Search Results (9,693)

The incidence and mortality of hepatocellular carcinoma (HCC) are increasing worldwide, underscoring the need for novel therapeutic strategies. Synthetic 2-naphthyl 2-butanamido-2-deoxy-1-thio-β-d-glucopyranoside (612) is a selective inhibitor of β1,4-galactosyltransferase 1 (β4GalT1). In this study, we investigated the cytotoxic effects of 612 across multiple cancer cell lines, with a focus on HCC, and explored the underlying mechanisms. We demonstrate that 612 preferentially exhibits cytotoxicity toward cancer cells with elevated expression of β4GalT family members, while human umbilical vein endothelial cells and immortalized human embryonic kidney epithelial cells are comparatively less sensitive. Treatment with 612 suppresses cancer cell migration and invasion and induces pronounced endoplasmic reticulum and Golgi stress, accompanied by G2/M cell cycle arrest. Furthermore, 612 activates apoptosis through ER stress–associated pathways by downregulating the anti-apoptotic protein Bcl-2 and upregulating pro-apoptotic proteins Bax and Bak, along with activation of caspase-3, -8, and -9. Collectively, these findings identify 612 as a promising anti-cancer candidate targeting β4GalTs-overexpressing HCC cells and warrant further therapeutic development. Full article

Green innovation efficiency (GIE) serves as a key indicator of urban development toward “dual carbon” goals and sustainable growth. However, systematic evidence remains scarce regarding the impact of the digital-real economy integration (DRI) in urban green innovation efficiency (UGIE). Based on the dual institutional perspectives of government environmental regulation (ER) and intellectual property protection (IPP), this paper proposes an integrated theoretical framework that incorporates integration level, institutional environment, and green innovation. Leveraging panel data from 281 prefecture-level and higher-administered cities in China spanning 2013 to 2023, this paper explores the underlying mechanism and the observed threshold effect of DRI on UGIE. The primary findings are summarized below: (1) DRI promotes UGIE, which is mediated significantly through the institutional roles of ER and IPP. (2) The influence of DRI on GIE is characterized by a threshold effect at a value of 0.9657. Beyond this threshold, the marginal effect rises from 0.47463 to 0.52555, thereby providing evidence for the positive feedback hypothesis between integration level and institutional response. (3) A more significant effect of DRI on GIE could be observed in non-resource-based cities, such as the central cities, southern cities and eastern cities. This paper expands the interdisciplinary research on digital economy and urban sustainability, providing micro-level evidence for the tailored development of digital–green institutional combinations. Full article

Ant Colony Optimization (ACO) is a widely adopted metaheuristic for solving complex combinatorial problems; however, performance is often deteriorated by premature convergence and limited exploration in later iterations. Eclipse Randomness–Ant Colony Optimization (ER-ACO) is introduced as a lightweight ACO variant in which an exponentially fading randomness factor is integrated into the state-transition mechanism. Strong early-stage exploration is enabled, and a smooth transition to exploitation is induced, improving convergence behavior and solution quality. Low computational overhead is maintained while exploration and exploitation are dynamically balanced. ER-ACO is positioned within real-time healthcare logistics, with a focus on Emergency Medical Services (EMS) routing and hospital resource scheduling, where rapid and adaptive decision-making is critical for patient outcomes. These systems face dynamic constraints such as fluctuating traffic conditions, urgent patient arrivals, and limited medical resources. Experimental evaluation on benchmark instances indicates that solution cost is reduced by up to 14.3% relative to the slow-fade configuration ($\gamma =1$) in the 20-city TSP sweep, and faster stabilization is indicated under the same iteration budget. Additional comparisons against Standard ACO on TSP/QAP benchmarks indicate consistent improvements, with unchanged asymptotic complexity and negligible measured overhead at the tested scales. TSP/QAP benchmarks are used as controlled proxies to isolate algorithmic behavior; EMS deployment is treated as a motivating application pending validation on EMS-specific datasets and formulations. These results highlight ER-ACO’s potential as a lightweight optimization engine for smart healthcare systems, enabling real-time deployment on edge devices for ambulance dispatch, patient transfer, and operating room scheduling. Full article

Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation. Full article

Background: The tumor microenvironment (TME), composed of diverse immune and stromal cells, plays a key role in cancer progression. Among its components, tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR) have emerged as important modulators of tumor behavior. While each has been extensively studied, their interrelationship and association with tumor grade and clinicopathological parameters remain unclear. Aim: This hypothesis-generating study aimed to explore the relationship between the presence of TANs, various types of DR, the grade of tumor malignancy, and other fundamental clinicopathological characteristics commonly studied in daily clinical practice. Materials and Methods: The study included a cohort of 65 cancer patients (N = 65). The average number of TANs was recorded. In hematoxylin and eosin (H&E)-stained sections, “hot spots” representing areas with the highest neutrophil density were first identified. The tumor-associated polymorphonuclear neutrophils were then counted in ten consecutive high-power fields (HPFs). In the same specimens, the DR was assessed and classified according to stromal texture. Results: TANs did not follow a normal distribution across any clinicopathological category (p < 0.05). Significant differences in TAN levels were observed among DR types (Kruskal–Wallis H = 9.890, p = 0.007), with higher counts in myxoid compared to mature stroma (Mean Rank = 41.58 vs. 24.80, p = 0.006). TAN levels also varied significantly with tumor grade (H = 22.384, p < 0.001), increasing from Grade 1 to Grade 3 (p < 0.013–0.001). Higher TAN counts were associated with cellular erythroblastic oncogene B2 (c-erbB2) positivity (H = 6.547, p = 0.038), perineural invasion (Mann–Whitney U = 179.5, p < 0.001), and ER/PR negativity (p = 0.016 and p = 0.044, respectively). No significant association was found with necrosis (p = 0.083). A near-significant relationship was identified between DR type and tumor differentiation grade (χ² = 9.448, p = 0.051), with mature stroma most common in Grade 1 tumors, keloid-like stroma in Grade 2, and myxoid stroma in Grade 3. Conclusions: High TAN levels were linked to aggressive tumor features and specific DR patterns. The association of myxoid stroma with elevated TAN infiltration may reflect a highly aggressive TME. These preliminary results warrant validation in larger, prospective studies. Full article

To ensure food security, integrated mulching and irrigation practices are widely used in arid maize fields. Mitigating climate change is vital for sustainable agricultural development. Yet, few studies have examined how different mulching and irrigation methods affect farmland carbon fluxes, particularly with maize variety shifts under policy guidance. In this study, we conducted experimental observations over five growing seasons using eddy covariance systems in maize fields (including seed maize fields and grain maize fields), where drip irrigation under plastic mulch (DM) and border irrigation under plastic mulch (BM) were employed in Northwest China. Results revealed that the multi-year mean gross primary productivity (GPP), net ecosystem productivity (NEP), and ecosystem respiration (ER) in maize fields under DM were 16.70%, 15.63% and 17.52% higher than those under BM, respectively. The changes in cumulative GPP, cumulative NEP and cumulative ER caused by the alteration of maize varieties were 7.64, 13.34 and 4.20 times, respectively, compared to the changes caused by the irrigation method. After mechanical harvesting, net biome productivity (NBP) was negative in seed maize fields but positive in grain maize fields. However, after the straws were returned to the fields, the NBP of both types of maize fields became positive. Interestingly, the carbon fluxes of seed maize and grain maize, respectively, exhibit strong dependence on soil temperature and leaf area index. Our study will provide important insights for the green and sustainable development of agriculture and the advancement of ecosystem models. Full article

Tropical Andean forests are biodiversity hotspots that have been transformed by anthropogenic activities, making ecosystem regeneration and restoration essential for their recovery. This study evaluated floristic composition, forest structure, and diversity in three land cover types within tropical Andean ecosystems: riparian forest (RF), natural regeneration (NR), and ecological restoration areas (RE). Vegetation was inventoried using standardized plots, recording species composition, diameter, and height. Basal area, size class distribution, and vertical structure were estimated. The Shannon Wiener and Simpson indices were evaluated. RF showed the highest structural complexity and basal area among the evaluated cover types, followed by ER, whereas NR showed the lowest values. NR showed the highest diversity values and a predominance of individuals in lower diameter and height classes, reflecting active recruitment and intermediate successional stages. Segment ER exhibited lower diversity and intermediate structural development, consistent with shorter recovery periods and limitations in restoration design. Overall, the integration of floristic, structural, and diversity attributes indicates distinct successional trajectories, conditioned by land-use history, disturbance intensity, and environmental heterogeneity. These findings highlight the great potential for natural regeneration under reduced anthropogenic pressure and emphasize the need to integrate passive and active restoration strategies to enhance biodiversity and resilience in Andean tropical forests. Full article

