Search Results (9,530)

TRIM48 is a human-specific tripartite motif (TRIM) family protein with E3 ubiquitin ligase activity that plays a significant role in the oxidative stress response and tumor suppression. However, the mechanisms regulating TRIM48 expression remain unknown. In this study, we demonstrate that TRIM48 is targeted for ubiquitination-dependent degradation by S-phase kinase-associated protein 1 (Skp1)-Cullin1 (Cul1)-F-box protein (SCF) ubiquitin ligase complex, containing F-box protein 22 (FBXO22) as a substrate recognition subunit. We found that TRIM48 is a rapid turnover protein, as evidenced by the fast and drastic decrease in its protein expression level in the presence of a protein synthesis inhibitor cycloheximide, which was suppressed by knocking down either Skp1, Cul1 or FBXO22. Exogenous FBXO22 expression promoted K48-linked polyubiquitination and degradation of TRIM48. FBXO22 deficiency accelerated oxidative stress-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and cell death, which was reversed by additional TRIM48 knockdown. Collectively, our findings identify the FBXO22 SCF complex as a key negative regulator of TRIM48-driven ASK1-activation and cell death under oxidative stress. The dysregulation of this axis may underlie human-specific pathologies, such as tumorigenesis and oxidative stress-associated disorders, highlighting its potential as a target for novel therapeutic interventions. Full article

The Source Region of the Yangtze and Yellow Rivers (SRYY), situated on the Qinghai-Tibet Plateau, serves as a vital ecological barrier and a critical component of the global carbon cycle. However, this region faces severe ecosystem degradation driven by climate change and human activities. This study establishes an integrated ecological security assessment framework that couples ecological risk, ecosystem health, and ecosystem services to evaluate ecological dynamics in the SRYY from 2000 to 2020. Leveraging multi-source data (vegetation, hydrological, meteorological) and advanced modeling techniques (spatial statistics, geographically weighted regression), we demonstrate that: (1) The Ecological Security Index (ESI) exhibited an initial increase followed by a significant decline after 2010, falling below its 2000 level by 2020. (2) The rising Ecological Risk Index (ERI) directly weakened both the ESI and Ecosystem Service Index (ESsI), with this negative effect intensifying markedly post-2010. (3) A distinct spatial gradient pattern emerged, shifting from high-security core areas in the east to low-security zones in the west, closely aligned with terrain and elevation; conversely, areas exhibiting abrupt ESI changes showed little correlation with permafrost degradation zones. (4) Vegetation coverage emerged as the key driver of ESI spatial heterogeneity, acting as the central hub in the synergistic regulation of ecological security by climate and topographic factors. Full article

Keratoconus (KC) is a progressive, multifactorial corneal ectatic disorder characterized by localized stromal thinning and irregular astigmatism, with incidence and prevalence varying markedly among populations. These differences are influenced by environmental exposures, behavioral factors, and genetic predisposition. A positive family history is a well-established high-risk factor, and KC has also been documented in association with syndromic disorders such as Down syndrome, connective tissue disorders, and certain metabolic diseases. Over the past decades, numerous candidate genes have been investigated, encompassing those involved in extracellular matrix (ECM) assembly, collagen synthesis and cross-linking, oxidative stress defense, wound healing, and transcriptional regulation. Modern genomic approaches, including genome-wide association studies (GWAS), linkage analyses, and next-generation sequencing, have identified multiple loci and variants with potential pathogenic roles. Nonetheless, several genes have also been systematically tested and found to show no association in specific populations, highlighting the genetic variability of KC and the potential influence of population-specific factors. This dual landscape of positive and negative genetic findings underscores the complexity of KC pathogenesis and the necessity for ethnically diverse cohorts. In this review, we synthesize current evidence on genes implicated in KC, integrating confirmed pathogenic variants, associations, and negative findings across diverse populations, to provide a comprehensive overview of the genetic architecture of KC and to outline priorities for future research aimed at improving diagnosis, risk stratification, and therapeutic development. Full article

