Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3ß.

BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.

Design of a Humidity Sensor for a PPE Kit Using a Flexible Paper Substrate.

The present work reports the rapid sweat detection inside a PPE kit using a flexible humidity sensor based on hydrothermally synthesized ZnO (zinc oxide) nanoflowers (ZNFs). Physical characterization of ZNFs was done using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transmission infrared spectroscopy (FTIR), UV-visible, particle size analysis, Raman analysis, and X-ray photoelectron spectroscopy (XPS) analysis, and the hydrophilicity was investigated by using contact angle measurement. Fabrication of a flexible sensor was done by deposition on the paper substrate using the spin coating technique. It exhibited high sensitivity and low response and recovery times in the humidity range 10-95%RH. The sensor demonstrated the highest sensitivity of 296.70 nF/%RH within the humidity range 55-95%RH, and the rapid response and recovery times were also calculated and found as 5.10/1.70 s, respectively. The selectivity of the proposed sensor was also analyzed, and it is highly sensitive to humidity. The humidity sensing characteristics were theoretically witnessed in terms of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and electronic properties of sensing materials in ambient and humid conditions. These theoretical results are evidence of the interaction of ZnO with humidity. Overall, the present study provides a scope of architecture-enabled paper-based humidity sensors for the detection of sweat levels inside PPE kits for health workers.

Dysfunction of Akt/FoxO3a/Atg7 regulatory loop magnifies obesity-regulated muscular mass decline.

BACKGROUND: Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of Atg7 gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity remain uncertain. The study aimed to elucidate the role and underly mechanism of Atg7 action in the context of obesity-induced muscle mass decline. METHODS: In this study, we established a murine model of high-fat diet-induced obesity (DIO) and introduced adeno-associated virus delivery of short hairpin RNA to knock down Atg7 (shAtg7) into the gastrocnemius muscle. We then examined the expressions of Atg7 and myoprotein degradation markers in the gastrocnemius tissues of obese patients and mice using immunofluorescence and western blotting techniques. To further investigate the effects of Atg7, we assessed skeletal muscle cell diameter and the myoprotein degradation pathway in C2C12 and HSkMC cells in the presence or absence of Atg7. Immunofluorescence staining for MyHC and western blotting were utilized for this purpose. To understand the transcriptional regulation of Atg7 in response to myoprotein degradation, we conducted luciferase reporter assays and chromatin immunoprecipitation experiments to examine whether FoxO3a enhances the transcription of Atg7. Moreover, we explored the role of Akt in Atg7-mediated regulation and its relevance to obesity-induced muscle mass decline. This was accomplished by Akt knockdown, treatment with MK2206, and GST pulldown assays to assess the interaction between Atg7 and Akt. RESULTS: After 20 weeks of being on a high-fat diet, obesity was induced, leading to a significant decrease in the gastrocnemius muscle area and a decline in muscle performance. This was accompanied by a notable increase in Atg7 protein expression (p < 0.01). Similarly, in gastrocnemius tissues of obese patients when compared to nonobese individuals, there was a significant increase in both Atg7 (p < 0.01) and TRIM63 (p < 0.01) levels. When palmitic acid was administered to C2C12 cells, it resulted in increased Atg7 (p < 0.01), LC3Ⅱ/Ⅰ (p < 0.01), and p62 levels (p < 0.01). Additionally, it promoted FoxO3a-mediated transcription of Atg7. The knockdown of Atg7 in the gastrocnemius partially reversed DIO-induced muscle mass decline. Furthermore, when Atg7 was knocked down in C2C12 and HSkMC cells, it mitigated palmitic acid-induced insulin resistance, increased the p-Akt/Akt ratio (p < 0.01), and reduced TRIM63 (p < 0.01). Muscular atrophy mediated by Atg7 was reversed by genetic knockdown of Akt and treatment with the p-Akt inhibitor MK2206. Palmitic acid administration increased the binding between Atg7 and Akt (p < 0.01) while weakening the binding of PDK1 (p < 0.01) and PDK2 (p < 0.01) to Akt. GST pulldown assays demonstrated that Atg7 directly interacted with the C-terminal domain of Akt. CONCLUSION: The consumption of a high-fat diet, along with lipid-induced effects, led to the inhibition of Akt signaling, which, in turn, promoted FoxO3a-mediated transcription, increasing Atg7 levels in muscle cells. The excess Atg7 inhibited the phosphorylation of Akt, leading to a cyclic activation of FoxO3a and exacerbating the decline in muscle mass regulated by obesity. Consequently, Atg7 serves as a regulatory point in determining the decline in muscle mass induced by obesity.

