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Abstract Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.

ObjectivesThis study constructs a quantitative assessment model of the impact of the marine environment on the offensive mine-laying operational performance of unmanned underwater vehicles (UUV), and draws quantitative evaluation conclusions.MethodsFirst, the attributes of offensive mine-laying marine environment assessment are researched and the optimal model of the TOPSIS and set pair analysis (SPA) method are proposed on the basis of the combined weight of the fuzzy analytic hierarchy process (FAHP) and entropy weight method (EWM). The current situation of UUV deployment and its impact on the marine environment are then analyzed, and the risk indexes of the marine environment on the offensive mine-laying performance of UUVs are constructed with reference to the main evaluation indexes of the operational performance of traditional and unmanned offensive mine-laying. Finally, according to the existing research results on the impact of the marine environment on UUV systems, a quantitative model of the risk indicators is completed.ResultsThe feasibility of the method and model presented in this paper is verified through a simulation experiment that optimizes the marine environmental risk scheme of the determined UUV offensive mine-laying.conclusionsIt is more effective to disassemble the marine environmental risk indications in the offensive mine-laying stage, and more scientific to construct a quantitative model of marine environmental risk indications. The dynamic preference coefficient of the combined weight takes into account both the authority of decision-making and objectivity of data, and the influence of the same and opposite factors on scheme selection is considered. Finally, the feasibility of the algorithm is verified by the simulation results.

Background & Aims: The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. Methods: A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. Results: The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2′,5′ oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Conclusions: Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD–NRF2–OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Lay summary: Liver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

Pig islet xenotransplantation is a potential treatment for patients with type 1 diabetes. Current efforts are focused on identifying the optimal pig islet source and overcoming the immunological barrier. The optimal age of the pig donors remains controversial since both adult and neonatal pig islets have advantages. Isolation of adult islets using GMP grade collagenase has significantly improved the quantity and quality of adult islets, but neonatal islets can be isolated at a much lower cost. Certain culture media and coculture with mesenchymal stromal cells facilitate neonatal islet maturation and function. Genetic modification in pigs affords a promising strategy to prevent rejection. Deletion of expression of the three known carbohydrate xenoantigens (Gal, Neu5Gc, Sda) will certainly be beneficial in pig organ transplantation in humans, but this is not yet proven in islet transplantation, though the challenge of the ‘4th xenoantigen’ may prove problematic in nonhuman primate models. Blockade of the CD40/CD154 costimulation pathway leads to long-term islet graft survival (of up to 965 days). Anti-CD40mAbs have already been applied in phase II clinical trials of islet allotransplantation. Fc region-modified anti-CD154mAbs successfully prevent the thrombotic complications reported previously. In this review, we discuss (I) the optimal age of the islet-source pig, (ii) progress in genetic modification of pigs, (iii) the immunosuppressive regimen for pig islet xenotransplantation, and (iv) the reduction in the instant blood-mediated inflammatory reaction.

Abnormal activation of protein kinases and phosphatases is implicated in various tumorigenesis, including hepatocellular carcinoma (HCC). Advanced HCC patients are treated with systemic therapy, including tyrosine kinase inhibitors, which extend overall survival. Investigation of the underlying mechanism of protein kinase signaling will help to improve the efficacy of HCC therapy. Combining single-cell RNA sequencing data and TCGA RNA-seq data, we profiled the protein kinases, phosphatases, and other phosphorylation-related genes (PRGs) of HCC patients in this study. We found nine protein kinases and PRGs with high expression levels that were mainly detected in HCC cancer stem cells, including POLR2G, PPP2R1A, POLR2L, PRC1, ITBG1BP1, MARCKSL1, EZH2, DTYMK, and AURKA. Survival analysis with the TCGA dataset showed that these genes were associated with poor prognosis of HCC patients. Further correlation analysis showed that these genes were involved in cell cycle-related pathways that may contribute to the development of HCC. Among them, AURKA and EZH2 were identified as two hub genes by Ingenuity Pathway Analysis. Treatment with an AURKA inhibitor (alisertib) and an EZH2 inhibitor (gambogenic) inhibited HCC cell proliferation, migration, and invasion. We also found that both AURKA and EZH2 were highly expressed in TP53-mutant HCC samples. Our comprehensive analysis of PRGs contributes to illustrating the mechanisms underlying HCC progression and identifying potential therapeutic targets for future clinical trials.

Gastric cancer (GC) is a malignant disease of the digestive tract and a life-threatening disease worldwide. Ferroptosis, an iron-dependent cell death caused by lipid peroxidation, is reported to be highly correlated with gastric tumorigenesis and immune cell activity. However, the underlying relationship between ferroptosis and the tumor microenvironment in GC and potential intervention strategies have not been unveiled. In this study, we profiled the transcriptome and prognosis data of ferroptosis-related genes (FRGs) in GC samples of the TCGA-STAD dataset. The infiltrating immune cells in GC were estimated using the CIBERSORT and XCELL algorithms. We found that the high expression of the hub FRGs (MYB, PSAT1, TP53, and LONP1) was positively correlated with poor overall survival in GC patients. The results were validated in an external GC cohort (GSE62254). Further immune cell infiltration analysis revealed that CD4+ T cells were the major infiltrated cells in the tumor microenvironment of GC. Moreover, the hub FRGs were significantly positively correlated with activated CD4+ T cell infiltration, especially Th cells. The gene features in the high-FRG score group were enriched in cell division, DNA repair, protein folding, T cell receptor, Wnt and NIK/NF-kappaB signaling pathways, indicating that the hub FRGs may mediate CD4+ T cell activation by these pathways. In addition, an upstream transcriptional regulation network of the hub FRGs by lncRNAs was also developed. Three lncRNAs (A2M-AS1, C2orf27A, and ZNF667-AS1) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA A2M-AS1, C2orf27A, and ZNF667-AS1 may target the hub FRGs and impair CD4+ T cell activation, which finally leads to poor prognosis of GC. Effective interventions for the above lncRNAs and the hub FRGs can help promote CD4+ T cell activation in GC patients and improve the efficacy of immunotherapy. These findings provide a novel idea of GC immunotherapy and hold promise for future clinical application.

