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Supply Chain Management (SCM) is an essential component of any successful enterprise’s supply chain. For a business’s continued operation and positive reputation, its well-organized product production and shipping processes are significant. With all the progress deep reinforcement learning has made in logistics, there are still models that cannot handle relational data in supply chain graphs or adapt quickly enough to new sustainability regulations. To bridge the gap, a Sustainability-aware Hierarchical Graph-driven Meta Reinforcement Learning Optimizer (SHG-MRLO) is proposed, integrating hierarchical policy architectures, Graph Neural Network (GNN), and meta learning for scalable adaptation and improved performance. The optimizer model supplies a supply chain as a dynamic graph, where a meta controller dynamically orchestrates decision strategies across multilevel graph-embedded states, ensuring robust adaptation to unexpected disruptions and demanding sustainability constraints. An experimental evaluation on benchmark datasets simulating a realistic supply chain scenario demonstrates that the proposed model achieves a 7.5% increase in on-time delivery, a 28.6% reduction in carbon emissions, and a path coverage rate of 93.3%, outperforming the baseline models. The presented SHG-MRLO technique can independently achieve SCM policies in the face of a complex, adaptive environment. This work contributes a scalable and interpretable framework for enhancing sustainable supply chain performance, merging the robustness of meta-learning with the expressiveness of graph-based modelling, and paves the way for the next generation of eco-efficient supply chain solutions.

This study investigated the effects of rumen-protected methionine (RPM) and rumen-protected choline (RPC) on energy balance, postpartum lactation performance, antioxidant capacity and immune response in transition dairy cows. Forty-eight multiparous transition cows were matched and divided into four groups: control, 15 g/d RPC, 15 g/d RPM or 15 g/d RPC + 15 g/d RPM. Diet samples were collected daily before feeding, and blood samples were collected weekly from the jugular vein before morning feeding from 21 days prepartum to 21 days postpartum. Postpartum dry matter intake (DMI) was increased by both additives (P < 0.05), and energy balance values in supplemented cows were improved after parturition (P < 0.05). Both RPC and RPM decreased the plasma concentrations of non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), but increased the plasma levels of glucose, very-low-density lipoprotein (VLDL) and apolipoprotein B100 (ApoB 100, P < 0.05). The supplements improved milk production (P < 0.05), and increased (P < 0.05) or tended to increase (0.05 < P < 0.10) the contents of milk fat and protein. The post-ruminal choline and methionine elevated the blood antioxidant status, as indicated by total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) activity and the vitamin E concentration (P < 0.05), and reduced the plasma malondialdehyde (MDA) level (P < 0.05). Furthermore, RPM and RPC elevated the plasma interleukin 2 (IL-2) concentration and the CD4+/CD8+ T lymphocyte ratio in peripheral blood (P < 0.05). Alternatively, the levels of tumor necrosis factor-α (TNF-α) and IL-6 were decreased by RPM and RPC (P < 0.05). Overall, the regulatory responses of RPC and RPM were highly correlated with time and were more effective in the postpartum cows. The results demonstrated that dietary supplementation with RPC and RPM promoted energy balance by increasing postpartal DMI and regulating hepatic lipid metabolism, improved postpartum lactation performance and enhanced antioxidant capacity and immune function of transition dairy cows.

Cytosolic free NAD/NADH ratio is fundamentally important in maintaining cellular redox homeostasis but current techniques cannot distinguish between protein-bound and free NAD/NADH. Williamson et al reported a method to estimate this ratio by cytosolic lactate/pyruvate (L/P) based on the principle of chemical equilibrium. Numerous studies used L/P ratio to estimate the cytosolic free NAD/NADH ratio by assuming that the conversion in cells was at near-equilibrium but not verifying how near it was. In addition, it seems accepted that cytosolic free NAD/NADH ratio was a dependent variable responding to the change of L/P ratio. In this study, we show (1) that the change of lactate/glucose (percentage of glucose that converts to lactate by cells) and L/P ratio could measure the status of conversion between pyruvate + NADH and lactate + NAD that tends to or gets away from equilibrium; (2) that cytosolic free NAD/NADH could be accurately estimated by L/P only when the conversion is at or very close to equilibrium otherwise a calculation error by one order of magnitude could be introduced; (3) that cytosolic free NAD/NADH is stable and L/P is highly labile, that the highly labile L/P is crucial to maintain the homeostasis of NAD/NADH; (4) that cytosolic free NAD/NADH is dependent on oxygen levels. Our study resolved the key issues regarding accurate estimation of cytosolic free NAD/NADH ratio and the relationship between NAD/NADH and L/P.

