Search Results (109)

Zhongshan Partridge duck is a unique indigenous dual-purpose waterfowl native to China’s Pearl River Delta. This once endangered breed has been restored through conserved breeding. Its slow growth and low breast muscle yield limit industrial application, and obvious sexual dimorphism in pectoral muscle growth and metabolism lacks systematic molecular explanation. Herein, we combined GWAS, pectoral RNA-seq and untargeted metabolome to dissect regulatory networks of growth and carcass traits using 365 standardized ducks. Ten growth and carcass phenotypes were collected, and the Gompertz model fitted growth trajectories with mean R² > 0.98. Critical trait-related genes, including FTO, ACVR2B and IGFBP3, were identified by GWAS. We detected 313 differentially expressed genes (DEGs) showed differentially expressed pattern between high- and low-breast-weight groups in males and 309 DEGs in females. Distinct sex-specific metabolic patterns were observed: males depended on pentose phosphate and glycine–serine–threonine pathways for muscle protein deposition, whereas females utilized fatty acid β-oxidation for energy and lipid control. Lipid gene ECHS1 and growth factor PRDM16 were identified as candidate regulators mediating sexually dimorphic breast muscle development. Joint enrichment of DEGs and differentially expressed metabolites (DEMs) pinpointed key pathways for myogenesis. This study elucidates multi-level sexual dimorphism in duck pectoral development, supplies molecular markers for indigenous duck conservation and breeding, and advances our understanding of poultry growth regulation. Full article

Myostatin (MSTN), a member of the transforming growth factor-β (TGF-β) superfamily, is a conserved negative regulator of muscle growth in vertebrates. In this study, nine MSTN-related genes were identified in Trachinotus ovatus, including two MSTN ligand genes (ToMSTNa and ToMSTNb) and seven putative receptor genes (ToACVR1A, ToACVR1Ba, ToACVR1Bb, ToACVR2Aa, ToACVR2Ab, ToACVR2Ba, and ToACVR2Bb). Comprehensive evolutionary and expression analyses revealed the conservation and potential functional diversification of MSTN-related genes in T. ovatus. The two MSTN ligands showed relatively conserved gene structures and motif compositions, whereas the receptor genes displayed greater structural diversity. Tissue expression analysis showed that ToMSTNa was relatively highly expressed in muscle, while ToMSTNb was relatively highly expressed in brain, suggesting potential tissue-specific functional divergence between the two MSTN paralogs. In addition, expression analysis between large and small individuals showed that ToMSTNa was more highly expressed in the brain and intestine of small individuals than in large individuals, whereas ToACVR1A and ToACVR2Bb showed higher expression levels in the liver of small individuals, suggesting their potential association with growth variation. The homology-based predicted protein association network suggested potential associations of ACVR1B- and ACVR2A-type receptors with components of MSTN-related signaling. Overall, this study provides new insights into the evolutionary conservation, tissue-specific functional divergence, and potential growth-associated roles of the MSTN ligand–receptor system in T. ovatus, providing a foundation for further functional studies of MSTN-related signaling and the identification of candidate molecular targets associated with growth traits in teleost fish. Full article

