Construction of a TP53 mutation-associated ceRNA network as prognostic biomarkers in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) continues to endanger human health worldwide. Regulatory networks of competing endogenous RNAs (ceRNAs) play important roles in HCC. TP53 is the second most often altered gene in HCC and has a significant role in regulating target genes such as miRNAs and lncRNAs. Methods: Data from patients with TP53 mutation were collected through the cBioPortal database and differential analysis was performed to screen RNAs related to TP53 mutation. The lncRNA-miRNA-mRNA relationship was predicted by the miRcode, miRDB, and TargetScan databases. The ceRNA networks were screened and visualized by Cytoscape. Core ceRNA networks were generated by differential analysis, coexpression analysis, prognostic analysis and subcellular localization. Finally, methylation, mutation, PPI, GSEA, immunity and drug sensitivity analyses of MEX3A were performed to determine the role of MEX3A in HCC. Results: We identified 1508 DEmRNAs, 85 DEmiRNAs and 931 DElncRNAs and obtained a ceRNA network including 28 lncRNAs, 4 miRNAs and 31 mRNAs. Twenty hub DERNAs in the TP53-altered-related ceRNA network were screened out by Cytoscape and the core ceRNA network (LINC00491/TCL6-hsa-miR-139-5p-MEX3A) was obtained by multiple analyses. In addition, we discovered that the methylation level of MEX3A was decreased and the mutation frequency was raised in HCC. Furthermore, elevated MEX3A expression was associated with alterations in the HCC immunological microenvironment. Conclusion: We successfully constructed a reciprocal ceRNA network, which could provide new ideas for exploring HCC mechanisms and therapeutic approaches.

Comprehensive pan-cancer analysis reveals CCDC58 as a carcinogenic factor related to immune infiltration.

CCDC58, a member of the CCDC protein family, has been primarily associated with the malignant progression of hepatocellular carcinoma (HCC) and breast cancer, with limited research conducted on its involvement in other tumor types. We aimed to assess the significance of CCDC58 in pan-cancer. We utilized the TCGA, GTEx, and UALCAN databases to perform the differential expression of CCDC58 at both mRNA and protein levels. Prognostic value was evaluated through univariate Cox regression and Kaplan-Meier methods. Mutation and methylation analyses were conducted using the cBioPortal and SMART databases. We identified genes interacting with and correlated to CCDC58 through STRING and GEPIA2, respectively. Subsequently, we performed GO and KEGG enrichment analyses. To gain insights into the functional status of CCDC58 at the single-cell level, we utilized CancerSEA. We explored the correlation between CCDC58 and immune infiltration as well as immunotherapy using the ESTIMATE package, TIMER2.0, TISIDB, TIDE, TIMSO, and TCIA. We examined the relationship between CCDC58 and tumor heterogeneity, stemness, DNA methyltransferases, and MMR genes. Lastly, we constructed a nomogram based on CCDC58 in HCC and investigated its association with drug sensitivity. CCDC58 expression was significantly upregulated and correlated with poor prognosis across various tumor types. The mutation frequency of CCDC58 was found to be increased in 25 tumors. We observed a negative correlation between CCDC58 expression and the methylation sites in the majority of tumors. CCDC58 showed negative correlations with immune and stromal scores, as well as with NK T cells, Tregs, CAFs, endothelial cells, and immunomodulators. Its value in immunotherapy was comparable to that of tumor mutational burden. CCDC58 exhibited positive correlations with tumor heterogeneity, stemness, DNA methyltransferase genes, and MMR genes. In HCC, CCDC58 was identified as an independent risk factor and demonstrated potential associations with multiple drugs. CCDC58 demonstrates significant clinical value as a prognostic marker and indicator of immune response across various tumor types. Its comprehensive analysis provides insights into its potential implications in pan-cancer research.

Characterization of stem cell subtypes and prognostic signature in hepatocellular carcinoma.