Animal studies show that sleep regulation depends on subcortical networks, but whether the connectivity between subcortical areas contributes to human sleep variability remains unclear. We investigated whether the effective connectivity between the LC and hypothalamic subparts during wakefulness relates to sleep electrophysiology. Thirty-three younger (~22 y, 27 women) and 18 late middle-aged (~61 y, 14 women) healthy individuals underwent 7-Tesla functional MRI during wakefulness to assess LC–hypothalamus effective connectivity. Additionally, sleep EEG was recorded at night in the lab to examine the relationships between effective connectivity measures and REM sleep theta energy as well as sigma power prior to REM. Connectivity analyses revealed strong mutual positive influences between the LC and both the anterior–superior and posterior hypothalamus, consistent with animal studies. Aging was negatively associated with the connectivity from the anterior–superior hypothalamus (including the preoptic area) to the LC. In late middle-aged adults, but not younger adults, stronger effective connectivity from the anterior–superior hypothalamus to the LC was associated with lower REM theta energy. This association extended to other low-frequency bands during REM and NREM sleep. These findings highlight the age-dependent modulation of LC–hypothalamus interactions and their potential roles in sleep regulation, providing new insights into neural mechanisms underlying age-related sleep changes. Full article

Background: Exercise duration at maximum oxygen uptake ($\dot{\mathrm{V}̇}$O₂max) appears to be influenced not only by metabolic factors but also by the interplay between brain dynamics and ventilatory regulation. This study examined how cortical activity, assessed via electroencephalography (EEG), relates to performance and acute fatigue regulation during a constant-load cycling test. We hypothesized that oscillatory activity in the theta, alpha, and beta bands would be associated with ventilatory coordination and endurance capacity. Methods: Thirty trained participants performed a cycling test to exhaustion at 90% maximal aerobic power. EEG and gas exchange were continuously recorded; ratings of perceived exertion were assessed immediately after exhaustion. Results: Beta power was negatively correlated with time spent at $\dot{\mathrm{V}̇}$O₂max (r = −0.542, p = 0.002). Theta and Alpha power alone showed no direct associations with endurance, but EEG–metabolic ratios revealed significant correlations. Specifically, the time to reach $\dot{\mathrm{V}̇}$O₂max correlated with Alpha/$\dot{\mathrm{V}̇}$O₂ (p < 0.001), Alpha/$\dot{\mathrm{V}̇}$CO₂ (p < 0.001), and Beta/$\dot{\mathrm{V}̇}$CO₂ (p = 0.002). The time spent at $\dot{\mathrm{V}̇}$O₂max correlated with Theta/$\dot{\mathrm{V}̇}$O₂ (p = 0.002) and Theta/$\dot{\mathrm{V}̇}$CO₂ (p < 0.001). The time-to-exhaustion was correlated with Theta/$\dot{\mathrm{V}̇}$CO₂ (p < 0.001) and Alpha/$\dot{\mathrm{V}̇}$CO₂ (p < 0.001). Conclusions: These findings indicate that cortical oscillations were associated with different aspects of acute fatigue regulation. Beta activity was associated with fatigue-related neural strain, whereas Theta and Alpha bands, when normalized to metabolic load, were consistent with a role in ventilatory coordination and motor control. EEG–metabolic ratios may provide exploratory indicators of brain–metabolism interplay during high-intensity exercise and could help guide future brain-body interactions in endurance performance. Full article

