Search Results (9,193)

The Wuding chicken, a renowned indigenous breed in Yunnan Province, is prized for its superior meat quality; however, its economic potential is limited by pronounced broodiness and suboptimal egg production. Central to alleviating these constraints is the precise regulation of ovarian granulosa cell (GC) proliferation and steroidogenic processes that dictate follicular development and laying performance. While Estrogen Receptor 2 (ESR2) is a known transcription factor implicated in follicular maturation, its spatiotemporal dynamics within the hypothalamic-pituitary-ovarian (HPO) axis and its specific regulatory mechanisms in Wuding chicken remain elusive. This study characterizes ESR2 expression across the HPO axis during the laying and broody periods and functionally validates its role in GCs. We observed that ESR2 expression was significantly higher throughout the HPO axis during the laying period compared to the broody period, with the most pronounced differential expression occurring in the ovary. Notably, subcellular localization analysis revealed that ESR2 is distributed in both the nucleus and the cytoplasm, indicating involvement in both nuclear transcriptional regulation and cytoplasmic signaling. Functional assays indicate that ESR2 modulates the expression of genes associated with GC proliferation, steroidogenesis, and apoptosis, potentially via the PI3K/AKT/mTOR signaling pathway. Our findings indicate that this process involves a synergistic interplay between genomic and potential non-genomic actions. Specifically, ESR2 overexpression upregulates the expression of key signaling components and steroidogenic genes, including CYP19A1, STAR, PTGS2, and FSHR, while its cytoplasmic localization suggests a potential for non-genomic interactions. Together, these coordinated mechanisms may maintain GC functional homeostasis and support follicular development. Collectively, these results suggest that ESR2 plays an important role in maintaining GC homeostasis and follicular development and may involve both genomic and non-genomic modes of action, highlighting its potential relevance for future studies on reproductive performance in indigenous poultry breeds. Full article

Background/Objectives: Physical activity (PA) is a modifiable determinant of health and quality of life (QoL) in kidney transplant recipients (KTRs). However, associations between PA, health-related QoL (HRQoL), inflammation, and clinical factors in KTRs remain incompletely defined. The aim was to evaluate PA levels in KTRs and explore their associations with HRQoL, clinical characteristics, and biochemical and inflammatory markers. Methods: We conducted a cross-sectional study of 32 stable KTRs (56% male; mean age 54.5 ± 14.2 years). PA was assessed using the International Physical Activity Questionnaire and classified as low (<700 MET-min/week) or high (≥700 MET-min/week) according to IPAQ categorical scoring. HRQoL was evaluated using the SF-36. Associations with demographic, clinical, biochemical (including potassium), and inflammatory markers—including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and ferritin—were analyzed using multivariable binary logistic regression models. Results: Sixty-three percent of participants achieved high PA, which was associated with better physical functioning (78.8 vs. 58.3; p = 0.016), fewer emotional role limitations, younger age at transplantation, and preemptive transplantation or peritoneal dialysis. Active patients had modestly higher potassium levels (4.61 vs. 4.25 mmol/L; p = 0.041), a hypothesis-generating finding that should be interpreted cautiously. Inflammatory indices showed no significant associations. Conclusions: Although most KTRs achieved adequate PA levels, physical inactivity persisted in over one-third. Targeted strategies addressing HRQoL and clinical factors may support PA engagement after transplantation. Full article

Male infertility, a global health issue marked by spermatogenic failure, hinges on selenium (Se) as a key element for normal spermatogenesis. Among different Se species, Se-methylselenocysteine (MeSeCys) has been developed as a natural organic Se supplement with potent antioxidant and anti-inflammatory properties, but its direct effects on male reproduction need to be further explored. This study investigated the effect of MeSeCys on GC-1 spg (GC-1) and GC-2 spd (ts) (GC-2) cell lines, which mimic early stages. Treatment with 75 μmol/L MeSeCys for 24 h markedly enhanced the viability of both cell lines, with a more pronounced effect observed in GC-1 than in GC-2 cells. Moreover, this study demonstrated that MeSeCys enters cells through SLC7A11 or LRP8 channels and elevates intracellular Se levels in both GC-1 and GC-2 cells, with higher levels observed in GC-1 cells. RNA sequencing (RNA-seq) and bioinformatics analysis revealed that MeSeCys may regulate selenocompound metabolism and the glutathione metabolism pathway in both cell lines, increasing their intracellular glutathione (GSH) levels. Importantly, in GC-1 cells, MeSeCys specifically modulates the mTOR pathway, which further modulates glutathione metabolism and intracellular redox balance. This finding provides novel insights into the beneficial effects of MeSeCys on male reproductive cells, highlighting its potential as a nutritional supplement for male reproductive health. Full article

