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Abstract Embryonic axis formation is essential for patterning and morphogenesis in vertebrates and is tightly regulated by the dorsal organizer. Previously, we demonstrated that maternally derived Huluwa (Hwa) acts as a dorsal determinant, dictating axis formation by activating β-catenin signaling in zebrafish and Xenopus. However, the mechanism of activation and fine regulation of the Hwa protein remains unclear. Through candidate screening we identified a mutation at Ser168 in the PPNSP motif of Hwa that dramatically abolishes its axis-inducing activity. Mechanistically, mutating the Ser168 residue reduced its binding affinity to Tankyrase 1/2 and the degradation of the Axin protein, weakening β-catenin signaling activation. We confirmed that Ser168 is phosphorylated and that phosphorylation increases Hwa activity in β-catenin signaling and axis induction. Several kinases including Cdk16, Cdk2, and GSK3β, were found to enhance Ser168 phosphorylation in vitro and in vivo. Both dominant-negative Cdk16 expression and pHwa (Ser168) antibody treatment reduce Hwa function. Lastly, a knock-in allele mutating Ser168 to alanine resulted in embryos lacking body axes, demonstrating that Ser168 is essential to axis formation. In summary, Ser168 acts as a phosphorylation switch in Hwa/β-catenin signaling for embryonic axis induction, regulated by multiple kinases.

Abstract Background Current biliary dilatation (BD) classifications are complex and based on cases including secondary BD, leading to unclear distinctions. Notably, congenital and secondary BD differ in etiology, symptoms, and prognosis. Objective To propose a more concise and more suitable classification of congenital biliary dilatation (CBD), and exploring the feasibility and effectiveness of this classification in diagnosis and treatment. Methods Based on the preoperative imaging data of patients with CBD admitted to the Department of Pediatric Surgery of West China Hospital of Sichuan University, from January 2015 to December 2018, a new classification of CBD was accomplished according to the site of bile duct dilatation lesions, which was named HUAXI CBD classification. The CBD was classified into 4 types: type I (distal extra-hepatic bile duct dilatation), type II (distal extra-hepatic combined with right and left primary hepatic bile duct dilatation), type III (extra-hepatic combined with secondary and above hepatic bile duct dilatation), and type IV (intra-hepatic bile duct dilatation). Meanwhile, the feasibility and reliability of the HUAXI CBD classification were analyzed by analyzing the clinical treatment strategies, perioperative complications and long-term follow-up results of different subtypes. Results A total of 300 patients with CBD were included in this study. According to the HUAXI CBD classification method, 240 cases were type I, 48 cases were type II, 10 cases were type III, and 2 cases were type IV. After treatment, patients with type I had a normal hepatobiliary function after surgery and a good prognosis; patients with type II had good recovery of liver function in 37 cases (77.1%), but 11 cases (22.9%) had postoperative complications during follow-up; patients with type III and IV had high incidence of cholangitis (6/10, 2/2, respectively) and choledocholithiasis (5/10, 2/2, respectively) after surgery, especially those with diffuse intrahepatic dilatation having a poor prognosis, eventually developing cirrhosis and necessitating liver transplantation. Conclusions The HUAXI CBD classification is consistent with treatment principles, concise and easy to remember, and more suitable for CBD clinical application.

Using CN05.1 and ECMWF Reanalysis v5 (ERA5) data, the characteristics of precipitation, water vapor content and precipitation conversion rate in eastern Southwest China (ESWC) during the summer of 1961-2020 were analyzed, and the influence of terrain distribution on the spatial distribution difference of precipitation conversion rate was preliminarily explored by means of synoptic analysis. Finally, the mesoscale numerical Weather Research and Forecasting Model (WRF4.0) was used to design terrain sensitivity tests to verify the effect of terrain on summer precipitation in the ESWC. The results are as follow. (1) In the summer of 1961-2020, the precipitation in the ESWC shows the characteristics of more precipitation in the east and less precipitation in the west, but there are two large value areas of water vapor content in the southeast and northwest of ESWC. The precipitation conversion rate in the large value area of water vapor is low, and the distribution of the strong precipitation area and the large value area of water vapor content are significantly different. By analyzing the situation of heavy precipitation areas in conjunction with horizontal wind fields and vertical velocity fields, it is found that topographic distribution is an important factor leading to this difference. (2) WRF model can well reflect the characteristics of summer precipitation in the ESWC. The terrain sensitivity test shows that the southwest to northeast mountain terrain distribution consisting of Dalou Mountain, Fangdou Mountain and Daba Mountain has a significant impact on the intensity of precipitation, and the decrease of terrain height will lead to a significant decrease of precipitation in the southeastern part of the region. (3) In particular, after reducing the topographic height of the region by half and to 0, respectively, the precipitation in the southeast of the region will decrease by 9.89% and 19.90% respectively on the monthly time scale. The change of topographic height will also cause the change of vertical velocity, horizontal wind field, water vapor transport and water vapor convergence, which will lead to the change of precipitation intensity. When the terrain height decreases, the upward motion and the southwest wind will weaken obviously, and the intensity of water vapor transport and water vapor convergence will decrease, which is not conducive to the formation of precipitation.

