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Abstract The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.

Recently, some travertine landscape groups in Huanglong Scenic Spot have been degraded to varying degrees. Surface water leakage, blackening and desertification have occurred on a large scale in the dense distribution area of Salix cupularis shrub, which has adversely affected the core value of the Huanglong World Natural Heritage Site. The relationship between shrub expansion and leakage enhancement has not been fully understood. In this study, travertine pool group of typical shrub area was selected in the north of Yingyue Pool in the upper reaches of Huanglong, and 4 shrub cover levels were set: no shrub (coverage 60%). In-situ infiltration test was conducted to determine the leakage intensity and to evaluate the changes of travertine pore structure and permeability parameters in shrub area. With the comparison of the leakage intensities in different shrub cover level areas, the mechanism of surface water leakage of travertine under the influence of Salix cupularis scrub is summarized. The results show that (1) the leakage intensity increases with the increase of coverage. When the coverage of Salix cupularis shrub exceeds 60%, the leakage intensity changes significantly, which should be related to the rapid diversion of large pores. (2) Under the influence of algae activities and decomposition of plant residues, new travertine with more pores and holes is formed in the scrub area, resulting in higher natural leakage intensity than that in the non-scrub area. (3) The root activities of Salix cupularis shrub changes the primary travertine structure, leading to loose primary travertine and increases of pore diameter, effective porosity, and permeability coefficient. The enhanced groundwater seepage resulted in enhanced overall surface water leakage in the travertine pool. (4) The transformation of travertine pore structure by Salix cupularis roots is depended on the root cleavage. The dissolution of travertine cement by root solution leads travertine to uniform loose accumulation. The results show that the root and algal activities in Salix cupularis scrub area mainly control the process of surface water leakage enhancement. This study have basic value for the evolution analysis and conservation of Huanglong travertine natural heritage landscape.

Abstract Background Toxoplasmosis, caused by Toxoplasma gondii , poses serious health issues for humans and animals. Individuals with impaired immune systems are more susceptible to severe toxoplasmosis. Pregnant women infected by T. gondii can face the possibility of birth defects and miscarriages. While pyrimethamine and sulfadiazine are commonly used drugs in clinical practice, concerns over their side effects and resistance are on the rise. A spider peptide XYP1 isolated from Lycosa coelestis had potent anti-T. gondii effects, but it had a high synthesis cost and strong cytotoxicity. Methods This study intended to modify XYP1 for producing derived peptides via amino acid truncation and substitution. The anti-T. gondii effect was evaluated by trypan blue staining assay and killing experiment of RH strain tachyzoites. The CCK8 and hemolysis assays were used to compare their safeties. The morphological changes of T. gondii were observed by scanning electron microscope and transmission electron microscope. In addition, the mechanism of XYP1 against T. gondii through RNA-sequencing was further explored. Results In vivo and in vitro experiments revealed that XYP1-18 and XYP1-18-1 had excellent anti-T. gondii activity with lower cytotoxicity and hemolysis activity than XYP1. XYP1, XYP1-18, and XYP1-18-1 were able to disrupt the surface membrane integrity of T. gondii tachyzoites, forming pores and causing the disruption of organelles. Furthermore, RNA-sequencing analysis indicated that XYP1 could stimulate the host immune response to effectively eliminate T. gondii and lessen the host’s inflammatory reaction. Conclusions XYP1-18 had lower cytotoxicity and hemolysis activity than XYP1, as well as significantly extending the survival time of the mice. XYP1 played a role in host inflammation and immune responses, revealing its potential mechanism. Our research provided valuable insights into the development and application of peptide-based drugs, offering novel strategies and directions for treating toxoplasmosis. Graphical Abstract

Abstract Background Serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population, its association with ASCVD incidence in Chinese maintenance hemodialysis (MHD) patients remains unclear. We aimed to evaluate the relationship between Lp(a) levels and ASCVD incidence among MHD patients in Beijing, China. Methods This retrospective, observational cohort study included MHD patients at Beijing Tongren Hospital from January 1, 2013 to December 1, 2020, and followed until December 1,2023. The primary outcome was ASCVD occurrence. Kaplan-Meier survival analysis was used to evaluate ASCVD-free survival in MHD patients, with stratification based on Lp(a) levels. Cox regression analyses were conducted to assess the association between Lp(a) levels and the occurrence of ASCVD. Results A total of 265 patients were enrolled in the study. The median follow-up period were 71 months.78 (29.4%) participants experienced ASCVD events, and 118 (47%) patients died, with 58 (49.1%) deaths attributed to ASCVD. Spearman rank correlation analyses revealed positive correlations between serum Lp(a) levels and LDL-c levels, and negative correlations with hemoglobin, triglyceride, serum iron, serum creatinine, and albumin levels. Multivariate Cox regression analysis showed that Lp(a) levels ≥ 30 mg/L, increased age, decreased serum albumin levels, and a history of diabetes mellitus were significantly associated with ASCVD incidence. Conclusions This study demonstrated an independent and positive association between serum Lp(a) levels and the risk of ASCVD in MHD patients, suggesting that serum Lp(a) could potentially serve as a clinical biomarker for estimating ASCVD risk in this population.

The availability of nitrogen (N) is crucial for both the productivity of terrestrial and aquatic ecosystems globally. However, the overuse of artificial fertilizers and the energy required to fix nitrogen have pushed the global nitrogen cycle (N-cycle) past its safe operating limits, leading to severe nitrogen pollution and the production of significant amounts of greenhouse gas nitrous oxide (N2O). The anaerobic ammonium oxidation (anammox) mechanism can counteract the release of ammonium and N2O in many oxygen-limited situations, assisting in the restoration of the homeostasis of the Earth’s N biogeochemistry. In this work, we looked into the characteristics of the anammox hotspots’ distribution across various types of ecosystems worldwide. Anammox hotspots are present at diverse oxic–anoxic interfaces in terrestrial systems, and they are most prevalent at the oxic–anoxic transition zone in aquatic ecosystems. Based on the discovery of an anammox hotspot capable of oxidizing ammonium anoxically into N2 without N2O by-product, we then designed an innovative concept and technical routes of nature-based anammox hotspot geoengineering for climate change, biodiversity loss, and efficient utilization of water resources. After 15 years of actual use, anammox hotspot geoengineering has proven to be effective in ensuring clean drinking water, regulating the climate, fostering plant and animal diversity, and enhancing long-term environmental quality. The sustainable biogeoengineering of anammox could be a workable natural remedy to resolve the conflicts between environmental pollution and food security connected to N management.

