Search Results (2,206)

Sheep are an economically important livestock species, and reproductive performance is a key trait affecting productivity. The Dorper × Hu hybrid sheep (DHS), widely bred in China, provides a valuable model for studying the genetic basis of prolificacy. This study aimed to investigate the genomic architecture and identify candidate genes associated with high litter size in DHS using whole-genome selective sweep analysis and genome-wide association study (GWAS). A total of 31 DHS individuals with complete reproductive records were sequenced and compared with publicly available genomic data from 20 Hu sheep (HUS) and 10 Dorper sheep (DPS). Population genetic structure and diversity were assessed using phylogenetic trees, principal component analysis (PCA), and ADMIXTURE analysis. To identify key genomic regions associated with litter size, we performed selective sweep analysis between the polytocous and monotocous subpopulations of DHS using multiple methods within a 50 kb sliding window framework, including $F_{ST}$, ${\theta }_{\pi }$ ratio, XP-CLR, and XP-EHH; we also conducted GWAS. DHS exhibited a distinct genetic structure with admixed ancestry and elevated genetic diversity. Genetic diversity analysis showed that DHS retained moderate levels of heterozygosity and polymorphism, comparable to or exceeding those of its parental breeds. Comparative analysis between polytocous and monotocous DHS identified reproduction-associated genes, including MUC1, PLCB4, SIN3A, and ELAVL2, enriched in pathways such as ovarian steroidogenesis, insulin secretion, and circadian entrainment. Furthermore, genome-wide association study (GWAS) identified 140 significant loci (p < 10⁻⁵) associated with reproductive traits. From these, 10 candidate SNPs were selected for validation through single-marker association analysis in 200 DHS individuals, among which two loci—g.88680390 C>A (SLC24A2/MLLT3) and g.18197516 T>C (ABCA1)—showed significant correlations with litter size. These findings enhance our understanding of the genetic basis of prolificacy in DHS and provide valuable molecular markers for genomic selection in sheep-breeding programs. Full article

With the increasing global burden of major depressive disorder (MDD), identifying modifiable environmental risk factors has become a critical priority. Per- and polyfluoroalkyl substances (PFASs), characterized by environmental persistence and bioaccumulation, have been linked to elevated mental health risks. However, the potential neurotoxicity of GenX—a novel PFAS developed to replace perfluorooctanoic acid (PFOA)—and its molecular association with MDD remain unclear. In this study, peripheral blood serum transcriptomic data from the Gene Expression Omnibus (GEO) were integrated with multidimensional bioinformatics analyses to elucidate molecular mechanisms connecting GenX exposure with MDD. Four hub genes (UCP2, AKR1B1, TP53, and F5) were identified, showing strong combined diagnostic performance (AUC = 0.925). Functional enrichment and immune infiltration analyses revealed their involvement in energy metabolism, oxidative stress, and immune-coagulation regulation. Molecular docking and dynamics simulations further confirmed stable interactions between GenX and these proteins, providing structural support for their mechanistic roles. Although classical dopaminergic markers (TH, SLC6A3, DRD1–5) were not detected in the serum-derived transcriptomes, the identified hub genes may still affect dopaminergic function indirectly by modulating metabolic, oxidative stress, and inflammatory/coagulation pathways, thereby influencing MDD susceptibility. This study provides the first integrated transcriptomic and structural evidence linking GenX to psychiatric risk, proposing a novel “GenX-dopamine-MDD” framework for understanding pollutant-mediated neuropsychiatric mechanisms. Full article