Abstract Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.

Abstract Pyroptosis is a type of programmed cell death characterized by cell swelling and osmotic lysis, resulting in cytomembrane rupture and release of immunostimulatory components, which play a role in several pathological processes. Significant cellular responses to various stimuli involve the formation of inflammasomes, maturation of inflammatory caspases, and caspase-mediated cleavage of gasdermin. The function of pyroptosis in disease is complex but not a simple angelic or demonic role. While inflammatory diseases such as sepsis are associated with uncontrollable pyroptosis, the potent immune response induced by pyroptosis can be exploited as a therapeutic target for anti-tumor therapy. Thus, a comprehensive review of the role of pyroptosis in disease is crucial for further research and clinical translation from bench to bedside. In this review, we summarize the recent advancements in understanding the role of pyroptosis in disease, covering the related development history, molecular mechanisms including canonical, non-canonical, caspase 3/8, and granzyme-mediated pathways, and its regulatory function in health and multiple diseases. Moreover, this review also provides updates on promising therapeutic strategies by applying novel small molecule inhibitors and traditional medicines to regulate pyroptosis. The present dilemmas and future directions in the landscape of pyroptosis are also discussed from a clinical perspective, providing clues for scientists to develop novel drugs targeting pyroptosis.

Background Nasopharyngeal carcinoma (NPC) is a distinct subtype of head and neck cancer which is prevalent in south of China and southeastern of Asia. Consistent activation of interferon (IFN) signaling, and impairment of T cell mediated antitumor immunity is frequent in NPC. Forkhead box A1 (FOXA1) is one of the earliest discovered pioneer factors, which can open up compact chromatin structures to facilitate the binding of other proteins to chromatin.Methods By using RNA sequencing, it was discovered that FOXA1 suppresses the activation of the interferon signaling pathway and the expression of the related interferon-responsive genes in NPC cells. The effect of FOXA1 on programmed death-ligand 1 (PD-L1) expression in C666-1 and HK1 cells under conditions with or without IFN-γ was detected through quantitative PCR (qPCR), western blot, and flow cytometry. After co-culturing T cells with IFN-γ-treated NPC cells in vitro, apoptosis of CD8+ T cells and the expression of cytotoxic cytokines were assessed by flow cytometry. The cytotoxic effects of T cells on tumor cells in nude mice were measured by tumorigenesis in nude mice and adoptive T cell therapy. The effects of IFN-γ on the expression and nuclear localization of STAT1, as well as the colocalization of FOXA1 with STAT1 were detected by immunofluorescence, qPCR, western blot, and co-immunoprecipitation experiments.Results In this study, we reported that loss of FOXA1, a pioneer factor downregulated in NPC, results in activation of IFN signaling in NPC cells. Repression of FOXA1 facilitates IFN-γ induced PD-L1 expression, whereas overexpression of FOXA1 exerts the opposite effect. Mechanistically, FOXA1 interacts with STAT1 and inhibits IRF1 expression and binding to PD-L1 promoter on IFN-γ treatment. Co-culture with FOXA1-silenced NPC cells promotes apoptosis of in vitro activated tumor-specific CD8+T cells and reduces the expression of cytotoxic effector molecules. Furthermore, overexpression of FOXA1 increases the therapeutic efficacy of PD-L1 antibody (atezolizumab) against NPC in nude mice receiving adoptive T-cell therapy.Conclusions We demonstrated that FOXA1 prevents tumor immune evasion by inhibiting IFN-γ induced PD-L1 expression in NPC cells. Our research findings provide new insights into the immunotherapeutic biomarkers and targets for NPC, which is important for the clinical application of programmed cell death protein-1/PD-L1 antibodies in NPC.

Abstract Immune evasion contributes to cancer growth and progression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) and programmed cell death ligands (PD-Ls) are considered to be the major immune checkpoint molecules. The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents dysregulated immunity and harmful immune responses. However, cancer cells exploit the PD-1/PD-L1 axis to cause immune escape in cancer development and progression. Blockade of PD-1/PD-L1 by neutralizing antibodies restores T cells activity and enhances anti-tumor immunity, achieving remarkable success in cancer therapy. Therefore, the regulatory mechanisms of PD-1/PD-L1 in cancers have attracted an increasing attention. This article aims to provide a comprehensive review of the roles of the PD-1/PD-L1 signaling in human autoimmune diseases and cancers. We summarize all aspects of regulatory mechanisms underlying the expression and activity of PD-1 and PD-L1 in cancers, including genetic, epigenetic, post-transcriptional and post-translational regulatory mechanisms. In addition, we further summarize the progress in clinical research on the antitumor effects of targeting PD-1/PD-L1 antibodies alone and in combination with other therapeutic approaches, providing new strategies for finding new tumor markers and developing combined therapeutic approaches.