Abstract Background Terpenes are important components of plant aromas, and terpene synthases (TPSs) are the key enzymes driving terpene diversification. In this study, we characterized the volatile terpenes in five different Chrysanthemum nankingense tissues. In addition, genome-wide identification and expression analysis of TPS genes was conducted utilizing an improved chromosome-scale genome assembly and tissue-specific transcriptomes. The biochemical functions of three representative TPSs were also investigated. Results We identified tissue-specific volatile organic compound (VOC) and volatile terpene profiles. The improved Chrysanthemum nankingense genome assembly was high-quality, including a larger assembled size (3.26 Gb) and a better contig N50 length (3.18 Mb) compared to the old version. A total of 140 CnTPS genes were identified, with the majority representing the TPS-a and TPS-b subfamilies. The chromosomal distribution of these TPS genes was uneven, and 26 genes were included in biosynthetic gene clusters. Closely-related Chrysanthemum taxa were also found to contain diverse TPS genes, and the expression profiles of most CnTPSs were tissue-specific. The three investigated CnTPS enzymes exhibited versatile activities, suggesting multifunctionality. Conclusions We systematically characterized the structure and diversity of TPS genes across the Chrysanthemum nankingense genome, as well as the potential biochemical functions of representative genes. Our results provide a basis for future studies of terpene biosynthesis in chrysanthemums, as well as for the breeding of improved chrysanthemum varieties.

Ti3C2, one typical MXene, has great potential to be coupled with various transition metals. Herein, a novel and effective catalyst is developed by synergistically loading VCoCOx onto Ti3C2‐modified nickel foam (VCoCOx–Ti3C2@NF). Field emission scanning electron microscope and high‐resolution transmission electron microscopy are employed to characterize the morphology and structure. As expected, the catalyst optimized by response surface methodology attains overpotentials of 290 and 64 mV and Tafel slopes of 82 and 79 mV dec−1 for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), respectively. By using the bifunctional VCoCOx–Ti3C2@NF catalyst, the water splitting current density achieves 10 mA cm−2 in 1.0 mol L−1 KOH electrolyte at cell voltage of 1.52 V, comparable with the noble metal electrolyzer Pt@C@NF||RuO2@NF (1.57 V). Furthermore, the resulting catalyst exhibits excellent cycling durability after 120 h of continuous catalysis, which retains 103.8% and 105.4% of potential (V vs reversible hydrogen electrode) for OER and HER, respectively. Density functional theory calculation reveals that the Gibbs free energy barriers for the OER and HER intermediates are reduced due to the integration of VCoCOx with Ti3C2@NF. The fabricated VCoCOx–Ti3C2@NF catalyst is a promising electrochemical material for clean energy production.

Summary: Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.

Abstract Global riverine nitrous oxide (N2O) emissions have increased more than 4-fold in the last century. It has been estimated that the hyporheic zones in small streams alone may contribute approximately 85% of these N2O emissions. However, the mechanisms and pathways controlling hyporheic N2O production in stream ecosystems remain unknown. Here, we report that ammonia-derived pathways, rather than the nitrate-derived pathways, are the dominant hyporheic N2O sources (69.6 ± 2.1%) in agricultural streams around the world. The N2O fluxes are mainly in positive correlation with ammonia. The potential N2O metabolic pathways of metagenome-assembled genomes (MAGs) provides evidence that nitrifying bacteria contain greater abundances of N2O production-related genes than denitrifying bacteria. Taken together, this study highlights the importance of mitigating agriculturally derived ammonium in low-order agricultural streams in controlling N2O emissions. Global models of riverine ecosystems need to better represent ammonia-derived pathways for accurately estimating and predicting riverine N2O emissions.

Abstract Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.

Abstract Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

Abstract Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models’ discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.

The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-β/Smad signaling, which could be reversed by TGF-β1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-β1 and enhanced the TGF-β1 mRNA stability. Notably, NaAsO2-induced TGF-β/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-β1, which may open up new therapeutic options for LF brought on by environmental hazards.

Abstract Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.

In the present study, an investigation is conducted into the effect of different aging treatments on the hardening properties of the 6151 aluminum alloy sheet. According to the research results, the artificial aging hardening response of the pre-aging sheet is significantly stronger compared to natural aging after the solution treatment. In the stage of artificial aging, 120 oC pre-aging treatment produces a more significant strengthening effect than 80 oC and 100 oC pre-aging treatment. The longer the artificial time, the higher the hardness value. When the artificial aging temperature reaches 200 oC, the time taken to achieve peak aging is the shortest, and the occurrence of softening is evident in the over-aged state. When the artificial aging temperature is 200 oC, the softening effect becomes more significant. Natural aging can inhibit the strengthening effect of artificial aging. With the extension of natural aging, the hardening effect of artificial aging diminishes gradually.

Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5 h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.

Cr(VI) is known to be seriously toxic and carcinogenic. Hypoxia-inducible factor-1α (HIF-1α) is a crucial regulator to promote tumor development. In this study, we found that Cr(VI) significantly increased the expression of HIF-1α in A549 cells and in lung of BALB/c mice but not in HELF cells. Treatment with Lificiguat (YC-1), HIF-1α inhibitor, or CoCl2, HIF-1α inducer, could alter Cr(VI)-induced autophagy, glycolysis, and cell growth in A549 cells but not in HELF cells, validating the involvement of HIF-1α in these effects of Cr(VI) in A549 cells. Co-treatments of pcATG4B with YC-1, or siATG4B with CoCl2 demonstrated the role of HIF-1α / autophagy axis in inducing glycolysis and cell growth in A549 cells. In HELF cells, however, only autophagy but not HIF-1α played a role in inducing glycolysis. The protein level of p53 was significantly lower in A549 cells than in HELF cells. RITA, a p53 inducer, attenuated Cr(VI)-induced HIF-1α and LC3-II in A549 cells, suggesting that p53 might be the mechanism underlying the different effects of Cr(VI) on HIF-1α in A549 and HELF cells. Thus, p53-dependent HIF-1α / autophagy-mediated glycolysis plays a role in facilitating Cr(VI)-induced carcinogenesis.