Ground settlement is a multifaceted geological phenomenon driven by natural and man-made forces, posing a significant impediment to sustainable urban development. Thus, ground settlement susceptibility (GSS) mapping has emerged as a critical tool for understanding and mitigating cascading hazards in seismically active and anthropogenically modified sedimentary basins. Here, we develop an integrated framework for assessing GSS in the Pohang region, South Korea, by integrating Persistent Scatterer Interferometric Synthetic Aperture Radar (PSInSAR)-derived vertical land motion (VLM) data with seismological, geotechnical, and topographic parameters (i.e., peak ground acceleration (PGA), effective shear-wave velocity (V_s³⁰), site period (T_s), general amplification factor (A_F), seismic vulnerability index (K_g), soil depth, topographic slope, and landform classes) through ensemble machine learning models such as Random Forest (RF), XGBoost, and Decision Tree (DT). Analysis of 56 Sentinel-1 SLC images (2017–2023) revealed persistent subsidence concentrated in Quaternary alluvium, reclaimed coastal plains, and basin-fill deposits. Among the tested models, RF achieved the best performance and strongly agreed with field evidence of sand boils, liquefaction, and structural damage from the 2017 Pohang earthquake. The very-high-susceptibility zones exhibited mean subsidence rates of −3.21 mm/year, primarily within soft sediments (V_s³⁰ < 360 m/s) and areas of thick alluvium deposits. Integration of the optimal RF-based GSS index with regional building inventories revealed that nearly 65% of existing buildings fell within high- to very-high-susceptibility zones. The proposed framework demonstrates that integrating PSInSAR and ensemble learning provides a robust and transferable approach for quantifying ground settlement hazards and supporting risk-informed urban planning in seismically active and complex geological coastal environments. Full article

This study aimed to investigate the chemical composition, antioxidant activity, and in vitro antidiabetic properties of extracts obtained from ripe, unripe, and fermented (unripe) cornelian cherry (Cornus mas L.) fruits. Polyphenols were identified using UPLC-ESI-qTOF-MS/MS and quantified by HPLC-PDA. Antioxidant activity was evaluated using ABTS, DPPH, and FRAP assays, while enzyme inhibitory activity was determined for α-glucosidase and α-amylase. Additionally, the effects of C. mas extracts on insulin sensitivity in adipocytes were investigated. The study’s results showed that each of the extracts tested contained varying proportions of substances with proven health-promoting properties. The extract from ripe fruits was characterized by the highest loganic acid content, whereas the extract from fermented unripe fruits contained a high amount of gallic acid, released through the hydrolysis of tannins during fermentation. The extract from unripe fruits exhibited the highest tannin content and the strongest antioxidant activity. All extracts inhibited α-glucosidase and α-amylase to a similar extent and improved insulin-stimulated glucose uptake in 3T3-L1 adipocytes without affecting INSR or SLC2A4 expression. In conclusion, extracts from unripe and fermented C. mas fruits may represent promising agents for alleviating insulin resistance and preventing type 2 diabetes. Full article

Background: Butana are native Sudanese Bos indicus cattle that are well adapted to arid environments and valued for their relatively high milk performance and resilience under harsh conditions. Despite their adaptive advantages, Butana cattle face the risk of genetic erosion due to low production performance and the absence of structured breeding programs underscoring the urgent need to conserve their unique genetic potential for climate-resilient livestock development. Methods: In this study, we analyzed whole-genome sequencing data from 40 Butana cattle to assess their genetic diversity, population structure, signatures of selection, and potential pathogen load. Results: Butana cattle exhibited high nucleotide diversity and low levels of inbreeding, indicating a stable gene pool shaped by natural selection rather than by intensive breeding. Signatures of selection and functional variant analysis revealed candidate genes involved in heat stress adaptation (COL6A5, HSPA1L, TUBA8, XPOT), metabolic processes (G6PD, FAM3A, SLC10A3), and immune regulation (IKBKG, IRAK3, IL18RAP). Enrichment analyses and RoH island mapping consistently highlighted immune and thermoregulatory pathways as key selection targets, distinguishing Butana from both the geographically neighbored Kenana cattle and the specialized dairy cattle breed Holstein. Furthermore, metagenomic screening of unmapped reads detected the tick-borne parasite Theileria annulata and the opportunistic pathogen Burkholderia cenocepacia in all animals, underscoring the importance of integrating pathogen surveillance into genomic studies. Conclusions: Taken together, our findings highlight the distinct adaptive genomic profile of Butana cattle and reinforce their value in breeding programs aimed at improving climate resilience and disease resistance in livestock through the utilization of local breeds. Full article