Abstract Triptolide (TPL) is a compound sourced from Tripterygium wilfordii Hook. F., a traditional Chinese medicinal herb recognized for its impressive anti-inflammatory, anti-angiogenic, immunosuppressive, and antitumor qualities. Notwithstanding its favorable attributes, the precise mechanism through which TPL influences tumor cells remains enigmatic. Its toxicity and limited water solubility significantly impede the clinical application of TPL. We offer a comprehensive overview of recent research endeavors aimed at unraveling the antitumor mechanism of TPL in this review. Additionally, we briefly discuss current strategies to effectively manage the challenges associated with TPL in future clinical applications. By compiling this information, we aim to enhance the understanding of the underlying mechanisms involved in TPL and identify potential avenues for further advancement in antitumor therapy.

Abstract Background Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. Methods RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. Results We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5′-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. Conclusions These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.

AbstractThe legitimacy recognition of comparative advertising is closely related to the production enthusiasm of operators and the protection of the rights and interests of consumers, and thus become an important factor that may affect market competition fairness and social sustainable development. However, few researches have summarized the existing study of comparative advertising, while it is significant to review the changes and explore the future development trend, so as to improve relevant legislation. In this study, to summarize its research status, hotspots, and trends, CiteSpace 6.2.R4 was used to analyze 856 WoS core collection articles and 20 CSSCI articles related to comparative advertising dated 1993–2023, which presents an overview of the study of comparative advertising and relevant legitimacy recognition in China and other countries. Based on the analysis including co-occurrence, co-citation, and reference cluster, this paper looked at the research status and built up the knowledge mapping, which reveals scholars and research teams from universities from eight countries play a more important role in promoting comparative advertising research. It shows scholars mainly studying its concept and characteristics, its impact on different market players, its role on players of different ages, and its coping strategies. The study of its legitimacy recognition has also been included mainly focusing on the fairness of market competition, protection of consumers’ interests, etc., but ignoring the issue of social sustainable development. According to its bibliometric research findings, this study also suggests some topics for future research to provide direction and guidance on related topics.

Abstract Background N6‐methyladenosine (m6A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. Methods RNA m6A levels were analysed in NPC using m6A dot blot assay. The expression level of methyltransferase‐like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT‐qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m6A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half‐life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP‐qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes. Results We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m6A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism‐related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl‐CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22‐mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC. Conclusions The identified METTL14‐ANKRD22‐SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers.

Key Clinical Message Chronic active Epstein‐Barr virus (EBV) infection‐associated enteritis (CAEAE) in nonimmunodeficient individuals is rare. To report a case of CAEAE, relevant articles were searched through databases. The clinical manifestations, endoscopic findings, strategies of treatment, prognoses, and follow‐up results of CAEAE patients were analyzed. Including this report, seven citations in the literature provide descriptions of 27 cases of CAEAE. There were 21 males and six females, with a mean age of 40 years. The main clinical manifestations were fever (25/27), abdominal pain (14/27), diarrhea (16/27), hematochezia or bloody stools (13/27), and decreased hemoglobin and red blood cell counts in routine blood tests (14/27). Elevations in inflammatory markers, white blood cell (WBC) counts, and C‐reactive protein (CRP) were common. Coagulation was often abnormal. Histopathology confirmed EBV‐encoded small nuclear RNA (EBER) in the affected tissue via in situ hybridization. The average serum EBV DNA load was 6.3 × 10^5 copies/mL. All patients had varying degrees of intestinal ulcers endoscopically, and the ulcers and pathology were uncharacterized and misdiagnosed mostly as inflammatory bowel disease (IBD). The course of the disease was progressive and later complicated by intestinal bleeding, intestinal perforation, septic shock, and a high rate of emergency surgery. However, the conditions of the patients often did not improve after surgery, and some patients soon died due to reperforation or massive hematochezia. Hormone and antiviral treatment had no obvious effect. There was a significant difference in surgical and nonsurgical survival (p

Abstract Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.

Background: The aim of this current study was to compare the safety and effectiveness between robotic and laparoscopic surgery in pediatric patients suffered from choledochal cysts associated with aberrant hepatic duct. Methods: Patients suffered from choledochal cysts associated with aberrant hepatic duct who were treated with laparoscopic or robotic procedures between January 2009 and June 2022 were retrospectively analyzed. The patients were divided into laparoscopic and robotic group according to different surgical methods. The data collected included the demographic information, imaging information, operative details and postoperative complications. Results: Twenty-two patients were included in the analysis consisting of 14 cases in laparoscopic group and 8 cases in robotic group. The male to female ratio was 1:6.33. The median age of the patients was 40.00 months with a mean weight of 16.99 kg. There were no significant differences in patient characteristics between the two groups. The operation and anesthesia time were significantly longer in the laparoscopic procedures group (238.14 ± 17.24 min, 265.93 ± 19.51 min, respectively) than robotic procedures group (208.00 ± 9.24 min, 230.13 ± 12.87 min, respectively) (p