To address issues of global energy sustainability, it is essential to develop highly efficient bifunctional transition metal-based electrocatalysts to accelerate the kinetics of both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Herein, the heterogeneous molybdenum and vanadium codoped cobalt carbonate nanosheets loaded on nickel foam (VMoCoCOx@NF) are fabricated by facile hydrothermal deposition. Firstly, the mole ratio of V/Mo/Co in the composite is optimized by response surface methodology (RSM). When the optimized composite serves as a bifunctional catalyst, the water-splitting current density achieves 10 mA cm−2 and 100 mA cm−2 at cell voltages of 1.54 V and 1.61 V in a 1.0 M KOH electrolyte with robust stability. Furthermore, characterization is carried out using field emission scanning electron microscopy-energy dispersive spectroscopy (FESEM-EDS), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Density functional theory (DFT) calculations reveal that the fabricated VMoCoCOx@NF catalyst synergistically decreases the Gibbs free energy of hydrogen and oxygen-containing intermediates, thus accelerating OER/HER catalytic kinetics. Benefiting from the concerted advantages of porous NF substrates and clustered VMoCoCOx nanosheets, the fabricated catalyst exhibits superior electrocatalytic performance. This work presents a novel approach to developing transition metal catalysts for overall water splitting.

Abstract Background Chronic infection with Clonorchis sinensis can cause hepatobiliary fibrosis and even lead to hepatobiliary carcinoma. Epstein-Barr virus-induced gene 3 protein (EBI3) is a subunit of interleukin 35, which can regulate inflammatory response and the occurrence of fibrotic diseases. Previous studies have reported that the expression of EBI3 in the serum of patients with liver cirrhosis is reduced. The present study aims to investigate the biological effects of EBI3 on liver fibrosis caused by C. sinensis and the underlying molecular mechanisms. Methods We first established a mouse model of liver fibrosis induced by C. sinensis infection and then measured the serum expression of EBI3 during the inflammatory and fibrotic phase. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to investigate the potential role of EBI3 in liver fibrosis by regulating the extracellular matrix structural constituent and collagen catabolic process. Recombinant protein EBI3 (rEBI3) was added to hepatic stellate cells (HSCs) in vitro with C. sinensis antigen to explore its function. Finally, the therapeutic effect of rEBI3 was verified by intravenous injection into C. sinensis-infected mice. Results The results showed that the serum expression of EBI3 increased in the inflammatory response phase but decreased in the fibrotic phase. The excretory-secretory products of C. sinensis (Cs.ESP) were able to stimulate HSC activation, while rEBI3 reduced the activation of HSCs induced by Cs.ESP. Also, the protein expression of gp130 and downstream protein expressions of JAK1, p-JAK1, STAT3 and p-STAT3 in HSCs were increased after rEBI3 incubation. Finally, intravenously injected rEBI3 inhibited hepatic epithelial-mesenchymal transition in C. sinensis-infected mice by inhibiting HSC activation and reducing liver injury. Conclusion This study confirms that rEBI3 can attenuate C. sinensis-induced liver fibrosis by inhibiting HSC activation and may be one of the potential treatments for liver fibrosis. Graphical Abstract

Managing user bias in large-scale user review data is a significant challenge in optimizing children’s book recommendation systems. To tackle this issue, this study introduces a novel hybrid model that combines graph convolutional networks (GCN) based on bipartite graphs and neural matrix factorization (NMF). This model aims to enhance the precision and efficiency of children’s book recommendations by accurately capturing user biases. In this model, the complex interactions between users and books are modeled as a bipartite graph, with the users’ book ratings serving as the weights of the edges. Through GCN and NMF, we can delve into the structure of the graph and the behavioral patterns of users, more accurately identify and address user biases, and predict their future behaviors. Compared to traditional recommendation systems, our hybrid model excels in handling large-scale user review data. Experimental results confirm that our model has significantly improved in terms of recommendation accuracy and scalability, positively contributing to the advancement of children’s book recommendation systems.

ObjectivesTo differentiate parotid pleomorphic adenoma (PA) from adenolymphoma (AL) using radiomics of grayscale ultrasonography in combination with clinical features.MethodsThis retrospective study aimed to analyze the clinical and radiographic characteristics of 162 cases from December 2019 to March 2023. The study population consisted of a training cohort of 113 patients and a validation cohort of 49 patients. Grayscale ultrasonography was processed using ITP-Snap software and Python to delineate regions of interest (ROIs) and extract radiomic features. Univariate analysis, Spearman’s correlation, greedy recursive elimination strategy, and least absolute shrinkage and selection operator (LASSO) correlation were employed to select relevant radiographic features. Subsequently, eight machine learning methods (LR, SVM, KNN, RandomForest, ExtraTrees, XGBoost, LightGBM, and MLP) were employed to build a quantitative radiomic model using the selected features. A radiomic nomogram was developed through the utilization of multivariate logistic regression analysis, integrating both clinical and radiomic data. The accuracy of the nomogram was assessed using receiver operating characteristic (ROC) curve analysis, calibration, decision curve analysis (DCA), and the Hosmer–Lemeshow test.ResultsTo differentiate PA from AL, the radiomic model using SVM showed optimal discriminatory ability (accuracy = 0.929 and 0.857, sensitivity = 0.946 and 0.800, specificity = 0.921 and 0.897, positive predictive value = 0.854 and 0.842, and negative predictive value = 0.972 and 0.867 in the training and validation cohorts, respectively). A nomogram incorporating rad-Signature and clinical features achieved an area under the ROC curve (AUC) of 0.983 (95% confidence interval [CI]: 0.965–1) and 0.910 (95% CI: 0.830–0.990) in the training and validation cohorts, respectively. Decision curve analysis showed that the nomogram and radiomic model outperformed the clinical-factor model in terms of clinical usefulness.ConclusionA nomogram based on grayscale ultrasonic radiomics and clinical features served as a non-invasive tool capable of differentiating PA and AL.