Background and Objectives: Apelin-13 and its receptor (APJ) are increasingly recognized as key regulators of metabolic pathways that may contribute to the pathophysiology of obstructive sleep apnea (OSA) syndrome. This study aimed to investigate the relationship between circulating apelin-13 and APJ levels with disease severity in patients diagnosed with OSA, considering the impact of obesity. Materials and Methods: A total of 105 subjects were enrolled: 35 obese patients with OSA, 35 non-obese patients with OSA, and 35 healthy controls. Demographic data, polysomnographic parameters, metabolic markers, Apelin-13, and APJ levels were compared across groups. Patients were further classified as mild-moderate, or severe OSA for subgroup analysis. Correlations between Apelin-13, APJ, BMI, minimum oxygen saturation (Min SaO₂), and apnea–hypopnea index (AHI) were assessed. ROC analysis was used to examine the potential of Apelin-13 and APJ to predict severe OSA. Results: Apelin-13 levels were significantly higher in obese patients with OSA compared to non-obese OSA and controls (p < 0.001), whereas APJ levels were lowest in obese OSA subjects. Apelin-13 showed significant positive correlations with BMI (r = 0.63, p < 0.001) and AHI (r = 0.33, p = 0.005), and a negative correlation with Min SaO₂ (r = −0.35, p = 0.004). Conversely, APJ levels were negatively correlated with BMI (r = −0.60, p < 0.001) and AHI (r = −0.40, p = 0.002) and positively correlated with minimum SaO₂ (r = 0.40, p = 0.002). In severe OSA, insulin and HOMA-IR levels were significantly higher than in mild-moderate OSA (p = 0.02 and p = 0.003, respectively). However, there was no significant difference in Apelin-13 and APJ levels by OSA severity category. ROC analysis revealed that neither Apelin-13 nor APJ demonstrated sufficient diagnostic performance to predict severe OSA (AUC = 0.50 and 0.63, respectively). Conclusions: Apelin and APJ levels are correlated with key metabolic and hypoxic parameters in OSA, indicating that the apelin/APJ system may play a compensatory role in mitigating hypoxia-induced and metabolic complications. However, neither marker alone provides sufficient predictive value for disease severity, emphasizing the need for further studies to clarify the mechanisms and potential clinical applications of this system in OSA management. Full article

In neonatal care, donor human milk (DHM) is used when maternal milk is unavailable or insufficient. In several countries, including Germany, raw (i.e., unpasteurised) DHM is occasionally administered under specific clinical conditions. However, the lack of standardised, evidence-based microbiological testing protocols raises concerns about the reliability of safety assessments for this high-risk patient group. The objective of this study was to assess the performance of four culture-based microbiological methods for detecting Enterobacterales in donor human milk, using both spiked samples and raw milk. We compared the detection limits of four culture-based microbiological methods, with and without enrichment, using spiked DHM samples and 93 raw DHM samples from a single donor (limited generalisation). Artificially inoculated samples contained defined concentrations of E. coli, K. pneumoniae, and S. ureilytica. Detection limits varied by several orders of magnitude (2.86 × 10² CFU/mL to 4.90 × 10⁰ CFU/mL). In real samples, enrichment-based methods detected Gram-negative pathogens in four out of ninety-three samples (three S. ureilytica, one P. juntendi); direct plating detected none. Increasing the sample volume and applying enrichment improved detection sensitivity. Whole-genome sequencing confirmed species identity and showed that the S. ureilytica isolates from a single donor were clonally related, indicating a recurring detection pattern and underscoring the need for longitudinal microbiological monitoring. In view of the new EU SoHO Regulation classifying DHM as a Substance of Human Origin, these findings highlight the urgent need for standardised, sensitive protocols to ensure neonatal safety. Full article

