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Mature cow weight (MWT) is a trait genetically correlated with body condition score (BCS). Previous research has shown that sire rankings can shift depending on how BCS is accounted for, indicating that different modeling strategies can influence selection outcomes. The recursive modeling approach has been established as a method for obtaining MWT that is genetically independent of BCS, providing an alternative to phenotypic pre-adjustment. The objective of this study was to determine whether different modeling approaches capture different genetic architectures or merely produce statistical artifacts. Genome-wide association studies (GWAS) and functional genomic analyses were performed to compare the genomic architecture of phenotypically pre-adjusted MWT (MWTadj) with MWT that is genetically independent of BCS, obtained using the recursive approach (MWTRM). A total of 42 significant SNP across 8 chromosomes were identified for MWTadj and 44 SNP across 9 chromosomes for MWTRM, with 28 SNP shared between models. These variants corresponded to 107 annotated genes in MWTadj and 137 in MWTRM, including 62 shared genes. Major association signals were concentrated on BTA20, BTA7, and BTA14 for both models, with all significant SNP jointly explaining 3.93% of the total additive genetic variance for MWTadj and 4.29% for MWTRM. The Pearson correlation coefficient of estimated SNP effects between the models was 0.76, while the correlation of genomic estimated breeding values was 0.87. Compared to MWTadj, which shared 19 genes with unadjusted MWT, the MWTRM shared 33 genes. In addition, 28 of the 31 pathways identified for MWTRM were also identified for unadjusted MWT, whereas no Gene Ontology pathways were shared between MWTadj and unadjusted MWT. The MWTRM was associated with genes annotated to growth, skeletal development, feed efficiency, and carcass-related traits, whereas MWTadj identified a distinct set of genes and pathways. Despite these differences, MWTadj and MWTRM converged on similar core biological signals, highlighting that they effectively capture the primary genetic drivers of MWT independent of BCS. Mature cow weight (MWT) is an important trait in cattle production because it influences feed requirements and overall efficiency. However, MWT is closely related to body condition score (BCS), which reflects a cow’s nutritional status and energy reserves. Because of this relationship, how BCS is accounted for can affect which animals are selected for breeding. This study compared two approaches for analyzing MWT: one that adjusts MWT for BCS before using it in national genetic evaluations, and another that separates the genetic effects of MWT and BCS during analysis via a recursive method. The goal was to determine whether these approaches identify different underlying genetics or simply produce statistical differences. Both methods detected many of the same key genetic regions, showing they capture the main biological drivers of MWT. However, the recursive approach identified more genes and biological pathways related to growth, skeletal development, feed efficiency, and carcass traits. In contrast, the pre-adjustment method may have missed some smaller genetic effects and introduced signals not detected in the unadjusted MWT. These findings suggest that despite the small differences in identified regions, both methods pointed to the same core biological factors affecting MWT.

Gibberellic acid (GA) plays a central role in regulating growth, development, and stress responses. Poplars exhibit woody-specific GA regulatory mechanisms due to their long-life cycle, continuous vascular cambium activity, and seasonal dormancy. While the GA biosynthetic pathway is highly conserved between herbaceous and woody plants, key poplar synthesis genes such as KS1 and KS2 show vascular tissue-specific expression. Centered on the GID1-DELLA signaling pathway, GA modulates downstream genes via ubiquitination and interacts synergistically or antagonistically with hormones like IAA, ABA, and JA to regulate poplar growth and stress responses. Under abiotic stress, poplars downregulate GA levels and accumulate DELLA proteins to enhance resistance. During biotic stress, GA integrates with miRNAs and transcription factors, maintaining growth-defense balance through the DELLA-MYC2 module. Addressing current gaps in holistic GA regulatory network studies and weak understanding of biotic stress mechanisms, this review summarizes poplar GA synthesis, metabolism, and signaling pathways, elucidating their roles in woody-specific traits and stress responses. We aim to provide a theoretical support for GA molecular mechanism research in woody plants and forest tree breeding.