Carboplatin/paclitaxel (CP) chemotherapy is the cornerstone of therapy for advanced stage ovarian cancer (OC). However, despite initial sensitivity, this regimen cannot avoid the emergence of resistance. Ixabepilone ± bevacizumab (IB) is a combination recently added to NCCN guidelines for the treatment of platinum-resistant OC. It would be desirable to identify biomarkers able to differentiate patients who are resistant to CP and IB, and biomarkers that identify which patients may benefit from IB treatment. We analyzed whole-exome-sequencing (WES) data from 49 OC patients exposed to CP, including 28 platinum-sensitive vs. 21 platinum-resistant, and 31 additional platinum-resistant patients, including 16 responders (i.e., CR/PR) vs. 15 non-responders (SD/PD) to ixabepilone ± bevacizumab. Comprehensive genetic analyses were performed to identify alterations correlated with resistance to CP and IB. WES analysis of CP responders vs. non-responders revealed differences in HRD-signatures (p < 0.05), OS (p < 0.005) and gain/loss-of-function in multiple genes associated with tumor growth/progression including but not limited to ACVR2A, INHBA, MAP3K7, ATG5, SGK1, FYN, RSPO3, NOD1 and LRRK2. WES analysis of platinum-resistant IB-treated patients revealed additional nominally significant genes and deranged pathways including gains in the DROSHA and SDHA genes in responders vs. non-responders (p < 0.05). Patients harboring HRD-signatures showed significantly higher sensitivity to CP and prolonged survival compared to HRD-negative patients. Alterations in genes associated with tumor growth/progression correlated with resistance to CP regimen and may represent novel “druggable” candidate biomarkers for the targeted treatment of CP/IB-resistant patients. Further validation in independent cohorts and preclinical experiments in CP/IB-resistant models are warranted to establish the clinical utility of these findings. Full article

Muscle wasting associated with gastric cancer represents a complex, multifactorial systems disorder involving inflammatory, anabolic, mechanosensory, calcium-regulatory, mitochondrial, and proteostatic disruption. This review synthesizes current evidence regarding the cellular and physiological mechanisms involved in skeletal muscle dysfunction in gastric cancer and provides a unifying framework centered on loss of signaling coherence. Specifically, it examines IL-6/STAT3 and NF-κB inflammatory signaling, the myostatin–activin–ACVR2B–SMAD pathway, PI3K/Akt/mTOR signaling, mechanotransduction, excitation–metabolism coupling, calcium homeostasis, mitochondrial function, and proteostasis. Although individual components of these pathways have been implicated in muscle wasting associated with chronic disease, current evidence suggests that they interact through positive feedback loops. Inflammation, anabolic resistance, impaired force-to-signal conversion, mitochondrial stress, altered intracellular calcium homeostasis, and disrupted protein quality control may reinforce one another, contributing to metabolic, structural, and transcriptional instability. Within this context, muscle wasting reflects not only loss of muscle mass or strength, but also loss of functional integrity resulting from disrupted integration of mechanical, metabolic, inflammatory, and anabolic signals. Given the systemic nature of these effects, this review proposes kinesitherapy as a potentially useful nonpharmacological adjunctive strategy that may modulate inflammation, restore responsiveness to mechanical stimuli, support calcium homeostasis and mitochondrial function, improve anabolic sensitivity, and maintain protein quality control. Overall, this review presents a systems-biology model of gastric cancer-associated muscle wasting and supports further investigation of exercise-based therapies for this condition. Full article

Hepcidin, a 25-amino-acid peptide hormone produced primarily by hepatocytes, is the master regulator of systemic iron homeostasis. By binding the cellular iron exporter ferroportin and inducing its internalization and lysosomal degradation, hepcidin restricts iron entry into plasma from enterocytes, macrophages, and hepatocytes. Its transcription is governed by an intricate molecular network that integrates iron status, erythropoietic demand, oxygen tension, and inflammation, with the BMP–HJV–ALK2/SMAD axis acting as the canonical activating pathway and erythroferrone (ERFE) and matriptase-2 (TMPRSS6) as physiological suppressors. Dysregulation of hepcidin underpins a wide spectrum of human diseases: insufficient hepcidin drives hereditary hemochromatosis and the iron overload of congenital and acquired ineffective erythropoiesis diseases and other ineffective erythropoiesis syndromes, whereas excessive or inappropriate hepcidin contributes to anemia of inflammation, anemia of chronic kidney disease, iron-restricted erythropoiesis in cancer, the iron-restrictive anemia of myelofibrosis, and pathogen-restrictive nutritional immunity. Within the myeloproliferative neoplasm spectrum, the divergent hepcidin patterns observed in polycythemia vera (suppressed) and myelofibrosis (inappropriately elevated through dual BMP/ACVR1/SMAD and IL-6/STAT3 hyperactivation) exemplify the clinical relevance of this axis and underpin two opposite pharmacologic strategies. Over the past decade, hepcidin pathway pharmacology has matured from proof-of-concept to regulatory milestones, shifting perspectives on several diseases and markedly improving clinical approaches. Full article