Targeted therapies such as oral tyrosine kinase inhibitors (TKIs) are the main therapeutic strategy effective for advanced hepatocellular carcinoma (HCC). Currently six tyrosine kinase inhibitors for HCC therapy have been approved. The newly approved first-line drug donafenib represent the major milestones in HCC therapeutics in recent years. However, drug resistance in HCC remains challenging due to random mutations in target receptors as well as downstream pathways. TKIs-based combinatorial therapies with immune checkpoint inhibitors such as PD-1/PD-L1 antibodies afford a promising strategy to further clinical application. Recent developments of nanoparticle-based TKI delivery techniques improve drug absorption and bioavailability, enhance efficient targeting delivery, prolonged circulation time, and reduce harmful side effects on normal tissues, which may improve the therapeutic efficacy of the TKIs. In this review, we summarize the milestones and recent progress in clinical trials of TKIs for HCC therapy. We also provide an overview of the novel nanoparticle-based TKI delivery techniques that enable efficient therapy.

Abstract The challenging synthesis of thermodynamic-unfavored cis-olefins through catalytic cross-coupling reactions requires the synergistic interaction of substrate-activating units and configuration-regulating catalysts. Successfully hitting these two birds with one stone, we herein develop a convenient photoredox access to Z-alkenes from alkynes and light alkanes with a bifunctional iron-catalyzed system possessing both C(sp3)−H activation and configuration-controlling abilities. The protocol exhibits 100% atom utilization, mild conditions, a broad substrate scope, and compatibility with multitudinous functional groups. The detailed reaction mechanism and the origin of geometry regulation are well investigated by experimental and computational studies. Progressively, a catalytic amount of diaryl disulfides is introduced for consecutive photoinduced Z−E isomerization via reversible radical addition and flipping. Big steric hindrance substituents assembled on the disulfide emerge necessity for suppressing double-bond migration. This tandem strategy paves a promising way for stereoselective alkene construction and will bring significant inspiration for the development of transition metal photocatalysis.

Abstract This study aimed to investigate the clinical outcomes of local muscle or myocutaneous flap transfer for emergent repair of Gustilo IIIB open tibiofibular fractures. This retrospective case series study included patients with Gustilo IIIB open tibiofibular fractures treated by local muscle or myocutaneous flap transfer in Weifang People’s Hospital between May 2016 and April 2021. Fifteenpatients (11 males aged 19–72 years) were included. The follow-up ranged from 8 to 24 months. The ranges of bone healing time and wound healing time were 6–17 months and 1–3 weeks, respectively. The length of hospital stay was 26 days (11–50 days). All patients reported acceptable functional recovery and satisfactory leg appearance, with Johner-Wruhs scores of excellent, good, and fair in 10, four, and one patients, respectively. The excellent-good rate was 93.3%. The complications included one case of infection and one case of nonunion. In conclusion, local muscle or myocutaneous flap transfer for emergent repair of Gustilo IIIB open tibiofibular fractures may be useful in providing adequate soft tissue coverage and fracture healing with low complication and infection rates.

Abstract Evaporation rates and land surface temperatures can be modified by planned water availability as well as land use and land cover changes. In general, a higher evaporation rate via its associated latent heat flux yields a cooler surface. Here we demonstrate that increasing energy at the land surface necessitates more intense latent heat fluxes for the same unit degree of surface cooling. When the wet-surface temperature is around 25 °C, a unit drop in land surface temperature requires about twice as much water to evaporate than when it is only 10 °C. As a consequence, today an estimated 5 ± 3% of extra water may be needed to evaporate globally for the same cooling effect as before the industrial era when near surface air temperature over land was about 1.5 °C cooler on average. This increase is a magnitude larger than what the thermal properties of water explain.

Abstract Objectives To develop and validate a quantitative model for predicting serosal invasion based on multi-parameters in preoperative dual-energy CT (DECT). Materials and methods A total of 342 LAGC patients who underwent gastrectomy and DECT from six centers were divided into one training cohort (TC), and two validation cohorts (VCs). Dual-phase enhanced DECT-derived iodine concentration (IC), water concentration, and monochromatic attenuation of lesions, along with clinical information, were measured and collected. The independent predictors among these characteristics for serosal invasion were screened with Spearman correlation analysis and logistic regression (LR) analysis. A quantitative model was developed based on LR classifier with fivefold cross-validation for predicting the serosal invasion in LAGC. We comprehensively tested the model and investigated its value in survival analysis. Results A quantitative model was established using IC, 70 keV, 100 keV monochromatic attenuations in the venous phase, and CT-reported T4a, which were independent predictors of serosal invasion. The proposed model had the area-under-the-curve (AUC) values of 0.889 for TC and 0.860 and 0.837 for VCs. Subgroup analysis showed that the model could well discriminate T3 from T4a groups, and T2 from T4a groups in all cohorts (all p

