Search Results (3,479)

Prosumer communities, aggregations of residential and commercial entities equipped with distributed energy resources (DER), including photovoltaic systems, battery storage, and flexible loads, are emerging as critical organizational units in decarbonising smart grid architectures. Managing these communities effectively requires balancing economic efficiency with equity, autonomy, and environmental sustainability, objectives that conventional centralized control methods and existing multi-agent reinforcement learning (MARL) implementations fail to address simultaneously. This article proposes a value-aligned hierarchical multi-agent reinforcement learning (VA-HMARL) framework as a formally unified architecture that embeds equity (Jain’s Fairness Index J ≥ 0.90), individual autonomy, and carbon sustainability as hard constraints within the MARL reward structure. The framework integrates: a multi-objective Value Alignment Module (VAM) combining economic, fairness, sustainability, and comfort objectives; attention-based implicit coordination for scalable agent interaction; and differentially private federated policy aggregation (ε = 1.0, δ = 10⁻⁵) for GDPR-compliant collaborative learning. Simulation on a 20-prosumer community modelled on the IEEE 33-bus feeder over 10 Monte Carlo runs (300 episodes each) demonstrates: a 6.2% energy cost reduction versus the Rule-Based baseline (p = 0.0004); a Jain’s Fairness Index of 0.912 ± 0.031 at policy convergence (final 50 episodes), satisfying the J ≥ 0.90 community equity floor; and an 18.0% reduction in CO₂ emissions. The economic efficiency trade-off relative to performance-optimized MARL baselines is limited to 2.4%, within the 5% design target. These results establish VA-HMARL as a technically feasible and ethically grounded paradigm for autonomous decentralized energy governance. Full article

Background and Aims: Anemia is seen in nearly >70% of patients with cirrhosis and is often non-responsive to nutritional supplements; therefore, we assessed the erythropoiesis and associated alteration in bone marrow (BM). Methods: It is a cross-sectional study. Flow cytometry was performed to assess the hematopoietic stem cells (HSCs) and erythroid population of 60 patients with cirrhosis compared with patients with 7 non-cirrhotic portal fibrosis (NCPF) and 3 controls. Proteomics were performed of the pure CD71 erythroid population taken from patients with cirrhosis to decipher the internal abnormalities supported by validation experiments. Real Time PCR, colony assay and heme quantification, cytokine array, and ELISA were performed to assess erythropoietic stimulating agents (ESA), inflammatory cytokines, and growth factors as an external factor affecting erythropoiesis. Results: We found a decrease in intermediate erythroid progenitors [IEPs; CD71+ CD235a+], conversely early erythroid precursors [EEP; CD71+ CD235a−] and late erythroid progenitors [LEP; CD71− CD235a+] were increased (p < 0.05) in cirrhotic and NCPF as compared to control. However, unlike NCPF, cirrhosis exhibited decreased CD71+ transferrin receptor (TfR1) expression over erythroid cells and increased immature erythrocytes (p < 0.05) in peripheral circulation. In vitro culture of erythroid precursors showed impaired differentiation and maturation that was confirmed by the reduced (p < 0.05) number of erythroid colonies (BFU-E). Proteomics analysis showed downregulated proteins associated with hemoglobin synthesis, ROS detoxification, translation, and mitochondrial activity. Furthermore, we found an altered expression of genes related to erythropoiesis and hemoglobin synthesis and increase (p < 0.05) in inflammatory cytokines such as IL-5, TRAIL-R2, TGF-α, and TGF-β in BM. Conclusions: This study suggests that the dysregulated erythropoiesis observed in patients with cirrhosis having anemia is maintained despite adequate nutrition. Full article