Abstract In seasonally frozen soil, soil sometimes is affected by freeze–thaw cycles and root systems. In order to study its mechanical characteristics, a series of consolidation drained triaxial tests under different confining pressures (25, 50, 100, 200 kPa), different freeze–thaw cycles (N = 0, 1, 5, 15) and different root-containing conditions (r = 0, 1, 3) were carried out. The test results show that the specimens exhibit strain softening behavior and volumetric dilatancy phenomena and shear failure under lower confining pressure, and strain hardening and volumetric contraction, bulging failure under higher confining pressure. With the increase of freeze–thaw cycles, the bearing capacity of the sample decreases and the volume strain increases. With the increase of volume ration of roots in the sample, the bearing capacity increases and the volume strain decreases. Based on the binary medium model, the soil is abstracted into bonded elements and frictional elements. At the same time, the bonded elements are transformed into frictional element when the bonded elements are broken during the loading process. Also, the root is abstracted into another non-destructive bonded elements material, which bears the load together. The linear elastic constitutive model is used for root and bonded elements, and the double-hardening model is used for friction elements. Considering the influence of freeze–thaw cycles, the extended binary model is derived here. Finally, the experimental results show that the predicted results of this model are in good agreement with the experimental results, and the new model can relatively well simulate the strain softening and volumetric dilatancy phenomena.

Abstract Background Congenital tibial hemimelia (CTH [MIM: 275220]) is a rare congenital limb deficiency that manifests as a shortened, curved, dysplastic or absent tibia with polydactyly. In previous studies, mutations of a distant sonic hedgehog (SHH) cis-regulator (ZRS) and a Shh repressor (GLI3) were identified. Case presentation Here, we admitted a 20-month-old boy who manifested with right tibial deformity, varus foot, ankle dislocation, and ipsilateral preaxial polydactyly. After genetic sequencing and data analysis, the results revealed a 443 A > G mutation in the father and a 536 C > T mutation in the mother in exon 2 of the Smoothed (SMO) gene at 7q32.1, with the coexistence of both mutant alleles in the proband/patient. Conclusions Our report suggests that even though not previously reported, SMO mutations may be associated with limb anomalies such as tibial hemimelia via Hh signaling in humans and has implications for genetic counseling.

Abstract The molecular dynamics method is used to further reveal, from the molecular point of view, the mechanisms of salt inhibiting the hydration of Na-MMT. The interaction between water molecules, salt molecules, and montmorillonite are calculated by establishing the adsorption models. According to the simulation results, the adsorption conformation, interlayer concentration distribution, self-diffusion coefficient, ion hydration parameters, and other data are compared and analyzed. The simulation results show that the volume and basal spacing increase in a stepwise manner with the increase of water content, and water molecules have different hydration mechanisms. The addition of salt will enhance the hydration properties of compensating cations of montmorillonite and affect the mobility of particles. The addition of inorganic salts mainly reduces the adsorption tightness between water molecules and crystal surfaces, thereby reducing the thickness of water molecules layer, while the organic salts can better inhibit migration by controlling interlayer water molecules. The results of molecular dynamics simulations reveal the microscopic distribution of particles and the influence mechanism when the swelling properties of montmorillonite are modified by chemical reagents.

Abstract REY‐rich mud, consisting of deep‐sea sediments with high concentrations of rare‐earth elements and yttrium (REY), holds significant economic potential. Many studies have been conducted on biogenic apatite, ferromanganese micronodule, and phillipsite within these deposits to ascertain the REY enrichment mechanisms. However, the knowledge of clay minerals in REY‐rich mud, which is the predominant component of pelagic sediments, is still limited. In this study, two adjacent gravity cores (core GC02: REY‐rich mud; core GC03: typical sediments of equatorial Pacific) were collected from the Clarion‐Clipperton Fracture Zone (CCFZ) of the Eastern Pacific to study the role of different clay minerals in REY enrichment. The clay minerals in core GC03 and core GC02 are primarily illite (averaging 60%) and smectite (averaging 63%), respectively, and the smectite in core GC02 was mainly Fe‐rich, which was probably formed via the reaction between opal and FeOOH. Moreover, multiple studies have reported similar smectite enrichment in REY‐rich mud, suggesting that it is a common characteristic. The presumed hydrothermal or volcanic origination of smectite in REY‐rich layers of core GC02 indicates the essential role of hydrothermal and volcanic activities in REY‐rich mud formation during the Oligocene in the western CCFZ.

Rational regulation of reactive oxygen species (ROS) plays a vital importance in maintaining homeostasis of living biological systems. For ROS-related pathologies, chemotherapy technology derived from metal nanomaterials currently occupies a pivotal position. However, they suffer from inherent issues such as complicated synthesis, batch-to-batch variability, high cost, and potential biological toxicity caused by metal elements. Here, we reported for the first time that dual-action 3,5-dihydroxy-1-ketonaphthalene-structured small-molecule enzyme imitator (DHKNase) exhibited 2-edged ROS regulation, catering to the execution of physiology-beneficial ROS destiny among diverse pathologies in living systems. Based on this, DHKNase is validated to enable remarkable therapeutic effects in 2 classic disease models, including the pathogen-infected wound-healing model and the dextran sulfate sodium (DSS)-caused inflammatory bowel disease (IBD). This work provides a guiding landmark for developing novel natural small-molecule enzyme imitator and significantly expands their application potential in the biomedical field.