In sports nutrition, performance adaptation emerges from the coordinated molecular interaction between physical training and nutrient availability. This narrative review with conceptual synthesis advances Training–Fuel Coupling (TFC) as a systems physiology framework that conceptualizes nutrient availability, timing, and recovery feeding as molecular control variables proposed to govern exercise-induced adaptation. Integrating evidence from exercise metabolism and nutritional science, the model conceptualizes how substrate availability may modulate the dynamic crosstalk between AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), shaping metabolic flexibility, anabolic recovery, and long-term performance optimization. Low-energy and low-glycogen contexts preferentially activate AMPK-dependent pathways supporting mitochondrial remodeling and oxidative efficiency, whereas nutrient-replete states facilitate mTOR-mediated protein synthesis and structural restoration. When strategically alternated through chrono-nutrition and nutritional periodization, these energetic states are hypothesized to generate oscillatory signaling patterns that enhance adaptive efficiency while limiting chronic metabolic strain. From a sports nutrition perspective, TFC provides a mechanistic rationale for energy availability management, recovery nutrition, and the prevention of maladaptive states such as Relative Energy Deficiency in Sport (RED-S). By reframing nutrients as regulatory signals rather than passive fuel, this framework integrates molecular nutrition with performance physiology, offering a unifying, systems-level and hypothesis-generating perspective on training–nutrition interactions that delineates testable pathways for future empirical investigation. Full article

Quaternary ammonium compounds (QACs) have dominated biocidal practice in cultural heritage conservation for decades, yet growing evidence of environmental persistence, aquatic ecotoxicity, and antimicrobial resistance induction has prompted the search for safer alternatives. Essential oils (EO) have emerged as promising bio-based biocides, though their environmental performance has rarely been quantified through rigorous life cycle approaches. This study presents a comparative Life Cycle Impact Assessment (LCIA) of EO-based and QAC-based biocidal formulations across representative conservation scenarios, following ISO 14040/14044 standards and the Environmental Footprint 3.1 methodology with USEtox^® 2.1 characterization factors. Three complementary functional units were employed: formulation-based, surface-based, and intervention-based. The results reveal a fundamental trade-off: EO-based systems exhibit 81% higher climate change impacts but 82–89% lower human toxicity and freshwater ecotoxicity impacts compared to QAC-based systems. Surface-normalized comparisons reduce the climate gap to 32%, while toxicity advantages remain robust across all sensitivity scenarios. Monte Carlo analysis confirms the robustness of toxicity findings (p > 99%), whereas climate comparisons remain scenario-dependent. These findings support context-dependent adoption of EO-based biocides in conservation practice and demonstrate that EO-related climate impacts are technically mitigable, while QAC toxicity is intrinsic to their molecular structure. Full article

DLBCLs constitute an aggressive type of lymphoma with varied clinical, molecular and genetic features. The cells are characterized by NFkB pathway disturbances and BCL-2 and mTOR protein deregulation, which significantly inhibit apoptosis. Hence, many treatment strategies have been established to target the functioning of these pathways. While early clinical trials have found mTOR, NFkB and Bcl-2 inhibitors to have activity in many hematological cancers, their activity as monotherapy agents may still be insufficient; therefore, combinations of these compounds with other molecules demonstrating activity in a given cancer subtype are under evaluation. In vitro studies were conducted on the Riva (ABC subtype) and Toledo (GCB subtype) cell lines. Three novel drugs were administered: AZD2014 (vistusertib)—an inhibitor of the serine–threonine kinase mTOR; IMD-0354—an NFκB inhibitor; and ABT-199 (venetoclax)—a highly selective inhibitor for BCL-2. Drugs were administered alone, in pairs and as a combination of all three agents. For the Riva cell line, ABT-199 had the strongest pro-apoptotic effect on cancer cells as monotherapy. As pairs, AZD2014+ABT-199 and ABT-199+IMD0354 demonstrated similar effects. The combination of the three drugs did not have a stronger effect than the drug pairs. For the Toledo cell line, no significant differences were noted between the drugs when used as monotherapy. In pairs, the strongest effect was observed for AZD2014+ABT-199; furthermore, this effect was not intensified by the combination of the three drugs. Our findings, including those for the BCL-2 and mTOR inhibitors, indicate that there is a need for further in vivo studies to evaluate these drugs as potentially effective treatments for DLBCL of the ABC and GCB subtypes. Full article