Decidualization in the human endometrium is not merely a hormone-dependent differentiation process; rather, it represents a multilayered adaptive program characterized by the tight integration of immune regulation, metabolic reprogramming, and cellular stress responses. In this review, endoplasmic reticulum (ER) stress and the associated unfolded protein response (UPR) are proposed as central regulatory mechanisms governing this process. Triggered by increased protein synthesis and secretory demand, UPR activation under physiological conditions preserves proteostasis and supports the secretory capacity of stromal cells. In contrast, chronic or dysregulated activation leads to a maladaptive response characterized by apoptosis, inflammation, and metabolic dysfunction. UPR signaling pathways shape immune tolerance through their effects on macrophage polarization, uterine natural killer (uNK) cell function, and T cell balance. At the metabolic level, adenosine monophosphate-activated protein kinase (AMPK) regulates cellular adaptation through bidirectional interactions with mitochondrial function and redox homeostasis. Within this framework, the ER stress–immune–metabolic axis operates not as a linear pathway but as a dynamic network incorporating multiple feedback loops, thereby constituting a critical threshold mechanism that determines the success of decidualization. Disruption of this axis provides a shared mechanistic basis for pathologies such as recurrent implantation failure, pregnancy loss, and preeclampsia. From a therapeutic perspective, agents including chemical chaperones, UPR modulators, AMPK activators, and anti-inflammatory compounds hold translational potential by targeting these pathological feedback circuits. However, key knowledge gaps remain, particularly regarding the cell type-specific and temporal regulation of ER stress, the molecular boundaries defining the transition from adaptive to pathological states, and interspecies differences. Future studies employing single-cell omics approaches and functional in vivo models will be essential to elucidate the dynamic organization of this axis and to enable the development of targeted and personalized therapeutic strategies. Full article

Spinal infections in general, and infectious spondylodiscitis in particular, are increasingly diagnosed in the Western world, in recent decades. This rise in incidence is associated with an ageing population and with an increased availability of accurate diagnostic modalities. Even so, due to the non-specific nature of clinical manifestations, and of the implicated blood and serum markers, there is a risk of underdiagnosis or misdiagnosis of the disease in its initial stages. Ionizing radiation methods, such as plain radiography (X-ray) and computed tomography (CT), are also not reliable in the early stages of the diseases, and the golden standard of imagistic diagnosis, magnetic resonance imaging (MRI), is not always available or requested. Still, MRI remains the most reliable method in most cases where there is a need for differential diagnosis with other pathologies, namely Andersson lesions, destructive spondyloarthropathy, erosive osteochondritis, micro-crystalline spondylitis, Modic 1 lesion, Charcot spinal arthropathy, osteoporotic fractures, SAPHO syndrome with spinal involvement, and Schmorl’s nodes. Infectious spondylodiscitis is caused by bacteria, and, less frequently, by fungi. Rare cases of parasitic causes have also been reported in the literature. Infectious spondylodiscitis of bacterial causes may be pyogenic, more frequently caused by Staphylococcus spp. or Streptococcus spp., or granulomatous, usually caused by Mycobacterium tuberculosis complex (MTBC) or from classical brucellosis. In all these cases, therapy may be conservative, with antibiotics, or surgical, when the former fails or in patients with significant spinal instability or other neurological manifestations. There are various surgical approaches, each with its own drawbacks, and usually used according to the preference of the attending physician. Even in cases of surgical treatment, antibiotic administration is prolonged, and it is important for a proper scheme to be selected based on antimicrobial susceptibility testing. However, given that in many cases, the causative agent cannot be identified, empirical treatment must be initiated. Finally, newer approaches, including the incorporation of antimicrobial substances, may offer better solutions for improving treatment and rehabilitation outcomes. Full article

Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug–herb interactions with standard anticancer agents—namely sorafenib—remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments. Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-α via nuclear factor-kappaB (TNF/NF-κB), mitogen-activated protein kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK–STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group. Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling. Full article