BACKGROUND: Cancer stem cells (CSCs) were linked to cancer aggressiveness and poor prognosis in patients with hepatocellular carcinoma (HCC). METHODS: We integrated two external HCC cohorts to develop the stem cell subtypes according to unsupervised clustering with 26 stem cell gene sets. Between the subtypes, differences in prognosis, clinical characteristics, recognized HCC subtypes, metabolic profile, immune-related features, somatic mutation, and drug sensitivity were examined. The prognostic signature was created, and validated by numerous cohorts, and used to assess the efficacy of immunotherapy and transcatheter arterial chemoembolization (TACE) treatment. The nomogram was developed based on the signature and clinical features. We further examined the function of KIF20A in HCC and proved that KIF20A had the potential to regulate the stemness of HCC cells through western blot. RESULTS: Low stem cell patterns, a good prognosis, positive clinical features, specific molecular subtypes, low metastatic characteristics, and an abundance of metabolic and immunological aspects were associated with Cluster 1, whereas Cluster 2 was the reverse. Chemotherapy and immunotherapy were more effective in Cluster 1. Cluster 1 and CTNNB1 and ALB mutation were more closely. Additionally, the prognosis, immunotherapeutic, and TACE therapy responses were all worse in the high-risk group. The nomogram could predict the survival probability of HCC patients. KIF20A was discovered to be overexpressed in HCC and was revealed to be connected to the stemness of the HepG2 cell line. CONCLUSIONS: Two stem cell subgroups with different prognoses, metabolic, and immunological characteristics in HCC patients were identified. We also created a 7-gene prognostic signature and a nomogram to estimate the survival probability. The function of KIF20A in HCC stemness was initially examined.

Buddhist culture as a safeguard for the subjective happiness of Chinese residents: mitigating anxiety regarding housing prices, unemployment, and inequality.

Introduction: This study examines whether Buddhist culture in China can safeguard the subjective happiness of residents by mitigating the detrimental impact of adversity. Considering Chinese traditional culture and referencing Baidu Search Index data, we focus on three sources of anxiety that are currently troubling Chinese residents: housing prices, unemployment, and inequality. Methods: We conduct logit regressiontoinvestigate the mitigating impact of Buddhist culture on anxiety. The frequency of droughts and floods that occurred during the Ming and Qing dynasties are employed as instrumental variables for the local density of Buddhist culture to avoid endogeneity problems. Results: Empirical analysis based on microdata shows that Chinese Buddhist culture demonstrates the ability to alleviate the negative effects of housing price pressures, unemployment anxiety, and perceived inequality on subjective well-being. Mechanism analyses reveal that Chinese Buddhist culture plays a role in ameliorating the adverse impacts of housing and unemployment pressures on factors such as job satisfaction, physical health status, social trust, and expectations of future social standing. Moreover, it works to reduce inclinations toward social comparisons, thereby acting as a safeguard for happiness. Heterogeneity analysis shows that this insurance effect is more pronounced among vulnerable groups, including those in rural areas, middle-aged and elderly demographics, individuals with fewer social connections, lower social security coverage, and suboptimal health conditions. Discussion: This study expands the landscape of happiness economics research and provides novel evidence about the correlation between religion and happiness. Psychotherapists may draw on certain aspects of religious philosophy in addressing mental disorders. From a governmental perspective, there is potential to effectively steer religious culture towards fostering social harmony and promoting economic development.