AbstractBackground Gut dysbiosis in peritoneal dialysis (PD) patients causes chronic inflammation and metabolic disorders which result in a series of complications, probably playing an important role in PD technique failure. The reduction in gut microbial diversity was a common feature of gut dysbiosis. The objective was to explore the relationship between gut microbial diversity and technique failure in PD patients.Methods The gut microbiota was analyzed by 16s ribosomal RNA gene amplicon sequencing. Cox proportional hazards models were used to identify association between gut microbial diversity and technique failure in PD patients.Results In this study, a total of 101 PD patients were enrolled. During a median follow-up of 38 months, we found that lower diversity was independently associated with a higher risk of technique failure (hazard ratio [HR], 2.682; 95% confidence interval [CI], 1.319–5.456; p = 0.006). In addition, older age (HR, 1.034; 95% CI, 1.005–1.063; p = 0.020) and the history of diabetes (HR, 5.547; 95% CI, 2.218–13.876; p

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. β-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between β-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether β-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and β-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of β-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, β-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, β-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. β-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.

The north-south striking landform perpendicular to the dominant collision zone between the Indian and Eurasian plates was constructed in east-southern Tibet (EST) during the Late Miocene. The building processes remain ambiguous, partly owing to the lack of recognition of crustal-scale architecture. Here we deployed an east-west-oriented 120 km-long short-period dense array across the northwestern corner of EST. Results from P-wave receiver functions show a mid-crustal ductile detachment atop the crystalline basement of the eastern Lhasa terrane that has displaced the overlying crust including the upper part of the Yardong-Gulu Rift (YGR) eastward for about 100 km and an offset Moho geometry left behind beneath the Nyainqentanghla Range. Combined previous studies on the vertical heterogeneity in crustal strength beneath the YGR, a synthetic view implies a decoupled crustal architecture of EST to respond the dynamic interactions between the eastward extrusion of the Tibetan Plateau and the northward penetration of the Indian plate that constitutes the Eastern Himalayan Syntaxis. The integrated processes eventually brought active landform construction in the plateau’s interior and partly contributing to the contemporaneous intensification of monsoon in SE Asia.

The paper proposes a three-scale binary medium-based constitutive model on the basis of the meso structures and micro components to describe the elasto-plastic mechanical behavior of mudstone samples. Based on the breakage mechanism of geomaterials, mudstone samples are considered as two different materials (bonded and frictional elements) at mesoscales. From micro to meso scales, given the similar but different mineralogy composition and porosity of the bonded and frictional elements at microscale, as well as their separate mechanical characteristics, different homogenization methods are adopted to obtain their respective meso mechanical properties. At the mesoscale, in view of the unique meso structures and the continuous material transformation, the extended self-consistent scheme (SCS) is improved to be adaptable to elasto-plastic composites with varying meso components. With the consideration of the evolution form of the breakage ratio under the external loading being given based on the assumed strength distribution of the meso bonded elements, the mechanical relations between meso and macro scales are established. Finally, on the basis of the mean-field method and combined with the critical mechanical connections between different scales, the micro-meso-macro constitutive model for mudstone samples are proposed. The model validation shows that, with a few model parameters, the proposed model can well reflect the stress and deformation features of mudstone samples with complex micro-components.

Abstract Background Circular RNAs (circRNAs) act as gene expression regulators and are involved in cancer progression. However, their functions have not been sufficiently investigated in nasopharyngeal carcinoma (NPC). Methods The expression profiles of circRNAs in NPC cells within different metastatic potential were reanalyzed. Quantitative reverse transcription PCR and in situ hybridization were used to detect the expression level of circPVT1 in NPC cells and tissue samples. The association of expression level of circPVT1 with clinical properties of NPC patients was evaluated. Then, the effects of circPVT1 expression on NPC metastasis were investigated by in vitro and in vivo functional experiments. RNA immunoprecipitation, pull-down assay and western blotting were performed to confirm the interaction between circPVT1 and β-TrCP in NPC cells. Co-immunoprecipitation and western blotting were performed to confirm the interaction between β-TrCP and c-Myc in NPC cells. Results We find that circPVT1, a circular RNA, is significantly upregulated in NPC cells and tissue specimens. In vitro and in vivo experiments showed that circPVT1 promotes the invasion and metastasis of NPC cells. Mechanistically, circPVT1 inhibits proteasomal degradation of c-Myc by binding to β-TrCP, an E3 ubiquiting ligase. Stablization of c-Myc by circPVT1 alters the cytoskeleton remodeling and cell adhesion in NPC, which ultimately promotes the invasion and metastasis of NPC cells. Furthermore, c-Myc transcriptionally upregulates the expression of SRSF1, an RNA splicing factor, and recruits SRSF1 to enhance the biosynthesis of circPVT1 through coupling transcription with splicing, which forms a positive feedback for circPVT1 production. Conclusions Our results revealed the important role of circPVT1 in the progression of NPC through the β-TrCP/c-Myc/SRSF1 positive feedback loop, and circPVT1 may serve as a prognostic biomarker or therapeutic target in patients with NPC.