Nitrogen (N) is the primary macronutrient that supports global agriculture. The Haber–Bosch process revolutionized the use of synthetic N fertilizers, enabling significant increases in crop yield. However, N losses from fertilization led to negative impacts on the environment. Improving crops’ N use efficiency (NUE) has been constrained by the limited understanding of N uptake and assimilation mechanisms, and the role of plant–microbe interactions. Among biological approaches, N fixation by cover crops and rhizobia symbioses represents a cornerstone strategy for improving NUE. The adoption of plant growth-promoting bacteria and arbuscular mycorrhizal fungi may enhance N acquisition by increasing root surface, modulating phytohormone levels, and facilitating nutrient transfer. Advances in plant molecular biology have identified key players and regulators of NUE (enzymes, transporters, and N-responsive transcription factors), which enhance N uptake and assimilation. Emerging biotechnological strategies include de novo domestication by genome editing of crop wild relatives to combine NUE traits and stress resilience back into domesticated cultivars. Additionally, novel fertilizers with controlled nutrient release and microbe-mediated nutrient mobilization, hold promise for synchronizing N availability with plant demand, reducing losses, and increasing NUE. Together, these strategies form a multidimensional framework to enhance NUE, mitigate environmental impacts, and facilitate the transition towards more sustainable agricultural systems. Full article

This study examines the moderating effect of bank capitalization on the relationship between economic freedom and banking performance, offering comparative evidence from both advanced and emerging economies. Using an unbalanced panel of 213 countries from 1993 to 2018, this study applies a two-step System Generalized Method of Moments approach to address dynamic effects, endogeneity, and unobserved heterogeneity. The results show that economic freedom exerts a negative and significant impact on bank profitability (ROA and ROE), particularly in emerging markets with weaker institutional safeguards. Strong internal capital buffers, on the other hand, mitigate these adverse effects and enhance resilience, supporting stable profitability under liberalized conditions. Regulatory capital shows a less consistent and sometimes restrictive role. Disaggregated results indicate that equity buffers most effectively cushion the risks of financial and investment freedom, whereas trade freedom is less sensitive to capital levels. The findings emphasize that successful liberalization depends on institutional capacity and capitalization strength, highlighting the importance of tailored prudential frameworks. The study contributes to debates on financial liberalization, Basel III, macroprudential regulation, and bank risk management, underscoring that a “one-size-fits-all” liberalization strategy may undermine stability and efficiency unless supported by robust capital buffers. Full article

Rice (Oryza sativa L.) is one of the major food crops. Yield and quality are affected by premature leaf senescence, a complex and tightly regulated developmental process. To elucidate the molecular regulatory mechanism controlling rice leaf senescence, the integrative transcriptome, metabolome and weighted gene co-expression network analysis (WGCNA) of flag leaves in five development stages (FL1–FL5) was performed. In this study, a total of 9412 differential expressed genes (DEGs) were identified. To further mine DEGs related to leaf senescence, a total of five stage-specific modules were characterized by WGCNA. Among them, two modules displayed continuous down-regulated and up-regulated trends from stages FL1 to FL5, which were considered to be highly negatively and positively correlated with the senescence trait, respectively. GO enrichment results showed that the genes clustered in stage-specific modules were significantly enriched in a vast number of senescence-associated biological processes. Furthermore, large numbers of senescence-related genes were identified, mainly participating in transcription regulation, hormone pathways, degradation of chlorophyll, ROS metabolism, senescence-associated genes (SAGs), and others. Most importantly, a total of 40 hub genes associated with leaf senescence were identified. In addition, the metabolome analysis showed that a total of 309 differential metabolites (DMs) were identified by WGCNA. The integrative transcriptome and metabolome analysis identified a key hub gene OsBELH4A based on the correlation analysis conducted between 40 hub genes and 309 DMs. The results of function validation showed that OsBELH4A overexpression lines displayed delayed leaf senescence, and significantly increased grain number per plant and grain number per panicle. By contrast, its knockout lines displayed premature leaf senescence and reduced grain yield. Exogenous hormone treatment showed that OsBELH4A significantly responded to SA and auxin. These findings provide novel insights into leaf senescence, and further contribute to providing genetic resources for the breeding of crops resistant to premature senescence. Full article