Novel compound heterozygous CCDC40 mutations in a familial case of primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by motile ciliary dysfunction and impaired ultrastructure. Despite numerous studies, the genetic basis for about 30% of PCD cases remains to be elucidated. Here, we present the identification and functional analysis of two novel mutations in the gene encoding coiled-coil domain-containing protein 40 (CCDC40), which are found in a familial case of PCD. These novel CCDC40 mutations, NM_017950.4: c.2236-2delA and c.2042_2046delTCACA, NP_060420.2: p.(Ile681fs), were identified by whole-exome sequencing (WES). Sanger sequencing was then performed to confirm the WES results and determine the CCDC40 gene sequences of the proband's parents. The c.2042_2046delTCACA mutation disrupts the reading frame of the protein and is therefore predicted to produce a non-functional protein. Using a minigene assay with the pcDNA3.1(+) plasmid, we further investigated the potential pathogenic effects of the c.2236-2delA mutation and found that this mutation leads to formation of a truncated protein via splicing disruption. Thus, in summary, we identified two mutations of the CCDC40 gene that can be considered pathogenic compound heterozygous mutations in a case of familial PCD, thereby expanding the known mutational spectrum of the CCDC40 gene in this disease.

Identification of Immune-Associated Genes in Diagnosing Aortic Valve Calcification With Metabolic Syndrome by Integrated Bioinformatics Analysis and Machine Learning.

Background: Immune system dysregulation plays a critical role in aortic valve calcification (AVC) and metabolic syndrome (MS) pathogenesis. The study aimed to identify pivotal diagnostic candidate genes for AVC patients with MS. Methods: We obtained three AVC and one MS dataset from the gene expression omnibus (GEO) database. Identification of differentially expressed genes (DEGs) and module gene via Limma and weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, protein-protein interaction (PPI) network construction, and machine learning algorithms (least absolute shrinkage and selection operator (LASSO) regression and random forest) were used to identify candidate immune-associated hub genes for diagnosing AVC with MS. To assess the diagnostic value, the nomogram and receiver operating characteristic (ROC) curve were developed. Finally, immune cell infiltration was created to investigate immune cell dysregulation in AVC. Results: The merged AVC dataset included 587 DEGs, and 1,438 module genes were screened out in MS. MS DEGs were primarily enriched in immune regulation. The intersection of DEGs for AVC and module genes for MS was 50, which were mainly enriched in the immune system as well. Following the development of the PPI network, 26 node genes were filtered, and five candidate hub genes were chosen for nomogram building and diagnostic value evaluation after machine learning. The nomogram and all five candidate hub genes had high diagnostic values (area under the curve from 0.732 to 0.982). Various dysregulated immune cells were observed as well. Conclusion: Five immune-associated candidate hub genes (BEX2, SPRY2, CXCL16, ITGAL, and MORF4L2) were identified, and the nomogram was constructed for AVC with MS diagnosis. Our study could provide potential peripheral blood diagnostic candidate genes for AVC in MS patients.

Identification of Molecular Subtypes and a Prognostic Signature Based on Inflammation-Related Genes in Colon Adenocarcinoma.

Both tumour-infiltrating immune cells and inflammation-related genes that can mediate immune infiltration contribute to the initiation and prognosis of patients with colon cancer. In this study, we developed a method to predict the survival outcomes among colon cancer patients and direct immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and captured inflammation-related genes from the GeneCards database. The package "ConsensusClusterPlus" was used to generate molecular subtypes based on inflammation-related genes obtained by differential expression analysis and univariate Cox analysis. A prognostic signature including four genes (PLCG2, TIMP1, BDNF and IL13) was also constructed and was an independent prognostic factor. Cluster 2 and higher risk scores meant worse overall survival and higher expression of human leukocyte antigen and immune checkpoints. Immune cell infiltration calculated by the estimate, CIBERSORT, TIMER, ssGSEA algorithms, tumour immune dysfunction and exclusion (TIDE), and tumour stemness indices (TSIs) were also compared on the basis of inflammation-related molecular subtypes and the risk signature. In addition, analyses of stratification, somatic mutation, nomogram construction, chemotherapeutic response prediction and small-molecule drug prediction were performed based on the risk signature. We finally used qRT-PCR to detect the expression levels of four genes in colon cancer cell lines and obtained results consistent with the prediction. Our findings demonstrated a four-gene prognostic signature that could be useful for prognostication in colon cancer patients and designing personalized treatments, which could provide new versions of personalized management for these patients.