This study investigated the cytotoxic, antiproliferative, and molecular interaction profiles of the phenylpropanoids verbascoside and isoverbascoside from Pyrostegia venusta using in silico approaches. Computational predictions suggested differential cytotoxicity trends between tumor and non-tumor breast cell models compared with tamoxifen. QSAR analyses indicated antiproliferative potential, while docking studies revealed stable ligand–protein interactions with estrogen-related targets and PTEN. ADMET predictions suggested favorable metabolic characteristics, including limited CYP3A4 interaction. Overall, these results provide predictive insights that support further experimental investigation of these phenylpropanoids in ER⁺ breast cancer models. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and inflammation play important roles in hepatic lipid accumulation. Although CILP2 has been implicated in lipid metabolism, its role in MASLD remains unclear. Hepatic steatosis was induced in mice by a high-fat diet in this study. CILP2 was overexpressed in mouse livers and in vitro hepatocytes using the Ad-CILP2 adenovirus. CILP2 KO mice were also used in the experiments. Liver tissues and hepatocytes were collected for further analysis. CILP2 expression was upregulated in steatotic liver tissue and hepatocytes. CILP2 overexpression upregulated genes related to fatty acid synthesis (Srebp-1c, Fasn, Acc, Scd1, and Cd36), promoted lipid accumulation, and elevated the expression of proinflammatory cytokines (Il6, Tnf, and Il1b). Conversely, CILP2 knockout reduced high-fat diet-induced hepatic steatosis and improved glucose metabolism. Mechanistically, CILP2 activated the IRE1α/XBP1 branch of the ER stress pathway, thereby promoting lipid synthesis and inflammation, effects that were partially alleviated by 4-PBA and STF-083010 treatments. Our findings indicate that CILP2 contributes to hepatic lipid accumulation and inflammation via the IRE1α/XBP1 pathway and may represent a potential therapeutic target for MASLD intervention. Full article

The present study intends to evaluate the ratcheting of ER9 wheel medium carbon steel and austenitic steel samples at room and elevated temperatures subjected to uniaxial loading cycles through the use of the Ahmadzadeh–Varvani (A–V) kinematic hardening rule. The A–V framework incorporated an exponential function in the dynamic recovery term to account for the dynamic strain aging (DSA) phenomenon at temperatures where solute atoms and moving dislocations showed increased interaction. Within the DSA domain at 573K for ER9 wheel steel samples, and at 423K for austenitic steel samples, the collision of carbon and nitrogen solute atoms with moving dislocations resulted in the materials hardening, and promoted the yield strength. The Voyiadjis–Song–Rusinek (VSR) multivariable model was used to capture the evolution of yield strength with temperature. The predicted ratcheting results within the DSA temperature domain were in close agreement with those of measured values. Full article

Expansins are crucial cell wall-loosening proteins that play a vital role in various plant developmental processes, including fruit ripening and softening. However, a comprehensive genome-wide analysis of the expansin family in apple (Malus × domestica) and the specific functions of its members in postharvest fruit ripening remain to be explored. In this study, we identified 51 expansin genes in the apple genome and classified them into four subfamilies (EXPA, EXPB, EXLA, and EXLB). Cis-element analysis of the promoters of apple expansin genes showed that these promoters are rich in various hormone-responsive elements, including abscisic acid (ABA)-responsive elements (ABREs) and ethylene-responsive elements (EREs), suggesting potential hormonal regulation of expansin genes. Expression profiling identified six ripening-associated expansin genes. Among them, MdEXPA5, MdEXPA17, and MdEXPA23 were positively regulated by both ethylene and ABA, while being suppressed by the ethylene action inhibitor 1-MCP. Further functional characterization demonstrated that transient overexpression of MdEXPA17 accelerated fruit softening, skin yellowing, ethylene production, and increased total soluble solid (TSS) content. Conversely, silencing of MdEXPA17 significantly delayed these ripening processes. Our study provides a systematic overview of the apple expansin gene family and supports a role for MdEXPA17 in promoting postharvest fruit ripening and softening. These findings offer valuable insights into the molecular mechanisms of apple fruit ripening and provide potential targets for genetic improvement of fruit quality and shelf life. Full article

