Electrocatalytic Activity of CO2 Reduction to CO on Cadmium Sulfide Enhanced by Chloride Anion Doping.

The electrocatalytic CO2 reduction (ECR) to produce valuable fuel is a promising process for addressing atmospheric CO2 emissions and energy shortages. In this study, Cl-anion doped cadmium sulfide structures were directly fabricated on a nickel foam surface (Cl/CdS-NF) using an in situ hydrothermal method. The Cl-anion doping could significantly improve ECR activity for CO production in ionic liquid and acetonitrile mixed solution, compared to pristine CdS. The highest Faradaic efficiency of CO is 98.1 % on a Cl/CdS-NF-2 cathode with an excellent current density of 137.0 mA cm-2 at -2.25 V versus ferrocene/ferrocenium (Fc/Fc+ , all potentials are versus Fc/Fc+ in this study). In particular, CO Faradaic efficiencies remained above 80 % in a wide potential range of -2.05 V to -2.45 V and a maximum partial current density (192.6 mA cm-2 ) was achieved at -2.35 V. The Cl/CdS-NF-2, with appropriate Cl anions, displayed abundant active sites and a suitable electronic structure, resulting in outstanding ECR activity. Density functional theory calculations further demonstrated that Cl/CdS is beneficial for increasing the adsorption capacities of *COOH and *H, which can enhance the activity of the ECR toward CO and suppress the hydrogen evolution reaction.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer. / USH2Açªå˜å’Œå ¶ä»–å ³é”®é©±åŠ¨åŸºå› çªå˜äºšåž‹ä¸Žå ç–«æ£€æŸ¥ç‚¹æŠ‘åˆ¶å‰‚åœ¨è‚ºç™Œæ‚£è€ ä¸­ä¸´åºŠè”ç³»çš„å ³è”ç ”ç©¶.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01|‒|1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49|‒|2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48|‒|1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39|‒|1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32|‒|0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38|‒|0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75|‒|8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88|‒|6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Transcriptome profiling of bovine endometrial epithelial cells induced by lipopolysaccharides in vitro.

Endometritis is an inflammation of the surface of the endometrium that does not penetrate the submucosa and can cause infertility and increase the elimination rate in cows. Endometrial epithelial cells are the first barrier of the endometrium against foreign stimuli and bacterial infection. Understanding the genetic changes in stimulated endometrial epithelial cells will help in the efforts to prevent and treat endometritis. This study investigated changes in bovine endometrial epithelial (BEEC) gene expression induced by lipopolysaccharide (LPS)-induced inflammation and compared transcriptome-wide gene changes between LPS- and phosphate-buffered saline (PBS)- treated BEECs by RNA sequencing. Compared with the PBS group, the LPS group showed 60 differentially expressed genes (DEGs) (36 upregulated, 24 downregulated). Gene Ontology enrichment analysis revealed that most enrichment occurred during CXCR chemokine receptor binding, inflammatory response, and neutrophil migration. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed DEGs mainly concentrated in cytokine-cytokine receptor interactions; IL-17, tumor necrosis factor, NOD-like receptor, chemokine, Toll-like receptor, and nuclear factor-κB signaling pathways; and the cytoplasmic DNA sensing pathway. Moreover, results revealed that cytokines SAA3 and HP increased significantly after LPS treatment. These effects of LPS on BEECs transcriptome and the molecular mechanism of endometritis provide a basis for improved clinical treatment and novel drug development.

Toxicogenomics scoring system: TGSS, a novel integrated risk assessment model for chemical carcinogenicity prediction.

BACKGROUND: Given the increasing exposure of humans to environmental chemicals and the limitations of conventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. OBJECTIVES: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets. METHODS: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts. RESULTS: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 ×10-5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts. CONCLUSION: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

Oral Administration of Artemisia argyi Polysaccharide Increases Estrogen Level and Maintains Blood Lipid Homeostasis in Ovariectomized Rats.