Di-2-ethylhexyl phthalate (DEHP), as a common endocrine disrupting chemicals, can induce toxicity to reproductive system. However, the mechanism remains to be explored. In our study, DEHP exposure induced testicular injury in rats. The high throughput transcriptional sequencing was performed to identify differentially expressed genes (DEGs) between the treatment and control groups. KEGG analysis revealed that DEGs were enriched in apoptosis, PPARα, and ER stress pathway. DEHP up-regulated the expression of PPARα, Bax, Bim, caspase-4. GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP. This view has also been confirmed in TM3 and TM4 cells. In vitro, after pre-treatment with GW6471 (an inhibitor of PPARα) or GSK (an inhibitor of PERK), the apoptosis was inhibited and mitochondrial dysfunction was improved. Moreover, the improvement of mitochondrial dysfunction decreased the expression of PERK pathway by using SS-31(a protective agent for mitochondrial function). Interestingly, ER stress promoted the accumulation of ROS by ERO1L (the downstream of CHOP during ER stress), and the ROS further aggravated the ER stress, thus forming a feedback loop during the apoptosis. In this process, a vicious cycle consisting of PERK, eIF2α, ATF4, CHOP, ERO1L, ROS was involved. Taken together, our results suggested that mitochondrial dysfunction and ER stress-ROS feedback loop caused by PPARα activation played a crucial role in DEHP-induced apoptosis. This work provides insight into the mechanism of DEHP-induced reproductive toxicity.

Objectives This study aimed to explore the potential risk factors associated with toileting-related falls in community-dwelling older adults who presented to the emergency department and were subsequently hospitalised.Design This was a cross-sectional study.Setting and participants This study was conducted in two teaching hospitals in Shanghai, China between October 2019 and December 2021 among community-dwelling adults aged ≥60 years.Methods In-person interviews, physical assessment and medical record review were performed to collect data on the characteristics and risk factors of falls. Associations of toileting-related falls with demographic characteristics and geriatric syndromes were examined using logistic regression models.Main outcome measures Potential risk factors for toileting-related falls.Results This study included 419 older patients with a mean age of 73.8±9.7 years. Among 60 (14.3%) patients with toileting-related falls (mean age: 78.8±9.2 years), 63.3% of toileting-related falls, mainly occurred between 00:00 and 05:59 hours, compared with 17.3% of non-toileting-related falls, which primarily occurred during the daytime. The rate of recurrent falls (35%) was significantly higher in the toileting-related falls group than in the non-toileting-related falls group (21.2%) (p=0.02). Logistic regression showed that visual impairment (OR 2.7, 95% CI 1.1 to 7.1), cognitive impairment (OR 3.3, 95% CI 1.3 to 8.4), gait instability (OR 3.1, 95% CI 1.1 to 8.8) and urinary incontinence (OR 3.4, 95% CI 1.2 to 9.9) were strongly associated with toileting-related falls. Twenty-three (38.3%) patients in the toileting-related falls group had moderate and severe injuries, compared with 71.7% in the non-toileting-related falls group (p

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs’ proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.

Toxoplasma gondii (T. gondii) is a nucleated intracellular parasitic protozoan with a broad host selectivity. It causes toxoplasmosis in immunocompromised or immunodeficient patients. The currently available treatments for toxoplasmosis have significant side effects as well as certain limitations, and the development of vaccines remains to be explored. Animal venoms are considered to be an important source of novel antimicrobial agents. Some peptides from animal venoms have amphipathic alpha-helix structures. They inhibit the growth of pathogens by targeting membranes to produce lethal pores and cause membrane rupture. Venom molecules generally possess immunomodulatory properties and play key roles in the suppression of pathogenic organisms. Here, we summarized literatures of the last 15 years on the interaction of animal venom peptides with T. gondii and attempt to explore the mechanisms of their interaction with parasites that involve membrane and organelle damage, immune response regulation and ion homeostasis. Finally, we analyzed some limitations of venom peptides for drug therapy and some insights into their development in future studies. It is hoped that more research will be stimulated to turn attention to the medical value of animal venoms in toxoplasmosis.

In general populations, insulin resistance (IR) is related to perfluorooctane sulfonate (PFOS), a persistent organic pollutant. However, the underlying mechanism remains unclear. In this study, PFOS induced mitochondrial iron accumulation in the liver of mice and human hepatocytes L-O2. In the PFOS-treated L-O2 cells, mitochondrial iron overload preceded the occurrence of IR, and pharmacological inhibition of mitochondrial iron relieved PFOS-caused IR. Both transferrin receptor 2 (TFR2) and ATP synthase β subunit (ATP5B) were redistributed from the plasma membrane to mitochondria with PFOS treatment. Inhibiting the translocation of TFR2 to mitochondria reversed PFOS-induced mitochondrial iron overload and IR. In the PFOS-treated cells, ATP5B interacted with TFR2. Stabilizing ATP5B on the plasma membrane or knockdown of ATP5B disturbed the translocation of TFR2. PFOS inhibited the activity of plasma-membrane ATP synthase (ectopic ATP synthase, e-ATPS), and activating e-ATPS prevented the translocation of ATP5B and TFR2. Consistently, PFOS induced ATP5B/TFR2 interaction and redistribution of ATP5B and TFR2 to mitochondria in the liver of mice. Thus, our results indicated that mitochondrial iron overload induced by collaborative translocation of ATP5B and TFR2 was an up-stream and initiating event for PFOS-related hepatic IR, providing novel understandings of the biological function of e-ATPS, the regulatory mechanism for mitochondrial iron and the mechanism underlying PFOS toxicity.