Manganese induced nervous injury by α-synuclein accumulation via ATP-sensitive K(+) channels and GABA receptors.

Manganese (Mn) is an environmental pollutant having a toxic effect on Parkinson's disease, with significant damage seen in the neurons of basal ganglia. Hence, Mn pollution is a public health concern. A Sprague-Dawley rat model was used to determine the damage to basal nuclei, and the effect of Mn intake was detected using the Morris water maze test and transmission electron microscopy. The SH-SY5Y cell line was exposed to Mn, and downstream signaling was assessed to determine the mechanism of toxicity. Mn exposure injured neurons, repressing GABAAR receptors and inducing GABABR receptors. The synergistic effect of the GABABR receptor and Kir6.1-SUR1 or Kir6.2-SUR1 was found to be one of the potential factors for the secretion of α-synuclein. The accumulation of α-synuclein regulated downstream factors calmodulin (CAM) cAMP response element-binding protein (CREB), thereby impairing learning and memory. Other genes downstream of CREB, rather than the feedback regulation of CREB, and brain-derived neurotrophic factor might also be involved.

Liver Function of Male Rats Exposed to Manganese at Different Time Points.

As an essential trace element in the human body, manganese (Mn) is involved in many important biochemical reactions. However, excessive exposure to manganese can cause multiple systematic damages to the body. This study aims to investigate the effects of manganese exposure on serum hepatic enzymes in male rats at different time points. After adaptive feeding for 7 days, male Sprague-Dawley (SD) rats were injected intraperitoneally with 30 mg/kg MnCl2·4H2O once a day for 21 days at zeitgeber time point 2 (ZT2), ZT8, ZT14, and ZT20, respectively. We found that short-term repeated exposure to manganese caused slower body weight gain and increased relative liver and spleen weight index in male rats at different time points. Moreover, serum total bile acid (TBA) increased while aspartate aminotransferase (AST) decreased at ZT2, ZT8, and ZT20. Cholinesterase (ChE) decreased at ZT2 and ZT20, lactic dehydrogenase (LDH) decreased at ZT2, ZT14, and ZT20, and acid phosphatase (ACP) decreased at ZT2 and ZT14. Alkaline phosphatase (ALP) decreased at ZT2, ZT14, and ZT20, but increased at ZT8. Alanine amino transferase (ALT) decreased at ZT2 and ZT20, but increased at ZT8. There was a negative correlation between relative liver weight index with AST, ACP, ALP, and LDH, while a positive correlation with TBA. However, relative spleen weight index had a positive correlation with relative liver weight index and TBA, while a negative correlation with ALT, AST, ACP, ALP, LDH, and ChE. Our study shows that the injury of liver function is caused by short-term repeated manganese exposure at different time points. The time effect should be considered in manganese toxicity evaluation.

Tunable-Focus Liquid Lens through Charge Injection.

Liquid lenses are the simplest and cheapest optical lenses, and various studies have been conducted to develop tunable-focus liquid lenses. In this study, a simple and easily implemented method for achieving tunable-focus liquid lenses was proposed and experimentally validated. In this method, charges induced by a corona discharge in the air were injected into dielectric liquid, resulting in "electropressure" at the interface between the air and the liquid. Through a 3D-printed U-tube structure, a tunable-focus liquid lens was fabricated and tested. Depending on the voltage, the focus of the liquid lens can be adjusted in large ranges (-∞ to -9 mm and 13.11 mm to ∞). The results will inspire various new liquid-lens applications.

Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling.