INTRODUCTION: Artemisia argyi polysaccharide (AAP) has a beneficial effect on menstruation-related symptoms and the potential regulation of lipid metabolism. It is expected to be a safe and effective ingredient for estrogen deficiency and lipid metabolic disorders. Here, we investigate the effect of AAP on body weight gain, estrogen level, and blood lipid changes in ovariectomized (OVX) rats. METHODS: Thirty-six female Wistar rats were randomly divided into six treatment groups, including a sham-operated (Sham) group, OVX group, estrogen replacement (OVX + E2) group, and AAP treatment (OVX + 125, 250, 500 mg/kg AAP) group. The body weight and feed intake were recorded every week. The level of estrogen and blood lipid was determined. The gene expressions and protein expressions of estrogen receptors (ERs), fatty acid synthetase (FAS), acetyl CoA carboxylase 2 (ACC2), and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) were determined. RESULTS: AAP treatment significantly decreased the body weight gain and average daily food intake of rats in the OVX group. Treatment with AAP significantly increased the relative weight of the uterus, plasma estrogen level, and the gene expression and protein expression of ER-α in the uterus. For blood lipids, plasma levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol were significantly reduced by AAP treatment in OVX rats. AAP treatment decreased the expression of FAS and HMGR in the liver of OVX rats. Furthermore, AAP treatment significantly increased the gene expression of ACC2, the protein expression of P-ACC2, and the ratio of P-ACC2/ACC2. CONCLUSION: In summary, AAP treatment exerts beneficial effects on body weight gain and lipid metabolism disorder induced by ovariectomy through increasing estrogen levels, inhibiting FAS, and promoting fatty acid oxidation.

Analysis of differentially expressed microRNAs in bovine mammary epithelial cells treated with lipoteichoic acid.

Mastitis is one of the most common diseases of dairy cattle and can be caused by physical stress, chemicals and microbial infection. Staphylococcus aureus is the most common pathogens that induce mastitis in dairy cattle. In this study, bovine mammary epithelial cells (BMECs) were treated either with lipoteichoic acid (LTA, 30 µg/ml) or 1 × phosphate-buffer saline (PBS, control) and RNA-Seq was applied to explore the effect of LTA on the expression microRNAs (miRNAs) in BMECs. Compared to the control group, 43 miRNAs were significantly up-regulated and eight miRNAs were significantly down-regulated. Additionally, 724 genes were significantly up-regulated and 13 genes were significantly down-regulated in LTA group relative to the control group. Bta-miR-196a, bta-miR-2285aj-5p, bta-miR-143, bta-miR-2433, bta-miR-2284f and bta-miR-2368-3p were selected from 51 differentially expressed miRNAs and are discussed in this manuscript. Target gene prediction revealed that the target genes of these six miRNAs were all differentially expressed, including MT1E, SPDYA, FGL1, TLR2, PAPOLG, ZDHHC17 and SMC4. Subsequently, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the target genes with differentially expressed miRNAs were enriched in mitogen-activated protein kinase (MAPK) signalling pathway, rheumatoid arthritis and cancer. Therefore, the results of this study provided new evidences for the molecular mechanism of LTA-induced mastitis, which may provide new targets for the diagnosis and treatment of mastitis in dairy cattle.

Identification of metastasis-related long non-coding RNAs in lung cancer through a novel tumor mesenchymal score.