Intramuscular fat (IMF) is a crucial indicator of meat quality. Recent studies increasingly suggest that methionine (Met) plays a role in fat accumulation. However, the mechanism by which Met affects the proliferation and differentiation of intramuscular adipocytes remains unclear. In this study, goat intramuscular adipocytes were cultured in basal complete medium supplemented with Met at 0, 50, 100, 200, 400, and 800 μM. This study demonstrates a quadratic relationship between the level of Met supplementation and cellular proliferation and differentiation, with an optimal effect observed at 100 μM Met. The results of RNA-seq analysis demonstrated that supplementation with Met led to the downregulation of genes involved in lipid metabolism, including the genes PER2, PRKG1, and SLC5A5. Furthermore, we found that overexpression of SLC5A5 inhibits adipogenic differentiation in goat intramuscular adipocytes, while Met supplementation reversed this inhibitory effect. In addition, silencing SLC5A5 significantly promoted adipogenic differentiation, whilst Met supplementation further enhanced this promotion effect. In conclusion, this study indicates that Met supplementation of basal complete medium benefits adipogenic differentiation of goat intramuscular adipocytes, likely by inhibiting the expression of SLC5A5. This research provides a foundation for improving goat meat quality. Full article

Breast cancer is highly heterogeneous, with multiple subtypes that differ in molecular and clinical characteristics. It remains the most common cancer among women worldwide. We conducted a hypothesis-generating study using a bioinformatics approach in order to identify potential prognostic biomarkers for breast cancer patients across multiple molecular subtypes. Given the influential role of the transforming growth factor beta (TGFB) pathway in shaping the immune microenvironment, we focused on the isoform, transforming growth factor beta 2 (TGFB2), which is upregulated in tumors, to identify TGFB2-dependent and -independent biomarkers for breast cancer patients’ overall survival (OS) responses. We evaluated the impact of TGFB2 mRNA expression, in conjunction with other potential prognostic markers, on overall survival (OS) in breast cancer patients using The Cancer Genome Atlas (TCGA) and KMplotter databases. We employed a multivariate Cox proportional hazards model to compute hazard ratios (HRs) for TGFB2 mRNA expression, integrating an interaction term that accounts for the multiplicative relationship between TGFB2 and marker gene expressions while controlling age at diagnosis and cancer subtype and differentiating between patients receiving chemotherapy alone and those undergoing alternative therapeutic interventions. We used the KMplotter database to confirm TGFB2-independent prognostic markers from TCGA data. In cases dependent on TGFB2, increased mRNA expression of TGFB2 alongside higher levels of GDAP1, TBL1XR1, RNFT1, HACL1, SLC27A2, NLE1, or TXNDC16 was correlated with improved OS among breast cancer patients, of which four genes were upregulated in tumor tissues (SLC27A2, TXNDC16, TBL1XR1, GDAP1). Future studies will be required to confirm breast cancer patients could improve OS outcomes for patients expressing high levels of TGFB2 and the marker genes in prospective clinical trials. Additionally, multivariate analysis revealed that the elevated expression of six genes (ENO1, GLRX2, PLOD1, PRDX4, TAGLN2, TMED9) were correlated with increases in HR, independent of TGFB2 mRNA expression; all except GLRX2 were identified as druggable targets. Future investigations assessing protein expression in breast cancer tumors to confirm the results of our retrospective analysis of mRNA levels will determine whether the protein products of these genes represent viable therapeutic targets. Protein–protein interaction (STRING) analysis indicated that TGFB2 is associated with EGFR and MYC from the PAM50 breast cancer gene signature. These findings suggest that correlation of TGFB2-related markers could potentially complement the PAM50 signature in the assessment of OS prognosis in breast cancer patients, but further validation of the TGFB2/EGFR/MYC proteins in tumors is warranted. Full article

SLC35A2 encodes the Golgi uridine diphosphate galactose transporter, which is essential for glycosylation of glycoproteins and glycolipids. Variants in this gene, either germline or somatic, have emerged as causes of diverse neurological disorders ranging from congenital disorders of glycosylation (SLC35A2-CDG) to focal cortical malformations such as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). This review summarizes the molecular function of SLC35A2, clinical phenotypes of congenital and somatic variants, insights from functional assays and animal models, and therapeutic perspectives including galactose supplementation and precision medicine. We aim to provide an integrative synthesis of human genetics, neuropathology, glycomics, and translational approaches. Full article