Most primitive religions originated from the devout worship of celestial deities, earthly spirits, and ghosts. In oracle bone inscriptions, rituals related to praying for rain, temple worship, river deity worship, and the worship of great deities were referred to as “fang” 方 or “yi fang” 以方. The Supreme God was the paramount deity of the Yin Shang Dynasty people; by the early Zhou Dynasty, the Supreme God and ancestral spirits began to merge. The hexagram of Contemplation 觀卦 (guan gua) establishes instruction through the concept of “contemplation” fully presenting the entire process of shamans, sorcerers, or ritual hosts participating in temple sacrifices, and completing the hand-washing ritual 盥 (guan) and the sacrifice-offering ritual 薦 (jian). It emphasizes the sincere communication between humans and Heaven. When a monarch performs the guan ritual, he embodies inner “sincerity and clarity” 誠明 (chengming); in response, the celestial deities will “show trust” 有孚 (youfu). Thus, it can be verified that deities exist in Heaven, and an interactive, responsive relationship is formed between Heaven and humans. The nine in the fifth place (the dominant line) possesses great inspiring power. The two fundamental dimensions for interpreting the hexagram structure are “the great view is above” 大觀在上 (da guan zai shang) and “[t]hose below look toward him and are transformed” 下觀而化 (xia guan er hua). These dimensions not only highlight the infinite transcendence, charisma, and appeal of the worshipped deities but also underscore humans’ profound reverence and faith in deities and the absolute existence. Sages 聖人 (sheng ren), as intermediaries between humans and deities, established religion for the sake of human life but did not regard themselves as religious leaders. However, from the Shang and Zhou dynasties to the Spring and Autumn period, a transition occurred in the spiritual life of the Chinese people: from shamanism to ritual propriety 禮 (li), and from theistic culture to humanistic culture. This transition laid the fundamental direction for the development and evolution of Chinese culture over the following 2500 years. Confucius attempted to replace or eliminate the shamanistic elements in early Confucians with personalized moral experience and ethical consciousness. Full article

Hepatitis C virus (HCV) still lacks a licensed vaccine. The envelope glycoprotein E2 is a key neutralizing target, but its dense N-glycan shield can hinder epitope exposure. In this study, we revisit E2 glycan editing and examine whether single-site deletion preserves antigen integrity while improving immune responses in mice under a DNA immunization setting. Using a secreted E2 ectodomain (sE2384–661), we generated five N to D mutants at conserved sites (N1, N2, N4, N6, and N11) and evaluated them in a unified DNA immunization model with identical CpG content and delivery conditions across groups. The N2 mutant (N423, sE2-N2) maintained expression, secretion, and ER localization; furthermore, in mice, it was associated with higher anti-E2 titers and greater inhibition of H77 (genotype 1a) HCVcc at the tested dilutions, with limited activity against Con1 (1b). Cellular analyses showed increased IFN-γ ELISPOT counts and higher frequencies of granzyme B⁺/perforin⁺ CD8⁺ T cells after N2 immunization, while IL-4 remained low. Functionally, N2 elicited stronger specific lysis of CT26-sE2 targets in vitro and slowed CT26-sE2 tumor growth in vivo. In HCV-infected ICR^4R+ mice, therapeutic vaccination with sE2-N2 reduced blood HCV RNA and hepatic readouts compared with sE2. A monoclonal antibody isolated from sE2-N2-immunized mice (1C1) neutralized HCVcc in vitro and, after passive transfer, lowered viremia and liver signals in infected mice. Collectively, these findings indicate that selective removal of the N2 glycan preserves antigen properties and is associated with improved humoral and cellular immunity and measurable in vivo activity, supporting targeted glycan editing as a practical strategy to refine E2-based HCV vaccines. Full article

The endoplasmic reticulum (ER) is critical in aiding cells in ensuring that proteins are folded and processed correctly, particularly during stressful situations. ER oxidoreductin-1 alpha (ERO1α) is an enzyme that is responsible for the formation of disulfide bonds during protein folding, along with protein disulfide isomerase (PDI). This redox pathway is often highly upregulated in cancer cells, allowing tumors to survive harsh conditions such as hypoxia and nutrient deprivation. This review discusses the role of the ERO1α–PDI system in cancer development through the regulation of oxidative stress, redox homeostasis, and tumor plasticity. It further shows the therapeutic potential of interrupting the ERO1α–PDI axis, which could lead to protein misfolding; enhanced generation of reactive oxygen species (ROS); and, eventually, cancer cell death. Full article

Calcium (Ca²⁺)signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca²⁺ homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca²⁺ dynamics associated with epileptiform activity. ER Ca²⁺ levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca²⁺ oscillations. VPA induced a concentration-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP₃R-mediated Ca²⁺ mobilization from the endoplasmic reticulum and identify ER Ca²⁺ release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca²⁺ signaling and excitability in epilepsy. Full article