Long non-coding RNAs (lncRNAs) have been proven to play critical roles in epithelial-mesenchymal transition (EMT) and metastasis of lung cancer. However, the biological functions and related mechanisms of lncRNAs are unclear. In addition, the EMT-based prognosis prediction in lung cancer still lacks investigation. Here, we established the methodology of identifying critical metastasis-related lncRNAs using comprehensive datasets of cancer transcriptome, genome and epigenome, and also provided tools for prognosis prediction in lung cancer. Initially, important mesenchymal marker genes were identified to compose the tumor mesenchymal score, which predicted patient prognosis in lung cancer, especially lung adenocarcinoma (LUAD). The score was also correlated with several crucial biological and physiological processes, such as tumor immune and hypoxia. Based on the score, lung cancer patients was classified into epithelial and mesenchymal subtypes, and lncRNAs which exhibited expressional dysregulation, promotor methylation alteration and copy number variation between the two subtypes in LUAD were identified and underwent further prognostic analyses. Finally, we identified 14 lncRNAs as EMT-related and significant biomarkers in prognosis prediction of LUAD. As validation, lncRNA RBPMS-AS1 was proven to be co-expressed with epithelial biomarkers, suppressive for A549 cell migration, invasion and EMT, and also significantly associated with better outcomes of LUAD patients, suggesting the potential of RBPMS-AS1 to serve as a lncRNA epithelial biomarker in metastasis of LUAD. Based on the identified lncRNAs, an EMT-linked lncRNA prognostic signature was further established. Taken together, our study provides robust predictive tools, potential lncRNA targets and feasible screening strategies for future study of lung cancer metastasis.

Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis.

Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, EDNRB, NR1H4, ARID4A, PRKCI, PABPC5, ACAN and TLN1. Furthermore, elevated mRNA expression level of SMARCA1 and EDNRB was associated with poor overall survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. Additionally, pathway and protein-protein interactions network analyses found the two genes were correlated with epithelial-mesenchymal transition process. In conclusion, mutations of EGFR and ALK were significantly correlated with NSCLC metastasis. In addition, thirteen novel genes were identified to be associated with NSCLC metastasis, especially SMARCA1 in LUAD and EDNRB in LUSC.

Analysis of miRNA expression changes in bovine endometrial stromal cells treated with lipopolysaccharide.

After parturition, bovine uterine stromal cells are often exposed to complex bacterial and viral stimuli owing to epithelial cell rupture, resulting in an inflammatory response. In this study, we used an in vitro model to study the response of bovine endometrial stromal cells to inflammatory mediators and the associated regulated microRNAs in response to lipopolysaccharide. Lipopolysaccharide (LPS) is a bacterial wall component in gram-negative bacteria that causes inflammation upon immune recognition, which is used to create in vitro inflammation models. Thus, we used high-throughput RNA sequencing to identify miRNAs that may have an anti-inflammatory role in the LPS-induced inflammatory response. Two groups of bovine uterine cells were treated with phosphate buffer saline (PBS) and LPS, respectively. Compared with the control (PBS) group, the LPS-treated group had 219 differentially expressed miRNAs, of which 113 were upregulated, and 106 were downregulated. Gene ontology enrichment analysis revealed that the target genes of differentially expressed miRNAs were significantly enriched in several activities, such as transferase activity, small molecule binding, and protein binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the target genes of differential miRNAs were significantly enriched in fluid shear stress and atherosclerosis, MAPK signaling pathway, TNF signaling pathway. By analyzing differentially expressed miRNAs, we found that miR-200c, miR-1247-3p, and let-7b are directly related to the inflammatory response. For instance, miR-200c target genes (MAP3K1, MAP4K3, MAPKAPK5, MAP3K8, MAP3K5) and let-7b target genes (CASP3, IL13, MAPK8, CXCL10) were significantly enriched in the MAPK and IL-17 signaling pathways, respectively. In summary, our research provides insight into the molecular mechanism underlying LPS-induced inflammation in vitro, which may unveil new targets for the treatment of endometritis.

Role of MicroRNAs in Protective Effects of Forsythoside A Against Lipopolysaccharide-Induced Inflammation in Bovine Endometrial Stromal Cells.