Abstract Global streamflow, crucial for ecology, agriculture, and human activities, can be influenced by elevated atmospheric CO2 (eCO2) though direct regulation of vegetation physiology and structure, which can either decrease or increase streamflow. Despite a 21.8% rise in CO2 over 40 years, its impact on streamflow is not obvious and remains highly debated. Using a full differential approach at the catchment scale and an optimum finger approach globally, both constrained by observed streamflow, here, we find that vegetation responses to eCO2 in 1981–2020 has limited impact on streamflow via direct regulation. The median eCO2 contribution approaches zero across 1116 unimpacted catchments, and global streamflow changes cannot be solely attributed to eCO2. These results offer key insights into the intricate dynamics of CO2 and other factors shaping streamflow changes over the past four decades. Such understanding is vital for attributing current streamflow changes under eCO2 conditions.

Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO2@Fe-TCPP, NPs) to produce FM@ORI@CaO2@Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.

Abstract Prediction of surface freshwater flux (precipitation or evaporation) in a CO2‐enriched climate is highly uncertain, primarily depending on the hydrological responses to physiological and radiative forcings of CO2 increase. Using the 1pctCO2 (a 1% per year CO2 increase scenario) experiments of 12 CMIP6 models, we first decouple and quantify the magnitude of global hydrological sensitivity to CO2 physiological and radiative forcings. Results show that the direct global hydrological sensitivity (for land plus ocean precipitation) to CO2 increase only is −0.09 ± 0.07% (100 ppm) −1 and to CO2‐induced warming alone is 1.54 ± 0.24% K−1. The latter is about 10% larger than the global apparent hydrological sensitivity (i.e., including all effects, not only direct responses to warming, ηa = 1.39 ± 0.22% K−1). These hydrological sensitivities are relatively stable over transient 2× to 4 × CO2 scenario. The intensification of the global water cycle are dominated by the CO2 radiative effect (79 ± 12%) with a smaller positive contribution from the interaction between the two effects (6 ± 12%), but are reduced by the CO2 physiological effect (−10 ± 8%). This finding underlines the importance of CO2 vegetation physiology in global water cycle projections under a CO2‐enriched and warming climate.

African swine fever virus (ASFV) causes highly contagious swine disease, African swine fever (ASF), thereby posing a severe socioeconomic threat to the global pig industry and underscoring that effective antiviral therapies are urgently required. To identify safe and efficient anti-ASFV compounds, a natural compound library was screened by performing an established cell-based ELISA in an ASFV-infected porcine alveolar macrophage (PAM) model. In total, 6 effective anti-ASFV compounds with low cytotoxicity were identified. Cepharanthine (CEP), a bisbenzylisoquinoline alkaloid, was the most potent inhibitor effect with an IC50 of 0.3223 μM. To further investigate the mechanism through which CEP inhibits ASFV replication, transcriptome profiles were generated in PAMs treated with CEP and/or infected with ASFV. ASFV infection dramatically altered immune response-associated gene expression. CEP treatment upregulated the expression of cholesterol biosynthesis-related genes, regardless of infection status. According to time-of-addition experiments, CEP primarily exerts its antiviral effect during the early stages of ASFV infection, specifically by inhibiting viral entry. Transcriptomic analysis suggested that CEP blocks ASFV entry through the clathrin-mediated endocytosis pathway by increasing EHD2 gene expression in macrophages. Disrupting EHD2 with small interfering RNA promoted ASFV entry into clathrin-positive vesicles. Finally, the protective effect of CEP in vivo was evaluated using ASFV-infected pigs. CEP could provide partial protection against ASFV infection, as indicated by an increase in survival time from 9.67 days to 16.67 days. Our findings imply that CEP exhibits potential antiviral activity against ASFV infection in PAMs, positioning it as a promising therapeutic strategy for ASF.

Study region: Yarlung Tsangpo River basin (YTRB) went through significant increases in precipitation, temperature and leaf area index (LAI) during 1982–2018. Study focus: This study aims to investigate the propagation effects of climate and vegetation change on actual evapotranspiration (AET) and streamflow signatures with simulation experiments using an improved hydrological model that couples a diagnostic evapotranspiration module. New hydrological insights: The improved hydrological model performs well in simulating streamflow, actual evapotranspiration and most streamflow signatures in six subcatchments of upper Nuxia region of YTRB (e.g. median Nash-Sutcliffe Efficiency of daily streamflow larger than 0.72). Changes in AET and streamflow are dominated by the long-term increase in precipitation (P), followed by considerable influence from the increase in LAI and marginal influence from the increase in temperature. Increases in both P and LAI have increased AET but caused wetting and drying effects on streamflow, respectively. LAI-induced increase in transpiration and interception evaporation is partly offset by the decrease in soil evaporation, resulting in marginal changes in AET. Subsequently, changes in streamflow signatures are amplified when propagating from AET to streamflow signatures, especially for those reflecting frequency and duration. This study advanced the understanding of the propagation effect of climate and vegetation variables on AET and streamflow signatures.

