Search Results (131,019)

Pearl millet, an African-origin crop with exceptional heat tolerance, maintains normal flowering and seed production even under extremely high temperatures. The MADS-box transcription factor family plays a central role not only in floral organs, but also in abiotic stress responses. However, its specific function in pearl millet’s heat stress response remains unclear. In this study, a total of 63 MADS-box genes were identified. These genes were classified into five subfamilies and distributed across seven chromosomes, with chromosome 6 containing the highest number (12 genes). Additionally, expression analysis revealed that 53 MADS-box genes exhibited increased expression levels following heat stress under high-temperature conditions. Differential expression analysis identified five key MADS-box genes responding to heat stress. Further analysis of their expression trends using qRT-PCR revealed that the expression levels of these genes first increased and then decreased after heat stress treatment, with differences in the timing of peak expression among different genes. PMA1G07218.1 was selected for further functional characterization, which exhibited a significant response to heat stress treatment and reached a peak at 6 h. Subcellular localization analysis confirmed that the encoded protein is exclusively nuclear-localized. Through the yeast one-hybrid method (Y1H), we found that PMA1G07218.1 interacts by binding to the AG cis-acting element of F-box gene PMA1G04890.1. These findings provide valuable insight into the role of MADS-box genes in the high-temperature stress response of pearl millet, highlighting PMA1G07218.1 as a promising candidate for enhancing thermotolerance in this species. Full article

Understanding the chronic thermal acclimation capacity of chum salmon (Oncorhynchus keta) is essential for predicting species resilience and developing mitigation strategies under ocean warming. We investigated the upper limit of chronic thermal acclimation and its underlying molecular mechanisms in chum salmon smolts exposed to four constant temperatures (10, 14, 18, and 22 °C) for 6 weeks. Transcriptional responses of genes related to cellular stress protection, endocrine feedback regulation, antioxidant defense, metabolic regulation (AMPKα and mTOR), and protein degradation were quantified in the liver, skeletal muscle, and brain. Chronic exposure to elevated temperature elicited tissue-specific molecular responses, with the most pronounced effects observed at 22 °C. At this temperature, all tissues showed marked induction of heat shock proteins and ubiquitin, accompanied by suppression of antioxidant defenses, glucocorticoid receptor signaling, and AMPKα–mTOR-mediated metabolic regulation, particularly in the liver and muscle. These responses were consistent with previously reported impairments in growth performance, lipid reserves, and hematological indices from the same growth trial. In contrast, smolts maintained at 18 °C exhibited molecular signatures indicative of effective physiological compensation without severe cellular stress. Collectively, these results indicate that chum salmon smolts can acclimate to chronic warming up to 18 °C, whereas exposure to 22 °C exceeds their acclimation capacity and induces a tertiary stress response. Full article

This study proposes a dual-shield framework to elucidate the capital structure dynamics within China’s policy-intensive real estate sector. We delineate a coercive policy shield wherein binding regulations supersede market-based incentives, and a proactive sustainability shield which recognizes how superior environmental performance can lead to reduced financing costs. Analyzing data from Chinese A-share firms during 2003 to 2021, we present robust evidence that supports both mechanisms. Notably, the effect of the debt tax shield is diminished in real estate sectors, underscoring the policy shield’s ability to negate traditional financial incentives. In addition, the macroprudential tightening implemented in 2017 has disproportionately disrupted leverage adjustments, especially among firms subsequently affected by the “Three Red Lines” policy. Rigorous quasi-experimental analyses additionally illustrate that green bond issuers experience a significant and enduring reduction in their cost of debt, thereby establishing a substantive sustainability shield. Our findings contribute to the literature on sustainable finance by conceptualizing approaches that extend beyond tax shields, effectively integrating regulatory and market forces to align the capital structures with objectives for sustainable transition. Full article

Cadmium (Cd) toxicity threatens global food security and agricultural sustainability. Transcription factors (TFs) act as master regulators of the complex molecular networks involved in Cd detoxification. This review provides a focused synthesis of the molecular mechanisms governing Cd tolerance in plants, encompassing antioxidant defense, Cd chelation and sequestration, Cd uptake and transport, signal transduction, and damage repair pathways. We highlight the pivotal roles of key TFs in these specific processes, such as OsMYB45 in antioxidant defense, OsIRO2 in regulating chelation and storage, OsNAC5 in modulating Cd transport, and OsE2F in facilitating the repair of DNA and protein damage. Furthermore, we evaluate the potential of harnessing these TF-mediated regulatory mechanisms for developing low-Cd rice varieties. By delineating precise correlations between specific TFs and detoxification pathways, this review proposes actionable molecular strategies to mitigate Cd contamination, thereby contributing to ecological and food safety. Full article