Lactation is a dynamic process characterised by a production peak at 6–8 weeks, followed by a steady decline. To understand the molecular drivers of these phases and the influence of production systems, this study aims to provide a transcriptomic characterisation of bovine milk somatic cells (BMSCs) in Holstein (HO), Simmental (SM), Simmental × Holstein crossbreed (SM × HO), and Podolica (POD) cows at 60 and 120 days in milk (DIM). Total RNA was sequenced at high coverage, and differential expression and functional enrichment analyses were performed. While a core set of milk protein and fatty acid genes was identified, breed-specific analysis showed SM × HO had the highest variation (677 differentially expressed genes, DEGs). Genes upregulated at 120 DIM involved mitochondrial metabolism and oxidative phosphorylation, while downregulated genes were associated with nuclear transcriptional regulation. At 60 DIM, SM × HO vs. HO showed 66 DEGs, with upregulated genes linked to chromatin remodelling and immune regulation. Comparing production systems, 28 DEGs between POD and HO/SM highlighted differences in mitochondrial activity and transcriptional regulation. This study bridges a knowledge gap by profiling the milk transcriptome of unexplored cattle breeds, providing novel insights into the molecular regulation of lactation. Full article

Fibrosis is a hallmark of the tumor microenvironment in many solid cancers, driving tumor progression, immune evasion, and treatment resistance; however, the molecular and cellular mechanisms underlying fibrogenesis—particularly stromal–immune crosstalk across organs—remain incompletely understood, compounded by organ-specific heterogeneity and a lack of reliable immune-related biomarkers. To address this, we performed an integrative single-cell RNA sequencing (scRNA-seq) analysis of fibrotic tissues from four major organs—liver, lung, heart, and kidney—alongside non-fibrotic controls, applying unsupervised clustering, trajectory inference, cell–cell communication modeling, and gene set variation analysis (GSVA) to map the fibro-immune landscape. Our analysis revealed both conserved and organ-specific features: fibroblasts were the dominant extracellular matrix (ECM)-producing cells in liver and lung, whereas endothelial-derived stromal populations prevailed in heart and kidney. Immune profiling uncovered distinct infiltration patterns—macrophages displayed organ-specific polarization states; T cells were enriched for tissue-resident subsets in lung and mucosal-associated invariant T (MAIT) cells in liver; and B cells exhibited marked heterogeneity, including a pathogenic interferon-responsive subset prominent in pulmonary fibrosis. GSVA further identified divergent signaling programs across organs and lineages, including TGF-β/TNF-α in the heart, NOTCH/mTOR in the kidney, glycolysis/ROS in the lung, and KRAS/interferon pathways in the liver. Cell–cell communication analysis highlighted robust crosstalk between macrophages, T/B cells, and stromal cells mediated by collagen, laminin, and CXCL signaling axes. Together, this cross-organ atlas delineates a highly heterogeneous fibro-immune ecosystem in human fibrotic diseases, revealing shared mechanisms alongside organ-specific regulatory networks, with immediate translational implications for precision anti-fibrotic therapy, immunomodulatory drug repurposing, and the development of context-specific biomarkers for clinical stratification and therapeutic monitoring. Full article

Digital Twin (DT) technologies are increasingly adopted as valuable methods to support the analysis and optimization of Business Processes (BPs). The use of simulation-based techniques in the BPM context is not new. Nonetheless, existing approaches for BP simulation primarily focus on performance-related aspects. In this respect, this paper introduces a data-driven framework for the automated generation of reliability-aware DTs derived from event and state logs. The proposed method integrates process mining techniques, resource reliability modeling, and model-driven transformations to produce executable DT simulations capable of predicting the failure behavior of process resources. The proposed framework has been applied to the predictive maintenance domain, where DT-based simulations are used to estimate resource availability, identify possible failure scenarios, and support the timely scheduling of preventive maintenance interventions. A manufacturing case study shows that the proposed approach can enhance process operability and reduce downtime compared to conventional BP execution without DT-based reliability insights. Full article