Emerging environmental persistent free radicals (EPFRs), can generate reactive oxygen species (ROS), posing potential exposure risks to human health. Incomplete coal combustion is a major source of EPFRs. Organic carbonaceous fractions are essential and important players in the formation of EPFRs during coal combustion. However, relationship between individual organic carbonaceous and non-carbon fractions with EPFRs in such emissions are not well known. This paper investigated the characteristics of EPFRs discharged from simulated coal combustion. Our results showed that the concentration of EPFRs was major concentrated on PM1.1 (51.66–81.85 %), and more easily oxidized by oxygen resulting in producing more oxygen-centered radicals (semiquinone-type) in PM1.1. The mean of line width (ΔHp-p) was 5.87 ± 0.41G higher than that of biomass combustion, indicating more free radical species were emitted from coal combustion. Humic-like substances-carbon (HULIS-C) was the major contributor of the formation of EPFRs and facilitate the generated of EPFRs. Secondary processes have also contributed to the formation of EPFRs during the coal combustion. Our result also noted that there was no relationship between transition metals and EPFRs, may be due to the variability and complexity of the chemical properties and composition of PM. This is critical for the prediction of geochemical behavior and risk assessment of EPFRs, which can provide basic data to support policy development to address rural air pollutant emissions.

Study area: The headwater catchment of the Yellow River (HCYR) (95°90′–103°42′E, 32°16′–36°13′N) is located on the northeast of the Tibetan Plateau, a presentative high-cold region catchment, China. Study focus: HCYR serves as the primary water supply during the dry season in downstream of the Yellow River Basin. Herein, we applied linear regression and the Bernaola-Galvan heuristic segmentation algorithm to identify the baseflow trends and abrupt changes. Four baseflow signatures (baseflow index (BFI), seasonal ratio (SR), concave index (CI), and slope of baseflow duration curve (SBDC)) were used to investigate the characteristics of baseflow changes and the drivers quantitatively. New hydrological insights for the region: The main findings are: (1) the baseflow generally exhibited an increasing trend (R2 > 0.35, p < 0.1), (2) baseflow variation has an apparent spatiality, and it shows a more pronounced change in the middle part than the upper and lower parts, and (3) precipitation, sunshine hours, soil moisture and evapotranspiration were the controlling factors on the baseflow characteristics. These findings provide a deeper insight into baseflow behavior and drivers in high-cold regions, which are vital for ecosystem health, water resource safety and management in critical headwater catchments.

Agroforestry intercropping is an effective way to optimize land use and ensure food security. However, the physiological mechanism by which the shading of dominant plants inhibits the yield of non-dominant plants in this mode remains to be investigated. A two-year location experiment of walnut-winter wheat intercrop combined with exogenous 6-benzyladenine (6-BA, the first synthetic cytokinin) treatment was conducted to reveal the mechanism of 6-BA in inhibiting wheat growth and yield formation under shade stress by measuring the photosynthetic characteristics, antioxidant capacity, hormone homeostasis of wheat flag leaves and yield. The results showed that compared with far canopy area (FCA), antioxidant enzyme activity [e.g. superoxide dismutase (SOD), peroxidase (POD)], zeatin (ZT) and abscisic acid (ABA) content and photosynthesis of wheat flag leaves were significantly reduced in below canopy area (BCA) treatment during flowering and grain filling stages, thereby inhibiting wheat dry matter accumulation and yield formation. Exogenous 6-BA significantly increased hormone [i.e. indoleacetic acid (IAA), ZT and gibberellin (GA)] levels, antioxidant enzyme activities and photosynthesis in flag leaves, thereby increasing dry matter and yield, especially in the FCA condition. Furthermore, net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci), activities of ribulose bisphosphate carboxylase (RuBPCase) and phosphoenolpyruvate carboxylase (PEPCase), ABA and ZT concentrations of flag leaves at flowering and filling stages had a significant contribution to yield formation under 6-BA and shade treatments. Overall, cytokinin regulates the inhibitory effects of shade stress on wheat photosynthesis, antioxidant capacity and hormone homeostasis to reduce wheat yield loss.

In recent years, the emergence and widespread dissemination of the coronavirus SARS-CoV-2 has posed a significant threat to global public health and social development. In order to safely and effectively prevent and control the spread of coronavirus diseases, a profound understanding of virus-host interactions is paramount. Cellular autophagy, a process that safeguards cells by maintaining cellular homeostasis under diverse stress conditions. Xenophagy, specifically, can selectively degrade intracellular pathogens, such as bacteria, fungi, viruses, and parasites, thus establishing a robust defense mechanism against such intruders. Coronaviruses have the ability to induce autophagy, and they manipulate this pathway to ensure their efficient replication. While progress has been made in elucidating the intricate relationship between coronaviruses and autophagy, a comprehensive summary of how autophagy either benefits or hinders viral replication remains elusive. In this review, we delve into the mechanisms that govern how different coronaviruses regulate autophagy. We also provide an in-depth analysis of virus-host interactions, particularly focusing on the latest data pertaining to SARS-CoV-2. Our aim is to lay a theoretical foundation for the development of novel coronavirus vaccines and the screening of potential drug targets.