Lymphoplasmacytic gastritis (LPG) is one of the most prevalent chronic diseases affecting cheetahs (Acinonyx jubatus) under human care, yet its underlying cause remains unresolved. Gastric inflammation occurs in the majority of adult captive cheetahs but is uncommon in free-ranging populations, suggesting that management-related factors contribute to disease pathogenesis. This review proposes that LPG represents a bile acid-driven gastroenteropathy arising from disruption of the natural feeding ecology of the cheetah. In free-ranging systems, cheetahs consume large episodic meals separated by prolonged fasting intervals and ingest whole-prey containing substantial connective tissue and collagen. In captivity, feeding patterns are typically characterized by smaller, more frequent meals and diets dominated by lean skeletal muscle with reduced structural complexity. I hypothesize that this mismatch alters gastric emptying kinetics, disrupts coordinated pancreatic and biliary secretion, and destabilizes fat digestion. Inefficient lipolysis may impair micelle formation and promote bile acid mislocalization within the gastrointestinal tract, increasing mucosal exposure to hydrophobic bile acids capable of inducing chemical epithelial injury. Within this framework, lymphoplasmacytic gastritis is interpreted as a secondary inflammatory reaction to chronic bile acid-mediated mucosal stress rather than a primary immune-mediated disorder. The model also provides a mechanistic explanation for the frequent coexistence of gastritis with fat and protein maldigestion in captive cheetahs. Differential responses to antimicrobial therapy, glucocorticoids, sulfasalazine, pancreatic enzyme supplementation, and bile acid-modifying agents are broadly consistent with this proposed mechanism. Recognition of LPG as a physiologically driven gastroenteropathy has important implications for management, emphasizing restoration of feast–fast feeding patterns, inclusion of collagen-rich carcass components, and targeted modulation of bile acid composition and signaling. Full article

Background: Neuroendocrine neoplasms are frequently diagnosed after the detection of liver metastases, often when the primary tumor remains occult. Accurate non-invasive differentiation of neuroendocrine liver metastases (NELMs) from other focal hepatic lesions is therefore crucial. This study aimed to characterize the magnetic resonance imaging (MRI) features of NELMs using hepatocyte-specific contrast agents and to identify a potential radiologic “signature” that may suggest a neuroendocrine origin. Methods: This retrospective study included three cohorts: patients with histologically confirmed NELMs (n = 51; 146 lesions), patients with colorectal cancer liver metastases (n = 18; 46 lesions), and patients with benign hepatic hemangiomas (n = 28; 51 lesions). All subjects underwent standardized liver MRI with Gd-EOB-DTPA. Lesions were evaluated for size, diffusion-weighted imaging characteristics, apparent diffusion coefficient values, arterial-phase enhancement, T2-weighted signal, hepatobiliary-phase appearance, and hemorrhagic components. Statistical analyses included univariate and multivariate testing and receiver operating characteristic curve analysis. Results: NELMs commonly demonstrated arterial hyperenhancement, diffusion restriction, and variable T2 and hepatobiliary-phase signal heterogeneity. Compared with colorectal metastases and hemangiomas, NELMs showed distinctive patterns, particularly higher rates of hepatobiliary-phase heterogeneity and arterial enhancement. Lesion size, ADC metrics, T2 heterogeneity, and hemorrhage were significant discriminators. Conclusions: Hepatocyte-specific MRI enables identification of characteristic imaging features of NELMs. An integrated assessment of morphologic, diffusion, and hepatobiliary-phase findings may facilitate early recognition of neuroendocrine metastases, even when the primary tumor is unknown, improving diagnostic confidence and clinical management. Full article