Background/Objectives: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder causing progressive heterotopic ossification. The dental phenotype has never been systematically characterised. We quantified dental pathologies and oral health-related quality of life across three age groups of genetically confirmed FOP patients and compared them with 156 matched healthy controls (2022–2025). Methods: A total of 52 FOP patients (Group I: 1–5 y, n = 14; Group II: 6–17 y, n = 21; Group III: 18–35 y, n = 17) underwent standardised dental examination (Decayed, Missing, and Filled Teeth index (DMFT), Oral Hygiene Index Simplified (OHI-S), Angle classification, temporomandibular joint (TMJ) assessment), computed tomography (CT) densitometry, sialometry, salivary crystal analysis, and Oral Health Impact Profile-14 (OHIP-14). Statistical analysis used Kruskal–Wallis, Mann–Whitney U, Benjamini–Hochberg false discovery rate (FDR) correction, and effect sizes. Results: Caries (DMFT ≥ 4) was highly prevalent across all FOP groups (82–86%) and significantly higher than in controls (84.6% vs. 38.5%, p < 0.001). Chronic stomatitis showed large age-group differences: 7.1% in Group I vs. 100% in Group III (p < 0.001); it was universal in FOP adults vs. 6.4% in controls. Enamel hypoplasia (21.4% → 58.8%) and Angle class II malocclusion (0% → 47.1%) also showed large age-group differences. Total TMJ disorders were observed in 7.1% of Group I and 100% of Group III (p < 0.001); maximal mouth opening was lower by 17.4 mm in Group III (Cohen’s d = 2.1). Salivary flow rate was 20% lower in adults (0.35 → 0.28 mL/min, p = 0.01). Calcium phosphate crystals were detected in 3/17 adults (17.6%) and showed a preliminary correlation with CT calcification grade (ρ = 0.67, p = 0.003); given the small number of crystal-positive patients, this finding should be considered hypothesis-generating. OHIP-14 total score was higher (worse) in Group III (48.9 vs. 12.4 in Group I, Cohen’s d = 1.95). Conclusions: This cross-sectional study provides a systematic characterisation of the dental phenotype in FOP across three age groups. It shows that chronic stomatitis and TMJ dysfunction become nearly universal by early adulthood, severely impairing quality of life. The correlation between salivary calcium phosphate crystals and CT calcification generates the hypothesis of a non-invasive biomarker, requiring prospective validation. The proposed clinical phenotype and minimally invasive recommendations provide a framework for safer dental management of FOP patients. Full article