ObjectiveThis study aims to report the application of 18F-AlF-NOTA-Octreotide PET/CT and 3D printing technology in the diagnosis and treatment of phosphaturic mesenchymal tumors (PMT) in patients with tumor-induced osteomalacia (TIO).Case presentationA 68-year-old male patient (Case 1) was admitted to the Weifang People’s Hospital in August 2022 with complaints of “persistent pain in the bilateral flank and lumbosacral region”. 18F-AlF-NOTA-Octreotide PET/CT showed high octreotide expression in the left femoral region. A 48-year-old male patient (Case 2) was admitted to the Weifang People’s Hospital in November 2022, complaining of “pain in the lumbar region and ribs”. 18F-AlF-NOTA-Octreotide PET/CT showed high octreotide expression in the pancreatic uncinate process and the left acetabulum. They were diagnosed with hypophosphatemic osteomalacia, with a strong consideration of an underlying neuroendocrine tumor. Preoperative design of 3D virtual surgery, CAD/CAM, and 3D printing technology were used to customize the digital surgical guide plates, and the surgery was carried out. They were both finally confirmed as phosphateuric mesenchymal tumors (PMT) based on postoperative pathology and immunohistochemistry results. Both patients experienced substantial relief from their clinical manifestations after surgery.Conclusion18F-AlF-NOTA-Octreotide PET/CT may be a precise diagnostic method for TIO, while 3D printing technology may serve as an effective and dependable adjunct for the treatment of PMT in patients with TIO.

This study aimed to assess the coherence between groundwater levels and various factors during two distinct periods, 2002–2020 and 2025–2050, in Miandoab aquifer in northwestern of the Iran. Partial wavelet coherence and multi-wavelet coherence analyses were employed to assess the coherence between individual parameters and their simultaneous coherence. The factors considered in the study were derived from remote sensing data, including Gravity Recovery and Climate Experiment data and Landsat data, which were utilized to examine water storage anomalies and anthropogenic activity, respectively. Additionally, General Circulation Models were employed to predict groundwater levels under future climate change scenarios via a feedforward neural network. To streamline the modeling process and categorize piezometers, with each group reflecting different patterns, clustering techniques were applied to group multiple piezometers. There were four final clusters, and representative piezometers from each cluster were chosen as targets for modeling and future predictions. Finally, the differences in coherence between past and future periods were compared and analyzed. The results revealed decreasing trends in groundwater level, precipitation and soil moisture index in 2025–2050; however, there were increasing trends in normalized difference vegetation index and temperature. In addition, wavelet analysis indicated that during the period 2025–2050, the delay in interaction between groundwater level and various factors decreased to 0–4 months, whereas longer delays were observed for the period 2002–2020. The analysis of multi- wavelet coherence showed that the combination of climate change and anthropogenic activity may have more significant coherence (0.9–1) with groundwater level than the combination of gravity recovery and climate experiment data and soil moisture index. The results highlight the greater significance of gravity recovery and climate experiment data in terms of coherence with groundwater levels compared to other factors.

Abstract Purpose Cutaneous metastasis (CM) accounts for 5–30% of patients with breast cancer (BC) and presents unfavorable response to treatment and poor prognosis. A better understanding of the molecular alterations involved in metastasis is essential, which would help identify diagnostic and efficacy biomarkers for CM. Materials : We retrospectively reviewed a total of 13 patients with histological or cytological diagnosis of breast cancer and CM. Clinical information was extracted from the medical records. The mutational landscape of matched primary tumors with their lymph nodes or CM tissues were analyzed using next-generation sequencing (NGS) of 425 cancer-relevant genes. All tissues were also analyzed by immunohistochemistry (IHC). The association of prognosis with various clinical and molecular factors was also evaluated. Results More than half of the patients were Ki67 low ( 50%) showed significantly shorter T1 than the Ki67 low group (≤ 50%) (median 12.5 vs. 50.0 months, P = 0.036). TP53, PIK3CA mutations, and TERT amplification group were associated with inferior T2 (median 11 vs. 36 months, P = 0.065; 8 vs. 36 months, P = 0.013, 7 vs. 36 months, P = 0.003, respectively). All p values were not adjusted. Conclusion We compared the genomic features of primary breast cancer tissues with their corresponding CM tissues and discussed potential genes and pathways that may contribute to the skin metastasis of advanced breast cancers patients. TP53, PIK3CA mutant, and TERT amplification may serve as biomarkers for poor prognosis for CM patients.

This work firstly oxidizes single-phase high entropy alloy (HEA) to form FCC and BCC dual-phase structure, and also introduces multi-component nano-oxides on surface to prepare oxidized HEA (OHEA) reinforcements, followed by preparation of OHEA/Al composites by spark plasma sintering. The introduction of O element accelerates interdiffusion between OHEA and Al matrix. FCC phase inside OHEA evolves into soft phase, and BCC matrix phase evolves into hard phase, forming heterogeneous interface in OHEA/Al composites. During tensile process, cracks preferentially initiated in hard phase due to severe stress concentration, and the soft phase effectively retarded crack propagation. Compared with 2024Al matrix, yield strength, tensile strength, and elongation of OHEA/Al composites increased by 35.31%, 57.34%, and 63.33%, respectively, realizing excellent combination of strength and toughness. Grain refinement, thermal mismatch, Orowan, and load transfer strengthenings synergistically improve the performance. The proposed method provides a promising avenue to optimize the properties of composites by pre-oxidizing HEA particles to construct heterogeneous interfacial structure.