Wetland restoration and creation efforts have been widely attempted as a way to compensate for wetland losses and to recover wetland functions; however, to date, there has been no comprehensive evaluation of the efficacy of soil carbon (C) and nitrogen (N) content recovery at a regional scale. This meta-analysis synthesizes 48 articles to identify the general patterns of soil C and N change after wetland restoration and creation in the United States. Our results indicate that, after 11–20 years, soil C and N in restored and created wetlands are still significantly lower by 51.7% and 50.3%, respectively, than those in natural wetlands. The soil C and N in restored wetlands recovered faster than in created wetlands. Furthermore, the soil C in restored organic flat and created depressional wetlands recovered more rapidly than in restored and created hydrologically open wetlands (riverine and tidal), respectively. Mean annual temperature and soil texture were recognized as two crucial abiotic factors affecting soil C and N recovery. Linear regression analysis revealed a positive relationship between the restoration and creation effect sizes on soil C and N, indicating that wetlands may alleviate N limitations intrinsically during C recovery processes.

Frequency security is the premise of realizing the net‐zero transition. A novel assessment scheme is proposed to quantify the frequency security levels of transmission systems under different inverter‐based resources (IBRs) and their control parameter combinations. A novel system frequency dynamic model is proposed as a parametric optimization method, where the saturation of generators, energy storage systems, and renewable energy sources is incorporated as differential algebra equations. This problem is further reformulated as a mixed‐integer linear programming problem to generate a sufficient amount of data under different IBR integration and control parameters. The frequency security assessment problem is formulated as a data‐driven multivariate classification problem, which is solved by the optimal classification tree (OCT) algorithm with better interptretionability. Simulations are conducted on a transmission system. Numerical results indicate that the proposed system frequency dynamic model can capture the frequency dynamic under different IBR reinforcement plans and the OCT can realize accurate classification of the synthetic data regarding frequency security. A novel frequency dynamic problem is formulated as an MIP problem with differential algebra equations, where the inverter‐based resources (IBRs) integration and their non‐linear control characteristics can be captured. The frequency security assessment of transmission systems with different IBR combinations and their control characteristics is formulated as a multivariate classification problem. An optimal classification tree is constructed to explore the main drivers to boost frequency security from a holistic perspective, that is, planning, operation, and control.

Epi-immunotherapy appears promising for hepatocellular carcinoma (HCC) treatment, but immunosuppressive macrophages limit the capacity of epigenetic regulation to activate T cell-mediated tumoricidal immunity. Here we report an epi-immune nanosatellite (stEiNS) that co-delivers siRNA targeting the YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) alongside the histone deacetylase IIa inhibitor TMP195, enabling epigenetic reprogramming of HCC tumor cells and M2 macrophages to enhance the immunotherapeutic response. stEiNS assembles size-mismatched nanoparticles via dynamic locks in a satellite-like structure, enabling deep tissue penetration. Knockdown of YTHDF1 by stEiNS in HCC cells, along with stEiNS-driven antitumor macrophage phenotype induction, intensifies macrophages-cytotoxic T lymphocytes interactions with tumor cells. stEiNS suppresses TNF/NF-κB signaling in tumor cells to inhibit CCL2-driven recruitment of myeloid-derived suppressor cells while activating the IFNγ/STAT1 pathway in M2-phenotype macrophages to promote their polarization toward an M1 phenotype. Collectively, these effects trigger robust tumoricidal immunity, leading to efficient tumor eradication, as validated in patient-derived tumor organoids, orthotopic HCC models, and recurrence models. In summary, we establish a dual-targeting stEiNS with promising epi-immunotherapeutic potential against advanced HCC and diverse malignancies. Epi-immunotherapy appears promising for hepatocellular carcinoma (HCC) treatment, but the therapeutic efficacy is limited by the immunosuppressive tumor microenvironment. Here this group reports co-delivering siRNA targeting YTHDF1 and the histone deacetylase IIa inhibitor TMP195, which enables the epigenetic reprogramming of HCC tumor cells and macrophages repolarization to enhance the immunotherapeutic response against HCC.

The bottom frame masonry structure (BFMS) in a semi-ruined state is vulnerable to secondary collapse under strong aftershocks, posing a significant risk to rescuers during post-earthquake operations. Therefore, investigating the mechanisms and characteristics of secondary collapse of BFMS in a semi-ruined state (BFMS-SR) under aftershocks is critical. This paper proposes a numerical modeling framework for BFMS under mainshock-aftershock conditions, utilizing a combination of the finite element method (FEM) and the finite discrete element method (FDEM). The validation demonstrates that FEM–FDEM can effectively reproduce the transition of BFMS from an intact state to a semi-ruined state, ultimately leading to a secondary collapse state. Subsequently, the mechanisms and structural response characteristics of BFMS-SR under aftershocks are analyzed. The secondary collapse of the BFMS-SR under aftershocks is primarily governed by column hinge development. Furthermore, according to the time-history curve of absolute vertical velocity, the secondary collapse of BFMS-SR exhibits four distinct stages: stabilization, structural response development, secondary collapse, and post-collapse. The end of the stabilization phase is proposed as the early-warning threshold for secondary collapse of BFMS-SR under aftershocks, aiding in post-earthquake rescue operations.