Exposure to organophosphate pesticides (OPs) has been associated with increased oxidative stress and a higher risk of attention-deficit/hyperactivity disorder (ADHD). However, metabolic insights underlying ADHD and the potential pathophysiological role of OPs exposure remain limited. This study characterized urinary metabolomic profiles associated with ADHD and examined their associations with OPs exposure and oxidative stress. Urinary metabolites from 67 children with ADHD and 98 controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy and ultra-perforamnce liquid chromatography quadrupole time-of-flight mass spectrometry analysis (UPLC-QTOF-MS). Dimethyl phosphate (DMP) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) were used as biomarkers of OPs exposure and oxidative stress, respectively. Children were classified into high- and low-exposure/concentration groups based on DMP or HNE-MA levels. Urinary metabolomic profiles differed significantly between children with ADHD and controls. Several metabolites also differed between children with high and low DMP or HNE-MA levels. Metabolites involved in the tricarboxylic acid cycle were significantly higher in ADHD children and positively correlated with both DMP and HNE-MA. Pathway analysis suggested alterations in energy-related and amino acid metabolic pathways. Stepwise logistic regression and receiver operating characteristic curve analysis identified an 11-compound biomarker panel with good discriminatory performance in the discovery (AUC: 0.8450) and validation (AUC: 0.8748) stages. This metabolomic analysis suggests that OPs exposure and oxidative stress may be associated with metabolic changes in ADHD, particularly in energy metabolism and amino acid pathways. The identified biomarker panel may help distinguish children with ADHD from controls. Larger studies with multiple exposure assessments are warranted.

Colorectal cancer (CRC) progression from benign polyps to malignant adenocarcinomas is a complex process involving the abnormal proliferation and differentiation of colon epithelial cells. Colorectal adenomas (CRAs), the precursors to most CRCs, are histologically classified into tubular adenomas (TAs), tubulovillous adenomas (TVAs), and villous adenomas (VAs). Despite new findings, the molecular signatures and pathways specific to each adenoma type remain poorly understood. This study aimed to identify specific biomarkers and pathways associated with the progression of TA, TVA, and VA to CRC. We analyzed gene expression data from 169 CRA samples and 65 adjacent normal tissues from the GSE117606 and GSE117607 datasets. Differentially expressed genes (DEGs) were identified for each adenoma type, followed by functional enrichment and protein-protein interaction network analysis. Our results revealed 1,024 DEGs common to all three adenoma types, with COL1A2 and CXCL8 highlighted as hub genes. Additionally, specific genes such as NTRK2, JUN, LAT, and DRD2 were identified for TA; H2AFZ, NME1, MRTO4, and SSRP1 were identified for TVA; and WDR43, POLR1B, and NHP2 were identified for VA. Functional enrichment analysis revealed key pathways involved in adenoma progression, providing insights into the molecular mechanisms driving their malignancy potential. The expression of candidate genes was further validated by RT-qPCR, and repeated cross-validated ROC analysis supported the discriminative potential of CXCL8 and COL1A2 for distinguishing CRA and CRC tissues from adjacent normal mucosa. These findings provide valuable insights into adenoma biology and offer potential applications for targeted therapies in CRC prevention and treatment.

Helenalin, a naturally occurring sesquiterpene lactone derived primarily from Arnica montana, has emerged as a promising multitarget therapeutic agent due to its diverse anti-inflammatory, antioxidant, cytotoxic, and antimicrobial activities. The review summarized the pharmacological spectrum and molecular mechanisms underlying helenalin bioactivity. Helenalin exerts anticancer activities by regulating key oncogenic signaling, especially, NF-κB and STAT3/MYC pathway. Helenalin demonstrated Nrf2 antioxidant pathway activation and muted P2X7R-dependent inflammation in osteoarthritis models. It was also found to have antimicrobial activity and was effective in melting the redox and quorum sensing in the pathogens, which were interesting to use in the drug-resistant infections. ADMET predictions support the good drug likeness, pharmacokinetics, and oral bioavailability, and it satisfies the Lipinski Rule of Five. The network pharmacological and GO/KEGG enrichment analyses indicated the implication of helenalin in cancer and inflammation -related pathways. Molecular docking also showed strong binding with COX-1, Bcl-2, and hub target proteins having docking scores of - 9.2 to 11.3, respectively, which confirmed its potential as a pharmacological agent. The learning of this multifaceted pharmacology profile together with the tools of systems biology, however, establishes helenalin as an attractive lead compound towards the development of novel anticancer, anti-inflammatory, antiarthritic, antioxidant, antiviral, antibacterial, and antiangiogenic agents. Its therapeutic index should be further confirmed using future translational research.