Background: Non-suicidal self-injury (NSSI) is defined as the intentional damage to one’s body tissue without suicidal intent and for reasons that are not socially sanctioned. While NSSI has been widely studied in the general population, its clinical correlates and management in autism spectrum disorder (ASD) remain less clearly characterized, and it is often conflated with self-injurious behavior (SIB) described within restricted and repetitive behaviors (RRBs). In individuals with ASD, NSSI may be associated with emotional, behavioral, cognitive, social, medical, and demographic factors, and it differs from SIB typically observed among individuals with severe intellectual disabilities. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Studies published between 2000 and 2025 that assessed NSSI in individuals with a formal ASD diagnosis were included. Etiological/clinical correlates, explanatory mechanisms, and management challenges were examined. Sixteen studies were selected from PubMed, Scopus, and Web of Science. Findings were synthesized using narrative and thematic approaches. Results: The prevalence of NSSI among individuals with ASD ranged from 24% to 50%. Associated factors included emotion dysregulation (including alexithymia and affective distress), behavioral dysregulation (e.g., impulsivity/hyperactivity and aggression), sensory processing difficulties, communication and social impairments, and medical comorbidities (i.e., gastrointestinal and sleep problems), with preliminary evidence also implicating perinatal factors. NSSI was linked to emotion regulation, sensation seeking, and social communication processes. Early intervention and parental involvement were identified as protective factors. Conclusions: NSSI in ASD is a complex, multifactorial phenomenon frequently linked to emotion-regulation needs. Affective imbalance represents a central—though not exclusive—pathway. The review supports standardized terminology, function-based assessment, and clearer differentiation from SIB/RRBs, with implications for individualized interventions and sustained monitoring in persistent or severe cases. Routine screening for medical and sensory contributors may further improve case management and reduce preventable clinical burden. Full article

Intensive pig production systems in China face dual challenges of heavy metal (HM) contamination and nutrient overloading from manure. However, stage-specific quantitative relationships between diet and excretion remain poorly characterized, hindering targeted mitigation. To address this, we conducted a comprehensive farm survey in the southern water network region—a major pig production hub in China—collecting 93 paired feed and manure samples from piglets, finishing pigs, and sows across 32 large-, medium-, and small-scale farms. The results revealed that essential trace elements (Cu, Zn, Fe, Mn) in feed exceeded safety guidelines by 3–19-fold, while toxic metals (As, Hg, Pb, Cd, Cr) remained below hygienic limits. Notably, Cu and Zn concentrations in manure significantly surpassed organic fertilizer standards, with piglet manure showing the highest exceedance rates (69–91%). Strong linear correlations (Pearson’s r = 0.360–0.766) were found between feed additives (Cu, Zn, As, Pb, Cd, Cr) and their excretion in manure, with Cu and Zn exhibiting the strongest relationships, especially in piglets. Feed crude protein (CP) and phosphorus (P) levels positively influenced nitrogen (N) and P excretion (r = 0.389–0.860), particularly in finishing pigs. Scenario analysis demonstrated that aligning Cu and Zn supplementation with safety guidelines could reduce HM excretion by 50–67%, while low-CP diets and precision P feeding lowered N and P losses by 10.2–10.8% and reduced feed costs by 4.1%. These findings highlight the potential of dietary interventions to mitigate environmental risks without compromising productivity, offering actionable strategies for sustainable pig production and revised feed regulations. This study provides quantitative, stage-specific evidence linking feed formulation to excretion patterns, addressing critical knowledge gaps in feed-to-manure transfer mechanisms and supporting the development of precision feeding standards and integrated manure management systems to decouple livestock intensification from environmental degradation. Full article

Torsional stress from DNA supercoiling is receiving renewed attention as a driving force for chromosome folding and the establishment of gene activity states. Transcription is a major source of DNA supercoiling, while topoisomerases relax supercoils and solve topological problems that arise during DNA replication, transcription, and chromosome segregation. Recent technological advancements have allowed for the mapping of how torsional stress distributes within the genome and distinguishing between occupancy of topoisomerases on chromatin and sites where they are catalytically engaged. Coupling these innovations to assessments of 3D chromosome conformation and nascent transcription at high resolution have provided a new understanding of the relationships between supercoiling and topoisomerase activity. Here, we summarize the insights obtained from these recent studies and discuss how the interplay between transcription, supercoiling, and topoisomerases shapes cellular gene activity states. Full article

