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Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models. Current strategies to boost anti-tumor immune response include the use of immune checkpoint inhibitors and bispecific T cell-engaging antibodies. Here the authors describe a versatile antibody immobilization nanoplatform that can be used to deliver different combinations of immunotherapeutics, showing therapeutic superiority in pre-clinical models.

Background N6‐methyladenosine (m6A) is of great importance in renal physiology and disease progression, but its function and mechanism in renal fibrosis remain to be comprehensively and extensively explored. Hence, this study will explore the function and potential mechanism of critical regulator‐mediated m6A modification during renal fibrosis and thereby explore promising anti‐renal fibrosis agents. Methods Renal tissues from humans and mice as well as HK‐2 cells were used as research subjects. The profiles of m6A modification and regulators in renal fibrosis were analysed at the protein and RNA levels using Western blotting, quantitative real‐time polymerase chain reaction and other methods. Methylation RNA immunoprecipitation sequencing and RNA sequencing coupled with methyltransferase‐like 3 (METTL3) conditional knockout were used to explore the function of METTL3 and potential targets. Gene silencing and overexpression combined with RNA immunoprecipitation were performed to investigate the underlying mechanism by which METTL3 regulates the Ena/VASP‐like (EVL) m6A modification that promotes renal fibrosis. Molecular docking and virtual screening with in vitro and in vivo experiments were applied to screen promising traditional Chinese medicine (TCM) monomers and explore their mechanism of regulating the METTL3/EVL m6A axis and anti‐renal fibrosis. Results METTL3 and m6A modifications were hyperactivated in both the tubular region of fibrotic kidneys and HK‐2 cells. Upregulated METTL3 enhanced the m6A modification of EVL mRNA to improve its stability and expression in an insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2)‐dependent manner. Highly expressed EVL binding to Smad7 abrogated the Smad7‐induced suppression of transforming growth factor‐β (TGF‐β1)/Smad3 signal transduction, which conversely facilitated renal fibrosis progression. Molecular docking and virtual screening based on the structure of METTL3 identified a TCM monomer named isoforsythiaside, which inhibited METTL3 activity together with the METTL3/EVL m6A axis to exert anti‐renal fibrosis effects. Conclusions Collectively, the overactivated METTL3/EVL m6A axis is a potential target for renal fibrosis therapy, and the pharmacological inhibition of METTL3 activity by isoforsythiaside suggests that it is a promising anti‐renal fibrosis agent. Prefibrotic stimuli overactivate MELTT3 and m6A modifications in TECs and renal tissues. Upregulated METTL3 enhances the m6A modification of EVL mRNA through an IGF2BP2‐dependent mechanism. EVL binds to Smad7 to attenuate its inhibition of TGF‐β1/Smad3, which conversely promotes renal fibrosis. Inhibition of METTL3 and the METTL3/EVL m6A axis markedly alleviates renal fibrosis. Isoforsythiaside is a potential antifibrotic agent that inhibits the METTL3/EVL m6A axis.

Although efficiency analysis could reflect the state and quality of tourism’s economic development, no research has been conducted investigating the spatiotemporal evolution and mechanisms of county-level tourism efficiency. We quantified tourism efficiency and its decomposition in 63 counties of Zhejiang, employing the bootstrap data envelopment analysis (DEA), hot spot analysis, and quantile regression to explore the spatiotemporal evolution and influencing factors of tourism efficiency, and examine its driving and constraining mechanisms. The results uncovered obvious upward trends in the tourism efficiency of Zhejiang’s counties, with the mean value increasing from 0.285 to 0.688. Compared with scale efficiency, the influence of technological efficiency on the growth of comprehensive efficiency increased remarkably. Significant differences were evident in the spatial distributions of the identified hot and cold spots of comprehensive efficiency, which were respectively distributed in northern and southern Zhejiang. The distributions of decomposition efficiency were found to be spatially dependent. The driving mechanism of tourism efficiency involve two driving influences and two constraining influences, including economy and resource driving, market and traffic driving, industry and traffic constraining, and market and industry constraining. The findings of this study contribute to understanding of tourism efficiency growth in regional destinations and provide insights for strategic policymaking in various counties of Zhejiang.