Growing evidence highlights the microbiota-Gut-Brain Axis (MGBA) as a critical pathway linking diet to neurological health. This review synthesizes current evidence on the complementary, additive, and potentially synergistic interactions between probiotics and plant-derived phytochemicals within the MGBA. While the individual benefits of these dietary components are well established, their combined synbiotic application offers expanded mechanistic breadth through coordinated modulation of microbial ecology, epithelial barrier integrity, immune inflammatory signaling, and neurochemical pathways. Probiotics and phytochemicals interact bidirectionally via microbial biotransformation, enhancing short-chain fatty acid production, reducing endotoxin translocation, and attenuating systemic and neuroinflammation. These effects are further linked to indirect modulation of neurotransmitter systems and neurotrophic signaling relevant to mood regulation, cognitive function, and neurodegenerative processes. Evidence from preclinical and emerging clinical studies supports the relevance of these mechanisms in conditions such as Alzheimer's disease, Parkinson's disease, mood disorders, and Autism Spectrum Disorder, although human data remain limited. Overall, this narrative review proposes a mechanistic framework describing how probiotics and plant-derived phytochemicals may interact through complementary microbial, immune, and neurochemical pathways within the Microbiota-Gut-Brain Axis. It also highlights current knowledge gaps and emphasizes the need for well-designed clinical studies to validate their combined therapeutic potential.

To review immunological studies in idiopathic orbital inflammation (IOI) to characterize immune cells, mediators and pathways to strengthen diagnostic evaluation, and identify priorities for future research. We searched 13 literature databases on October 22, 2025. Eligible studies performed flowcytometric or immunohistochemical analyses on immune cells, mediators, or pathways in IOI. Studies were reviewed qualitatively across several themes: cellular composition of B- and T-cells, T-cell subsets, B-cells, plasma cells, immunoglobulin subclasses (IgG2, IgG4), mast cells, fibrocytes, mononuclear phagocytes, antigen-presenting cells, toll-like receptors, cytokines, chemokines, and clinical correlates of immune profiles and disease severity. Twenty-five studies were included (910 participants, 511 with IOI, 109 healthy controls and 290 other orbital disease comparators). IOI tissue showed mixed, polyclonal lymphoid infiltrates, typically T-cell enriched. Innate and stromal components were implicated with mast cell accumulation and TLR-2/3/4 expression. Cytokine profiling of the lesions indicated a Th1-polarized milieu, with elevated IFN-γ, IL-12, TNF-α, IL-10, and IL-8. Peripheral blood demonstrated reduced plasmacytoid dendritic cells and type 2 conventional dendritic cells, but increased CD40+ fibrocytes with IL-6 release upon ligation. Regulatory T-cells were increased, but functionally impaired and plastic by a Th17-like phenotype in blood and Th2-like phenotype in the orbit. IOI lesions had low IgG4+ plasma cell counts and low IgG4/IgG ratio. Overall risk of bias was moderate across studies. IOI emerges as an integrated innate-adaptive immune process. Polyclonal κ/λ and low IgG4/IgG ratios distinguish IOI from orbital lymphoma and IgG4-related ophthalmic disease. Our findings highlight TNF-α, IL-12, IL-6, and CD40-CD154 as present and future treatment modalities.

The electrocatalytic nitrogen reduction reaction (ENRR) offers a sustainable pathway for ammonia synthesis under mild conditions, yet its practical implementation is hindered by poor N2 activation efficiency and the lack of a clear structure-activity relationship for rational catalyst design. Herein, we systematically investigate the electrocatalytic performance of vacancy-engineered M2CT2 (M = Ti, Nb, and Mo; T = O, S, Cl, and Br) MXenes for the ENRR using well-defined density functional theory calculations combined with microkinetic modeling. Our results demonstrate that surface vacancies significantly modulate the local electronic structure of MXenes, thereby promoting N2 adsorption and activation. The results demonstrated that the ENRR proceeded on VT-M2CT2 through the distal pathway according to free energy calculations. A novel descriptor, Ψ, based on the valence of the transition metal and the lattice constant, is proposed to establish a quantitative structure-activity relationship, enabling rapid screening of high-performance catalysts. Among the candidates, vacancy-engineered Ti2CBr2 exhibits outstanding ENRR activity, as further validated by microkinetic analysis. This work provides a universal strategy for the design of defect-mediated MXene catalysts and paves the way for the development of efficient ENRR electrocatalysts.

