomical features. Full article

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases. Full article

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies. Full article

Pancreatic cancer is frequently accompanied by cancer-associated cachexia, a debilitating metabolic syndrome marked by progressive skeletal muscle wasting and systemic metabolic dysfunction. This study presents a systems biology framework to simultaneously identify therapeutic targets for both pancreatic ductal adenocarcinoma (PDAC) and its associated cachexia (PDAC-CX), using cell-specific genome-scale metabolic models (GSMMs). The human metabolic network Recon3D was extended to include protein synthesis, degradation, and recycling pathways for key inflammatory and structural proteins. These enhancements enabled the reconstruction of cell-specific GSMMs for PDAC and PDAC-CX, and their respective healthy counterparts, based on transcriptomic datasets. Medium-independent metabolic biomarkers were identified through Parsimonious Metabolite Flow Variability Analysis and differential expression analysis across five nutritional conditions. A fuzzy multi-objective optimization framework was employed within the anticancer target discovery platform to evaluate cell viability and metabolic deviation as dual criteria for assessing therapeutic efficacy and potential side effects. While single-enzyme targets were found to be context-specific and medium-dependent, eight combinatorial targets demonstrated robust, medium-independent effects in both PDAC and PDAC-CX cells. These include the knockout of SLC29A2, SGMS1, CRLS1, and the RNF20–RNF40 complex, alongside upregulation of CERK and PIKFYVE. The proposed integrative strategy offers novel therapeutic avenues that address both tumor progression and cancer-associated cachexia, with improved specificity and reduced off-target effects, thereby contributing to translational oncology. Full article

Background/Objectives： Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a prevalent Mendelian disorder caused by mutations in the NOTCH3 gene, primarily impacting cerebral small blood vessels. This review aims to explore the involvement of large intracranial arteries in CADASIL, particularly focusing on the association with RNF213 polymorphisms, especially in Asian populations. Methods： A comprehensive literature review was conducted to gather data on the morphological features of both small and large intracranial arteries in CADASIL, examining clinical manifestations, imaging findings, and genetic associations. Results： The findings indicate that while CADASIL is predominantly characterized by small vessel disease, a significant number of patients also exhibit large artery involvement, particularly Asian populations where RNF213 polymorphisms may play a critical role. The review highlights the evidence of intracranial stenosis and the potential implications of traditional vascular risk factors, such as hypertension and diabetes mellitus, which are prevalent in these populations. Conclusions： The involvement of larger intracranial arteries in CADASIL underscores the complexity of the disease, suggesting that both genetic predispositions and environmental factors contribute to vascular abnormalities. Further research is needed to clarify these relationships and improve diagnostic and therapeutic strategies for CADASIL patients. Full article

Greenhouse gas (GHG) emissions evaluations from agroecosystems are critical, particularly as technology improves. Consistent GHG measurement methods are essential to the evaluation of GHG emissions. The objective of the study was to evaluate potential differences in gas-flux-determination (GFD) options and carbon dioxide (CO₂), methane (CH₄), and nitrous oxide (N₂O) fluxes and growing-season-long emissions estimates from furrow-irrigated cotton (Gossypium hirsutum) in southeast Arkansas. Four GFD methods were evaluated [i.e., linear (L) or exponential (E) regression models, with negative fluxes (WNF) included in the dataset or replacing negative fluxes (RNF)] over the 2024 growing season using a LI-COR field-portable chamber and gas analyzers. Exponential regression models were influenced by abnormal CO₂ and N₂O gas concentration data points, indicating the use of caution with E models. Season-long CH₄ emissions differed (p < 0.05) between the WNF (−0.51 kg ha⁻¹ season⁻¹ for L and−0.54 kg ha⁻¹ season⁻¹ for E) and RNF (0.01 kg ha⁻¹ season⁻¹ for L and E) GFD methods, concluding that RNF options over-estimate CH₄ emissions. Gas concentration measurements following chamber closure should remain under 300 s, with one concentration measurement obtained per second. The choice of GFD method needs careful consideration to result in accurate GHG fluxes and season-long emission estimates. Full article

This study identified genomic variants and potential candidate genes associated with 11 primal cut traits (back fat, belly fat, total fat, loin fat, ham fat, picnic fat, butt fat, loin intramuscular fat content, ham side fat, shoulder dorsal fat, and belly side fat thicknesses) in Canadian commercial crossbred pigs. Genome-wide association studies using whole genome sequencing data were conducted using genotyping data from 1118 commercial crossbred pigs. This analysis revealed multiple QTLs across chromosomes SSC1, 2, 3, 6, 7, 9, 14, 15, and 17, associated with fat traits. Notably, an SNP at position 160,230,075 bp on SSC1 was significantly associated with multiple fat traits, including belly fat, butt fat, ham fat, loin fat, picnic fat, and side fat. Common genes in windows associated with multiple traits, such as MC4R, RNF152, and CDH20 were shared across these traits, suggesting pleiotropic effects. Some of the QTLs were near previously identified QTLs or candidate genes that have been reported to be linked to meat quality traits associated with backfat and intramuscular fat. Other candidate genes identified in the study include TNFRSF11A, LEPR, and genes from the SERPINB family, highlighting their roles in fat deposition and composition. Additional candidate genes were also implicated in regulation of fat metabolism, adipogenesis, and adiposity. These findings offer valuable insights into the genetic architecture of fat traits in pigs, which could inform breeding strategies aimed at improving the pork quality. Full article

RNA-binding E3 ubiquitin ligases (RBULs) provide a link between RNA metabolic processes and the ubiquitin proteasome system (UPS). In humans, RBULs are involved in various biological processes, such as cell proliferation and differentiation, as well as sexual development. To date, little is known about their role in the protozoan parasite Plasmodium falciparum, the causative agent of malaria tropica. We previously identified a novel P. falciparum RBUL, the RING finger E3 ligase PfRNF1, which is highly expressed during gametocyte development. Here, we conducted BioID-based proximity interaction studies to unveil the PfRNF1 interactome. We show that in immature gametocytes, PfRNF1 forms an interaction network that is mainly composed of RNA-binding proteins, including the translational repressors DOZI and CITH and members of the CCR4-NOT complex, as well as UPS-related proteins. In particular, PfRNF1 interacts with recently identified regulators of sexual development like the zinc finger protein PfMD3, with which it shares the majority of interactors. The common interactome of PfRNF1 and PfMD3 comprises several uncharacterized proteins predominantly expressed in male or female gametocytes. Our results demonstrate that PfRNF1 engages with RNA-binding proteins crucial for sex determination in gametocytes, thereby linking posttranscriptional regulation with the UPS. Full article