HIF-1A as a prognostic biomarker related to invasion, migration and immunosuppression of cervical cancer.

Background: The incidence of cervical cancer ranks second among malignant tumors in women, exerting a significant impact on their quality of life and overall well-being. The hypoxic microenvironment plays a pivotal role in the initiation and progression of tumorigenesis. The present study aims to investigate the fundamental genes and pathways associated with the hypoxia-inducible factor (HIF-1A) in cervical cancer, aiming to identify potential downstream targets for diagnostic and therapeutic purposes. Methods: We obtained dataset GSE63514 from the Comprehensive Gene Expression Database (GEO). The dataset comprised of 24 patients in the normal group and 28 patients in the tumor group. Gene set difference analysis (GSVA) and gene set enrichment analysis (GSEA) were used to identify the genes related to HIF-1A expression and the specific signaling pathways involved.The association between HIF-1A and tumor immune infiltration was examined in the TCGA dataset. The WGCAN network was constructed to identify key genes within the blue module, and subsequent gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to determine the pathways and functional annotations associated with HIF-1A. The protein interaction network of the HIF-1A gene was obtained from the STRING database and visualized using Cytoscape in the meantime.The function of HIF-1A and its related gene expression were verified in vivo. Results: HIF-1A was a risk factor in both univariate and multivariate Cox regression analysis of cervical cancer patients. A total of 344 genes significantly correlated with the expression of HIF-1A were identified through correlation analysis, and the genes exhibiting the strongest correlation were obtained. The major signaling pathways involved in HIF-1A encompass TNF-α/NF-κB, PI3K/AKT/MTOR, TGF-ß, JAK-STAT, and various other signaling cascades. Reinforced by qRT-PCR, we identified Integrin beta-1 (ITGB1), C-C motif chemokine ligand 2 (CCL2), striatin 3 (STRN3), and endothelin-1 (EDN1) as pivotal downstream genes influenced by HIF-1A. HIF-1A is associated with immune infiltration of natural killer (NK) cells, mast cells, CD4+T cells, M0 macrophages, neutrophils, follicular helper T cells, CD8+T cells, and regulatory T cells (Treg). HIF-1A is associated with sensitivity to chemotherapy drugs. The identification of the HIF-1A pathway and its function primarily focuses on cytoplasmic translation, aerobic respiration, cellular respiration, oxidative phosphorylation, thermogenesis, among others. The results of in vivo experiments have confirmed that HIF-1A plays a crucial role in promoting the migration and invasion of cervical cancer cells. Moreover, the overexpression of HIF-1A led to an upregulation in the expressions of ITGB1, CCL2, STRN3, and EDN1. Conclusions: The role of HIF-1A in cervical cancer was determined through a combination of bioinformatics analysis and experimental validation. The genes potentially implicated in the tumorigenesis mechanism of HIF-1A were identified. These findings has the potential to enhance our comprehension of the progression of cervical cancer and offer promising therapeutic targets for its clinical management.

Sumoylation of SAP130 regulates its interaction with FAF1 as well as its protein stability and transcriptional repressor function.