Abstract Background Delay in care seeking is one of the causes for neonatal death. Mothers’ knowledge of neonatal danger signs is imperative to promote early recognition of neonatal illness and reduce the delay in care seeking. Currently, no study has been conducted on the knowledge about neonatal danger signs in China, especially in economically less developed areas. This study aimed to examine the knowledge of neonatal danger signs and risk factors of poor knowledge among mothers in a rural county of southwest of China. Methods A cross-sectional study was conducted in Wenshan, a rural county of southwest of China. A total of 112 respondents were included from November 2020 to February 2021 among women who had babies aged 0–12 months and brought their babies to health care centers for immunization within the study period. A questionnaire with 18-item key neonatal danger signs was used to measure their knowledge about these signs. Mothers who scored above average were considered to have relatively good knowledge whereas those who scored below average were considered to have relatively poor knowledge. Independent predictors of mothers’ knowledge were identified by multivariable logistic regression analysis. Results The mean knowledge score of neonatal danger signs of mothers was 18.1 (SD = 8.6). Fifty-eight percentage of mothers (65/112) had poor knowledge of neonatal danger signs. Danger signs of “bluish or pale skin”, “chest indrawing”, and “convulsion” were mostly recognized, whereas danger signs of “not able to feed since birth, or stopped feeding well”, “excessive crying” and “eyes draining pus” were recognized poorly. Less than four antenatal visits [AOR = 4.348], younger than 25 years old [AOR = 3.839], ethnic minority [AOR = 3.956] and family financial difficulty [AOR = 4.944] were significant indicators of relatively poor knowledge. Conclusions Mothers’ knowledge about neonatal danger signs in rural China is poor even though the coverage of maternal and child health care services are expanded. Existing efforts should be enhanced for antenatal care visits, avoiding early marriage as well as early childbearing. More attention should be paid to low-income ethnic minority mothers. Educating and training should be strengthened for danger signs, especially those who are predicted to have insufficient knowledge.

Natural gas is an eco-friendly energy source with low carbon emissions, making it attractive globally. Understanding gas reservoirs is crucial for sustainable extraction and optimizing potential. However, the complicated fluid flow and production dynamics within intricate gas reservoirs, particularly those characterized by abnormally high pressures and tight porous media, remain partially understood and demand further investigation. In a tight porous medium subjected to high pressure, the assumption of constant permeability is no longer valid. Consequently, a novel composite seepage model has been developed in this study, which considers the responsiveness of permeability to stress. Perturbation theory is employed to address the inherent non-linearity demonstrated by the permeability modulus. The solution of dimensionless pressure responses under constant production conditions is accomplished in the Laplace domain by implementing integral transformation methods. Overall, a comprehensive model is provided to understand the production behaviors of tight gas reservoirs. Moreover, in order to comprehend the transient flow characteristics of tight gas reservoirs, log–log plots are generated through the Stehfest numerical inversion approach, with the flow regimes categorized based on the normalized time phases of the pressure curves. Parametric investigations reveal that stress sensitivity detrimentally affects permeability, resulting in more pronounced pressure declines during the intermediate and late flow phases. The transient seepage model elaborated in this study is able to consider the pertinent formation and well parameters. These interpreted parameters bear significance in designing hydraulic fracturing operations, assessing the potential of tight gas reservoirs, and ultimately enhancing gas production. The presented model not only enhances our understanding of the behavior of horizontal wells in stress-sensitive tight gas reservoirs but also makes a valuable contribution to the broader discussion on transient flow phenomena in petroleum engineering.

Precise identification and spatial analysis of land salinity in China’s Yellow River Delta are essential for the rational utilization and sustainable development of land resources. However, the accurate retrieval model construction for monitoring land salinity remains challenging. This study constructed a land salinity retrieval framework using a harmonized UAV and Landsat-9 multi-spectral dataset. The Kenli district of the Yellow River Delta was selected as the case study area, and a land salinity monitoring index (LSMI) was proposed based on field survey data and UAV multi-spectral image and applied to the reflectance-corrected Landsat-9 OLI image. The land salinity distribution patterns were then mapped and spatially analyzed using Moran’s I and Getis-Ord GI* analysis. The results demonstrated the following: (1) The LSMI-based method can accurately retrieve land salinity content with a validation determination coefficient (R2), root mean square error (RMSE), and residual predictive deviation (RPD) of 0.75, 1.89, and 2.11, respectively. (2) Land salinization affected 93.12% of the cultivated land in the study area, and the severely saline soil grade (with a salinity content of 6–8 g/kg) covered 38.41% of the total cultivated land area and was widely distributed throughout the study area. (3) Saline land exhibited a positive spatial autocorrelation with a value of 0.311 at the p = 0.000 level; high–high cluster types occurred mainly in the Kendong and Huanghekou towns (80%), while low–low cluster types were mainly located in the Dongji, Haojia, Kenli, and Shengtuo towns (88.46%). The spatial characteristics of various salinity grades exhibit significant variations, and conducting separate spatial analyses is recommended for future studies.

The B oilfield is a large integrated oilfield in the Middle East. Asphaltene precipitates from crude oil and deposits on solid surfaces, affording considerable blockages of the formation, wellbore, and production equipment. To fully understand the asphaltene precipitation trend and deposition mechanism deeply, and solve the abovementioned problems in the B oilfield, fourier-transform infrared spectroscopy, proton nuclear magnetic resonance, and isothermal depressurization experiments (IDEs) have been conducted to predict the asphaltene precipitation trend of an oil sample. According to the experiments, the saturate, aromatic, resin, and asphaltene ratios were 5.6%, 37.4%, 33.1%, and 15.9%, respectively. The calculated colloidal instability index reached 0.88, indicating a risk of asphaltene precipitation. Based on IDEs, asphaltene precipitation was observed in the view cell window at 3196, 3545, and 3750 psi at different temperatures. Furthermore, the asphaltene deposition mechanism was studied on a string surface at the microscale based on molecular simulations and control measures were proposed. According to the simulations, the deposition process is found to be spontaneous. Asphaltene molecules were self-assembled and formed nanoaggregates in the form of a π–π conjugation. They were deposited parallelly on the string with a “face-to-face” pattern. When the simulation temperature reached 325 K, asphaltene deposition reached the maximum under the simulation conditions. Compared with omitting dispersants, the average distance between the asphaltene molecules and string mass center improved and the energy of the system had considerably lowered after adding dispersants, implying that dispersants can effectively weaken the asphaltene deposition process. This paper provides some suggestions for preventing and removing blockages of electric pumps caused by asphaltene deposition.