Candida albicans is a common opportunistic pathogen. Long-term use of azole antifungals faces challenges like resistance, necessitating novel agents. Tea tree oil (TTO), a natural broad-spectrum antimicrobial, shows promise, but its molecular mechanisms, particularly concerning novel cell death pathways, require clarification. This study comprehensively evaluated the antifungal mechanism of TTO against C. albicans using transcriptomics. Antifungal susceptibility assays were conducted to assess the effects of TTO and its components (4-terpineol, terpenes, and γ-pinene) on the growth of C. albicans hyphae and biofilms. Fluorescent labeling and biochemical analysis were employed to detect ferroptosis markers. Transcriptomic results indicate that TTO induces 423 differentially expressed genes and systematically inhibits the development of C. albicans hyphae through mechanisms such as oxidative stress, iron homeostasis disruption, disruption of cell wall integrity, and interference with ergosterol metabolism. Notably, the significant enrichment of redox enzyme activity and iron ion binding functions, along with changes in the glutathione metabolic pathway, suggest that ferroptosis may be involved in this process. Subsequent studies revealed that the compound 4-pinene most effectively inhibits the pathogenicity of C. albicans by suppressing its adhesion, hyphae formation, and biofilm formation, whereas terpinene induces the accumulation of reactive oxygen species (ROS) and increases lipid peroxidation in C. albicans; furthermore, following treatment with an iron-mediated apoptosis inhibitor, terpinene enhances the viability of the treated C. albicans cells. Full article

Brown seaweeds are recognized for their rich content of phlorotannins with promising antidiabetic properties through multi-targeted modulation of glucose metabolism. This study investigated the antidiabetic potential of the ethyl acetate fraction of Ecklonia cava (EC-ETAC) and its major phlorotannin, dieckol, focusing on inhibition of carbohydrate-digesting enzymes, intestinal glucose absorption, dipeptidyl peptidase-IV (DPP-IV) activity, and hepatic glucose metabolism. EC-ETAC potently inhibited α-glucosidase (IC₅₀ = 2.2 ± 0.2 µg/mL) and α-amylase (IC₅₀ = 41.0 ± 1.2 µg/mL), outperforming acarbose by 26-fold and 6-fold, respectively. Pure dieckol showed strong activity with IC₅₀ values of 2.213 ± 0.04 µM (α-glucosidase) and 156.87 ± 0.124 µM (α-amylase). In differentiated Caco-2 cells, both EC-ETAC and dieckol downregulated SGLT1 and GLUT2 protein expression to ~0.5-fold of control and suppressed 2-NBDG glucose uptake by 46–53% over 120 min, effects not seen with acarbose. Dieckol inhibited DPP-IV activity (IC₅₀ = 12.12 ± 0.021 µM), reducing in situ activity to 53.89% at 25 µM without changing DPP-IV protein levels. Molecular docking revealed high-affinity binding of dieckol to DPP-IV (−10.396 kcal/mol), directly occluding the catalytic triad (Ser630, His740). In insulin-resistant HepG2 cells, dieckol restored glucose uptake to 108.97% of control via AMPK activation (1.21-fold), GLUT2 normalization (0.84-fold), and PGC-1α recalibration (0.96-fold), matching or surpassing 1 mM metformin. These results demonstrate dual-inhibition mechanism combined with hepatic AMPK restoration, establishing dieckol as a promising marine-derived multi-targeted agent for T2DM management. Full article

Today’s cargo bay uses Halon 1301 gas for fire suppression. While effective, this fluid is broadly banned due to its high global warming potential (GWP) of 5700 and its high ozone depletion potential. Hence, alternative agents for cargo fire protection are being sought. In this framework, tests were conducted in the Fraunhofer Flight Test Facility with the goal of evaluating the uniformity of spread of various fire suppression agents, specifically a blend of a Hydrofluoroolefine (HFO) and CO₂. The facility’s cargo area, with a volume of 38 m³, features a low-pressure vessel integrating a previously operated aircraft segment. In a series of tests, the alternative extinguishing agent was supplied into the cargo hold demonstrator and concentrations were measured in different locations to understand the uniformity of distribution and the system behaviour under a realistic flight envelope. Test results show several interesting outcomes. In the empty cargo hold with air movement due to leakage, initial bottle filling weight and extinguishing agent initial concentration are consistent. When no flow movement is applied to the cargo hold, a separation between upper and lower cargo hold concentrations is found. The heavy extinguishing agent necessitates a buoyancy correction of the measured pressure differential by air density and elevation. Full article