BACKGROUND: Fas-associated factor 1 (FAF1) is a multidomain protein that interacts with diverse partners to affect numerous cellular processes. Previously, we discovered two Small Ubiquitin-like Modifier (SUMO)-interacting motifs (SIMs) within FAF1 that are crucial for transcriptional modulation of mineralocorticoid receptor. Recently, we identified Sin3A-associated protein 130 (SAP130), a putative sumoylated protein, as a candidate FAF1 interaction partner by yeast two-hybrid screening. However, it remained unclear whether SAP130 sumoylation might occur and functionally interact with FAF1. RESULTS: In this study, we first show that SAP130 can be modified by SUMO1 at Lys residues 794, 878 and 932 both in vitro and in vivo. Mutation of these three SUMO-accepting Lys residues to Ala had no impact on SAP130 association with Sin3A or its nuclear localization, but the mutations abrogated the association of SAP130 with the FAF1. The mutations also potentiated SAP130 trans-repression activity and attenuated SAP130-mediated promotion of cell growth. Additionally, SUMO1-modified SAP130 was less stable than unmodified SAP130. Transient transfection experiments further revealed that FAF1 mitigated the trans-repression and cell proliferation-promoting functions of SAP130, and promoted SAP130 degradation by enhancing its polyubiquitination in a sumoylation-dependent manner. CONCLUSIONS: Together, these results demonstrate that sumoylation of SAP130 regulates its biological functions and that FAF1 plays a crucial role in controlling the SUMO-dependent regulation of transcriptional activity and protein stability of SAP130.

MicroRNA-152 specifically targets kinesin family member 14 to suppress the advancement of bladder cancer cells via PI3K/AKT pathway.

BACKGROUND: Kinesin family member 14 (KIF14) overexpression has been linked to tumor progression and metastasis in different malignancies, but its precise molecular mechanism in bladder cancer (BLCA) remains unclear. METHODS: The expression of KIF14 in BLCA and its relationship with clinical outcomes were assessed. Functional investigations on KIF14 were conducted using CCK-8, Transwell experiment, colony formation, scratch motility assays, and flow cytometry. We examined the downstream route of KIF14 and identified its upstream regulatory factor through luciferase reporter experiments and bioinformatics tools. RESULTS: Our findings demonstrated that increased KIF14 expression was associated with poor survival prognosis in BLCA patients. Deletion of KIF14 affected cell cycle progression, induced apoptosis, and inhibited cell growth, migration, and invasion. GSEA analysis revealed a strong association between KIF14 expression and the PI3K/AKT signaling pathway. Further research showed that KIF14 deletion decreased the levels of p-PI3K, p-AKT, FOXM1, and CCNB1. We also found that has-miR-152-3p (miR-152) suppressed BLCA cell growth by post-transcriptionally regulating KIF14 expression. CONCLUSIONS: Our findings suggest that targeting KIF14 could alter the PI3K/AKT and FOXM1-CCNB1 axis, leading to growth inhibition, cell cycle arrest, and induction of apoptosis in BLCA cells. Additionally, miR-152 directly regulates KIF14 expression at the post-transcriptional level. Overall, KIF14 represents a promising therapeutic target for BLCA clinical therapy.

Combined influence of nutritional and inflammatory status and depressive symptoms on mortality among US cancer survivors: Findings from the NHANES.

BACKGROUND: Inflammation and nutrition and depression are interrelated, and both are related to changes in mortality rates. We investigated the association of nutritional and inflammation index or depressive symptoms with the risk of all-cause mortality or cause-specific mortality among cancer survivors. METHODS: A prospective cohort of a nationally representative sample of cancer survivors, aged 40 years or older (n = 2331; weighted population, 15 248 255; 67.6 ± 11.0 years; 50.6 % males), were recruited from the US National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Advanced lung cancer inflammation index (ALI) reflected inflammation and nutritional status and Patient Health Questionnaire 9 (PHQ-9) demonstrated depressive symptoms. The independent and joint associations of ALI and PHQ-9 score with mortality outcomes were examined among cancer survivors and Cox regression analysis based on weights was used to calculate the relative risk. RESULTS: We identified 605 all-cause deaths (cancer, 204; non-cancer, 401) over a median of 6.2 years of follow-up (15,385 person-years; interquartile range, 3.3-9.8 years). High ALI was observed to be consistently associated with lower risks of all-cause (hazard ratio [HR], 0.516; 95 % CI, 0.400-0.667) and non-cancer (HR, 0.414; 95 % CI, 0.291-0.588) mortality compared with low ALI in a series of adjusted models. Meanwhile, lower PHQ-9 score (0-4) was associated with lower risks of all-cause (HR, 0.686; 95 % CI, 0.521-0.903) and non-cancer (HR, 0.686; 95 % CI, 0.474-0.992) mortality compared with higher PHQ-9 score (≥10). Furthermore, joint analyses showed that high ALI was associated with a decreased risk of death among cancer survivors who were not depressive. Specifically, survivors with high ALI but not depressive symptoms had the lowest overall (HR, 0.404; 95 % CI, 0.228-0.715) risks. CONCLUSION: In this cohort study, we observed impact of nutritional and inflammatory status and depressive symptoms on mortality among cancer survivors, with the lowest risks of death from both all causes and non-cancer being noted among the combination of high level ALI with no depression.