Photovoltaic-powered drip irrigation is a vital approach to address the irrigation requirements in regions with limited water resources and energy deficiencies, thereby ensuring the provision of sustenance and horticultural produce for local inhabitants. However, the susceptibility of the drip irrigation system to clogging as well as the fluctuations in photovoltaic output can significantly impact irrigation quality. Moreover, conventional storage methods commonly employed in photovoltaic-powered drip irrigation systems, such as elevated water tanks and batteries, exhibit notable technological, economic, and environmental limitations. The present study introduces a novel photovoltaic drip irrigation technology (CAES-PVDI) that utilizes solar energy as the exclusive source of power, enabling stable and cost-effective high-quality drip irrigation. This technology actively regulates solar energy through compressed air energy storage, employing a cyclic pulse discharge method to ensure uniformity in irrigation outflow and significantly enhance the anti-clogging performance of the drip irrigation system. The proposed technology was implemented in a solar greenhouse for drip irrigation, and subsequent tests were conducted to assess its hydraulic performance and anti-clogging properties The results demonstrated that the system achieved a discharge uniformity of no less than 91.76 %. Furthermore, there was no blocked emitter in CAES-PVDI system, and the sedimentation inside the capillary tube decreased by 78.95 %-93.36 % compared to traditional drip irrigation system. In comparison to existing photovoltaic-powered drip irrigation technology, the CAES-PVDI system exhibited exceptional technical indicators and offered significant economic and environmental benefits, thereby presenting a novel approach to promote environmentally friendly and efficient operation of drip irrigation systems.

Oxytocin (OT) is a posterior pituitary hormone that, in addition to its role in regulating childbirth and lactation, also exerts direct regulatory effects on the skeleton through peripheral OT and oxytocin receptor (OTR). Bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), chondrocytes, and adipocytes all express OT and OTR. OT upregulates RUNX2, BMP2, ALP, and OCN, thereby enhancing the activity of BMSCs and promoting their differentiation towards OB rather than adipocytes. OT also directly regulates OPG/RANKL to inhibit adipocyte generation, increase the expression of SOX9 and COMP, and enhance chondrocyte differentiation. OB can secrete OT, exerting influence on the surrounding environment through autocrine and paracrine mechanisms. OT directly increases OC formation through the NκB/MAP kinase signaling pathway, inhibits osteoclast proliferation by triggering cytoplasmic Ca2+ release and nitric oxide synthesis, and has a dual regulatory effect on OCs. Under the stimulation of estrogen, OB synthesizes OT, amplifying the biological effects of estrogen and OT. Mediated by estrogen, the OT/OTR forms a feedforward loop with OB. Apart from estrogen, OT also interacts with arginine vasopressin (AVP), prostaglandins (PGE2), leptin, and adiponectin to regulate bone metabolism. This review summarizes recent research on the regulation of bone metabolism by OT and OTR, aiming to provide insights into their clinical applications and further research.

The annual prevalence of gastric cancer has increased in recent years. Curcumin (CUR) has shown great potential in the treatment of gastric cancer; however, its low bioavailability and poor efficacy hinder its widespread clinical application. Additionally, CUR has been found to be excellent photosensitizer in photodynamic therapy. In this study, the Fe-based metal-organic framework (MOF) Fe Tetrakis (4-carboxyphenyl) porphyrin (Fe-TCPP，FT) was used as a photosensitizer and mononuclear agent. The natural anti-tumor active ingredient CUR was loaded as both a chemotherapeutic agent and photosensitizer to form the nanoparticles CUR@FT (CF). Finally, a cell-penetrating peptide (CPP10) was modified on the surface of the nanoparticles to construct a drug delivery system (named CPP10-PEG@CUR@FT, CCF) that could actively target tumor cells while exerting a synergistic therapeutic effect of chemotherapy and photodynamic therapy. This can improve the efficacy of CUR as a chemotherapeutic drug or photosensitizer, and the high drug load and pH sensitivity of FT nanoparticles provide an excellent carrier for the efficient delivery of CUR. The polyethene glycol (PEG)-conjugated CPP10 (PEG-CPP10) coating allows nanoparticles to specifically target gastric cancer cells, significantly improving the absorption of nanoparticles in vivo and in vitro and improving biosafety. We evaluated the thermal stability, drug loading capacity, and safety of FT as a drug delivery vehicle. We also assessed the in vitro photodynamic performance and toxicity of various nanoparticles and the targeting and biocompatibility of CPP10-PEG@CUR@FT. CPP10-PEG@CUR@FT could specifically target tumor cells, and its effect on killing gastric cancer cells (MKN45) under light was much stronger than that of free CUR. Its toxicity and side effects to other organs and tissues are low, offering good biosafety. The experimental results showed that FT and CUR exerted synergistic effects on photodynamic therapy and chemotherapy. In summary, our novel CUR-loaded targeted nano drug delivery system offers significant advantages by combining photodynamic therapy and chemotherapy for tumor treatment. This approach introduces a new concept for integrating chemotherapy, photodynamic therapy and targeted drug delivery, potentially providing a new strategy for the clinical treatment of gastric cancer.