Background: Microsatellite instability (MSI) is an important biomarker for the diagnosis of Lynch syndrome and for guiding immunotherapy in various solid tumors. Droplet digital PCR (ddPCR) has emerged as a highly sensitive method for detecting MSI, particularly in circulating tumor DNA (ctDNA). This study aimed to evaluate the analytical and clinical performance of a ddPCR assay using three MSI markers (BAT-26, ACVR2A, and DEFB105A/B) in colorectal, gastric, and endometrial cancers. Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 190 patients (83 colorectal, 44 gastric, and 63 endometrial cancers) and 21 plasma samples from patients with metastatic solid tumors were analyzed. MSI status determined by ddPCR was compared with conventional PCR using a pentaplex panel and immunohistochemistry (IHC). Analytical performance, including limit of blank (LoB) and limit of detection (LoD), was evaluated using cell line DNA, and clinical cut-offs were established using receiver operating characteristic analysis. Results: The ddPCR assay demonstrated high analytical sensitivity, with LoD values of 0.075% for BAT-26, 0.1% for ACVR2A, and 0.025% for DEFB105A/B. Using optimized clinical cut-offs, the concordance rate between ddPCR and conventional PCR assays was 98.4% in tissue samples. Marker performance varied by cancer type, with reduced sensitivity observed in endometrial cancer. In plasma samples, MSI-H was detected in 1 of 21 cases (4.8%), and the overall concordance rate with tissue-based MSI status was 94.7%. Conclusions: The ddPCR assay demonstrated high concordance with conventional MSI testing methods and showed potential as a sensitive tool for MSI detection in both tissue and plasma samples. However, optimization of marker panels and establishment of sample-type-specific clinical cut-offs are required, particularly for ctDNA-based analysis. Further large-scale studies are needed to validate the clinical utility of ddPCR for MSI detection and monitoring. Full article

Heterotopic ossification (HO), the pathological formation of mature bone in non-skeletal soft tissues (e.g., muscles, tendons), severely impairs patient mobility and quality of life. Despite decades of research, systematic analysis of signaling networks across HO subtypes (acquired traumatic HO, hereditary Fibrodysplasia Ossificans Progressiva (FOP), Progressive Osseous Heteroplasia (POH)) remains insufficient, and clinical therapies suffer from high recurrence and severe side effects. This review synthesizes recent advances in HO pathogenesis: FOP involves gain-of-function activin A receptor type I (ACVR1) mutations (mostly R206H), disrupting bone morphogenetic protein (BMP)/Activin A signaling; POH arises from paternal guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) loss-of-function mutations, derepressing Hedgehog signaling via reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activity; tHO features trauma-induced inflammation/hypoxia activating BMP/transforming growth factor–beta (TGF-β) pathways. Key signaling crosstalk (e.g., BMP-Yes-associated protein (YAP)-Indian hedgehog (IHH)) is integrated, and novel therapies (ACVR1 inhibitors, Activin A antibodies, retinoic acid receptor gamma (RARγ) agonists, adeno-associated virus (AAV)-mediated ACVR1 silencing) are highlighted, with emphasis on subtype-specific efficacy. A stratified, mechanism-based HO management framework is proposed, aiming to accelerate precision therapy development and advance understanding of aberrant tissue regeneration. Full article

Most glaucoma genetic data derive from European and East Asian cohorts, leaving high-consanguinity Middle Eastern populations under-characterized. This review synthesizes 33 Saudi-specific genetic studies (2014–2024, >9000 participants) to define a population-level glaucoma genetic architecture that diverges substantially from global models and carries direct precision medicine implications. Three findings distinguish the Saudi landscape. First, CYP1B1 functions as the dominant causal gene across both primary congenital glaucoma (PCG) and juvenile-onset open-angle glaucoma (JOAG), accounting for 76–86% of cases, with two founder alleles, p.G61E (penetrance 87.7%) and p.R469W (penetrance 93%), driving severe, early-onset phenotypes. Critically, MYOC and LTBP2, the primary JOAG genes in other populations, carry no pathogenic variants in Saudi cohorts, rendering standard multi-ethnic gene panels inadequate for this population. Second, adult-onset glaucoma follows a distinct polygenic architecture where APOE ε2 confers a near five-fold risk for primary angle-closure glaucoma (OR = 4.82), an effect absent or inconsistent in global datasets, and NOS3 variants associate with primary open-angle glaucoma specifically in men, a sex-stratified signal unreported outside Saudi cohorts. The MTHFR T/T genotype, common in European and Asian POAG patients, is entirely absent locally, indicating population-specific allelic distributions that alter folate-metabolism-related optic nerve susceptibility. Third, ACVR1 rs12997 associates across POAG, PACG, and pseudoexfoliation glaucoma (PXG), positioning BMP/TGF-β signaling as a shared mechanistic pathway spanning multiple subtypes. These findings argue for Saudi-specific genetic panels, CYP1B1-centered cascade testing in consanguineous families, and polygenic risk models incorporating local allele frequencies rather than globally derived weights. Full article