Proscillaridin A inhibits lung cancer cell growth and motility through downregulation of the EGFR-Src-associated pathway.

First-generation tyrosine kinase inhibitors (TKIs) have been associated with good responses in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations. However, this therapeutic strategy inevitably promotes resistance to TKIs. This study aimed to investigate the functional role and mechanism of proscillaridin A in NSCLC with or without EGFR mutations. Cellular function assays showed that proscillaridin A could inhibit cell proliferation, migration and invasion in vitro independent of EGFR mutation status. Real-time PCR of the human chromosome 17 α-satellite region revealed that proscillaridin A significantly suppressed tumour micrometastasis in vivo. In immunofluorescence experiments, we found that proscillaridin A decreased filopodia length in NSCLC cells. Furthermore, proscillaridin A also downregulated EGFR-Src-mediated cytoskeleton-related pathways, including FAK-paxillin signalling, which has been shown to promote cell filopodia formation by regulating small G-proteins. Therefore, we used the GST-PBD pull-down assay to demonstrate that proscillaridin A could decrease Cdc42 activity. Moreover, survival analyses of 591 lung adenocarcinoma patients from the GEO database indicated that the expression levels of Src and paxillin and the risk score of the gene signature based on these two factors were negatively correlated with overall survival and could be used as independent prognostic factors. In conclusion, we speculate that proscillaridin A inhibits lung cancer cell growth and motility by regulating EGFR-Src-associated pathways.

The Effect of Temperature on the Embryo Development of Cephalopod Sepiella japonica Suggests Crosstalk between Autophagy and Apoptosis.

Temperature is a crucial environmental factor that affects embryonic development, particularly for marine organisms with long embryonic development periods. However, the sensitive period of embryonic development and the role of autophagy/apoptosis in temperature regulation in cephalopods remain unclear. In this study, we cultured embryos of Sepiella japonica, a typical species in the local area of the East China Sea, at different incubation temperatures (18 °C, 23 °C, and 28 °C) to investigate various developmental aspects, including morphological and histological characteristics, mortality rates, the duration of embryonic development, and expression patterns of autophagy-related genes (LC3, BECN1, Inx4) and apoptosis marker genes (Cas3, p53) at 25 developmental stages. Our findings indicate that embryos in the high-temperature (28 °C) group had significantly higher mortality and embryonic malformation rates than those in the low-temperature (18 °C) group. Furthermore, high temperature (28 °C) shortened the duration of embryonic development by 7 days compared to the optimal temperature (23 °C), while low temperature (18 °C) caused a delay of 9 days. Therefore, embryos of S. japonica were more intolerant to high temperatures (28 °C), emphasizing the critical importance of maintaining an appropriate incubation temperature (approximately 23 °C). Additionally, our study observed, for the first time, that the Early blastula, Blastopore closure, and Optic vesicle to Caudal end stages were the most sensitive stages. During these periods, abnormalities in the expression of autophagy-related and apoptosis-related genes were associated with higher rates of mortality and malformations, highlighting the strong correlation and potential interaction between autophagy and apoptosis in embryonic development under varying temperature conditions.