Although the Himalayan-Tibetan orogen is a result of compressional tectonics, the orogen also hosts active rifts accommodating east-west extension orthogonal to the north-south India-Asia convergence. In this study we address the question of how the north-trending rifts were formed by conducting high-resolution seismic imaging survey across southeastern Tibet where the Cona rift is exposed. Our work shows that the crustal structures of this youngest rift in southern Tibet was constructed by multiple-scale structures that are decoupled with depth and long rift trend. We suggest this deformation style to have resulted from eastward extrusion of the middle and upper crust with increasing speeds to the north towards the Yarlunbg-Zangpo suture. The differential eastward extrusion in turn may have contributed to the formation and evolution of the eastern Himalayan syntaxis.

Yes-associated protein (YAP) is a transcriptional regulator that affects cell proliferation, organ size and tissue development and regeneration, and has therefore, been an important object of study. In recent years, there has been an increasing research focus on YAP in inflammation and immunology, and the role of YAP in the development of inflammation and in immune escape by tumors has been progressively elucidated. Because YAP signaling involves a variety of different signal transduction cascades, the full range of functions in diverse cells and microenvironments remains incompletely understood. In this article, we discuss the complex involvement of YAP in inflammation, the molecular mechanisms through which it exercises pro- and anti-inflammatory effects under different conditions, and the progress achieved in elucidating the functions of YAP in inflammatory diseases. A thorough understanding of YAP signaling in inflammation will provide a foundation for its use as a therapeutic target in inflammatory diseases.

Abstract Lung cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.

Abstract Character strengths could effectively prevent negative psychological outcomes in adults. However, there was little research conducted among early adolescents. The present study aimed to explore character strengths that were independently related to fewer behavior problems in early adolescents. In total, 521 early adolescents (mean age 10.92 ± 0.04, range 10–12 years) were recruited from primary schools in Sichuan, China. Character strengths were measured using the Values in Action Inventory of Strengths for Youth (VIA-Youth). Behavior problems were measured using the Conners Parent Symptom Questionnaire (PSQ). The results showed that behavior problems were negatively correlated with character strengths (r = −0.14 to −0.3, p < 0.05 Bonferroni corrected). Character strengths explained a significant proportion of additional variance (14–22%) in five types of behavior problems after controlling the effect of demographic factors (residence, left-behind experiences, maternal education level). Moreover, several specific character strengths showed an independent contribution (β = −0.34 to −0.14 for self-regulation, perseverance, zest, humility, and leadership; β = 0.21 to 0.34, for hope; all p < 0.05) to behavior problems. Our study revealed that character strengths were protective factors against behavior problems in early adolescents.

Abstract Ferroptosis is a type of cell death that depends on iron and reactive oxygen species (ROS). The accumulation of iron and lipid peroxidation primarily initiates oxidative membrane damage during ferroptosis. The core molecular mechanism of ferroptosis includes the regulation of oxidation and the balance between damage and antioxidant defense. Tumor cells usually contain a large amount of H2O2, and ferrous/iron ions will react with excessive H2O2 in cells to produce hydroxyl radicals and induce ferroptosis in tumor cells. Here, we reviewed the latest studies on the regulation of ferroptosis in tumor cells and introduced the tumor-related signaling pathways of ferroptosis. We paid particular attention to the role of noncoding RNA, nanomaterials, the role of drugs, and targeted treatment using ferroptosis drugs for mediating the ferroptosis process in tumor cells. Finally, we discussed the currently unresolved problems and future research directions for ferroptosis in tumor cells and the prospects of this emerging field. Therefore, we have attempted to provide a reference for further understanding of the pathogenesis of ferroptosis and proposed new targets for cancer treatment.

Mechanism driving continental growth on modern Earth has long been debated. By interpreting the long deep seismic reflection data across the ongoing India-Eurasia collision zone, the authors report crustal-scale magma accretion onto the south of central Lhasa terrane produced net continental growth.

Background and aimsThe pathogenesis of primary biliary cholangitis (PBC) is associated with alterations of gut microbiota. We compared the gut microbiota of PBC patients and healthy controls from Zhejiang Province and assessed the use of these data for the diagnosis of PBC.MethodsFirst, 16S rRNA gene sequencing was used to characterize the gut microbiota of treatment-naive PBC patients (n=25) and matched healthy controls (n=25). Then, the value of gut microbiota composition for the diagnosis of PBC and assessment of PBC severity was determined.ResultsThe gut microbiota of PBC patients had lower diversity based on three different metrics of alpha-diversity (ace, Chao1, and observed features) and fewer overall genera (all p

Abstract Freezing–thawing actions can affect the mechanical features of soil greatly, which is vital for the stability of soil slope in cold regions. Firstly, triaxial compression tests on sand samples under undrained conditions were performed to investigate the influences of freezing–thawing cycles, which shows that the freezing–thawing actions can weaken their strength and stiffness, and with the increasing freezing–thawing cycles, both the deviatoric stress and pore water pressure decrease gradually. Then, the double hardening constitutive model was revised to model the influences of freezing–thawing cycles in consideration of the influences of freezing–thawing actions, and the model was also validated by the test results. Finally, the proposed constitutive model was incorporated into a finite element code to numerically simulate the distribution of displacement and pore water pressure of sand slope subjected to freezing–thawing cycles, which shows that the freezing–thawing actions accelerate the dissipation of the pore water pressure and enlarge the displacement of the slope. The study here can provide a help in designing and construction of civil engineering in cold regions.

