Search Results (76,184)

Escalating climate volatility, particularly the El Niño/Southern Oscillation (ENSO), poses severe operational and financial risks to corporate sustainability in the energy sector. However, quantitative evidence regarding how macro-level climate shocks transmit to micro-level operational performance remains scarce. Integrating dynamic capability and social network theories, this study analyzes a panel of 103 Chinese listed energy firms (2005–2022) using System GMM, mediation, and moderation models. The results indicate that ENSO intensity significantly impairs performance; specifically, a 1 °C rise in sea surface temperature anomalies decreases firms’ return on assets (ROAs) by 0.142%. We identify supply chain resilience as a critical strategic mechanism for climate adaptation, where response capacity acts as the dominant mediating channel, while recovery capacity functions as an independent compensatory mechanism. Conversely, supply network complexity—across horizontal, vertical, and spatial dimensions—amplifies the negative impact of climate disruptions by hindering resource mobility. Heterogeneity analysis reveals that state-owned enterprises exhibit stronger institutional resilience, and firms in southern regions partially offset impacts through hydropower advantages. This study bridges climate science with operations management, offering strategic guidance for managers to configure resilient, sustainable supply chains capable of withstanding environmental turbulence. Full article

Introduction: Brain metastases represent a major clinical challenge due to a distinct immunosuppressive microenvironment and limited, heterogeneous efficacy of PD-1/PD-L1 immune checkpoint inhibition. The adenosine pathway, mediated by the ectonucleotidases CD39 and CD73, has emerged as an alternative immune escape mechanism, yet its relevance in brain metastases across tumor entities remains insufficiently characterized. Methods: We conducted targeted panel sequencing of brain metastases from multiple primary tumor entities and evaluated compartment-resolved expression of CD39, CD73, and PD-L1 by immunohistochemistry, distinguishing tumor cell and immune cell expression. Tumor mutational burden (TMB), recurrent gene alterations, and gene fusions were analyzed and integrated with immune marker profiles to define immunogenomic subtypes. Results: Brain metastases displayed a heterogeneous mutational landscape with recurrent alterations including TP53, KRAS, PIK3CA, and APC. CD39 and CD73 expression was frequent and highly variable, occurring on both tumor cells and tumor-infiltrating immune cells, and only partially overlapping with PD-L1 expression. A substantial subset of cases exhibited an adenosine-high phenotype despite low or absent PD-L1. Marker-associated enrichment analyses identified distinct genetic correlates, including enrichment of KRAS alterations in tumors with CD39/CD73 positivity on malignant cells, and APC/PIK3CA-associated patterns linked to immune compartment marker expression. TMB did not significantly differ across major tumor entity groups. Gene fusions were detected in a subset of tumors but were largely independent of immune phenotypes. Conclusions: Adenosine pathway activation is a frequent, genetically associated immune escape feature of brain metastases that complements PD-L1-based stratification. Integrating CD39/CD73 with PD-L1 enables actionable immunogenomic subtyping and supports rational immunotherapy strategies targeting adenosine-mediated immunosuppression. Full article

Visual cues are critical for orientation and migration in riverine fishes, providing potential mechanisms for behavioral guidance. This study investigated how light spectrum and intensity interact to modulate phototactic responses in two schizothoracine fishes from the upper Yalong River. Results showed Schizopygopsis malacanthus preferred blue light and avoided red light, with preferences shifting with flow intensity; Schizothorax kozlovi favored green light and avoided light-red light, with minimal flow impact. We propose that engineers build fishway entrances or ideal habitat attractors that prioritize low-intensity blue light (10 lx) and medium-intensity green light (50 lx), supplemented by medium-intensity blue light (50 lx). This study provides scientific evidence and application value for restoring fish habitats, fish passages, and fisheries. Full article