Inherited retinal degenerations (IRDs), driven by pathogenic mutations, often involve primary dysfunction of the retinal pigment epithelium (RPE)—a pathogenic feature shared with atrophic age-related macular degeneration (aAMD), despite aAMD’s multifactorial etiology. Prominin-1 (Prom1), traditionally linked to photoreceptor pathology, has an unclear role in RPE homeostasis. We assessed Prom1 expression in C57BL/6J mouse retina sections and RPE flat mounts using immunohistochemistry and generated Prom1-knockout (KO) mouse RPE cells via CRISPR/Cas9. Bulk RNA sequencing with DESeq2 and gene set enrichment analysis (GSEA) revealed Prom1-regulated pathways. Prom1-KO cells exhibited upregulation of Grem1, Slc7a11, Serpine2, Il1r1, and IL33 and downregulation of Ablim1, Cldn2, IGFBP-2, BMP3, and OGN. Hallmark pathway interrogation identified reduced expression of PINK1 (mitophagy) and MerTK (phagocytosis), implicating defects in mitochondrial quality control and outer segment clearance. Enrichment analysis revealed activation of E2F/MYC targets, mTORC1 signaling, oxidative phosphorylation, and TNFα/NF-κB signaling, alongside suppression of apical junctions, bile acid metabolism, and Epithelial-Mesenchymal Transition (EMT) pathways. These findings suggest Prom1 safeguards RPE integrity by modulating stress responses, mitochondrial turnover, phagocytosis, metabolism, and junctional stability. Our study uncovers Prom1-dependent signaling networks, providing mechanistic insights into RPE degeneration relevant to both IRD and aAMD, and highlights potential therapeutic targets for preserving retinal health. Full article

Omega-3 fatty acids, particularly DHA, are potent modulators of adipose tissue biology. However, reported effects on adipogenesis vary with dose and adipocyte maturation. We examine the effects of prolonged exposure to 60 μM DHA on lipogenesis, lipolysis, and glucose uptake in 3T3-L1 adipocytes. DHA was administered either during early differentiation (days 1–9, followed by maturation in maintenance medium) or during the mature stage (days 9–18), with all analyses performed on day 18. DHA supplementation of immature adipocytes markedly inhibited adipogenesis. Intracellular lipid accumulation was reduced by 56%, accompanied by a strong downregulation of Pparγ and Fasn, and undetectable levels of Gpr120. Correspondingly, Slc2a4 (GLUT4) was suppressed, accompanied by a 44% reduction in glucose uptake. The strong suppression of the adipogenic program and increased Cpt1-linked mitochondrial β-oxidation in immature adipocytes align with DHA’s well-known anti-inflammatory and ROS-lowering effects. When applied to mature adipocytes at the same dose and duration, DHA also decreased intracellular lipid accumulation and glucose utilization, although more modestly (by 30% and 8%, respectively). However, unlike in immature adipocytes, the lipolysis rate in mature cells was increased by 34% and Pparγ expression remained unchanged, indicating an entirely different metabolic pathway of modulation. In mature adipocytes, DHA promoted lipid mobilization rather than the general suppression of lipogenesis and glucose uptake. Overall, these findings highlight a distinct, stage-specific antiadipogenic mechanism of DHA action, but also underline that its context-dependent effects may become detrimental when high physiological doses overlap with conditions of energy surplus. Full article

Endometrial cancers (ECs) are mainly adenocarcinomas arising from the uterine endometrium. In this work, we employed data-independent acquisition (DIA) mass spectrometry (MS)-based label-free quantification (LFQ-MS) proteomics to analyze the proteome of tissue washings collected from 25 control (CTRL) subjects, 25 patients with low-grade type 1 endometrial cancer (EC), and 24 patients with high-grade type 1 EC. Following quantification and statistical analysis, we identified 42 proteins able to discriminate CTRL from EC patients, and 151 proteins differentiating high-grade EC cases from low-grade EC cases. Notably, PRRC2A and SYDE2 effectively distinguished both EC patients from controls and advanced EC cases from low-grade EC cases. Validation by Western blot analysis in an independent cohort comprising 19 CTRL patients, 19 patients with low-grade EC, and 19 patients with high-grade EC confirmed the upregulation of PRRC2A and SYDE2. These proteins are implicated in the translocation of SLC2A4, the regulation of MECP2, and extracellular matrix (ECM) proteoglycan pathways, all of which are associated with tumor growth. Our results demonstrate that DIA-based proteomic analysis of tissue washings enables the identification of potential biomarkers for endometrial cancer (EC). Moreover, this study highlights tissue washings as a promising biological fluid for biomarker discovery in EC. Full article