Association between intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid (n-3 PUFA DHA) and reduced risk of ovarian cancer: A systematic Mendelian Randomization study.

BACKGROUND & AIMS: Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. METHODS: We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. RESULTS: In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. CONCLUSION: Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.

The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.

In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.

Knockdown of kinesin family member 4A inhibits cell proliferation, migration, and invasion while promoting apoptosis of urothelial bladder carcinoma cells.

BACKGROUND: Kinesin family member 4A (KIF4A) is upregulated in a variety of cancers. However, its expression and potential downstream targets in urothelial bladder carcinoma (UBC) remain unclear. METHODS: Expression data of KIF4A in UBC and noncancerous tissues were downloaded from the GEPIA database. Cell proliferation, migration, invasion, and apoptosis of T24 and 5637 UBC cells were examined using wound healing, transwell, colony formation, CCK-8, and flow cytometry assays. KIF4A and potential downstream genes were analyzed using qRT-PCR, western blot analysis, and immunohistochemistry. RESULTS: In UBC samples, KIF4A expression was significantly higher than in corresponding noncancerous samples. UBC patients with high KIF4A expression had poor cancer-specific survival and overall survival. Knockdown of KIF4A significantly inhibited proliferation and promoted apoptosis of UBC cells, accompanied by dephosphorylation of AKT and increased the protein level of proapoptotic factors. Additionally, knockdown of KIF4A reduced migration and invasion of UBC cells whereas overexpression of KIF4A exhibited opposite effects, along with altered protein level in epithelial-mesenchymal transition-related genes. Furthermore, overexpression of YAP1 promoted KIF4A expression whereas knockdown of YAP1 suppressed KIF4A expression in UBC cells. Alternatively, KIF4A knockdown reduced YAP1 nuclear protein level whereas KIF4A overexpression suppressed YAP1 phosphorylation and facilitated YAP1 nuclear translocation. CONCLUSIONS: KIF4A upregulation correlates with poor prognosis of UBC. Knockdown of KIF4A inhibits proliferation, migration, and invasion of UBC cells while inducing apoptosis possibly through dephosphorylation of AKT, changes in EMT-related genes, and interaction with YAP1.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.

Exogenous myo-inositol increases salt tolerance and accelerates CAM induction in the early juvenile stage of the facultative halophyte Mesembryanthemum crystallinum but not in the late juvenile stage.

Mesembryanthemum crystallinum L. (ice plant) develops salt tolerance during the transition from the juvenile to the adult stage through progressive morphological, physiological, biochemical, and molecular changes. Myo -inositol is the precursor for the synthesis of compatible solute D-pinitol and promotes Na+ transport in ice plants. We previously showed that supplying myo -inositol to 9-day-old seedlings alleviates salt damage by coordinating the expression of genes involved in inositol synthesis and transport, affecting osmotic adjustment and the Na/K balance. In this study, we examined the effects of myo -inositol on physiological parameters and inositol-related gene expression in early- and late-stage juvenile plants. The addition of myo -inositol to salt-treated, hydroponically grown late juvenile plants had no significant effects on growth or photosynthesis. In contrast, supplying exogenous myo -inositol to salt-treated early juvenile plants increased leaf biomass, relative water content, and chlorophyll content and improved PSII activity and CO2 assimilation. The treatment combining high salt and myo -inositol synergistically induced the expression of myo -inositol phosphate synthase (INPS ), myo -inositol O -methyltransferase (IMT ), and inositol transporters (INTs ), which modulated root-to-shoot Na/K ratio and increased leaf D-pinitol content. The results indicate that sufficient myo -inositol is a prerequisite for high salt tolerance in ice plant.

Biowaste Eggshell Membranes for Bio-triboelectric Nanogenerators and Smart Sensors.