Due to the non-specific distribution of drugs in the body and the low concentration at the tumor site in traditional chemotherapy, there are challenges associated with significant side effects and tumor resistance. Therefore, a drug delivery system (DDS) urgently needs to be developed that can precisely target tumors. Metal-organic frameworks (MOFs) possess advantageous characteristics derived from organic and inorganic materials, including small particle size, large specific surface area, high drug loading capacity, adjustable structure and pore size, as well as ease of modification. Consequently, MOFs offer unique advantages for designing active targeting, passive targeting, and stimulus-responsive targeting strategies and have become a hot topic of current research on tumor-targeted drug delivery systems. This review will elaborate on the application of MOFs in tumor-targeted drug delivery systems from the perspective of different targeting strategies. We hope that this paper can provide assistance for tumor-targeted therapy.

Abstract This article introduces a high‐precision SAR echo simulation method aimed at providing a large‐scale SAR echo simulation algorithm that includes complex target information. This method independently simulates targets and ground clutter, calculating the shadow areas of targets and the dihedral effects between targets and the ground by constructing virtual rough surfaces and using ray tracing. Furthermore, this method can provide data sources for algorithms that improve detector performance using shadow or specular reflection characteristics. Finally, after comparing the simulation results with the publicly available MSTAR dataset, the experimental results show that this method ensures the accuracy of the results. This research provides a rich data source for the study of SAR detection and tracking algorithms and offers strong support for practical applications.

We have carried out modeling and computation of mass transfer in a membrane contactor for removal of organic compounds from aqueous solutions. Both computational fluid dynamics (CFD) and Artificial Intelligence (AI) methods were utilized for modeling separation process. For the AI, we explored the application of three distinct regression models, namely Kernel Ridge Regression, Gaussian Process Regression, and Poisson Regression to predict the concentration of a component, C, based on r and z. To enhance the performance of these models, the hyper-parameter tuning process employs Glowworm Swarm Optimization (GSO). The findings illustrate the effectiveness of the utilized models. Gaussian Process Regression achieves a noteworthy R2 score of 0.99791, with a RMSE of 3.9666×101(mol/m3) and an AARD% of 4.52000×10-1. Kernel Ridge Regression, while slightly less accurate, achieves a commendable R2 value of 0.97865, with an RMSE of 1.2446×102(mol/m3) and an AARD% of 2.63808. Poisson Regression offers a respectable performance, yielding an R2 score of 0.95509, along with an RMSE of 1.8011×102(mol/m3) and an AARD% of 4.28969. Moreover, the separation efficiency was estimated to be greater than 70 % using the membrane process.

Abstract High‐quality liquid gate‐all‐around (LGAA) silicon nanowire (NW) field‐effect transistor (FET) biosensors are fabricated and studied their properties in 1 mm phosphate‐buffered saline solution with pH = 7.4 using transport and noise spectroscopy. At small VDS, the conventional current behavior of FET with a linear dependence on voltage is registered in the output current‐voltage (I‐VM) characteristics with M = 1. At drain‐source voltage VDS > 0.6 V, the I‐V characteristics with stronger power M are revealed. It is shown that the current in LGAA NW FETs follows current proportional to voltage in power M = 4 dependence on small liquid gate voltages. Transport and noise spectroscopy analyses demonstrate that the obtained results are associated with the space‐charge‐limited current (SCLC) effect. Moreover, a strong two‐level random telegraph signal (RTS) is found in the region corresponding to SCLC at VDS values exceeding 0.6 V. The RTS related to single trap phenomena results in a well‐resolved Lorentzian component of noise spectra. The results demonstrate that the SCLC and two‐level RTS phenomenon are correlated effects. They should be taken into account during the development of single‐trap‐based devices, including biosensors.

Introduction: Osteochondral repair poses a significant challenge due to its unique pathological mechanisms and complex repair processes, particularly in bacterial tissue conditions resulting from open injuries, infections, and surgical contamination. This study introduces a biomimetic honeycomb-like scaffold (Zn-AlgMA@Mg) designed for osteochondral repair. The scaffold consists of a dicalcium phosphate dihydrate (DCPD)-coated porous magnesium scaffold (DCPD Mg) embedded within a dual crosslinked sodium alginate hydrogel (Zn-AlgMA). This combination aims to synergistically exert antibacterial and osteochondral integrated repair properties.Methods: The Zn-AlgMA@Mg scaffold was fabricated by coating porous magnesium scaffolds with DCPD and embedding them within a dual crosslinked sodium alginate hydrogel. The structural and mechanical properties of the DCPD Mg scaffold were characterized using scanning electron microscopy (SEM) and mechanical testing. The microstructural features and hydrophilicity of Zn-AlgMA were assessed. In vitro studies were conducted to evaluate the controlled release of magnesium and zinc ions, as well as the scaffold’s osteogenic, chondrogenic, and antibacterial properties. Proteomic analysis was performed to elucidate the mechanism of osteochondral integrated repair. In vivo efficacy was evaluated using a rabbit full-thickness osteochondral defect model, with micro-CT evaluation, quantitative analysis, and histological staining (hematoxylin-eosin, Safranin-O, and Masson’s trichrome).Results: The DCPD Mg scaffold exhibited a uniform porous structure and superior mechanical properties. The Zn-AlgMA hydrogel displayed consistent microstructural features and enhanced hydrophilicity. The Zn-AlgMA@Mg scaffold provided controlled release of magnesium and zinc ions, promoting cell proliferation and vitality. In vitro studies demonstrated significant osteogenic and chondrogenic properties, as well as antibacterial efficacy. Proteomic analysis revealed the underlying mechanism of osteochondral integrated repair facilitated by the scaffold. Micro-CT evaluation and histological analysis confirmed successful osteochondral integration in the rabbit model.Discussion: The biomimetic honeycomb-like scaffold (Zn-AlgMA@Mg) demonstrated promising results for osteochondral repair, effectively addressing the challenges posed by bacterial tissue conditions. The scaffold’s ability to release magnesium and zinc ions in a controlled manner contributed to its significant osteogenic, chondrogenic, and antibacterial properties. Proteomic analysis provided insights into the scaffold’s mechanism of action, supporting its potential for integrated osteochondral regeneration. The successful in vivo results highlight the scaffold’s efficacy, making it a promising biomaterial for future applications in osteochondral repair.