Nasopharyngeal carcinoma (NPC) is a head and neck malignancy strongly associated with Epstein–Barr virus (EBV) infection and characterized by high radiosensitivity but frequent therapy resistance. Despite advances in radiotherapy, chemotherapy, and immunotherapy, relapse and metastasis remain major challenges, underscoring the need for novel therapeutic approaches. This review aims to provide an integrated overview of the molecular mechanisms governing ferroptosis in NPC and to clarify how these pathways contribute to therapy resistance while revealing potential therapeutic vulnerabilities. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising target in NPC. Core regulators include the system xCT–GSH–GPX4 antioxidant axis, iron metabolism, and lipid remodeling enzymes such as ACSL4, with epigenetic modifiers (METTL3, IGF2BP2, HOXA9) and EBV-driven signaling further shaping ferroptosis responses. EBV-driven oncogenic programs substantially reshape ferroptosis sensitivity in NPC by activating the Nrf2/Keap1 antioxidant axis, stabilizing SLC7A11 and GPX4, and modulating iron and redox metabolism. These viral mechanisms suppress ferroptotic stress and contribute to both radioresistance and chemoresistance. Suppression of ferroptosis underlies both radioresistance and chemoresistance, whereas restoration of ferroptosis re-sensitizes tumors to treatment. Natural compounds including solasodine, berberine, cucurbitacin B, and celastrol-curcumin combinations, as well as pharmacologic modulators such as HO-1 inhibitors and GPX4 antagonists, have shown ferroptosis-inducing effects in preclinical models, although their translational potential remains to be clarified. Nanotechnology-based platforms (e.g., Bi₂Se₃ nanosheet hydrogels) further enhance efficacy and reduce toxicity by enabling controlled drug delivery. Biomarker discovery, encompassing ferroptosis-related gene signatures, epigenetic regulators, immune infiltration patterns, EBV DNA load, and on-treatment redox metabolites, provides a foundation for patient stratification. Integration of ferroptosis modulation with radiotherapy, chemotherapy, and immunotherapy represents a compelling strategy to overcome therapy resistance. In synthesizing these findings, this review highlights both the mechanistic basis and the translational promise of ferroptosis modulation as a strategy to overcome treatment resistance in NPC. Future directions include biomarker validation, optimization of drug delivery, early-phase clinical trial development, and multidisciplinary collaboration to balance ferroptosis induction in tumors while protecting normal tissues. Collectively, ferroptosis is emerging as both a vulnerability and a therapeutic opportunity for improving outcomes in NPC. Full article

The calyx of Held is a giant axo-somatic synapse classically confined to the auditory brainstem. We recently identified morphologically similar calyx-like terminals in the extended amygdala (EA) that arise from the ventrolateral parabrachial complex and co-express PACAP, CGRP, VAChT, VGluT1, and VGluT2, targeting PKCδ⁺/GluD1⁺ EA neurons. Here, we asked whether this parabrachial–EA pathway participates in compensation during acute hypotension. In rats given hydralazine (10 mg/kg, i.p.), we quantified Fos protein during an early phase (60 min) and a late phase (120 min). Early after hypotension, Fos surged in a discrete subpopulation of the parabrachial Kölliker–Fuse (KF) region and in the EA, whereas magnocellular neurons of the supraoptic and paraventricular nuclei (SON/PVN) remained largely silent. By 120 min, magnocellular SON/PVN neurons were robustly Fos-positive. Confocal immunohistochemistry showed that most Fos+ PKCδ⁺/GluD1⁺ EA neurons were encircled by PACAP+ perisomatic terminals (80.8%), of which the majority co-expressed VGluT1 (88.1%). RNAscope in situ hybridization further identified a selective KF population co-expressing Adcyap1 (PACAP) and Slc17a7 (VGluT1) that became fos-positive during the early phase. Together, these data suggest that a KF PACAP⁺/VGluT1⁺ projection forms calyceal terminals around PKCδ⁺/GluD1⁺ EA neurons, providing a high-fidelity route for rapid autonomic rebound to falling blood pressure, while slower endocrine support is subsequently recruited via neurohormone-magnocellular activation. This work links multimodal parabrachial output to temporally layered autonomic–neuroendocrine control. Full article