Background/Objectives: Liver diseases cause more than 2 million annual deaths globally, accounting for 4% of the total global mortality rate. Hepatic fibrosis (HF) acts as an indispensable pathological mediator in the progressive deterioration of chronic liver diseases. Thus, the identification of effective anti-fibrotic targets and rational development of corresponding therapeutic agents are expected to deliver profound clinical value for patients suffering from chronic liver disorders. Methods: An in vivo HF model was established to detect Kupffer cell (KC) polarization and periostin (POSTN) protein expression. In vitro, the CCK-8 (Cell Counting Kit-8) assay was applied to evaluate the regulatory effects of Postn-knockdown macrophages on LX-2 cell activity. Conditional knockout mice with Postn were constructed in vivo, and liver tissue samples were used for single-cell sequencing. Functional enrichment and cell differentiation prediction analyses were performed. CellChat was further utilized to characterize alterations in intercellular communication between Postn-deficient KCs and adjacent liver cells. Finally, POSTN-targeted inhibitors were screened and validated via virtual drug screening and experiments. Results: In the HF model, the M2 polarization of KCs was associated with the upregulated expression of POSTN. In contrast, in vitro Postn knockdown correlated with significantly suppressed LX-2 cell activation. Single-cell profiling suggests that Postn deficiency in Kupffer cells is linked to remodeling of the hepatic microenvironment. In drug repurposing, Rhodiosin exhibited binding affinity to POSTN and was observed to inhibit macrophage M2 polarization. Conclusions: POSTN may contribute to KC M2 polarization and be associated with remodeling of the intercellular interaction network among liver cells. Rhodiosin, as a POSTN-binding compound, shows potential for anti-hepatic fibrotic effects. Full article

Aquaculture is the fastest-growing food production sector, supplying more than half of the world’s seafood and projected to expand further to meet rising global protein demands. Among the various pressures confronting this industry, harmful algal blooms (HABs) rank among the most alarming. Ichthyotoxic flagellates are microalgae known for producing toxins or inducing gill damage that leads to widespread fish mortality. Their increasing frequency poses a critical threat to aquaculture, emphasizing the urgent need for effective and environmentally sustainable strategies to regulate and mitigate these harmful episodes. This study investigated the responses of three ichthyotoxic flagellates renowned for impacting aquaculture operations (Prymnesium parvum, Heterosigma akashiwo, and Fibrocapsa japonica) and tested their susceptibility to two routinely applied chemical agents, hydrogen peroxide (H₂O₂) and copper sulfate (CuSO₄). Mortality, viability, and motility were assessed alongside trajectory-based metrics, including mean squared displacement (MSD) and probability density function (PDF). The results revealed species-specific sensitivities: P. parvum was highly susceptible to H₂O₂, while H. akashiwo and F. japonica were more susceptible to copper toxicity. Ichthyotoxic flagellates exhibited differential sensitivities to chemical treatments, with copper sulfate generally achieving lower EC₅₀ thresholds and greater inhibition of motility than hydrogen peroxide, except in P. parvum. The rapid attenuation of motility at sublethal concentrations highlights swimming behavior as a functional vulnerability, reinforcing the potential for behavior-based mitigation strategies that minimize chemical loading and reduce unintended impacts on cultured fish and surrounding ecosystems. Full article