Pulmonary arterial hypertension (PAH) is characterized by dysfunction and remodeling of the pulmonary artery endothelium and smooth muscle. In heritable PAH, heterozygous loss-of-function mutations in the type II Bone Morphogenetic Protein (BMP) receptor gene (BMPR2) are the most common genetic cause. However, the mechanisms by which reduced BMPR2 levels alter endothelial signaling to drive PAH pathogenesis remain incompletely understood. To determine how BMPR2 levels govern signaling output and endothelial functional responses, we modulated BMPR2 expression in human pulmonary artery endothelial cells (PAECs) and assessed ligand-dependent SMAD1/5/8 signaling, proliferation, and caspase-3/7 activity. We found that BMP9 and BMP10 robustly activated SMAD1/5/8 signaling and promoted proliferation in PAECs, whereas the other ligands in this panel did not elicit a comparable signaling or proliferative response under these assay conditions. A moderate (~50%) reduction in BMPR2 protein levels (an in vitro approximation of haploinsufficiency) attenuated BMP9/10-induced SMAD1/5/8 activation, abolished proliferative responses, and was associated with a modest increase in caspase-3/7 activity, consistent with caspase pathway activation and early stress/injury signaling. Under BMPR2-limiting conditions, BMP9/10 responses became sensitive to Activin type II receptor blockade by bimagrumab, consistent with a context-dependent contribution of Activin type II receptors. Conversely, BMPR2 overexpression enhanced BMP9/10-dependent SMAD signaling and proliferation. Together, these findings support a receptor–dosage model where physiological BMPR2 expression is required to sustain homeostatic BMP9/10 signaling in pulmonary artery endothelium. This framework provides a basis for interpreting context-dependent pathway effects in PAH. Full article

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00). Full article

Background: The exact pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder, remains unclear. Ferroptosis is a form of cell death characterized by intracellular iron accumulation, and has emerged as a potential contributor to the pathological cascade of AD. Therefore, this study aims to identify core genes that may function as reliable biomarkers for AD through an in-depth analysis of the genetic relationship between ferroptosis-related genes and AD. Methods: This study first obtained the gene expression profiles (GSE140831, GSE63060 and GSE63061 expression profiles). The GSE140831 dataset served as the discovery cohort, and the GSE63060 and GSE63061 datasets were used as independent validation cohorts. R language 4.4.1 was used for standardizing and identifying differentially expressed genes (DEGs) in AD patients in all datasets. Secondly, the ferroptosis-related genes were obtained. By integrating the ferroptosis-related genes, ferroptosis-related DEGs (FRDEGs) were detected. Then, the FRDEGs were verified and evaluated, and the biological functions of the core genes were analyzed. Finally, miRNAs interacting with these core FRDEGs were explored. Results: The study identified nine FRDEGs (ACVR1B, BRPF1, G6PD, KLHDC3, LAMP2, MTCH1, P4HB, PTPN6, RBMS1), which are potentially related and may serve as biomarkers for AD. All nine genes demonstrated statistically significant differential expression (up-regulation) in both independent validation cohorts and in the combined analysis (p < 0.05). Although the area under the curve (AUC) values of these nine genes ranged from 0.61 to 0.71, indicating moderate discriminatory power, these findings suggest that they may be involved in pathways related to AD and are worthy of further investigation as potential auxiliary biomarkers. Finally, a network of hub FRDEGs-miRNAs interaction was constructed. There were 11 miRNAs that may regulate these hub FRDEGs simultaneously. Conclusions: This study showed the significant association of the identified FRDEGs with AD. Also, a core ferroptosis-related biomarker network for miRNAs regulation of AD was constructed. The specific regulatory mechanism is worthy of further investigation. Full article