The cooling effect of urban forests has been widely investigated to support climate-adaptive spatial planning. However, studies on the impacts of key landscape drivers have often produced conflicting results, limiting their practical applicability. These inconsistencies may stem from an oversimplified focus on the global effects of individual factors, while neglecting non-linear threshold behaviors and pairwise interactions. To address this gap, this study employed an interpretable machine learning framework (XGBoost-SHAP) to quantify the seasonal non-linearities, thresholds, and interaction effects of landscape drivers on urban forest cooling in Suzhou, a subtropical Chinese city. The results indicate that the combined explanatory power of neighboring water body proportion (NWP), neighboring green space proportion (NGP), vegetation density (NDVI), spatial characteristics (Area, SHAPE), and elevation on the cooling intensity of urban forest patches was strongest in summer (R² = 0.615) and weakest in winter (R² = 0.316). Among these, NWP, NGP, and NDVI were the dominant drivers, while patch area and shape exhibited weaker marginal effects. NWP significantly enhances cooling only after exceeding seasonal critical thresholds (11%–15%). NGP contributed positively above ~40% in warm seasons but suppressed cooling above 37% in winter. Patch area exhibits a logarithmic relationship with cooling intensity, with a critical threshold of approximately 2.48 ha and saturation thresholds between 12 and 14 ha. SHAPE exerted positive effects in spring and winter, negative effects in summer, and a transition from negative to positive in autumn. Notably, significant, threshold-modulated interactions were identified, including those between NDVI and NWP, SHAPE and NDVI, SHAPE and NGP, NWP and NDVI, NWP and NGP, and NGP and NDVI. In each interaction, the first factor regulates and reverses the effect of the second once specific thresholds are exceeded. This study provides actionable, evidence-based guidance for the planning and optimized design of urban forests. Full article

Cell division is critical for the survival, growth, pathogenesis, and antibiotic susceptibility of Mycobacterium tuberculosis (Mtb). However, the regulatory networks governing the transcription of genes involved in cell growth and division in Mtb remain poorly understood. This study aimed to investigate the impact of BlaI overexpression on cell division and growth in Mtb and elucidate the underlying mechanisms. Mycobacterium smegmatis mc²155 was used as the model organism. Recombinant strains overexpressing BlaI were constructed. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), ethidium bromide and Nile red uptake assays, minimum inhibitory concentration (MIC) determination, drug resistance analysis, quantitative real-time PCR (qRT-PCR) assays, and electrophoretic mobility shift assay (EMSA) were employed to assess changes in bacterial morphology, cell wall permeability, antibiotic susceptibility, gene transcription levels, and the interaction between BlaI and its target genes. Overexpression of BlaI disrupted bacterial division in M. smegmatis, leading to growth delay, cell elongation, and formation of multi-septa. It also altered the lipid permeability of the cell wall and enhanced the sensitivity of M. smegmatis to β-lactam antibiotics. BlaI overexpression affected the transcription of cell division-related genes, particularly downregulating ftsQ. Additionally, BlaI negatively regulated the transcription of Rv1303—a gene co-transcribed with ATP synthase-encoding genes—inhibiting ATP synthesis. This impaired the phosphorylation of division complex proteins, ultimately affecting cell division and cell wall synthesis. Overexpression of BlaI in Mtb interferes with bacterial division, slows growth, and alters gene expression. Our findings identify a novel role for BlaI in regulating mycobacterial cell division and β-lactam susceptibility, providing a foundation for future mechanistic studies in M. tuberculosis, with validation required to assess relevance to clinical tuberculosis—though validation in M. tuberculosis and preclinical models is required. Full article