Salicylic acid (SA) plays a crucial role in plant innate immunity. The deployment of SA-associated immune responses is primarily affected by SA concentration, which is determined by a balance between SA biosynthesis and catabolism. However, the mechanisms regulating SA homeostasis are poorly understood. In this study, we characterized a unique UDP-glycosyltransferase, UGT76D1, which plays an important role in SA homeostasis and associated immune responses in Arabidopsis (Arabidopsis thaliana). Expression of UGT76D1 was induced by treatment with both the pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 and SA. Overexpression of UGT76D1 resulted in high SA accumulation, significant up-regulation of pathogen-related genes, and a hypersensitive response (HR)-like lesion mimic phenotype. This HR-like phenotype was not observed following UGT76D1 overexpression in SA-deficient NahG transgenic or sid2 plants, suggesting that the phenotype is SA dependent. Biochemical assays showed that UGT76D1 glycosylated 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), the major catabolic forms of SA, to their Glc and Xyl conjugates in vitro and in vivo. Moreover, in a mutant background blocked in the formation of 2,3-DHBA and 2,5-DHBA, UGT76D1 overexpression did not cause a HR-like lesion mimic phenotype. Following infection with Pst DC3000, UGT76D1 knockout mutants displayed a delayed immune response, with reduced levels of DHBA glycosides and SA, and down-regulated SA synthase expression. By contrast, UGT76D1 overexpression lines showed an enhanced immune response and increased SA biosynthesis before and after pathogen infection. Thus, we propose that UGT76D1 plays an important role in SA homeostasis and plant immune responses by facilitating glycosylation of dihydroxybenzoic acids.

Plant systemic acquired resistance (SAR) provides an efficient broad-spectrum immune response to pathogens. SAR involves mobile signal molecules that are generated by infected tissues and transported to systemic tissues. Methyl salicylate (MeSA), a molecule that can be converted to salicylic acid (SA), is an essential signal for establishing SAR, particularly under a short period of exposure to light after pathogen infection. Thus, the control of MeSA homeostasis is important for an optimal SAR response. Here, we characterized a uridine diphosphate-glycosyltransferase, UGT71C3, in Arabidopsis (Arabidopsis thaliana), which was induced mainly in leaf tissue by pathogens including Pst DC3000/avrRpt2 (Pseudomonas syringae pv tomato strain DC3000 expressing avrRpt2). Biochemical analysis indicated that UGT71C3 exhibited strong enzymatic activity toward MeSA to form MeSA glucosides in vitro and in vivo. After primary pathogen infection by Pst DC3000/avrRpt2, ugt71c3 knockout mutants exhibited more powerful systemic resistance to secondary pathogen infection than that of wild-type plants, whereas systemic resistance in UGT71C3 overexpression lines was compromised. In agreement, after primary infection of local leaves, ugt71c3 knockout mutants accumulated significantly more systemic MeSA and SA than that in wild-type plants. whereas UGT71C3 overexpression lines accumulated less. Our results suggest that MeSA glucosylation by UGT71C3 facilitates negative regulation of the SAR response by modulating homeostasis of MeSA and SA. This study unveils further SAR regulation mechanisms and highlights the role of glucosylation of MeSA and potentially other systemic signals in negatively modulating plant systemic defense.

Key messageThis study revealed that the Arabidopsis UGT75B1 plays an important role in modulating ABA activity by glycosylation when confronting stress environments.The cellular ABA content and activity can be tightly controlled in several ways, one of which is glycosylation by family 1 UDP-glycosyltransferases (UGTs). Previous analysis has shown UGT75B1 activity towards ABA in vitro. However, the biological role of UGT75B1 remains to be elucidated. Here, we characterized the function of UGT75B1 in abiotic stress responses via ABA glycosylation. GUS assay and qRT-PCR indicated that UGT75B1 is significantly upregulated by adverse conditions, such as osmotic stress, salinity and ABA. Overexpression of UGT75B1 in Arabidopsis leads to higher seed germination rates and seedling greening rates upon exposure to salt and osmotic stresses. In contrast, the big UGT75B1 overexpression plants are more sensitive under salt and osmotic stresses. Additionally, the UGT75B1 overexpression plants showed larger stomatal aperture and more water loss under drought condition, which can be explained by lower ABA levels examined in UGT75B1 OE plants in response to water deficit conditions. Consistently, UGT75B1 ectopic expression leads to downregulation of many ABA-responsive genes under stress conditions, including ABI3, ABI5 newly germinated seedlings and RD29A, KIN1, AIL1 in big plants. In summary, our results revealed that the Arabidopsis UGT75B1 plays an important role in coping with abiotic stresses via glycosylation of ABA.