Background/Objectives: Spotty liver disease (SLD), caused by Campylobacter hepaticus, is an emerging disease that leads to substantial production losses in the egg industry. The shift toward antibiotic-free and cage-free production systems has further intensified the impact of SLD. The current control measures largely rely on autogenous killed vaccines; however, their use is constrained by the slow and fastidious growth of C. hepaticus and inconsistent efficacy. To overcome these limitations, this study aimed to identify immunogenic mimotopes as vaccine candidates and express them on the surface of an avian pathogenic Escherichia coli (APEC) vector. Methods: To identify immunogenic mimotopes, Ph.D.-12 phage display peptide library was screened using the hyperimmune serum raised against killed whole-cell C. hepaticus in specific pathogen-free chickens. Subsequently, the outer membrane protein C (OmpC) of E. coli was used as a scaffold for constructing a surface display library. A single restriction site, PstI, located in the seventh external loop of OmpC, was strategically utilized to insert each 12-amino-acid mimotope with a six-histidine (6xHis) tag sequence at its N-terminus, generating ompC + mimotope fusion constructs. These constructs were cloned into the inducible expression vector pTrc and electroporated into an E. coli DH5α ∆ompC strain, which lacked ompC. The surface expression of the mimotopes was confirmed in vitro. The verified ompC + mimotope constructs were subsequently subcloned into the pYA3422 constitutive expression vector and electroporated into the APEC PSUO78 ∆aroA ∆asd vaccine vector strain. A chicken vaccination–challenge trial was conducted using nine groups of chickens, including an unvaccinated challenged control and an unvaccinated–unchallenged negative control. Each experimental group received a mixture of two recombinant E. coli strains carrying different mimotopes at a dose of 1 × 10⁹ CFU, which were administered orally twice at 16 and 18 weeks of age. Results: Fourteen immunogenic mimotopes corresponding to 13 different C. hepaticus proteins were identified as potential vaccine candidates. The expression of these mimotopes on the surface of the E. coli was successfully demonstrated using the OmpC-mediated surface display system. Of the 14 mimotopes tested, two flagellar-related peptides and one major outer membrane protein (MOMP)-derived peptide elicited significant immune responses and conferred protection against the C. hepaticus challenge. Conclusions: We successfully developed a functional E. coli surface display system that was capable of expressing 12-amino-acid mimotopes of C. hepaticus, providing a robust platform for evaluating vaccine candidates against SLD. Immunogenicity and efficacy studies in chickens demonstrated that three identified mimotopes conferred protection against C. hepaticus colonization of the bile and liver. Future in vivo investigations are necessary to develop and evaluate the immunogenicity and protective efficacy of a multivalent mimotope vaccine consisting of three identified mimotopes against both C. hepaticus and APEC, utilizing the ΔaroA Δasd APEC PSU078 strain as the vaccine vector. Full article

In this study, a novel layered WO₃@Co₃O₄ composite electrode was synthesized via a controlled electrodeposition method employing different surfactants to finely tune its nanostructure. The incorporation of polyacrylic acid (PAA) surfactant yielded an optimized P-W@Co electrode with a hierarchical porous morphology and reduced crystallite size, markedly enhancing electroactive site exposure and electron transport. Structural analyses confirmed the amorphous nature of WO₃ and crystalline spinel Co₃O₄ phases forming an integrated composite architecture. Electrochemical characterizations in a three-electrode system revealed that the P-W@Co electrode exhibited superior pseudocapacitive behavior, with an areal capacitance of 11.70 F/cm² at 20 mA/cm² and excellent rate capability, retaining 80% capacitance at 40 mA/cm². Kinetic studies demonstrated enhanced diffusion-controlled charge storage attributed to improved ion accessibility and charge transfer kinetics. To evaluate practical feasibility, asymmetric supercapacitor devices incorporating P-W@Co as the positive electrode coupled with activated carbon as the negative electrode were fabricated. This device showcased a widened operational voltage (1.5 V), outstanding areal capacitance (211 mF/cm²), and energy density (0.066 mWh/cm²). Importantly, the device exhibited exceptional cycling stability, retaining 81.8% capacitance after 7000 cycles. This work signifies a major advancement in surfactant-mediated design of WO₃@Co₃O₄ layered electrodes for scalable, high-performance supercapacitor applications, combining structural stability, enhanced conductivity, and multifaceted charge storage mechanisms. Full article