Vascular calcification frequently occurs in the process of chronic kidney disease, atherosclerosis and aging, resulting in an increased prevalence of cardiovascular events. Piperlongumine (PLG) is a natural product isolated from Piper longum L. Here, we aimed to explore the effect of PLG in high calcium- and phosphate-induced vascular calcification and the associated mechanism. Flow cytometry assays showed that PLG at concentrations <10 µM did not promote vascular smooth muscle cells (VSMCs) apoptosis, and PLG at concentrations >2.5 µM inhibited VSMCs proliferation. Thus, 2.5 µM PLG was selected for subsequent experiments. Alizarin red staining and ALP activity assays showed that PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN, as determined by qRT-PCR and western blotting. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs. PLG may act as a promising herbal extract for the clinical management of vascular calcification.

Effects of Sub-Acute Manganese Exposure on Thyroid Hormone and Glutamine (Gln)/Glutamate (Glu)-γ- Aminobutyric Acid (GABA) Cycle in Serum of Rats.

Excessive manganese (Mn) exposure may adversely affect the central nervous system, and cause an extrapyramidal disorder known as manganism. The glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle and thyroid hormone system may be involved in Mn-induced neurotoxicity. However, the effect of Mn on the Gln/Glu-GABA cycle in the serum has not been reported. Herein, the present study aimed to investigate the effects of sub-acute Mn exposure on the Gln/Glu-GABA cycle and thyroid hormones levels in the serum of rats, as well as their relationship. The results showed that sub-acute Mn exposure increased serum Mn levels with a correlation coefficient of 0.733. Furthermore, interruption of the Glu/Gln-GABA cycle in serum was found in Mn-exposed rats, as well as thyroid hormone disorder in the serum via increasing serum Glu levels, and decreasing serum Gln, GABA, triiodothyronine (T3) and thyroxine (T4) levels. Additionally, results of partial correlation showed that there was a close relationship between serum Mn levels and the detected indicators accompanied with a positive association between GABA and T3 levels, as well as Gln and T4 levels in the serum of Mn-exposed rats. Unexpectedly, there was no significant correlation between serum Glu and the serum T3 and T4 levels. In conclusion, the results demonstrated that both the Glu/Gln-GABA cycle and thyroid hormone system in the serum may play a potential role in Mn-induced neurotoxicity in rats. Thyroid hormone levels, T3 and T4, have a closer relationship with GABA and Gln levels, respectively, in the serum of rats.

Downregulated Expression of Chromobox Homolog 7 in Hepatocellular Carcinoma.

Background: As an essential member of the Polycomb group (PcG) proteins, chromobox homolog 7 (CBX7) is found deregulated in some human cancers, and is thought to be a contributing factor in carcinogenesis. However, the expression and role of CBX7 in hepatocellular carcinoma (HCC) is still not well characterized. Materials and Methods: The levels of the CBX7 protein were quantified in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry; comparisons were made using McNemar's chi-square test. The Kaplan-Meier estimate was used for survival analysis. Results: We found that the expression of CBX7 in HCC tissues was significantly lower than that of adjacent nontumor tissues. In addition, decreased CBX7 expression levels were correlated with liver cirrhosis in HCC patients. Furthermore, the survival times of HCC patients who were CBX7-expression-negative were shorter than HCC patients who were CBX7-expression-positive. Conclusion: Our results show that downregulation of CBX7 is related to HCC progression and a poor prognosis in HCC patients.

Expression and Clinical Significance of CMTM6 in Hepatocellular Carcinoma.

This study aimed to examine the expression level and clinical significance of chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) in paired hepatocellular carcinoma (HCC) and adjacent nontumor tissues. The expression of CMTM6 was detected in 75 paired HCC and adjacent nontumor tissues by immunohistochemistry. Chi-square test was used to compare the difference of CMTM6 expression between HCC tissues and adjacent nontumor tissues. The clinic-pathological features and prognosis of HCC patients were collected to analyze the relationship with CMTM6 expression. The positive expression of CMTM6 in HCC tissues was significantly lower than that of adjacent nontumor tissues. The difference of CMTM6 expression between HCC tissues and paired adjacent nontumor tissues was statistically significant (p < 0.05). Furthermore, CMTM6 expression was correlated with HCC metastasis and alpha-fetoprotein (AFP) (p < 0.05). Multivariate logistic regression analysis showed tumor staging, metastasis, and AFP had a significant relationship with CMTM6 expression. In addition, the survival time of HCC patients was different between CMTM6 positive group and CMTM6 negative group by Kaplan-Meier survival analysis (p < 0.05). Downregulation of CMTM6 is related to HCC metastasis and the prognosis of HCC patients.