The gut microbiota is increasingly recognized as a key contributor in the pathogenesis and progression of inflammatory bowel disease (IBD). Compared with healthy individuals, patients with IBD show marked dysbiosis, characterized by reduced microbial diversity, an expansion of facultative anaerobes such as Proteobacteria, and a depletion of obligate anaerobes within the Firmicutes phylum. These changes have been implicated in the perpetuation of intestinal inflammation, disruption of mucosal immune homeostasis, and altered metabolic functions, further underscoring the microbiota’s relevance in IBD pathophysiology. However, microbiota-driven insights have not yet been consistently translated into therapeutic stratification or clinical decision-making. A major challenge lies in the complex and dynamic interplay between the gut microbiota and various treatment modalities, including conventional immunosuppressants, biologics, and small-molecule inhibitors. While accumulating evidence suggests that IBD treatments may modulate microbial composition and function, it remains unclear whether these changes represent a direct pharmacological effect or are secondary to inflammation control. Additionally, there is a lack of comparative data on microbiota profiles associated with differential responses to various therapeutic classes, limiting the implementation of microbiota-informed precision medicine. In this review, we synthesize current evidence on the association between gut microbiota composition and treatment outcomes, focusing on biologic agents and small-molecule therapies. Furthermore, we discuss the potential of microbiota-targeted strategies, such as fecal microbiota transplantation (FMT) and precision probiotics, in enhancing therapeutic response. A deeper understanding of host–microbe interactions could enable a more personalized and effective approach to IBD management. Full article

The limited regenerative capacity of articular cartilage (AC) following injury has led to a high prevalence of degenerative AC-related disorders, including osteoarthritis (OA). Current clinical treatments for OA have failed to halt disease progression, driving growing interest in cartilage tissue engineering (CTE) strategies aimed at developing biomimetic substitutes to regenerate damaged AC tissue. Among the available biofabrication techniques, electrospinning has gained attention due to its ability to generate fibrous scaffolds that closely mimic the architecture of the native AC extracellular matrix, while also serving as versatile drug delivery platforms with high surface area and elevated drug loading efficiency. Small molecules, low-molecular-weight therapeutic agents capable of interacting with both cell membrane and intracellular components, can be incorporated into these scaffold systems to target the underlying mechanisms of OA. This review examines the current state of the art of small molecule-loaded electrospun scaffolds for CTE applications. Small molecules targeting pain, inflammation, and cartilage function restoration show considerable therapeutic potential, and their incorporation into coaxial and other advanced electrospinning setups enables controlled and sustained drug release. Recent examples of small molecule-loaded electrospun scaffolds for AC repair demonstrate enhanced chondrogenic differentiation and neo-cartilage formation, supporting their potential as viable CTE strategies. Nevertheless, challenges related to drug release kinetics, scaffold load-bearing properties, manufacturing scalability, reproducibility, and regulatory approval remain critical barriers to clinical translation. Emerging fabrication strategies, AI-assisted optimization, personalized medicine approaches, and stimuli-responsive drug delivery systems offer promising avenues to overcome these limitations and advance the clinical adoption of these platforms. Full article

Hypoderma diana Brauer, 1858, poses a significant threat to species of deer, yet records of this species in China remain fragmented and lack comprehensive documentation. Following high mortality in wapiti populations in Inner Mongolia during 2023–2024, surveys were conducted in the Gaogesitai Hanwula Nature Reserve in March 2025. Species identity was established through rigorous morphological analysis of third-instar larvae and an emerged adult female using light and scanning electron microscopy, supplemented by a 689 bp COI fragment. Results confirmed H. diana as the causative agent, with larvae localized along the host’s vertebral column. Comparative SEM analysis of the antennomaxillary sensory complex in H. diana, H. bovis (Linnaeus, 1758), and H. lineatum (Villers, 1789) revealed undifferentiated, volcano-like warts, contrasting sharply with the highly differentiated antennae and sensilla of Oestrus ovis Linnaeus, 1758. This study represents an inaugural record of H. diana in the Chifeng region and provides the first atlas of diagnostic features for both third-instar larvae and adults. These findings document H. diana as a critical agent of myiasis in the Manchurian wapiti, refining its known epidemiological profile in China and establishing an essential morphological reference for future wildlife health surveillance. Full article