The negative–positive-uncoupled stiffness device (NPUSD) is a novel variable stiffness system recently developed by the authors, designed to efficiently and cost-effectively achieve multi-level seismic fortification in structures. This study aims to integrate the NPUSD with a viscous damper in parallel, forming an innovative negative–positive-uncoupled stiffness amplifying damper (NPUSAD). Additionally, it establishes the collapse capacity spectra for a degrading single-degree-of-freedom (SDOF) system equipped with the NPUSAD under three distinct seismic record sets. The study investigates the influence of both the SDOF structural parameters and the NPUSAD parameters on the collapse capacity spectra. The results indicate that the NPUSAD-SDOF system significantly enhances the collapse resistance of long-period structures, with improvements of 30%, 40%, and 50% under far-field non-impulsive, near-field non-impulsive, and near-field impulsive seismic record sets, respectively. Among the parameters of structural element, the ductility ratio, soften stiffness coefficient, and stability coefficient have a significant impact on the collapse capacity spectra. For the NPUSAD parameters, the transition displacement ratio has the greater influence, followed by the positive-to-negative stiffness ratio, while the connecting stiffness ratio has the least impact.

A correlation between UA levels and the development of hypertension has been demonstrated. However, the relationship between UA and all-cause mortality in patients with hypertension remains underexplored. A nonlinear association between UA and all-cause mortality across sexes was observed through smoothed curve fitting. The correlation between UA and all-cause mortality was calculated by threshold and saturation effect analysis, along with Cox regression models. The stability of the results in the presence of different comorbidities was verified through stratified analysis for interaction testing. Smoothed curve fitting was also used to examine the association between UA and various diseases. The association between UA and all-cause mortality in patients with hypertension exhibited a U-shaped curve, with inconsistent inflection points between the sexes. In male patients with hypertension, all-cause mortality gradually decreased with increasing UA levels when UA levels were ≤ 7.2 mg/dL (HR  0.975; 95% CI 0.929–1.024) and gradually increased with increasing UA levels when UA levels were > 7.2 mg/dL (HR  1.204; 95% CI 1.120–1.294). Similar findings were observed in female patients with hypertension, with UA as a protective factor when UA levels were ≤ 5.1 mg/dL (HR 0.902; 95% CI 0.820–0.991) and a risk factor when UA levels were > 5.1 mg/dL (HR 1.120; 95% CI 1.072–1.169). The association between UA and all-cause mortality in patients with hypertension exhibits a U-shaped curve. All-cause mortality tends to decrease and then increase with increasing UA levels, with the inflection point varying between sexes.

BackgroundThe development of prostate cancer (PCa) remains a major health threat for men worldwide. Calcium/Calmodulin signaling pathway has been implicated to the initiation and progression of diverse human cancers. Loss or downregulation of Purkinje cell protein 4 (PCP4), is frequently observed in some prostate cancer patients, particularly those with castration-resistant prostate cancer (CRPC).MethodsPublic datasets were used to analyze PCP4 expression and the relationship between PCP4 expression and clinicopathological characteristics of PCa patients. Gain- and loss-of-function studies in PCa cell lines and mouse models were performed to characterize the role of PCP4 in tumor progression. A series of molecular and biochemical experiments were carried out in PCa cell lines to investigate the mechanism underlying PCP4-mediated tumor suppression.Results(1) PCP4 gene loss occurs at high frequency in PCa patients, and decreased expression of PCP4 correlates with poor prognosis of PCa, particularly CRPC development; (2) TMPRSS2-ERG fusion frequently co-occurs with PCP 4 deletion; (3) PCP4 suppresses prostate cancer progression in vitro and in vivo ; (4) PCP4 is an androgen receptor (AR) suppressed gene; (5) PCP4 was involved in the stabilization of CAMKK2 protein; (6) PCP4 inhibits PCa progression by regulating Ca2+/CAMKK2/AMPK/AR signaling axis.ConclusionOur findings elucidate the molecular mechanism that PCP4 downregulation promotes PCa progression via Ca2+/CAMKK2/AMPK/AR pathway, highlighting its significance in CRPC development.