Bovine endometrial stromal cells (bESCs) are exposed to a complex environment of bacteria and viruses due to the rupture of epithelial cells after delivery. Inflammatory responses are elicited by the activation of host pattern recognition receptors through pathogen-related molecules such as lipopolysaccharides (LPS) on the cell membrane. Forsythoside A (FTA) is a major active constituent of Forsythia suspensa (Thunb.) Vahl. is a flowering plant widely employed as a traditional Chinese herbal medicine to treat various inflammatory diseases such as nephritis, eye swelling, scabies, ulcers, and mastitis; however, the molecular mechanisms underlying its therapeutic effects on bovine endometritis are still unclear. The aim of this study was to explore the role of miRNA and the mechanisms underlying the protective activity of FTA on the inflammation of bovine endometrial stromal cells induced by LPS. Based on previous research, we isolated and cultured bESCs in vitro and categorized them into LPS and LPS+FTA groups with three replicates. Upon reaching 80% confluence, the bESCs were treated with 0.5 µg/mL of LPS or 0.5 µg/mL of LPS + 100 µg/mL of FTA. We, then, performed high-throughput sequencing (RNA-Seq) to investigate the effects of FTA on LPS-stimulated primary bESCs and their underlying mechanisms. We identified 167 miRNAs differentially expressed in the LPS groups; 72 miRNAs were up-regulated, and 95 were down-regulated. Gene ontology enrichment analysis revealed that differentially expressed microRNA (DEGs) were most enriched during the cellular metabolic process; they were mostly located intracellularly and participated in protein, enzyme, and ion binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were most enriched in the mitogen-activated protein kinase, tumor necrosis factor, and Interleukin-17 signaling pathways. These results reveal the complex molecular mechanism involved in the FTA and provide a basis for future studies of bovine endometritis treatment with traditional Chinese medicine monomer.

Zfx-induced upregulation of UBE2J1 facilitates endometrial cancer progression via PI3K/AKT pathway.

Emerging documents revealed that E2 enzyme family has been implicated in regulating the progression of numerous human cancers. Ubiquitin-conjugating enzyme E2 J1 (UBE2J1), a member of E2 enzyme family, has been reported to participate in the biological process of medulloblastoma, while little is known about its functionality in endometrial cancer (EC). Gene expression at the mRNA and protein levels were identified using RT-qPCR and western blot analysis, separately. The alteration on cell proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) process was determined through 5-Ethynyl-2'-deoxyuridine, cell adhesion, wound healing and transwell assays as well as western blot analysis. The role of UBE2J1 in xenograft tumor in mice was determined. Luciferase reporter and chromatin immunoprecipitation assays were conducted to reveal the undering mechanism of UBE2J1. Our results indicated that UBE2J1 displayed high level in EC tissues and cells and predicted poor prognosis of EC patients. In addition, UBE2J1 depletion inhibited cell proliferation, adhesion, motion, EMT process invitro, and repressed tumor growth invivo. Rescue assays manifested that ethyl 2-amino-6-chloro-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate treatment reversed the effects of UBE2J1 on PI3K/AKT pathway activation and malignant phenotypes of EC cells. Finally, zinc finger X-chromosomal protein (zfx), with high expression in EC tissues, was verified to activate UBE2J1 transcription by binding to UBE2J1 promoter. In conclusion, all facts signified that zfx-induced upregulation of UBE2J1 accelerated the progression of EC via regulating the PI3K/AKT signaling pathway, which suggested that UBE2J1 might be of great significance in probing into the underlying therapeutic strategies of EC.

Silencing PAQR3 protects against oxygen-glucose deprivation/reperfusion-induced neuronal apoptosis via activation of PI3K/AKT signaling in PC12 cells.