Euryhaline fishes provide excellent material for the theoretical study of the broad-spectrum adaptability of organisms and the use of low-salinity and even freshwater environments, or high-salinity and seawater environments, for the domestication of fishes. Here, we studied the molecular mechanisms of osmotic pressure regulation in a euryhaline fish, marine medaka (Oryzias melastigma). As the fish progressed from seawater to freshwater, the changes in stress indicators (cortisol—COR; malondialdehyde—MDA; reactive oxygen species—ROS; superoxide dismutase—SOD) indicated that they gradually adapted to the freshwater environment. The transcriptome analysis also showed that there were 6850 DEGs (differentially expressed genes) involved in the process. By analyzing these DEGs deeply, we screened and identified the Hnf1ba-slc12a1 signal pathway involved in osmotic pressure regulation. The results of a dual-luciferase reporter assay in HEK293T cells, as well as an overexpression experiment by in vitro cultured gill cells of O. melastigma, confirmed that Hnf1ba transcriptionally regulates the slc12a1 gene. Fragment deletion and site-directed mutagenesis assays revealed a Hnf1ba-binding sequence (GATTAATCATTTACT, located at −1877 to −1863) in the slc12a1 promoter. Based on this result, we conducted a targeted regulation experiment on the slc12a1 gene using the CRISPR-dCas9 & Sun-Tag system. The most effective activation of slc12a1 gene expression was observed in the sgRNA2 group. These results enhance our understanding of adaptation mechanisms in salt-tolerant fish and provide a reference for efficiently promoting the domestication of fish adaptive to salinity changes. Full article

Background/Objectives: Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, accompanied by a major decline in local myocardial pH. However, the mechanisms of pH regulation and the homeostasis of H⁺ neutralizing buffers, such as HCO₃⁻, in cardiomyocytes remain incompletely understood. We identified a solute carrier, Slc26a6, in mouse and human hearts playing key roles in the regulation of cardiac pH, excitability, and contractility. Slc26a6 is an acid loader, so we hypothesized that ablation of Slc26a6 may protect the heart from ischemia/reperfusion (I/R) injury. Methods: The I/R model was generated using wild type (WT) and Slc26a6 knockout (Slc26a6^−/−) mice. Multidisciplinary in vivo, in vitro, and ex vivo approaches were used, including echocardiography, electrophysiology, hemodynamic monitoring, fluorescence microscopy, histochemistry, and cellular Ca²⁺ transients, sarcoplasmic reticulum Ca²⁺ load, and sarcomere shortening were recorded. Results: Troponin I level was lower in Slc26a6^−/− I/R mice. Slc26a6^−/− mice showed better systolic and diastolic function, reduced collagen deposition, and reduced infarct size compared to that of WT mice. Cellular experiments in measurement of sarcomere shortening, Ca²⁺ transients, and sarcoplasmic reticulum Ca²⁺ load in cardiomyocytes from the infarct zone supported the in vivo findings, demonstrating better single cell function in Slc26a6^−/− compared to WT mice. Ex vivo pH_i measurement showed elevated pH_i in Slc26a6^−/− mouse heart. Conclusions: Ablation of Slc26a6 protects the heart from I/R injury, suggesting the importance of Cl⁻/HCO₃⁻ exchange in cardiac pH regulation and I/R injury. The elevated pH_i in Slc26a6^−/− mouse heart may counterbalance the effects of the myocardium acidosis resulting from ischemia. Full article