Cyclin E1 (CCNE1), a critical regulator of cell cycle progression, has been implicated in various cancers; however, its prognostic significance and functional role across breast cancer (BC) subtypes remain inadequately defined. This study aims to comprehensively analyze CCNE1 mRNA expression and evaluate its potential as both a prognostic biomarker and a therapeutic guide. We analyzed CCNE1 mRNA expression using large-scale BC cohorts (TCGA, METABRIC, GEO) and assessed associations with tumour grade, overall survival, and mutation status. The muTarget platform was employed to investigate associations between CCNE1 expression and key genetic alterations. Furthermore, gene set enrichment analysis was performed to identify enriched biological pathways, and functional studies were conducted using mTORC1 inhibition in TP53-mutant, RB1-deficient TNBC cells to evaluate cell viability and CCNE1 expression levels. CCNE1 expression was significantly associated with higher tumour grade, overall survival, and distinct mutation statuses. Gene set enrichment analysis revealed enrichment of proliferation-related pathways, including G2-M checkpoint, E2F targets, and mTORC1 signaling in CCNE1-high tumors. Moreover, functional studies showed that mTORC1 inhibition successfully reduced CCNE1 expression and impaired viability in TP53-mutant, RB1-deficient TNBC cells. CCNE1 overexpression characterises a clinically aggressive subset of breast cancers, particularly TNBC. Targeting mTORC1 may represent a promising therapeutic approach in CCNE1-high, TP53-mutated, and RB1-deficient tumours, supporting the clinical utility of CCNE1 in patient stratification and targeted therapy.

The inverse association of farm exposure with asthma and atopic conditions has been attributed to the diversity of environmental bacteria and fungi, but the specific taxa and the underlying mechanisms remain elusive. We performed sequencing of the bacterial 16S ribosomal ribonucleic acid (16S rRNA) gene in mattress dust samples from 1018 schoolchildren from two German populations of the cross-sectional GABRIELA (Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community [GABRIEL] Advanced Study) survey. Bacterial metabolic pathways and enzymes were assessed bioinformatically, and metabolites were measured by using mass spectrometry. Statistical methods included network, interaction, and mediation analyses. Within the highly diverse microbial exposure in a farm environment, the study identified nine gram-positive environmental bacterial genera, whose composite score explained two thirds of the inverse association of farm exposure and asthma in a mediation analysis. The effect was independent of gram-negative farm-associated bacteria. A PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) analysis revealed nine pathways, whose enzymes were encoded by the identified genera and whose metabolites were detected in cowshed dust by using mass spectrometry. The metabolites included ligands of the human aryl hydrocarbon receptor (kynurenine and xanthine) and the peroxisome proliferator-activated receptor-γ (α-linoleic and stearidonic acid). Single nucleotide polymorphisms of the corresponding human receptor genes interacted with the composite score of the bacterial genera for asthma. Fungi and bacteriophages co-occurred with the beneficial bacteria but did not carry the protective effect. All results were replicated in independent populations. In this analysis, the inverse association of childhood asthma and farm exposure was largely mediated by exposure to gram-positive bacterial genera. Gene-environment interactions of a compound score of these bacteria with human receptors recognizing bacterial metabolites suggest novel approaches to asthma prevention.

Immunosenescence is a complex biological process characterized by progressive remodeling of immune function during aging, leading to increased susceptibility to infections, chronic inflammatory diseases, cancer, and reduced vaccine efficacy. While cumulative antigen exposure, infections, lifestyle factors, environmental exposures, and epigenetic influences contribute to immune decline, a growing body of evidence suggests that genetic predisposition also plays an important modulatory role in shaping the molecular trajectory of immune aging. This review discusses how inherited variation in cytokine-regulatory pathways may influence IL-6, TNF-α, interferon, and TGF-β signaling, thereby contributing to inflammatory set points that favor chronic immune activation and inflammaging. Inherited differences in innate and adaptive immune signaling, including KIR-HLA interactions, DNA-sensing pathways, and downstream JAK-STAT and NF-κB cascades, may alter activation thresholds and immune-cell differentiation. Variants affecting mitochondrial redox balance and autophagy may enhance reactive oxygen species accumulation and metabolic exhaustion, thereby potentially contributing to immune-cell senescence. Genetic factors affecting folate metabolism, epigenetics, telomeres, and DNA repair drive epigenetic drift, cellular aging, and clonal instability in immune cells. These mechanisms appear as measurable molecular and cellular biomarkers, including inflammatory signals, immune cell activation, oxidative stress, telomere shortening, and multi-omic indicators. Understanding this molecular architecture provides a foundation for identifying predictive biomarkers and developing precision strategies to preserve immune competence and promote healthy aging.