Objectives: Deep tissue injury is a common form of pressure ulcers in muscle tissues under bony prominences caused by sustained pressure or shear, which has a great impact on patients with restricted mobility such as spinal cord injury. Frequent spasms in spinal cord injury patients featured by muscle stiffening may be one of the factors leading to deep tissue injury. The purpose of this study was to investigate the relationship between the gluteal muscle shear modulus and intramuscular compressive/shear stress/strain. Methods: A semi-3D finite element model of the human buttock was established using COMSOL software and the acquired biomechanical data were analyzed through Pearson correlation and Spearman correlation. Results: Results showed that the compressive stress, strain energy density, and average von Mises stress increased with the increase of the gluteal muscle shear modulus. Conclusion: These results may indicate muscle stiffening caused by muscle spasms could lead to higher deep tissue injury development risk as well as shed light on effective treatments for relieving muscular sclerosis mechanically.

Summary: Substrate degradation by the ubiquitin proteasome system (UPS) in specific membrane compartments remains elusive. Here, we show that the interplay of two lipid modifications and PDE6δ regulates compartmental substrate targeting via the SCFFBXL2. FBXL2 is palmitoylated in a prenylation-dependent manner on cysteines 417 and 419 juxtaposed to the CaaX motif. Palmitoylation/depalmitoylation regulates its subcellular trafficking for substrate engagement and degradation. To control its subcellular distribution, lipid-modified FBXL2 interacts with PDE6δ. Perturbing the equilibrium between FBXL2 and PDE6δ disrupts the delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2 is enriched on the endoplasmic reticulum (ER). Depalmitoylated FBXL2(C417S/C419S) promotes the degradation of IP3R3 at the ER, inhibits IP3R3-dependent mitochondrial calcium overload, and counteracts calcium-dependent cell death upon oxidative stress. In contrast, disrupting the PDE6δ-FBXL2 equilibrium has the opposite effect. These findings describe a mechanism underlying spatially-restricted substrate degradation and suggest that inhibition of FBXL2 palmitoylation and/or binding to PDE6δ may offer therapeutic benefits.

Abstract Background Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved. Methods Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism. Result Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis. Conclusions Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

The immune imbalance caused by excessive inflammatory reactions is the primary cause of sepsis. Macrophages with M1 and M2 polarization states are important immune cells that regulate the balance of the inflammatory response in sepsis. Encouraging the conversion of macrophages from the M1 to the M2 type is an important strategy for relieving sepsis. Here, we demonstrated the upregulation of vascular endothelial growth factor A (VEGFA) in a mouse model of sepsis. Then, siRNA technology was applied to inhibit the expression of VEGFA in macrophages. Flow cytometry and RT‒qPCR results showed that low expression of VEGFA inhibited LPS-induced M1 polarization of macrophages. Decreased VEGFA was also proven to lower TNF-α, IL-1β, and IL-6 secretion by LPS-induced macrophages. In addition, the effects of knocking down VEGFA on the energy metabolism pattern of macrophages were investigated by glycolysis pressure tests and mitochondrial pressure tests, and VEGFA knockdown reversed the induction of glycolysis in macrophages by LPS. The mitochondrial content and ATP content results also confirmed this finding. After the tail vein of septic mice was injected with macrophages transfected with si-VEGFA, the liver and kidney damage and the pathological conditions of the lung were alleviated. The secretion of TNF-α and IL-6 was decreased, while IL-10 was increased in their serum. Immunohistochemical staining revealed decreased expression of CD86 and increased expression of CD206 in the si-VEGFA group. This study demonstrates that decreased VEGFA inhibits glycolysis and thus inhibits LPS-induced M1 polarization of macrophages, ultimately relieving sepsis.

Aesculus L. (buckeye and horse chestnut) are woody plant species with important horticultural and medicinal values. Aesculus seeds are widely used as biomedicine and cosmetic ingredients due to their saponins. We report a chromosomal-scale genome of Aesculus wilsonii. Sequences amounting to a total of 579.01 Mb were assembled into 20 chromosomes. More than half of the genome (54.46%) were annotated as repetitive sequences, and 46,914 protein-coding genes were predicted. In addition to the widespread gamma event with core eudicots, a unique whole-genome duplication (WGD) event (17.69 Mya) occurred in Aesculus after buckeye differentiated from longan. Due to WGD events and tandem duplications, the related synthetic genes of triterpene saponins unique to Aesculus increased significantly. Combined with transcriptome characterization, the study preliminarily resolved the biosynthetic pathway of triterpenoid saponins like aescin in A. wilsonii genome. Analyses of the resequencing of 104 buckeye accessions revealed clear relationship between the geographic distribution and genetic differentiation of buckeye trees in China. We found that the buckeye species found in southern Shaanxi is A. wilsonii rather than A. chinensis. Population dynamics analysis further suggests that the population size and evolution of existing buckeye species have been influenced by climate fluctuations during the Pleistocene and recent domestication events. The genome of A. wilsonii and population genomics of Aesculus provide a resource for future research on Hippocastanaceae. These findings will contribute to the utilization and diversity protection of Aesculus.

Background: The cure rates of Helicobacter pylori (H. pylori) treatment using a proton pump inhibitor (PPI) are gradually decreasing due to antibiotic resistance, poor compliance, high gastric acidity, and cytochrome P450 2C19 (CYP2C19) polymorphism, and the effects of PPI depend on metabolic enzymes, cytochrome P450 enzymes. The aim of this meta-analysis was to determine whether CYP2C19 polymorphisms affect H. pylori cure rates in patients treated with different proton pump inhibitors (PPIs) according to stratified analysis.Materials and methods: The literature was searched with the key words “H. pylori” and “CYP2C19” in PubMed, CNKI, and Wanfang up to 31 May 2022, and the studies were limited to clinical observational or randomized controlled trials (RCTs). Finally, seven RCTs and 29 clinical observational studies met the inclusion criteria and were used for the meta-analysis via STATA version 16.Results: The cure rates were significantly different between genotypes of homozygous extensive metabolizers (EM) and poor metabolizers (PM) (OR = 0.58, 95% CI: 0.47–0.71) and between EM and heterozygous extensive metabolizers (IM) (OR = 0.71, 95% CI: 0.59–0.86), but not between IM and PM. Moreover, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with omeprazole (66.4% vs. 84.1%), lansoprazole (76.1% vs. 85.6%), but not rabeprazole, esomeprazole, or pantoprazole. In addition, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with a PPIs for 7 days (77.4% vs. 82.1%), but not 14 days (85.4% vs. 90.0%).Conclusion: Carriers of CYP2C19 loss-of-function variant alleles (IM and PM) exhibit a significantly greater cure rate of H. pylori than noncarriers (EM) regardless of other factors (84.7% vs. 79.2%). In addition, pantoprazole- and rabeprazole-based quadruple therapy for H. pylori treatment is less dependent on the CYP2C19 genotype and should be prioritized in Asian populations with H. pylori.