Consumer food waste is a major global challenge to sustainable development, generating massive carbon and water footprints, exacerbating food insecurity, and undermining the United Nations Sustainable Development Goals. While extensive research has documented individual and contextual drivers of consumer food waste, critical gaps remain in understanding how core marketing tools shape wasteful behavior, particularly the unintended post-purchase consequences of ubiquitous price promotions. Addressing this gap, we unpack the psychological mechanism underlying the classic social dilemma of promotions: short-term individual economic savings from discounts conflict with long-term collective ecological welfare. Across four rigorous studies, including a real-world field experiment in a university canteen, we establish a causal effect of price promotions on increased consumer food waste behavior. We further demonstrate that this effect is mediated by enhanced perceived resources: price promotions generate subjective feelings of windfall gains and resource abundance, which in turn increase consumers’ willingness to discard edible food. We identify two practical actionable boundary conditions that attenuate this pro-waste effect: the impact of price promotions on food waste is eliminated when consumers focus on money spent (rather than money saved) from the transaction, and when they perceive their spending as exceeding their psychological budget. Our findings advance the literature on price promotions and sustainable consumption by documenting a previously unrecognized hidden cost of promotional marketing, unpacking the micro-psychological foundations of the social dilemma in food waste decisions, and providing evidence-based, actionable implications for policymakers, food retailers, and food service operators to curb promotion-induced food waste. Full article

Endometriosis affects approximately 10% of reproductive-age women and is associated with genomic instability; however, the contribution of specific DNA repair deficiencies remains poorly understood. This study investigated the expression and function of GEN1, a Holliday junction resolvase critical for homologous recombination, in patient-derived endometrial epithelial organoids (EEOs). Endometrial tissue was obtained by pipelle biopsy from women with laparoscopically confirmed endometriosis (n = 3, stage III–IV) and controls without endometriosis (n = 3). GEN1 mRNA and protein expression were reduced in primary endometrial cells from endometriosis patients compared with controls (mRNA: 0.52 ± 0.14 vs. 1.00 ± 0.19, p = 0.05; immunofluorescence intensity: 0.54 ± 0.18 vs. 1.00 ± 0.22, p = 0.05). Patient-derived EEOs from the endometriosis group showed trends toward lower formation efficiency (18.4 ± 5.6% vs. 25.2 ± 6.8%, p = 0.10) and reduced mean diameter (124.6 ± 34.2 vs. 155.8 ± 32.6 µm, p = 0.10). RNA interference (RNAi)-mediated GEN1 knockdown reduced proliferation in both groups, with a more pronounced effect in endometriosis-derived EEOs (49.7% vs. 39.5% reduction, p = 0.05). Endometriosis-derived EEOs exhibited elevated baseline γH2AX (phosphorylated histone H2AX) immunofluorescence compared with controls (2.32 ± 0.44 vs. 1.00 ± 0.28, p = 0.05), indicating increased DNA double-strand break accumulation. Furthermore, GEN1 knockdown directly increased γH2AX intensity in both groups, with endometriosis-derived EEOs showing a greater absolute increase (Δ1.26 vs. Δ0.72). To our knowledge, this study provides the first organoid-based evidence that GEN1 is downregulated in endometriosis and functionally linked to impaired proliferation and elevated DNA damage, suggesting a potential contribution of homologous recombination dysregulation to endometriosis pathogenesis. Full article