Abstract Predicting flood event classes aids in the comprehensive investigation of flood behavior dynamics and supports flood early warning and emergency plan development. Existing studies have mainly focused on historical flood event classification and the prediction of flood hydrographs or certain metrics (e.g., magnitude and timing) but have not focused on predicting flood event classes. Our study proposes a new approach for predicting flood event classes based on the class membership functions of flood regime metrics and hydrological modeling. The approach is validated using 1446 unimpacted flood events in 68 headstream catchments widely distributed across China. The new approach performs well, with class hit rates of 68.3% ± 0.4% for all events; 65.8% ± 0.6%, 56.8% ± 0.9%, and 69.5% ± 0.9% for the small, moderate and high spike flood event classes, respectively; and 82.5% ± 1.2% and 75.4% ± 1.1% for the moderate and high dumpy flood event classes, respectively. Furthermore, it performs better in the basins of northern China than in those of southern China, particularly for the small spike flood event class in the Songliao and Yellow River Basins, with hit rates of 80.0% ± 3.2% and 78.8% ± 3.2%, respectively. Our results indicate that the new approach will help improve the prediction performance of flood events and their corresponding classes, and provide deep insights into the comprehensive dynamic patterns of flood events for early warning and control management.

[INLINE:1] β-Sitosterol is a type of phytosterol that occurs naturally in plants. Previous studies have shown that it has anti-oxidant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, and anti-tumor effects, but it is unknown whether β-sitosterol treatment reduces the effects of ischemic stroke. Here we found that, in a mouse model of ischemic stroke induced by middle cerebral artery occlusion, β-sitosterol reduced the volume of cerebral infarction and brain edema, reduced neuronal apoptosis in brain tissue, and alleviated neurological dysfunction; moreover, β-sitosterol increased the activity of oxygen- and glucose-deprived cerebral cortex neurons and reduced apoptosis. Further investigation showed that the neuroprotective effects of β-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke. In addition, β-sitosterol showed high affinity for NPC1L1, a key transporter of cholesterol, and antagonized its activity. In conclusion, β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

UAVs have entered various fields of life, and object tracking is one of the key technologies for UAV applications. However, there are various challenges in practical applications, such as the scale change of video images, motion blur and too high shooting angle leading to the tracked objects being too small, resulting in poor tracking accuracy. To cope with the problem that small targets are poorly tracked by UAVs due to less effective information output from the deep residual network, a SiamMFF tracking method that introduces an efficient multi-scale feature fusion strategy is proposed. The method aggregates features at different scales, and at the same time, replaces the ordinary convolution with deformable convolution to increase the sense field of convolution operation to enhance the feature extraction capability. The experimental results show that the proposed algorithm improves the success rate and accuracy of small target tracking.

Background: Osteoarthritis (OA) is the most common joint disease worldwide, but its cause remains unclear. Oestrogen protects against OA, but its clinical use is limited. G protein-coupled receptor 30 (GPR30) is a receptor that binds oestrogen, and GPR30 treatment has benefitted patients with some degenerative diseases. However, its effects on OA prevention and treatment remain unclear. Moreover, several studies have found that activation of estrogen receptors exerting anti-ferroptosis effects, which plays an important role in chondrocyte survival. Therefore, this study explored the general and ferroptosis-related effects and mechanisms of GPR30 in OA. Methods: Genome-wide RNA sequencing, western blotting, and immunohistochemistry were used to evaluate GPR30 expression and ferroptosis-related indicators in cartilage tissues from clinical patients. Next, we investigated the effects of G1 (a GPR30 receptor agonist) on the function and pathology of OA in an animal model. We also treated chondrocytes with erastin (ferroptosis agonist) plus G1, G15 (GPR30 receptor antagonist), GPR30 short hairpin RNA, or ferrostatin-1 (ferroptosis inhibitor), then measured cell viability and ferroptosis-related indices and performed proteomics analyses. Finally, western blotting and reverse transcription-polymerase chain reaction were used to assess the effects of G1 on yes-associated protein 1 (YAP1) and ferritin heavy chain 1 (FTH1) expression. Results: GPR30 expression was lower in the OA cartilage tissues than in the normal tissues, and G1 treatment significantly improved the locomotor ability of mice. Moreover, chondrocyte cell viability significantly decreased after erastin treatment, but G1 treatment concentration-dependently mitigated this effect. Furthermore, G1 treatment decreased phosphorylated YAP1 expression, increased activated YAP1 expression, and increased FTH1 transcription and protein expression, protecting against ferroptosis. Conclusion: GPR30 activation inhibited ferroptosis in chondrocytes by suppressing YAP1 phosphorylation, which regulates FTH1 expression.The Translational Potential of this Article: These results provide a novel potential target for therapeutic OA interventions.