Background/Objectives: This study aimed to determine the potential roles of miR-4295, miR-4720-5p, miR-4773, miR-6831-5p, and miR-7161-5p in colorectal cancer by evaluating their expression levels in matched tumor and adjacent non-tumor tissues from 86 patients. Methods: A total of 172 samples were analyzed, and the associations between miRNA expression levels and clinicopathological characteristics were assessed, along with correlations among the miRNAs. Functional enrichment analyses, including GO and KEGG pathway evaluations, were performed using DIANA-mirPath v.3 to characterize biological processes and signaling pathways associated with the predicted target genes. Results: The results showed that miR-4295 and miR-4720-5p were significantly upregulated in tumor tissues, while miR-4773 and miR-6831-5p were significantly downregulated (p < 0.001). No significant difference in miR-7161-5p expression was observed between tumor and non-tumor tissues (p = 0.877). KEGG analysis indicated that miR-4295, miR-4720-5p, miR-4773, and miR-6831-5p regulate genes involved in the TGF-β, mTOR, ErbB, FoxO, and endocytosis signaling pathways. Conclusions: These findings suggest that miR-4295 and miR-4720-5p may have oncogenic functions, while miR-4773 and miR-6831-5p may have tumor-suppressing functions, and that this relationship may contribute to the development of colorectal cancer. Full article

The treatment landscape for endometrial carcinoma (EC) is undergoing a paradigm shift from traditional histopathological dualism to precision medicine grounded in the Cancer Genome Atlas (TCGA) molecular classification. The “No Specific Molecular Profile” (NSMP) subgroup, the largest molecular cohort, has emerged as a particularly promising target for endocrine-based strategies. While endocrine therapy (ET) has been a mainstay for over 60 years due to its favorable safety profile, its efficacy as monotherapy remains modest. This review provides a comprehensive overview of current endocrine strategies, including traditional agents like progestins and aromatase inhibitors, and focuses on novel combination therapies designed to overcome resistance. Recent clinical trials have demonstrated that integrating molecularly targeted agents, such as CDK4/6 and mTOR inhibitors, significantly improves clinical outcomes. Specifically, patients with TP53 wild-type status and CTNNB1 mutations exhibit exceptional responses to these combinations. Furthermore, we discuss the potential of next-generation selective estrogen receptor degraders (SERDs) and the importance of refining patient selection through robust predictive biomarkers. Driven by molecular insights, endocrine therapy is transitioning from a secondary palliative option into a definitive cornerstone of precision oncology, offering a personalized and effective treatment for patients with advanced or recurrent endometrial carcinoma. Full article

Breast cancer is the leading cause of cancer-related death in women, and despite advances in preventive screening as well as in molecular classification, many patients still do not benefit from existing therapies, highlighting the importance of identifying new molecular determinants of treatment resistance. The Paired-box (PAX) family of developmental transcription factors are central regulators of tissue morphogenesis and lineage specification, yet their reactivation in tumors and contribution to breast cancer progression remain only partially defined. Here, a multi-level analysis integrating RNA sequencing and protein profiling in twenty-one primary breast carcinomas shows that distinct PAX members are directly correlated to distinct fundamental cancer hallmarks, including proliferation, cell death, epithelial–mesenchymal transition, immune evasion, and genomic instability. Specifically, PAX1 and PAX9 correlates with both cell death and proliferative markers, indicating dual roles in the regulation of cell fate. PAX1 and PAX9 correlate with both proliferative and apoptotic markers, indicating dual roles in cell fate regulation. PAX3, PAX5, and PAX8 are mainly associated with immune checkpoint expression, including PD-L1 and TIGIT, while PAX6 is linked to microsatellite instability and tumor mutational burden, implicating it in genomic dysregulation. Therefore, PAX-based molecular signatures identify that accurately predict lymph node metastasis at transcriptomic (PAX2–PAX7) levels. These findings establish PAX transcription factors as key modulators of breast cancer biology and support their potential as clinically relevant biomarkers for prognostic refinement and therapeutic stratification. Full article