Background/Objectives: FcγRIIIA presents a single nucleotide polymorphism at position 158 (V/F), which affects its binding affinity to the fragment crystallizable (Fc) of antibodies (Abs). In the presence of immune complexes, FcγRIIIA can mediate the inflammatory signaling, severity of bone disease, and osteoclastogenic activity. Based on this functional relevance, we hypothesized that the FcγRIIIA F158V polymorphism may influence the clinical presentation of multiple myeloma (MM). Methods: FcγRIIIA F158V genotyping was performed on genomic DNA extracted from peripheral blood samples of patients affected by MM or asymptomatic conditions named MGUS and SMM. We compared the allele frequency of FcγRIIIA-F158V polymorphism in 72 MM, 42 MGUS and 31 SMM and evaluated the association with clinical features and occurrence of high-risk chromosome abnormalities. Targeted NGS mutation analysis was performed on genomic DNA isolated from purified CD138⁺ bone marrow plasma cells (BMPCs) of 41 patients, to evaluate the association between somatic mutations and the FcγRIIIA F158V genotype. Results: the FcγRIIIA-158 V/V homozygous genotype was associated with high-risk cytogenetics, anemia, high beta-2 microglobulin levels, and more than 10 osteolytic lesions. V/V homozygous genotype was significantly associated with at least one mutation in RAS pathway genes (N-RAS, K-RAS or B-RAF). In the immune microenvironment, patients carrying the V/V homozygous genotype had a higher percentage of CD14⁺CD16⁺⁺ non-conventional inflammatory monocytes than the V/F or FF genotype. Conclusions: Our study contributes to a better understanding of the interactions between genetic variants, tumor microenvironment, and therapeutic response in plasma cell dyscrasias, to identify molecular biomarkers for precision medicine in MM, MGUS and SMM. Full article

Caffeine (CAF) is one of the most widely consumed psychoactive substances worldwide. It is primarily metabolized to paraxanthine (PAR), theobromine (THR), and theophylline (THY). While CAF metabolism has been extensively characterized in humans and rodent models, corresponding data in zebrafish (Danio rerio) larvae remain limited. This study provides a comprehensive characterization of CAF biotransformation in zebrafish larvae using validated LC-QQQ-MS for quantitative metabolite profiling and FTIR imaging for spatially resolved tissue distribution mapping. Zebrafish larvae at 4 days post fertilization (dpf) were exposed to CAF at concentrations of 15, 25, and 50 mg/L for 18 h. The LC–MS/MS analysis demonstrated dose-dependent conversion of CAF to PAR (up to 4.54%), THR (up to 1.32%), and THY (up to 0.27%). The PAR/CAF and THR/CAF ratios increased as CAF concentration rose, while the THY/CAF ratio declined. In parallel, FTIR imaging was applied to visualize the spatial distribution of CAF and selected metabolites in larval tissue sections, confirming the presence of CAF, PAR, and THR and revealing their localization within the tissue. However, THY was not detected by this method. Metabolite localization differed across larval tissues, indicating compartmentalized metabolic processes. This study provides the first comprehensive characterization of CAF metabolism in zebrafish larvae, revealing low but detectable CYP450-mediated metabolic activity prior to full hepatic maturation. The findings support the utility of zebrafish larvae as a model for developmental pharmacokinetic studies. Full article

The mitochondrial anti-viral signaling protein, MAVS, is a central regulator of innate anti-viral immunity. Recently, we demonstrated that MAVS is overexpressed in cancer, where its downregulation resulted in reduced cell proliferation and the expression and nuclear translocation of proteins associated with transcriptional regulation and inflammation. In this study, we demonstrate that CRISPR/Cas9-mediated MAVS depletion in PC-3 prostate cancer cells suppresses proliferation, disrupts immune evasion, and alters the tumor microenvironment. Proteomic profiling of the MAVS-KO cells by LC-MS/MS revealed changes in the expression of proteins associated with immunity, cell signaling, mitochondrial function, metabolism, protein synthesis and degradation, and epigenetic regulation. In contrast to MAVS-expressing cells, MAVS-KO cells implanted subcutaneously in mice formed very small tumors. This inhibited tumor growth was linked to reduced proliferation, and enhanced apoptosis, as indicated by strong TUNEL staining and elevated activated caspase-3. Importantly, the small “tumors” derived from MAVS-KO cells displayed a distinct morphology: diminished cancer stem-cell populations, an altered tumor microenvironment and inflammatory response, increased immune cell infiltration, and reduced PD-L1 expression. Together, these findings establish MAVS as a key mediator of cancer-cell survival, inflammation, and immune regulation, and, thus, its upregulation in tumors makes it a potential anti-cancer target. Full article

Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H₂S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H₂S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary vascular structural remodeling is unknown. In this study, we aimed to test whether H₂S donor therapy can reverse the existing PAH in a chronic-hypoxia rat model. Methods: After 3 weeks of hypoxia exposure, rats with established hypoxia-induced pulmonary hypertension (HPH) were randomized to receive either continued hypoxia alone or hypoxia plus the H₂S donor NaHS (56 μmol/kg·d, ip) for an additional 6 weeks. Pulmonary artery pressure, pulmonary artery muscularization, and right ventricular hypertrophy were assessed. Furthermore, the cell proliferation (Ki-67 and PCNA), ERK1/2 phosphorylation, and persulfidation of the endothelin type A receptor (ETAR) were examined and detected in rat lung tissues and pulmonary artery smooth muscle cells (PASMCs). Results: H₂S therapy effectively reversed established HPH and pulmonary artery structural remodeling, reducing RVSP, mPAP, and the proportion of fully muscularized small pulmonary arteries by 13.8%, 12.0%, and 62.7%, respectively. Moreover, the PAT/PET ratio was normalized to normoxic levels. The right ventricular hypertrophy index decreased by 29.2%. Mechanistically, H₂S therapy suppressed PASMC proliferation, reduced ERK1/2 phosphorylation, and enhanced ETAR persulfidation. Furthermore, dithiothreitol-mediated reduction of ETAR persulfidation abrogated these antiproliferative effects of H₂S therapy, establishing persulfidation as an obligatory mechanism. Conclusions: H₂S donor therapy effectively reverses established HPH and pulmonary vascular structural remodeling by inhibiting PASMC proliferation, which is linked to enhanced ETAR persulfidation. These data provide preclinical proof-of-concept for H₂S-based interventions in patients with manifest PAH. Full article

At the dawn of the 20th century, seminal studies revealed that muscle fibers produce less heat and generate greater force during elongation than during shortening actions, laying the foundation for contemporary research on eccentric exercise. Today, eccentric exercise is widely used by athletes to enhance strength and by older adults to maintain functional capacity, yet it may cause muscle damage, particularly in unaccustomed muscles. Despite more than a century of investigation, the precise mechanisms of eccentric exercise-induced muscle damage remain incompletely resolved. Nevertheless, eccentric exercise serves as a valuable model for studying muscle injury and repair and adaptation. This review organizes current evidence into nine key themes: (1) eccentric exercise-induced muscle damage and flawed biomarkers, (2) satellite cell-mediated and alternative repair pathways, (3) high-force, low-cost contractions and metabolic impact, (4) repeated bout effect and protective adaptations, (5) architectural remodeling of fascicles, sarcomeres and tendon, (6) distinct neural control, proprioception, and cross-education adaptations, (7) mitochondrial, sarcoplasmic reticulum, and cytoskeletal stress remodeling, (8) connective tissue perturbation, remodeling, and joint stability, and (9) targeted, cautious use of antioxidant supplementation. Rather than offering a comprehensive overview, this review highlights pivotal experiments, concepts, and controversies within these themes to guide readers to the most impactful discoveries in eccentric exercise and muscle damage. Full article