Effective and timely collision avoidance decision support is essential for super-large vessels navigating in port waters. To guarantee the navigational safety of super-large vessels, this work proposes a collision avoidance decision support method based on the curve increment strategy with adaptive particle swarm optimization (CIPSO). Firstly, the objective function is constructed based on the multi-objective optimization method. Here, a fuzzy comprehensive evaluation (FCE)-based vessel collision hazard model and vessel speed-varying energy-loss model integrating the Convention on the International Regulations for Preventing Collisions at Sea (COLREGS) are involved. Furthermore, in response to the limitations of the PSO algorithm, which is prone to falling into local optima in the later stages of iteration, a curve increment strategy is incorporated. To improve the performance of the global optimization, it is optimized using a local followed by global search method. The iterative evolution of CIPSO is used to obtain the optimal decision value in the set domain of feasible solutions. Finally, the effectiveness and feasibility of the proposed method are verified by the numerical simulation and large vessel maneuvering simulator, which can provide collision avoidance decision support for ship pilots.

Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.

Abstract Background Langerhans cell histiocytosis (LCH) is a rare condition that has a variety of clinical manifestations. But LCH in children localized only in the hepatobiliary system is unusual. Case presentation. Here we reported a rare case of a 2-year-old boy who was serendipitously found to have elevated liver enzymes while undergoing treatment of a perianal abscess. After a period of earlier conservative treatment in another hospital, the perianal abscess had resolved but the levels of liver enzymes were still rising slowly. The child was then referred to our institution for a definitive diagnosis. After laboratory tests, imaging and pathological examinations, a diagnosis of liver cirrhosis and sclerosing cholangitis was established, although the cause was unclear. Subsequently, living-donor liver transplantation was performed due to deterioration in liver function. Following successful liver transplantation, a diagnosis of LCH localized only within the hepatobiliary system was finally confirmed, based on additional pathological and imaging investigation. Additionally, the BRAF V600E mutation in this patient was also confirmed. The child has now recovered without evidence of LCH recurrence. Conclusions LCH localized only within the hepatobiliary system is unusual. The presence of unexplainable sclerosing cholangitis and liver cirrhosis in any child should raise the suspicion of LCH.

ObjectiveTo explore the relationship between the Duration of Untreated Psychosis (DUP) and long-term clinical outcome, cognitive and social function in patients with chronic schizophrenia (SCZ).MethodsA total of 248 subjects with chronic SCZ were enrolled in this study, including 156 in the short DUP group and 92 in the long DUP group. The Positive and Negative Symptoms Scale (PANSS), the Brief Negative Symptoms Scale (BNSS), the Global Assessment of Functioning (GAF) scale and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were used to assess all of the subjects.ResultsThe negative symptom scores (the PANSS and BNSS) of subjects with long DUP were significantly higher than that in subjects with short DUP. The scores of visual span and speech function in the short DUP group were significantly higher, indicative of decreasing cognitive function with time. In terms of social function, the short DUP group scored higher, with a statistically significant difference. Meanwhile, we found that the length of DUP was positively correlated with the negative symptom score of the PANSS, negatively correlated with visual span scores, and GAF scores.ConclusionThis study demonstrated that the DUP remained a significant association with negative symptom and cognition in long period of chronic SCZ.

Abstract The cyclic signal amplification technology has been widely applied for the ultrasensitive detection of many important biomolecules, such as nucleic acids, proteins, enzymes, adenosine triphosphate (ATP), metal ions, exosome, etc. Due to their low content in the complex biological samples, traditional detection methods are insufficient to satisfy the requirements for monitoring those biomolecules. Therefore, effective and sensitive biosensors based on cyclic signal amplification technology are of great significance for the quick and simple diagnosis and treatment of diseases. Fluorescent biosensor based on cyclic signal amplification technology has become a research hotspot due to its simple operation, low cost, short time, high sensitivity and high specificity. This paper introduces several cyclic amplification methods, such as rolling circle amplification (RCA), strand displacement reactions (SDR) and enzyme-assisted amplification (EAA), and summarizes the research progress of using this technology in the detection of different biomolecules in recent years, in order to provide help for the research of more efficient and sensitive detection methods. Graphical Abstract

Abstract Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analog misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury.