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an immune-mediated neurological disorder driven by dysregulated neuroimmune interactions, yet the molecular architecture linking tumor-associated immune activation, peripheral immunity, and neuronal dysfunction remains insufficiently understood. In this study, we established an integrative computational framework that combines multi-tissue transcriptomic profiling, weighted gene co-expression network analysis, immune deconvolution, and machine learning-based feature prioritization to systematically characterize the regulatory landscape of the disease. Joint analysis of three independent GEO datasets spanning ovarian teratoma tissue and peripheral blood transcriptomes identified 2001 consistently dysregulated mRNAs, defining a shared tumor–immune–neural transcriptional axis. Across multiple feature selection algorithms, ACVR2B and MX1 were reproducibly prioritized as immune-associated candidate genes and were consistently downregulated in anti-NMDAR encephalitis samples, showing negative correlations with neutrophil infiltration. Reconstruction of an integrated mRNA-miRNA-lncRNA regulatory network further highlighted a putative core axis (ENSG00000262580–hsa-miR-22-3p–ACVR2B), proposed as a hypothesis-generating regulatory module linking non-coding RNA regulation to immune-neuronal signaling. Pathway and immune profiling analyses demonstrated convergence of canonical immune signaling pathways, including JAK-STAT and PI3K-Akt, with neuronal communication modules, accompanied by enhanced innate immune signatures. Although limited by reliance on public datasets and small sample size, these findings delineate a systems-level neuroimmune regulatory program in anti-NMDAR encephalitis and provide a scalable, network-based multi-omics framework for investigating immune-mediated neurological and autoimmune disorders and for guiding future experimental validation. Full article

Non-coding RNAs (ncRNAs) have emerged as promising biomarkers for prostate cancer (PCa), yet evidence remains dispersed across heterogeneous studies and their regulatory context is seldom analyzed in an integrated manner. This study systematically maps ncRNAs reported as diagnostic biomarkers for PCa and characterizes their molecular interactions through in silico analyses. A comprehensive evidence-mapping strategy across major bibliographic databases identified 693 studies, of which 58 met eligibility criteria. Differentially expressed ncRNAs were extracted and classified by RNA type. Subsequently, miRNA–target prediction, miRNA–protein interaction network construction, and functional enrichment analyses were performed to explore the regulatory landscape of miRNA-associated proteins. Results: The final dataset included 4500 participants (2871 PCa cases and 2093 controls) and reported 94 differentially expressed miRNAs, eight lncRNAs, and several circRNAs, snoRNAs, snRNAs, and piRNAs. In silico analyses predicted 13,493 miRNA–mRNA interactions converging on 4916 unique target genes, with an additional 2481 prostate tissue-specific targets. The miRNA–protein network comprised 845 nodes and 2335 edges, revealing highly connected miRNAs (e.g., hsa-miR-16-5p, hsa-miR-20a-5p) and protein hubs (QKI, YOD1, TBL1XR1; prostate-specific CDK6, ACVR2B). Enrichment analysis showed strong overrepresentation of metabolic process-related GO terms and cancer-associated KEGG pathways. Conclusions: These findings refine the list of promising ncRNA biomarkers and highlight candidates for future clinical validation. Full article

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development (p < 0.05). Functionally, overexpression of IGF2BP2 in skeletal muscle satellite cells (SMSCs) was associated with significant changes in the expression of several genes linked to muscle development and signaling pathways, including upregulation of IGF1, EGFR, FGF19, BMP6, BMP2, ACVR1C and WNT5A and downregulation of MYBPC3, NODAL, HOXD13, TNXB, and ADD2 (Padj < 0.01). Furthermore, protein–protein interaction (PPI) network analysis of these genes suggests that IGF2BP2 may coordinate key genes, contributing to its potential role in skeletal muscle development in geese. Full article