Using creativity to promote recreational services is crucial. Accordingly, creative linguistic landscapes (CLLs) are being used to improve visitors’ experiences in some recreational zones. However, relevant research is still in its early stages. Therefore, this study was conducted. It summarized the leisure function categories and function evaluation indicators of CLLs in recreational zones respectively based on image materials and related online reviews. The leisure function outcomes of all CLL types were ranked using the fuzzy PROMETHEE method; based on this ranking, a CLL configuration optimization mode was suggested. The findings reveal the following. (1) Currently, there are mainly nine leisure function types of CLL in practice, although the type structure is severely imbalanced; there are 12 primary corresponding function evaluation indicators, although each of them draws significantly different attention. (2) There are notable variations among the outcomes of different types of functions of CLL: mood adjustment is the most advantageous function of CLL for leisure services, followed by emotional guidance and cognitive building functions; (3) According to the study findings, in the configuration of CLL, which aims at leisure function optimization, the “function focusing and coordinating mode (the superior functions of CLL are focused on and its various functions are coordinated)” should be adopted. The results provide meaningful lessons for the establishment of rational and effective CLL in recreational zones.

Reservoir heterogeneity, fluid property variations, and permeability contrasts across different geological layers result in significant disparities in water absorption capacities during oilfield development, often leading to premature water breakthrough, uneven sweep efficiency, and suboptimal waterflooding outcomes. The accurate determination of layer-specific water injection volumes is critical to addressing these challenges. This study focuses on a study area in China, employing comprehensive on-site investigations to evaluate the current state of layered water injection practices. The injection allocation strategy was optimized using a hybrid approach combining the splitting coefficient method and grey correlation analysis. Key challenges identified in the study area include severe reservoir heterogeneity, poor injection–production correspondence, rapid water cut escalation, and low recovery rates. Seven dominant influencing factors—the sedimentary microfacies coefficient, effective thickness, stimulation factor, well spacing, permeability, connectivity, and permeability range coefficient—were identified through grey correlation analysis. Field application of the proposed method across fourteen wells demonstrated significant improvements: a monthly oil production increase of 40 tons, a water production reduction of 399.24 m3/month, and a 2.45% decline in the water cut. The obtained results substantiate the method’s capability in resolving interlayer conflicts, optimizing oil recovery performance, and effectively controlling water channeling problems.

Whether hydraulic fractures could connect multiple gas zones in the vertical plane is the key to fracturing treatment to jointly exploit coalbed methane and tight sandstone gas through integrative hydraulic fracturing in tight sandstone–coal interbedded formations. Laboratory true triaxial hydraulic fracturing experiments were conducted on layered specimens with different combination types of natural sandstone and coal to simulate the propagation behavior of hydraulic fractures. The effects of the fracture initiation position, fracturing fluid viscosity and injection rate were discussed. The results showed that different fracture morphologies could be found. When initiating from coal seams, three patterns of fracture initiation and propagation were obtained: (1) The main hydraulic fracture initiated and propagated along the natural fractures and then diverged due to the effects of in situ stress and formed secondary fractures. (2) The hydraulic fracture initiated and propagated in the direction of the maximum horizontal stress. (3) Multiple fractures initiated and propagated at the same time. With the same fracturing fluid viscosity and injection rate, the hydraulic fractures initiating in sandstones had greater chances than those in coal seams to penetrate interfaces and enter neighboring layers. Excessively small or large fracturing fluid viscosity and injection rate would do harm to the vertical extension height of the induced fracture and improvement of the stimulated reservoir volume. Compared with operation parameters (fracturing fluid viscosity and injection rate), the natural weak planes in coals were considered to be the key factor that affected the fracture propagation path. The experimental results would make some contributions to the development of tight sandstone–coal interbedded reservoirs.

Key message Rice glycosyltransferase gene UGT2 was identified to play a crucial role in salt tolerance. The transcription factor OsbZIP23 was demonstrated to regulate the UGT2 expression under stress conditions.UDP-glycosyltransferases (UGTs) play key roles in modulating plant responses to environmental challenges. In this study, we characterized a novel glycosyltransferase, UGT2, which plays an important role in salt stress responses in rice (Oryza sativa L). We found that seedlings overexpressing UGT2 exhibited better growth than wild type in shoot and root under hydroponic culture with salt stress treatments, while ugt2ko mutant lines suffered much more growth inhibition. When the soil-grown UGT2 transgenic plants were subjected to salt stress, we also found that ugt2ko mutant lines were severely withered and most of them died, while the overexpression lines grew well and had higher survival rate. Compared with wild-type plants, UGT2 overexpression greatly increased the expression levels of the reactive oxygen species scavenging genes and stress-responsive genes. Furthermore, the upstream regulatory mechanism of the UGT2 gene was identified and we found that a bZIP transcription factor, OsbZIP23, can bind to the UGT2 promoter and enhance the UGT2 transcription levels. This work reveals that OsbZIP23-UGT2 module may play a major role in regulating the salt stress tolerance in rice.