Understanding belowground carbon dynamics is essential for predicting the carbon balance of forest ecosystems. This study aimed to investigate links between soil CO₂ efflux (R_S), soil physicochemical properties, and fine-root morphology across four middle-aged plantations of different species (Robinia pseudoacacia, Quercus mongolica, Pinus koraiensis, and Metasequoia glyptostroboides) in Mt. Ansan, Seoul, Republic of Korea. Seasonal measurements of R_S, soil temperature (T_S), and soil water content (SWC) were conducted, and soils and fine roots (≤2.0 mm) were analyzed for physicochemical properties and morphological traits, with a focus on very-fine roots (≤0.5 mm). The results showed that R_S was positively correlated with T_S (r = 0.77) and negatively with SWC (r = −0.33). R_S normalized at 25 °C (R₂₅), differed significantly among plantations, and exhibited strong positive correlations with electrical conductivity (r = 0.81), as well as with total nitrogen and carbon concentrations and clay content. Among fine root traits, the length, surface area, and volume of very-fine roots exhibited the strongest associations with R₂₅, underscoring their pivotal role in regulating belowground respiration. These findings suggest that species-specific fine root strategies and soil conditions jointly control R_S dynamics, particularly under warmer conditions, and highlight very-fine root traits as key indicators of soil carbon flux in forest ecosystems. Full article

The proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are key pathological features of vascular remodeling during pulmonary hypertension. Platelet-derived growth factor (PDGF) signaling is a major contributor to these processes. Given the importance of microRNA (miRNA) regulation in the PDGF signaling pathway in PASMCs, we hypothesized that imatinib, a tyrosine kinase inhibitor, modulates the expression levels of miRNAs responsive to PDGF signaling to ameliorate the PDGF signaling-induced PASMC phenotype. In this study, we investigated the role of miR-335-5p in PDGF signaling-induced PASMC proliferation and migration, as well as the involvement of imatinib in the regulatory network of miR-335-5p. miR-335-5p was identified as a critical negative regulator of PDGF signaling. Functional assays revealed that miR-335-5p significantly inhibits PASMC proliferation and migration. Through target prediction and validation, Rho GTPase Activating Protein 18 (ARHGAP18) was identified as a novel direct target of miR-335-5p. In addition, ARHGAP18 was found to play an essential role in regulating PASMC proliferation and migration. Although miR-335-5p was downregulated upon PDGF-BB stimulation, its expression was restored by imatinib. These findings highlight the important role of the imatinib–miR-335-5p–ARHGAP18 axis as a potential therapeutic target for pathological vascular remodeling. Full article

Background/Objectives: Breast cancer represents a diverse group of malignancies and continues to rank among the leading causes of cancer-related deaths in women. Altered Hippo pathway signaling has been increasingly recognized as a contributor to tumor growth, therapeutic resistance, and metastatic spread. This study aimed to identify miRNAs targeting Hippo pathway-related genes that are consistently dysregulated across all five breast cancer subtypes. Methods: The study cohort included patients representing five breast cancer subtypes: 130 luminal A, 96 HER2-positive luminal B, 100 HER2-negative luminal B, 36 non-luminal HER2-positive, and 43 triple-negative breast cancer (TNBC). Tumor samples were collected during surgery, along with adjacent healthy tissue that served as controls. Expression of Hippo-related genes was analyzed using mRNA microarrays and validated with reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein levels were assessed via enzyme-linked immunosorbent assay (ELISA), while miRNA expression profiling was performed with miRNA microarrays. Potential mRNA targets were predicted using the miRDB database. Results: We identified consistent downregulation of STK4, RASSF6, and FGF1, alongside overexpression of BIRC5 and SERPINE1. miRNA analysis revealed that STK4 is potentially regulated by miR-522-3p, SERPINE1 by miR-199b-5p and miR-30a-3p, whereas RASSF6, FGF1, and BIRC5 appeared to be predominantly regulated at the transcriptional level. These alterations reflect both the suppression of upstream Hippo activation and activation of downstream oncogenic effectors across all subtypes. Conclusions: Our findings reveal a conserved Hippo dysregulation program in breast cancer, highlighting subtype-independent Hippo-related genes and their miRNA regulators as potential universal biomarkers and therapeutic targets, complementing subtype-specific treatment strategies. Full article