Cancer immunoprevention leverages the immune system’s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA–4–1BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA–4–1BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA–4–1BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4⁺ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA–4–1BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA–4–1BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151–TGF-β axis. These findings demonstrate that SA–4–1BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development. Full article

Glutamine metabolism has emerged as one of the most critical bioenergetic and biosynthetic programs sustaining leukemic cell growth, survival, stemness and therapeutic resistance. In both acute and chronic leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), malignant cells display a strong dependency on extracellular glutamine to support mitochondrial respiration, anabolic biosynthesis and redox homeostasis. This dependency is reinforced by oncogenic signaling networks, post-transcriptional metabolic regulation and microenvironmental adaptation within the bone marrow niche. Therapeutic strategies targeting glutamine utilization, including glutaminase inhibition, transporter blockade and enzymatic glutamine depletion, have demonstrated robust antileukemic activity in preclinical models, and early clinical efforts have begun to explore glutamine-directed interventions in myeloid neoplasms. However, metabolic plasticity, microenvironment-derived nutrient buffering and systemic toxicity remain significant limitations to clinical translation. This review provides a detailed synthesis of the biochemical framework of glutamine metabolism in leukemia, the molecular mechanisms enforcing glutamine addiction, the downstream functional consequences on proliferation, redox balance and leukemic stem cell biology, the current landscape of therapeutic strategies and emerging directions aimed at overcoming resistance and improving clinical efficacy. Full article

Pseudomonas aeruginosa is a Gram-negative pathogen with a remarkable capacity to acquire multiple resistance mechanisms, severely limiting current therapeutic options. Consequently, the identification of new antimicrobial agents remains a critical priority. In this study, an integrated in silico-guided strategy was applied to identify small molecules with antibacterial potential against P. aeruginosa, targeting the quorum-sensing regulator LasR (PDB ID: 2UV0) and elastase (PDB ID: 1U4G). Pharmacophore modeling was performed for both targets, followed by ligand-based virtual screening, structure-based virtual screening (SBVS), and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) binding free energy calculations. Top-ranked compounds based on predicted binding affinity were selected for in vitro cytotoxicity and antibacterial evaluation. Antimicrobial activity was assessed against three P. aeruginosa strains: an American Type Culture Collection (ATCC) reference strain, a clinically susceptible isolate, and an extensively drug-resistant (XDR) clinical isolate. SBVS yielded docking scores ranging from −6.96 to −12.256 kcal/mol, with MM-GBSA binding free energies between −18.554 and −88.00 kcal/mol. Minimum inhibitory concentration (MIC) assays revealed that MolPort-001-974-907, MolPort-002-099-073, MolPort-008-336-135, and MolPort-008-339-179 exhibited MIC values of 62.5 µg/mL against the ATCC strain, indicating weak-to-moderate antibacterial activity consistent with early-stage hit compounds. MolPort-008-336-135 showed the most favorable activity against the clinically susceptible isolate, with an MIC of 62.5 µg/mL, while maintaining HepG2 cell viability above 70% at this concentration and an half-maximal inhibitory concentration (IC₅₀) greater than 500 µg/mL. In contrast, all tested compounds displayed MIC values above 62.5 µg/mL against the XDR isolate, reflecting limited efficacy against highly resistant strains. Overall, these results demonstrate the utility of in silico-driven approaches for the identification of antibacterial hit compounds targeting LasR and elastase, while highlighting the need for structure–activity relationship optimization to improve potency, selectivity, and activity against multidrug-resistant P. aeruginosa. Full article