Facile Strategy to Low-Cost Synthesis of Hierarchically Porous, Active Carbon of High Graphitization for Energy Storage.

To achieve high energy/power output, long serving life, and low cost of carbon-based electrodes for energy storage, we have developed a unique synthesis method for the fabrication of hierarchically porous carbon of high graphitization (HPCHG), derived from pyrolysis of an iron-containing organometallic precursor in a molten ZnCl2 media at relatively low temperatures. The as-prepared HPCHG has a large specific surface area (>1200 m2 g-1), abundant micro/mesopores, and plenty of surface defects. When tested in a supercapacitor (SC), the HPCHG electrode delivers 248 F g-1 at 0.5 A g-1 and a high capacitance retention of 52.4% (130 F g-1) at 50 A g-1. When tested in a sodium-ion battery (SIB), the HPCHG electrode exhibits a reversible capacity of 322 mA h g-1 at 100 mA g-1 while maintaining ∼75% of the initial stable capacity after 2000 cycles with the applied current density as high as 5000 mA g-1, implying that the HPCHG electrode is very promising for energy storage.

A Green Route to a Na2FePO4F-Based Cathode for Sodium Ion Batteries of High Rate and Long Cycling Life.

Sodium ion batteries (SIBs) are considered one of the most promising alternatives for large-scale energy storage due largely to the abundance and low cost of sodium. However, the lack of high-performance cathode materials at low cost represents a major obstacle toward broad commercialization of SIB technology. In this work, we report a green route strategy that allows cost-effective fabrication of carbon-coated Na2FePO4F cathode for SIBs. By using vitamin C as a green organic carbon source and environmentally friendly water-based polyacrylic latex as the binder, we have demonstrated that the Na2FePO4F phase in the as-derived Na2FePO4F/C electrode shows a high reversible capacity of 117 mAh g-1 at a cycling rate of 0.1 C. More attractively, excellent rate capability is achieved while retaining outstanding cycling stability (∼85% capacity retention after 1000 charge-discharge cycles at a rate of 4 C). Further, in operando X-ray diffraction has been used to probe the evolution of phase structures during the charge-discharge process, confirming the structural robustness of the Na2FePO4F/C cathode (even when charged to 4.5 V). Accordingly, the poor initial Coulombic efficiency of some anode materials may be compensated by extracting more sodium ions from Na2FePO4F/C cathode at higher potentials (up to 4.5 V).

[Application of multi-coeffieient of variation significance test for toxicology study].

OBJECTIVE: To establish the methods of calculating and analyzing the multi-coefficient of variation significance test for the toxicology study. METHODS: The paper aimed to confirm the significance level with the method of Bonferroni and then compared the methods of calculating and analyzing of the experiment groups with the control group respectively. RESULTS: The significance level of multi-coefficient of variation significance test was confirmed as alpha1=0.0167. Compared with the control groups, the activity of ALT in serum both in 30 mg/kg and 60 mg/kg groups did not change in the average significance test, which was not statistically significant (P>0.05), while it changed in the variation significance test, which was of statistical significance (P<0.0167). The activity of AST in serum in 60 mg/kg group did not change in the average significance test (P>0.05), while it changed in the variation significance test (P<0.0167). CONCLUSION: The complete changes of the indexes can only be shown by use of both the average significance test and the variation significance test together.