Hexavalent chromium [Cr (VI)] exists environmentally and occupationally. It has been shown to pose a carcinogenic hazard in certain occupations. This study was to investigate the role of high mobility group A2 (HMGA2) in Cr (VI)-induced metabolism reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in A549 and HELF cells. First, knockdown of HMGA2 by siHMGA2 significantly attenuated Cr (VI)-reduced expression of OXPHOS-related proteins (COX IV and ND1) and mitochondrial mass, indicating that HMGA2 was involved in Cr (VI)-reduced OXPHOS. Overexpression of HMGA2 by transfection of HMGA2-DNA plasmids reduced the expression of COX IV, ND1 and mitochondrial mass, suggesting the negative role of HMGA2 in OXPHOS. Secondly, both CCCP, the inhibitor of mitochondrial function, and the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), decreased the level of HMGA2, indicating that the interaction of mitochondrial dysfunction and ER stress resulted in Cr (VI)-induced HMGA2 expression. Further study demonstrated that ER stress/HMGA2 axis mediated the metabolism rewiring from OXPHOS to aerobic glycolysis. Notably, Cr (VI) induced the accumulation of HMGA2 proteins in mitochondria and ChIP assay demonstrated that HMGA2 proteins could bind to D-loop region of mitochondrial DNA (mtDNA), which provided the proof for HMGA2-modulating OXPHOS. Taken together, our results suggested that the interaction of mitochondria and ER stress-enhanced HMGA2 played an important role in Cr (VI)-induced metabolic reprogramming from OXPHOS to glycolysis by binding directly to D-loop region of mtDNA. This work informs on the potential mode of action for Cr (VI)-induced tumors and builds on growing evidence regarding the contribution of cellular metabolic disruption contributing to carcinogenicity.

ObjectivesChildren with autism spectrum disorder (ASD) can exhibit persistent deficits in social communication, causing their mothers to experience elevated parenting stress during the childrearing process. Some internal and external psychosocial resources may mediate or moderate the mother-child relationship, though the underlying mechanisms remain unclear. This study aimed to explore the predictors of parenting stress in mothers of children with ASD and elucidate the mechanisms underlying the relationship between child social impairment and parenting stress.MethodsA cross-sectional study was conducted between October 2020 and March 2022 in Shanghai, China. Mothers of children with ASD completed a survey investigating child social impairment, parenting stress, parental self-efficacy, and social support.ResultsA total of 185 mothers of children with ASD were included in the final analysis. 70.27 percent of mothers experienced a clinically significant level of parenting stress. Child social impairment (r = 0.46, P < 0.001), parental self-efficacy (r = −0.58, P < 0.001), and social support (r = −0.35, P < 0.001) were significantly correlated with parenting stress. Parental self-efficacy completely mediated the relationship between child social impairment and parenting stress (B = 0.51, P < 0.001), after controlling for socioeconomic status (SES) correlated with parenting stress. There was no significant moderating effect of social support between child social impairment and parenting stress (B = 0.01, P = 0.09).ConclusionFuture early intervention programs that focused on child's social communication skills and empowered mothers with related strategies through group-based parent training programs may help reduce parenting stress.

Toxoplasmosis, caused by Toxoplasma gondii (T. gondii), is a serious zoonotic parasitic disease. We previously found that Lycosin-I exhibited anti-T. gondii activity, but its serum stability was not good enough. In this study, we aimed to improve the stability and activity of Lycosin-I through fatty acid chain modification, so as to find a better anti-T. gondii drug candidate. The α/ε-amino residues of different lysine residues of Lycosin-I were covalently coupled with lauric acid to obtain eight lipopeptides, namely L-C12, L-C12-1, L-C12-2, L-C12-3, L-C12-4, L-C12-5, L-C12-6, and L-C12-7. Among these eight lipopeptides, L-C12 showed the best activity against T. gondii in vitro in a trypan blue assay. We then conjugated a shorter length fatty chain, aminocaproic acid, at the same modification site of L-C12, namely L-an. The anti-T. gondii effects of Lycosin-I, L-C12 and L-an were evaluated via an invasion assay, proliferation assay and plaque assay in vitro. A mouse model acutely infected with T. gondii tachyzoites was established to evaluate their efficacy in vivo. The serum stability of L-C12 and L-an was improved, and they showed comparable or even better activity than Lycosin-I did in inhibiting the invasion and proliferation of tachyzoites. L-an effectively prolonged the survival time of mice acutely infected with T. gondii. These results suggest that appropriate fatty acid chain modification can improve serum stability and enhance anti-T. gondii effect of Lycosin-I. The lipopeptide derivatives of Lycosin-I have potential as a novel anti-T. gondii drug candidate.

5-Nitro-2,4-dihydro-3H-1,2,4-triazol-3-one (NTO) is a representative and insensitive energetic compound mainly used as a component of low vulnerable ammunition, but its decomposition process is not clear up to date. Herein, online photoionization mass spectrometry combined with theoretical simulations was employed to shed light on the thermal decomposition mechanism of NTO. The experimental and calculated results provide evidences for the thermal decomposition of NTO through direct ring rupture and intermolecular hydrogen transfer pathways. The initial decomposition step of NTO single molecule is direct ring rupture, followed by NO2 removal. The remaining structure undergoes C-N bond cleavage leading to HN2 dissociation, the CONCH finally decomposes into CO and HCN. The major products of NTO decomposition include N2, CO2, H2N2, NH3, and the minor products are HN2, H3N3, H2O, which is basically consistent with experiments. The formation mechanism of decomposition products is also discussed in detail and the total decomposition pathways are constructed.