Morbid obesity is a complex, multifactorial disorder characterized by metabolic and inflammatory dysregulation. The aim of this study was to observe changes in obese patients adhering to a personalized nutrition plan based on multi-omic data. This study included 14 adult patients with a body mass index (BMI) > 40 kg/m² who were consecutively recruited from those presenting to our outpatient clinic and who met the inclusion criteria. Clinical, biochemical, hormonal, and glycomic parameters were assessed, along with whole-genome sequencing (WGS) that included a focused analysis of obesity-associated genes and an extended analysis encompassing genes related to cardiometabolic disorders, hereditary cancer risk, and nutrigenetic profiles. Patients were stratified into nutrigenetic clusters using a patented unsupervised machine learning platform (German Patent Office, No. DE 20 2025 101 197 U1), which was employed to generate personalized nutrigenetic dietary recommendations for patients with morbid obesity to follow over a six-month period. At baseline, participants exhibited elevated glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides, and C-reactive protein (CRP) levels, consistent with insulin resistance and chronic low-grade inflammation. The majority of participants harbored risk alleles within the fat mass and obesity-associated gene (FTO) and the interleukin-6 gene (IL-6), together with multiple additional significant variants identified across more than 40 genes implicated in metabolic regulation and nutritional status. Using an AI-driven clustering model, these genetic polymorphisms delineated a uniform cluster of patients with morbid obesity. The mean GlycanAge index (56 ± 12.45 years) substantially exceeded chronological age (32 ± 9.62 years), indicating accelerated biological aging. Following a six-month personalized nutrigenetic dietary intervention, significant reductions were observed in both BMI (from 52.09 ± 7.41 to 34.6 ± 9.06 kg/m², p < 0.01) and GlycanAge index (from 56 ± 12.45 to 48 ± 14.83 years, p < 0.01). Morbid obesity is characterized by a pro-inflammatory and metabolically adverse molecular signature reflected in accelerated glycomic aging. Personalized nutrigenetic dietary interventions, derived from AI-driven analysis of whole-genome sequencing (WGS) data, effectively reduced both BMI and biological age markers, supporting integrative multi-omics and machine learning approaches as promising tools in precision-based obesity management. Full article

Ascending placentitis is a significant cause of equine pregnancy loss, yet the upstream inflammatory triggers are poorly defined. Recently, we identified S100A8/S100A9 (S100A8/A9) alarmins as potential upstream regulators in a chronic equine placentitis model. The current study aimed to determine whether this upregulation is sustained in the acute model and in clinical cases, and to elucidate the expression of their downstream inflammatory mediators. Using an experimental model, we quantified S100A8/A9 mRNA expression in acute (n = 5) and chronic (n = 6) placentitis induced by Streptococcus equi ssp. zooepidemicus. We found mRNA expression of S100A8 and S100A9 was significantly upregulated in chorioallantois during both acute (p < 0.001) and chronic (p < 0.0001) disease compared to controls (n = 5), demonstrating their role is not limited to chronic pathology. A strong positive correlation (r = 0.945) underscored their coordinated expression. Immunohistochemistry revealed minimal staining in controls but dense infiltrations of S100A8/A9-positive neutrophils and macrophages in placentitis tissues. To define the clinical relevance of the downstream pathway, we analyzed RNA sequencing data from clinical placentitis cases (placentitis, n = 4) compared to normal postpartum placenta (control, n = 4). This confirmed upregulation of S100A8/A9 and revealed a concurrent increase in their receptors (TLR4, RAGE) and a spectrum of NF-κB-driven effectors, including pro-inflammatory cytokines (IL1β, IL6, TNF), chemokines (CXCL8, CCL2, CXCL10), and the apoptotic mediator CASP3. Our findings establish that S100A8/A9 upregulation is a sustained feature of equine placentitis and delineates a coherent S100A8/A9-TLR4/RAGE-NF-κB signaling axis that drives inflammation and tissue damage in clinical disease. These findings highlight the diagnostic potential of S100A8/A9 and position this alarmin system as a promising therapeutic target for mitigating infection-induced pregnancy loss. Full article

Berberine, a benzyl isoquinoline alkaloid, is used in food for its diverse spectrum of biological activities. Inflammatory bowel disease (IBD) is a widespread condition characterized by frequent occurrence and limited therapeutic success. Berberine has been shown to alleviate colitis through enhancement of the intestinal barrier and modulation of gut microbial balance. However, the further mutualistic balance mechanism between microbes and the mucus of berberine in alleviating IBD still needs to be clarified. Our findings demonstrated a strong association between berberine’s therapeutic efficacy and alterations in the gut microbiota. This includes enhancements in the level of IgA-coated bacteria, Zg16, Reg3g, and Pla2g2a, all of which contribute to microbiota homeostasis. Moreover, the beneficial effect on gut barrier function of berberine was mostly attributed to Akkermansiam and Bacteriodes-associated mucin–SCFA metabolism. This study lays a critical groundwork for the development of berberine-based functional food additives that harness its nutraceutical potential. Full article