3D cell systems for in vitro experimental studies are able to mimic the in vivo efficacy of drugs before they are tested on animals. However, many studies are still needed in order to mimic the physiological environment with 3D cell-growth systems. The mechano-physical properties of the microenvironment are relevant for the invasiveness of cancer cells and for their drug resistance. In this study, 3D tumoroids of human oral squamous cell carcinoma (OSCC) CAL27 cells of different stiffnesses were produced using a tunable PEG–silk fibroin hydrogel (PSF), and the antitumor activity of the peptide CIGB300, an anticancer therapeutic peptide, with respect to these 3D tumoroid models was assessed. Furthermore, spectroscopic studies on the CIGB300 peptide are reported regarding its structure, stability, aggregation and diffusion properties. For the first time, the diffusion of the peptide CIGB300 in tunable silk fibroin hydrogels of different stiffnesses is investigated over time via fluorescence spectroscopy as a potential tool in drug-screening using hydrogel-based 3D tumoroids. Full article

Broodiness in poultry represents a major bottleneck for reproductive performance, governed by complex remodeling of the hypothalamic-pituitary-ovarian (HPO) axis. CYP11A1, the rate-limiting enzyme in steroidogenesis, is essential for hormone synthesis; however, its spatiotemporal dynamics within the HPO axis during reproductive transitions remain unclear. Using the Wuding chicken as a model, this study characterized the expression profile and cellular function of CYP11A1. We identified a distinct “ovary-hypothalamus expression inversion” pattern: CYP11A1 expression was ovary-dominant during the egg-laying period to support folliculogenesis, but shifted to a hypothalamus-dominant pattern during the broodiness period, suggesting a role in central neurosteroid modulation. In vitro assays in granulosa cells (GCs) demonstrated that CYP11A1 overexpression significantly upregulated AKT1 and mTOR transcription, promoted the G0/G1 to S/G2/M cell cycle transition, and enhanced cell proliferation. Conversely, CYP11A1 knockdown arrested the cell cycle and suppressed the PI3K/AKT/mTOR pathway. Additionally, CYP11A1 coordinated the expression of steroidogenic genes (STAR, HSD3B1), reflecting a coupling between steroid metabolism and cell growth. These findings reveal CYP11A1 as a critical molecular node linking HPO axis remodeling, granulosa cell proliferation, and steroidogenesis, providing a potential target for molecular breeding to mitigate broodiness in indigenous chickens. Full article

Background: Diabetic nephropathy is characterized by metabolic dysregulation, renal fibrosis, and impaired autophagy. MicroRNA-451 (miR-451) has been implicated in metabolic and stress-response pathways, but its role in diabetic kidney disease remains unclear. This study examined the effects of systemic miR-451 overexpression on renal injury and autophagy in BTBR ob/ob mice. Methods: Wild-type (WT) and BTBR ob/ob (OB) mice were treated with miR-451 mimics. Body weight, blood glucose, and urine albumin were assessed for three consecutive weeks. Renal miR-451 expression was measured by qRT-PCR, while protein levels of YWHAZ, mTOR, and autophagy markers were analyzed by Western blotting. Renal fibrosis was evaluated using Masson’s trichrome staining. Results: OB mice exhibited increased body weight, hyperglycemia, and albuminuria compared with WT controls. miR-451 treatment resulted in robust renal overexpression of miR-451 in OB treated mice (8.4-fold, p = 0.039) but did not normalize metabolic parameters. miR-451 overexpression significantly reduced renal expression of YWHAZ and mTOR. Histological analysis revealed increased glomerular fibrosis in OB mice, which was significantly attenuated following miR-451 treatment in WT-treated and OB-treated mice. In addition, miR-451 treatment increased expression of autophagy-related proteins ATG101 and Beclin-1 and reduced the LC3-II/I ratio, indicating altered autophagic signaling. Conclusions: miR-451 overexpression attenuates renal fibrosis and modulates autophagy-associated pathways in diabetic kidney disease, independent of metabolic control, highlighting miR-451 as a potential therapeutic target for diabetic kidney disease. Full article