The aim of this following study is to systematically review and analyze the published data comparing laparoscopic surgery and robotic assisted surgery for choledochal cyst excisions through the metrics of operative time, length of hospital stay and postoperative outcome. PubMed, Web of Science, Embase, Ovid, and the Cochrane Library databases were combed through and data was retrieved from the timespan between January 1995 and October 2021. The primary measures included operative time, intraoperative bleeding, hospital stay, and postoperative complications. Quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scale. Making use of random-effects models, we pooled the odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs). Six studies comprising a total 484 patients who had undergone either laparoscopic surgery [307 (63.43%) patients] or robot-assisted surgery [177 (36.57%) patients] were included in this analysis. Three of the articles involved adults while the other three involved children. All of the studies were published after 2018 and were retrospective case–control studies. Patients undergoing robotic surgery had a shorter hospital stay (MD, 0.95; 95% CI, 0.56 to 1.35; p

This study aimed to preliminary examine the psychometric properties of the Chinese version 96-item VIA Inventory for Youth (VIA Youth-96) by analyzing the internal consistency, factorial validity, and criterion validity, and to examine the age-related changes in character strengths (CSs) among adolescents. The sample consisted of 959 adolescents aged 10–17 (49.5% boys). Participants completed the Chinese version VIA Youth-96, along with the Perceived Parental Autonomy Support Scale, and questionnaires assessing life satisfaction and self-efficacy online. The Chinese version VIA Youth-96 showed a good fit for the original four-factor structure, and CS scores were significantly correlated with life satisfaction and self-efficacy indicating a good criterion validity of the scale. The internal consistency was 0.54–0.86 for subscales. Moreover, this study revealed significant age-related changes in CSs among adolescents, eight CSs significantly linearly declined by age. These results suggested that the Chinese version VIA Youth-96 is a valid tool for assessing CSs in adolescents and that CSs are declined linearly by age during adolescence.

BackgroundCavernous transformation of the portal vein (CTPV) causes portal hypertension in children. Among Meso-Rex treatments, it is unclear whether the Meso-Rex bypass shunt (MRB) or the Meso-Rex transposition shunt (MRT) offers lower postoperative morbidity. Our objective was to evaluate postoperative outcomes, comparing MRB and MRT for children with CTPV.MethodsA retrospective study was conducted on children undergoing Meso-Rex for CTPV from January 2010 to December 2020. The primary outcome was shunt complications, including shunt stenosis and thrombus. The secondary outcome was re-operation.ResultsOf the 43 patients included, 21 underwent MRT and 22 underwent MRB. MRT was associated with a higher rate of shunt complications when compared to MRB (23.8 vs. 9.1%, p = 0.191). The patients exhibited a higher rate of re-operation under the MRT than under the MRB (19 vs. 4.5%, p = 0.138). The operative time in the MRT group was significantly shorter than in the MRB group. Compared to MRT, the reduction in the length and thickness of the spleen was significantly greater in the MRB group. The increases in platelets were significantly higher in the MRB group than in the MRT group. The postoperative shunt velocity of MRB was notably faster than MRT. There was no significant difference in postoperative portal pressure between the two groups (p > 0.05).ConclusionBoth MRB and MRT result in acceptable postoperative outcomes, but MRT is associated with higher post-shunt complications, which often increase the re-operation rate. This study suggests that MRB may offer advantages for children with CTPV.

To improve understanding of the characteristics of extreme summer rainfall and its water vapor transport in the eastern part of southwestern China (ESWC), this study analyzed data on daily precipitation from 118 meteorological stations in the ESWC from 1979 to 2020, as well as daily reanalysis data from ERA5 and daily reanalysis data from NCEP/NCAR. The study employed polynomial fitting, correlation, regression, clustering, and mixed single-particle Lagrangian trajectory (HYSPLITv5.0) modeling methods to simulate extreme summer precipitation and its water vapor transport characteristics in the ESWC and its possible formation mechanism. The results show that: (1) The contribution rate of extreme precipitation in the ESWC from 1979 to 2020 varied significantly on the interannual time scale. When the number of extreme precipitation days is high (low), the contribution rate of extreme precipitation is also high (low), while the contribution rate of general precipitation (the percentage of the sum of general precipitation to the total summer precipitation of that year) is often low (high). (2) When extreme precipitation occurs in the ESWC, compared with general precipitation, the high-level potential vortices are stronger, and the cold air from higher latitude is more likely to move southward. Meanwhile, the amount of water vapor input to the region is significantly larger than that of general precipitation. (3) There are four channels of water vapor sources in the ESWC during the period of extreme precipitation: the Bay of Bengal, the Arabian Sea, the western Pacific, and the northwest. The contribution of water vapor from the Bay of Bengal is the highest. The number of extreme summer precipitation days in the ESWC is significantly negatively correlated with the water vapor budget of the eastern boundary and positively correlated with Indian Ocean Basin-Wide (IOBW) index in the previous winter. (4) When the winter SST is high in the IOBW mode, it can cause the western Pacific subtropical high and the South Asian high to be stronger and shifted southward in summer, resulting in an increase in the number of extreme precipitation days in the ESWC.

Abstract Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.

Abstract Background Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated. Methods Cell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1β and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively. Results Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model. Conclusions This study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.