Pseudorabies (PR) is an acute and highly contagious disease caused by the pseudorabies virus (PRV). This virus has a wide range of susceptible hosts and has caused major economic losses to the global swine industry. While rosmarinic acid possesses broad antioxidant and antiviral properties, its efficacy against PRV has remained unexplored. Therefore, this study aimed to evaluate the anti-PRV activity of rosmarinic acid and to elucidate its underlying mechanism, with a focus on the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The results revealed that rosmarinic acid exhibited potent, concentration-dependent antiviral activity in vitro, with a half-maximal inhibitory concentration (IC50) of 0.02654 mg/mL, a half-maximal cytotoxic concentration (CC50) of 0.1043 mg/mL, and a selectivity index (SI) of 3.9. Rosmarinic acid inhibited virus adsorption, entry, and intracellular replication. It also significantly suppressed the expression of the gB protein. In a mouse model, rosmarinic acid treatment (200 mg/kg) significantly enhanced the survival rate to 28.5%. This treatment reduced the viral load in the brain, lungs, kidneys, heart, and spleen. It also alleviated the tissue damage caused by PRV infection. Furthermore, rosmarinic acid counteracted PRV-induced oxidative stress by elevating the activity of the antioxidant factors SOD and CAT and reducing the level of the oxidative factor MDA. Combined network pharmacology and molecular docking analyses predicted the Nrf2 signaling pathway as a key target for rosmarinic acid. Subsequent mechanistic studies confirmed that rosmarinic acid upregulated the expression of the Nrf2, HO-1, GPX, SOD, and CAT genes, as well as Nrf2 and HO-1 proteins, thereby promoting the nuclear translocation of Nrf2. These results identify rosmarinic acid as a promising anti-PRV agent that acts through multi-phase viral inhibition and activation of the Nrf2-mediated antioxidant defense, suggesting its potential as a novel pharmacological strategy against PRV. Full article

The yak represents a distinct domestic animal species that predominantly inhabits the Qinghai–Tibet Plateau and adjacent areas, possessing considerable value in both scientific and economic contexts. Compared to animals that mainly dwell on plains, such as cattle, the sperm maturation process in yak exhibits a certain degree of species specificity to adapt to their unique reproductive needs in high-altitude environments. Serving as the main storage site for functionally competent sperm, the cauda epididymis plays an integral role in mediating their post-testicular maturation. MiRNAs are vital regulatory molecules in the epididymis, influencing sperm maturation by modulating gene expression after transcription. To investigate the unique regulatory mechanisms of sperm maturation in yak, this study compared the miRNA expression profiles in the cauda epididymis of yak and cattle using high-throughput small RNA (sRNA) sequencing. The comparative analysis identified and characterized sRNA populations in the cauda epididymis of yak and cattle, revealing a similar length distribution that peaked at 22 nt and a predominance of known miRNAs. Notably, eight miRNAs were found to be highly expressed in both species. Furthermore, the first-nucleotide bias differed significantly between known and novel miRNAs within each species. A total of 31 differentially expressed (DE) miRNAs were identified, with 11 upregulated and 20 downregulated in yak compared to cattle. Among these, bta-miR-1298 exhibited the most significant upregulation, while bta-miR-2344 displayed the most pronounced downregulation. Bioinformatic analysis linked the predicted target genes of these miRNAs to numerous critical signaling pathways, including calcium signaling, the mitogen-activated protein kinase (MAPK) signaling pathway, the Ras-associated protein 1 (Rap1) signaling pathway, and the cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway. Furthermore, eight significantly DE miRNAs, including bta-miR-2443, bta-miR-503-3p, bta-miR-6517, bta-miR-2440, bta-miR-2431-3p, bta-miR-2436-3p, bta-miR-6523a, and bta-miR-6775, were predicted to target genes involved in various aspects of sperm structural and functional maturation. These aspects include flagellum formation, sperm motility, chromatin remodeling, acrosome reaction, acrosome structure, sperm capacitation, chemotaxis, and nuclear chromatin condensation. Multiple miRNAs and their corresponding predicted target genes were analyzed by quantitative real-time PCR (qPCR), demonstrating an inverse correlation between miRNA expression and target gene levels. These findings reveal a distinct, species-specific miRNA signature in the yak cauda epididymis, which suggests a potential contribution to regulating the epididymal luminal environment and the process of sperm maturation. This study provides preliminary foundational data for elucidating the differences in sperm maturation mechanisms between yak and cattle, and offers potential novel targets for improving reproductive efficiency in plateau livestock. Full article