Chronic inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are systemic immune-mediated disorders driven by dysregulated immune responses. The gut–skin axis is a bidirectional network linking intestinal microorganisms, their metabolites, and host immunity. It connects microbiome composition and function with systemic inflammation and cutaneous pathology, shaping disease-specific mechanisms such as Th2/IL-4/IL-13-mediated barrier dysfunction in AD and Th17/IL-23/IL-17-driven hyperproliferation in psoriasis. Microbiota-derived metabolites, including short-chain fatty acids, tryptophan-derived aryl hydrocarbon receptor ligands, and bile acid-dependent FXR/TGR5 signaling, modulate immune homeostasis and epithelial integrity. Gut dysbiosis, impaired metabolite production, and barrier dysfunction disrupt regulatory networks, amplifying inflammation. Microbiota-targeted interventions, including probiotics, synbiotics, postbiotics, and precision nutrition, may serve as adjunctive therapies, although further well-controlled clinical studies are needed. Integrating multi-omics, metabolomics, and functional microbial profiling, alongside investigations of the gut mycobiome and virome, will be critical to identify predictive biomarkers and optimize therapeutic strategies. These concepts remain mechanistically compelling but largely theoretical, requiring validation in longitudinal and interventional studies. Full article

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in the mouse anteroventral cochlear nucleus (AVCN) and to determine the underlying ion channel mechanisms. Whole-cell patch-clamp recordings were performed in acute brain slices obtained from postnatal day 12–17 mice. Bath application of serotonin (25 µM) induced membrane depolarization (~5 mV) and increased action potential firing. Pharmacological experiments demonstrated that antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors partially reversed the depolarization and reduced serotonin-induced inward currents, indicating that multiple receptor subtypes contribute to serotonergic excitation. Blockade of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with extracellular Cs⁺ suppressed approximately 95% of the serotonin-induced depolarization and inward current, implicating HCN channel-mediated Ih as a principal ionic mechanism. Serotonin significantly increased Ih amplitude. Analysis of steady-state activation revealed no statistically significant shift in V0.5; however, under near-resting membrane potential conditions, serotonin significantly reduced the slope factor of the activation curve, consistent with altered voltage sensitivity of Ih gating. Immunohistochemical analysis confirmed the presence of 5-HT1A, 5-HT2A, and 5-HT2C receptors in the AVCN. Together, these findings indicate that serotonergic excitation of AVCN stellate cells is mediated by coordinated activation of multiple 5-HT receptor subtypes and primarily involves modulation of HCN-dependent subthreshold membrane dynamics. Full article

Background: Post-episiotomy wound healing remains largely managed through supportive care, despite growing evidence that local biochemical conditions critically influence tissue regeneration. Lactic acid is of particular interest in this context because it is both an endogenous metabolic intermediate and a physiologic component of the vaginal microenvironment, where it contributes to acidic pH maintenance, microbial homeostasis, and mucosal protection. Beyond these local effects, lactate has emerged as a signaling metabolite involved in angiogenesis, immune regulation, and extracellular matrix remodeling, making it a relevant candidate for regenerative wound care. Methods: This narrative translational review integrates evidence from molecular biology, biomaterials science, and clinical obstetrics to examine the therapeutic potential of lactic acid-loaded hydrogels for post-episiotomy tissue repair. Literature from PubMed, Scopus, and Web of Science was analyzed to evaluate physicochemical design parameters, lactate-mediated signaling pathways, and available clinical outcomes. Results: Lactic acid may function both as a microenvironmental regulator and as a metabolic signal capable of stabilizing hypoxia-inducible factor-1α signaling, enhancing vascular endothelial growth factor expression, modulating macrophage polarization, and influencing fibroblast-mediated extracellular matrix synthesis. Hydrogel matrices provide tunable platforms for controlled lactate release, pH buffering, and mucosal compatibility. Clinical studies suggest improved epithelialization, reduced infection risk, and lower pain scores following topical lactic acid formulations in episiotomy repair. In parallel, platelet-rich plasma provides autologous growth factor enrichment that may complement regenerative signaling pathways. Conclusions: Integrating microenvironment stabilization through lactic acid-based hydrogels with biologically active regenerative strategies represents a promising direction for post-episiotomy wound healing. Further controlled trials and standardized biomaterial characterization are required to define optimal therapeutic protocols and confirm long-term clinical benefit. Full article