AIMS: Neuronal apoptosis acts as the pivotal pathogenesis of cerebral ischemia/reperfusion (I/R) injury after ischemic stroke. PAQR3 (progestin and adipoQ receptor family member 3) is a crucial player who participates in the regulation of cell death. We aim to explore the specific function and the underlying mechanism of PAQR3 in cerebral I/R induced neuronal injury. MAIN METHODS: We established a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and rat adrenal pheochromocytoma (PC12) cell oxygen-glucose deprivation/reperfusion (OGD/R) model to detect the expression and of PAQR3 after I/R treatment in vivo and in vitro. We used lentivirus to knockdown PAQR3 and investigated the function of PAQR3 in I/R induced neuronal apoptosis. KEY FINDINGS: PAQR3 expression is markedly increased in the ischemic hemisphere of C57BL/6 mice and PC12 cells after I/R stimulation. Knockdown PAQR3 can attenuate neuronal apoptosis induced by I/R in PC12 cells and exerts neuroprotective effects. PAQR3 deficiency can significantly raise cell viability and suppress LDH leakage under I/R treatment. Silencing PAQR3 attenuates neuronal apoptosis remarkably with fewer TUNEL-positive cells and lower apoptosis rate under I/R treatment. Mechanistically, knockdown of PAQR3 can inhibit the apoptosis pathway through inducing anti-apoptotic proteins and inhibiting pro-apoptotic proteins. Besides, PI3K/AKT signaling suppression with LY294002 abolished the neuroprotective functions induced by silencing PAQR3. SIGNIFICANCE: Our results elucidate that silencing PAQR3 can protect PC12 from OGD/R injury via activating PI3K/AKT pathway. And therefore, provide a novel therapeutic target for the prevention of cerebral I/R injury.

Autophagy and Tumor Database: ATdb, a novel database connecting autophagy and tumor.

Autophagy is an essential cellular process that is closely implicated in diverse pathophysiological processes and a variety of human diseases, especially tumors. Autophagy is regarded as not only an anti-cancer process in tumorigenesis but also a pro-tumor process in progression and metastasis according to current research. It means the role of autophagy in tumor is considered to be complex, controversial and context dependent. Hence, a comprehensive database is of great significance to obtain an in-depth understanding of such complex correlations between autophagy and tumor. To achieve this objective, here we developed the Autophagy and Tumor Database (named as ATdb, http://www.bigzju.com/ATdb/#/) to compile the published information concerning autophagy and tumor research. ATdb connected 25 types of tumors with 137 genes required for autophagy-related pathways, containing 219 population filters, 2650 hazard ratio trend plots, 658 interacting microRNAs, 266 interacting long non-coding RNAs, 155 post-translational modifications, 298 DNA methylation records, 331 animal models and 70 clinical trials. ATdb could enable users to search, browse, download and carry out efficient online analysis. For instance, users can make prediction of autophagy gene regulators in a context-dependent manner and in a precise subpopulation and tumor subtypes. Also, it is feasible in ATdb to cluster tumors into distinguished groups based on the gene-related long non-coding RNAs to gain novel insights into their potential functional implications. Thus, ATdb offers a powerful online database for the autophagy community to explore the complex world of autophagy and tumor. Database URL: http://www.bigzju.com/ATdb/#/.

The ethylene response factor OsERF109 negatively affects ethylene biosynthesis and drought tolerance in rice.

Drought is an important factor limiting plant development and crop production. Dissecting the factors involved in this process is the key for enhancement of plant tolerance to drought stress by genetic approach. Here, we evaluated the regulatory function of a novel rice ethylene response factor (ERF) OsERF109 in drought stress. Expression of OsERF109 was rapidly induced by stress and phytohormones. Subcellular localization and transactivation assay demonstrated that OsERF109 was localized in nucleus and possessed transactivation activity. Transgenic plants overexpressing (OE) and knockdown with RNA interfering (RI) OsERF109 exhibited significantly reduced and improved drought resistance, respectively, indicating that OsERF109 negatively regulates drought resistance in rice. Furthermore, measurement by gas chromatography showed that ethylene contents were less in OE while more in RI lines than these in wild types, supporting the data of drought tolerance and water loss in transgenic lines. Quantitative real-time PCR analysis also proved the regulation of OsERF109 in the expression of OSACS6, OSACO2, and OsERF3, which have been identified to play important roles in ethylene biosynthesis. Based on these results, our data evidence that OsERF109 regulates drought resistance by affecting the ethylene biosynthesis in rice. Overall, our study reveals the negative role of OsERF109 in ethylene biosynthesis and drought tolerance in rice.