In this study, we used a simple and cost-effective method to fabricate triboelectric nanogenerators (TENGs) based on biowaste eggshell membranes (EMs). We prepared stretchable electrodes with various types of EMs (hen, duck, goose, and ostrich) and employed them as positive friction materials for bio-TENGs. A comparison of the electrical properties of the hen, duck, goose, and ostrich EMs revealed that the output voltage of the ostrich EM could reach up to 300 V, due to its abundant functional groups, natural fiber structure, high surface roughness, high surface charge, and high dielectric constant. The output power of the resulting device reached 0.18 mW, sufficient to power 250 red light-emitting diodes simultaneously, as well as a digital watch. This device also displayed good durability when subjected to 9000 cycles at 30 N at a frequency of 3 Hz. Furthermore, we designed an ostrich EM-TENG as a smart sensor for the detection of body motion, including leg movement and the pressing of different numbers of fingers.

Insight into the causality between basal metabolic rate and endometrial and ovarian cancers: Analysis utilizing systematic Mendelian randomization and genetic association data from over 331,000 UK biobank participants.

BACKGROUND: Observational studies have demonstrated that basal metabolic rate (BMR) is associated with the risk of endometrial cancer (EC) and ovarian cancer (OC). However, it is unclear whether these associations reflect a causal relationship. OBJECTIVE: To reveal the causality between BMR and EC and OC, we performed the first comprehensive two-sample Mendelian randomization (MR) analyses. METHODS: Genetic variants were used as proxies of BMR. GWAS summary statistics of BMR, EC and OC were obtained from the UK Biobank Consortium, Endometrial Cancer Association Consortium and Ovarian Cancer Association Consortium respectively. The inverse variance weighted method was employed as the main approach for MR analysis. A series of sensitivity analyses were implemented to validate the robustness and reliability of the results. RESULTS: BMR was significantly related to an increased risk of EC (ORSD  = 1.49; 95% CI: 1.29-1.72; p-Value < .001) and OC (ORSD  = 1.21; 95% CI: 1.08-1.35; p-Value < .001). Furthermore, the stratified analysis indicated that BMR was positively associated with endometrioid endometrial cancer (EEC) (ORSD  = 1.45; 95% CI, 1.23-1.70; p-Value < .001), clear cell ovarian cancer(CCOC) (ORSD  = 1.89; 95% CI:1.35-2.64; p-Value < .001) and endometrioid ovarian cancer risk (EOC) (ORSD  = 1.45; 95% CI: 1.12-1.88; p-Value = .005). However, there were no significant associations of BMR with invasive mucinous ovarian cancer (IMOC), high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC). The robustness of the above results was further verified in sensitivity analyses. CONCLUSION: The MR study provided etiological evidence for the positive association of BMR with the risk of EC, EEC, OC, CCOC and EOC. But this study did not provide enough evidence suggesting the causal associations of BMR with IMOC, HGSOC and LGSOC.

Enhanced triboelectric properties of Eu2O3-doped BaTiO3/PVDF-HFP nanofibers.

Because triboelectric nanogenerators (TENGs) convert mechanical energy into electricity, they are sustainable energy sources for powering a diverse range of intelligent sensing and monitoring devices. To enhance the electrical output of polymer-based TENGs, nanofillers are commonly incorporated into polymers. In this study, we developed a simple low-temperature process for preparing high-performance ceramic powder-based TENGs comprising electrospun fibrous surfaces based on poly(vinylidene difluoride-co-hexafluoropropylene) (PVDF-HFP) and dispersed Eu2O3-doped BaTiO3 nanofillers. Herein, we discuss the effect of the modified dielectric properties and transferred charge of the electrification film on the performance of the TENGs. After incorporating the Eu2O3-doped BaTiO3 nanofiller, the maximum output voltage of the 10 wt% Eu2O3-BaTiO3/PVDF-HFP electrospun-nanofiber TENG reached as high as 1004 V with a corresponding current density of 9.9 µA cm-2. The enhancement in the triboelectric properties of the Eu2O3-BaTiO3/PVDF-HFP electrospun-nanofiber TENGs was due to their high amounts of interface polarization and transferred charge, suggesting improved capture and storage of triboelectric electrons. These Eu2O3-BaTiO3/PVDF-HFP electrospun-nanofiber TENGs could harvest mechanical energy and power electronic devices; they were robust and not affected by the operating temperature or humidity. Furthermore, we used a fabricated device as a sensor for application as a light-emitting diode dimmer switch and for the tracking of leg movement.