A power source–power grid coordinated typhoon defense strategy is proposed in this study to minimize the cost of power grid anti-typhoon reinforcement measures and improve defense efficiency. It is based on multiagent dynamic game theory. This strategy regards a typhoon as a rational gamer that always causes the greatest damage. Together with the grid planner and black start unit (BSU) planner, it forms a multiagent defense–attack–defense dynamic game model naturally. The model is adopted to determine the optimal reinforcements for the transmission lines, black start power capacity, and location. Typhoon Hato, which struck a partial coastal area in Guangdong province in China in 2017, was adopted to formulate a step-by-step model of a typhoon attacking coastal area power systems. The results were substituted into the multiagent defense–attack–defense dynamic game model to obtain the optimal transmission line reinforcement positions, as well as optimal BSU capacity and geographic positions. An effective typhoon defense strategy and minimum load shedding were achieved, demonstrating the feasibility and correctness of the proposed strategy. The related theories and methods of this study have positive significance for the prevention of uncertain large-scale natural disasters.

Coptis chinensis represents an early-diverging eudicot lineage with diverse medicinal applications. Here, the authors report its chromosome-scale genome assembly, infer a single ancient whole-genome duplication, and characterize the function of CYP719 in diversification of protoberberine-type alkaloids.

Toxoplasma gondii infection is a severe health threat that endangers billions of people worldwide. T. gondii utilizes the host cell membrane to form a parasitophorous vacuole (PV), thereby fully isolating itself from the host cell cytoplasm and making intracellular clearance difficult. PV can be targeted and destroyed by autophagy. Autophagic targeting results in T. gondii killing via the fusion of autophagosomes and lysosomes. However, T. gondii has developed many strategies to suppress autophagic targeting. Accordingly, the interplay between host cell autophagy and T. gondii is an emerging area with important practical implications. By promoting the canonical autophagy pathway or attenuating the suppression of autophagic targeting, autophagy can be effectively utilized in the development of novel therapeutic strategies against T gondii. Here, we have illustrated the complex interplay between host cell mediated autophagy and T. gondii. Different strategies to promote autophagy in order to target the parasite have been elucidated. Besides, we have analyzed some potential new drug molecules from the DrugBank database using bioinformatics tools, which can modulate autophagy. Various challenges and opportunities focusing autophagy mediated T. gondii clearance have been discussed, which will provide new insights for the development of novel drugs against the parasite.

The translation of Intangible Cultural Heritage (ICH) terms is an important practical aspect of cross-lingual expressions related to ICH knowledge. Chinese ICH terms are heavily loaded with specific historical and cultural knowledge and regional characteristics. Based on cognitive psychology, this paper analyzes the metonymic mechanism of traditional translation techniques such as substitution in the English translation of Chinese ICH terms. The English translation of Chinese ICH nominal terms can be realized based on the metonymic mechanism of replacing either a superordinate with a subordinate of the linguistic structure or a subordinate of the linguistic structure with a subordinate of the linguistic structure in the pair language, English-Chinese. The English translation of Chinese ICH verbal terms can regard the whole verbal action as an event process and can highlight one aspect of the process through a metonymic mechanism as well. This paper holds that metonymy is an important psychological motivation and cognitive mechanism for translation skills such as substitution as it brings the relationship between the corresponding items of the target language and the source language into a unified interpretation framework. Hence, this may add some significance to the research of translation theory and translation practice. This also contributes to the UN Sustainable Development Goal number 17 which seeks global parternship for sustainable development.

Glioblastoma (GBM) is one of the most prevalent and aggressive cancers worldwide. The overall survival period of GBM patients is only 15 months even with standard combination therapy. The absence of validated biomarkers for early diagnosis mainly accounts for worse clinical outcomes of GBM patients. Thus, there is an urgent requirement to characterize more biomarkers for the early diagnosis of GBM patients. In addition, the detailed molecular basis during GBM pathogenesis and oncogenesis is not fully understood, highlighting that it is of great significance to elucidate the molecular mechanisms of GBM initiation and development. Recently, accumulated pieces of evidence have revealed the central roles of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of GBM by binding with DNA, RNA, or protein. Targeting those oncogenic lncRNAs in GBM may be promising to develop more effective therapeutics. Furthermore, a better understanding of the biological function and underlying molecular basis of dysregulated lncRNAs in GBM initiation and development will offer new insights into GBM early diagnosis and develop novel treatments for GBM patients. Herein, this review builds on previous studies to summarize the dysregulated lncRNAs in GBM and their unique biological functions during GBM tumorigenesis and progression. In addition, new insights and challenges of lncRNA-based diagnostic and therapeutic potentials for GBM patients were also introduced.

Transforming growth factor-β (TGF-β) is a multifunctional regulatory cytokine that maintains tolerance in the immune system by regulating the proliferation, differentiation and survival of lymphocytes. TGF-β blockade therapy for cancer has achieved some results but shows limited efficacy and side effects because these drugs are not selective and act on various types of cells throughout the body. We demonstrate here that dominant negative TGF-β receptor type II specifically targeting T cells decreases tumor load in tumor-bearing mice. In addition, the dominant negative TGF-β receptor type II promotes the proliferation and differentiation of T cells and increases the expression of T-bet, which in turn promotes the secretion of granzyme A, granzyme B, perforin and IFN-γ secreted by T cells, and enhances the cytotoxicity and anti-tumor effects of T cells. Moreover, we also found that dominant negative TGF-β receptor type II reduces the proportion of regulatory T cells (Tregs) in tumor tissue and spleen of tumor-bearing mice. Co-culture experiments with T cells and tumor cells revealed that dominant negative TGF-β receptor type II inhibited tumor cell proliferation and increased apoptosis. Our results indicate that specifically inhibiting TGF-β receptor type II in T cells increases anti-tumor immunity and has a strong therapeutic potential.