Pain Incidence and Associated Risk Factors among Cancer Patients within 72 Hours after Surgery: A Large Retrospective Analysis.

BACKGROUND: A fundamental principle of pain management is to determine the distribution and causes of pain. However, relevant data among postoperative cancer patients based on a large amount of data remain sparse. OBJECTIVE: We aimed to investigate the incidence of postoperative pain in cancer patients and to explore the associated risk factors. METHODS: We retrospectively collected information on postoperative pain-evaluation records of cancer patients who underwent surgery between 1 January 2014 and 31 December 2019. Descriptive statistics were presented, and multinominal logistic regression analysis was performed to explore the risk factors associated with postoperative pain. RESULTS: Among the 11,383 patients included in the study, the incidence of mild/moderate to severe pain at the 24th hour after surgery was 74.9% and 18.3%, respectively. At the 48th and 72nd hour after surgery, the incidence of mild pain increased slightly, while the incidence of moderate to severe pain continued to decrease. Female patients experienced a higher risk of pain (ORs: 1.37-1.58). Undergoing endoscopic surgery was associated with a higher risk of pain (ORs: 1.40-1.56). Patients with surgical sites located in the respiratory system had a higher risk of pain compared to in the digestive system (ORs: 1.35-2.13), and other patients had a relatively lower risk of pain (ORs: 0.11-0.61). CONCLUSION: The majority of cancer patients experienced varying degrees of postoperative pain but may not receive adequate attention and timely treatment. Female, young age and endoscopic surgery were associated with increased pain risk, and effective identification of these high-risk groups had positive implications for enhanced postoperative pain management.

Regulatory B cells protect against chronic hypoxia-induced pulmonary hypertension by modulating the Tfh/Tfr immune balance.

Hypoxia-induced pulmonary hypertension (HPH) is a progressive and lethal disease characterized by the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) and obstructive vascular remodelling. Previous research demonstrated that Breg cells were involved in the pathogenesis of pulmonary hypertension. This work aimed to evaluate the regulatory function of Breg cells in HPH. HPH mice model were established and induced by exposing to chronic hypoxia for 21 days. Mice with HPH were treated with anti-CD22 or adoptive transferred of Breg cells. The coculture systems of Breg cells with CD4+ T cells and Breg cells with PASMCs in vitro were constructed. Lung pathology was evaluated by HE staining and immunofluorescence staining. The frequencies of Breg cells, Tfh cells and Tfr cells were analysed by flow cytometry. Serum IL-21 and IL-10 levels were determined by ELISA. Protein levels of Blimp-1, Bcl-6 and CTLA-4 were determined by western blot and RT-PCR. Proliferation rate of PASMCs was measured by EdU. Compared to the control group, mean PAP, RV/(LV + S) ratio, WA% and WT% were significantly increased in the model group. Anti-CD22 exacerbated abnormal hemodynamics, pulmonary vascular remodelling and right ventricle hypertrophy in HPH, which ameliorated by adoptive transfer of Breg cells into HPH mice. The proportion of Breg cells on day 7 induced by chronic hypoxia was significantly higher than control group, which significantly decreased on day 14 and day 21. The percentage of Tfh cells was significantly increased, while percentage of Tfr cells was significantly decreased in HPH than those of control group. Anti-CD22 treatment increased the percentage of Tfh cells and decreased the percentage of Tfr cells in HPH mice. However, Breg cells restrained the Tfh cells differentiation and expanded Tfr cells differentiation in vivo and in vitro. Additionally, Breg cells inhibited the proliferation of PASMCs under hypoxic condition in vitro. Collectively, these findings suggested that Breg cells may be a new therapeutic target for modulating the Tfh/Tfr immune balance in HPH.