Impact of weekday of esophageal cancer surgery on long-term oncological outcomes.

BACKGROUND: Studies about the influence of weekday of esophagectomy on survival are limited and show conflicting results. This study aimed to explore whether weekday of esophagectomy affects patient's survival outcomes. METHODS: Patients who underwent esophagectomy in a grade-A tertiary hospital from January 2015 to December 2016 were enrolled. The primary outcome was 5-year overall survival (OS). The secondary outcomes were 5-year disease-free survival (DFS) and days of hospitalization. The impact of weekday surgery on 5-year OS and DFS were evaluated with Cox regression, and impact on days of hospitalization was assessed using logistic regression. Propensity score matching (PSM) analysis was used to balance the confounding factors. RESULTS: A total of 1478 patients were included. The 5-year OS and DFS were 63.77% and 59.26% respectively. Multivariate analyses adjusted for covariables indicated that weekday was not significantly associated with OS (P = 0.076), nor days of hospitalization (P = 0.824), but it appeared to be associated with DFS (P = 0.044). Additionally, PSM analysis showed no significant effect of weekday on the 5-year OS, nor DFS and days of hospitalization. CONCLUSION: In patients diagnosed with squamous esophageal cancer, the survival outcome of patients was not influenced by weekday.

scWECTA: A weighted ensemble classification framework for cell type assignment based on single cell transcriptome.

Rapid advances in single-cell transcriptome analysis provide deeper insights into the study of tissue heterogeneity at the cellular level. Unsupervised clustering can identify potential cell populations in single-cell RNA-sequencing (scRNA-seq) data, but fail to further determine the identity of each cell. Existing automatic annotation methods using scRNA-seq data based on machine learning mainly use single feature set and single classifier. In view of this, we propose a Weighted Ensemble classification framework for Cell Type Annotation, named scWECTA, which improves the accuracy of cell type identification. scWECTA uses five informative gene sets and integrates five classifiers based on soft weighted ensemble framework. And the ensemble weights are inferred through the constrained non-negative least squares. Validated on multiple pairs of scRNA-seq datasets, scWECTA is able to accurately annotate scRNA-seq data across platforms and across tissues, especially for imbalanced data containing rare cell types. Moreover, scWECTA outperforms other comparable methods in balancing the prediction accuracy of common cell types and the unassigned rate of non-common cell types at the same time. The source code of scWECTA is freely available at https://github.com/ttren-sc/scWECTA.

Transcription profiling-guided remodeling of sulfur metabolism in synthetic bacteria for efficiently capturing heavy metals.

Heavy metal contamination is becoming a global problem threatening human health. Heavy metal removal by engineered microbes by cellular adsorption and uptake is a promising strategy for treatment of heavy metal contamination. However, this strategy is confronted with limited heavy metal-capturing elements. In this study, we performed a transcription profiling-guided strategy for construction of heavy metal-capturing synthetic bacteria. Transcription profiling of a heavy metal-tolerating Cupriavidus taiwanensis strain revealed up-regulation of sulfur metabolism-related operons (e.g., iscSAU and moaEDAB) by Pb2+ and Cd2+. A synthetic Escherichia coli strain, EcSSMO, was constructed by design of a synthetic sulfur metabolism operon (SSMO) based on iscSAU/moaEDAB. Biochemical analysis and X-ray photoelectron spectroscopy (XPS) revealed that the synthetic bacteria had remodeled sulfur metabolism and enhanced heavy metal-tolerating capacity, with higher surviving EcSSMO cells than the surviving control cells Ec0 (not containing SSMO) at 50 mg/L of Pb2+ and Cd2+ (>92 % versus <10 %). Moreover, EcSSMO exhibited much higher heavy metal-capturing capacity than Ec0, removing>90 % of Pb2+ and Cd2+ at 5 mg/L of Pb2+ and Cd2+, and >40 % of both heavy metals even at 50 mg/L of Pb2+ and Cd2+. This study reveals emphasizes feasibility of transcription profiling-guided construction of synthetic organisms by large-scale remodeling metabolic network.

Candida albicans infection disturbs the redox homeostasis system and induces reactive oxygen species accumulation for epithelial cell death.

Candida albicans is a common pathogenic fungus with high mortality in immunocompromised patients. However, the mechanism by which C. albicans invades host epithelial cells and causes serious tissue damage remains to be further investigated. In this study, we established the C. albicans-293T renal epithelial cell interaction model to investigate the mechanism of epithelial infection by this pathogen. It was found that C. albicans infection causes severe cell death and reactive oxygen species (ROS) accumulation in epithelial cells. Further investigations revealed that C. albicans infection might up-regulate expression of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX), inhibit the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and suppress the p38-Nrf2-heme oxygenase-1 (HO-1) pathway which plays an important role in the elimination of intracellular ROS. Furthermore, epithelial cell death caused by the fungal infection could be strikingly alleviated by addition of the antioxidant agent glutathione, indicating the critical role of ROS accumulation in cell death caused by the fungus. This study revealed that disturbance of the redox homeostasis system and ROS accumulation in epithelial cells is involved in cell death caused by C. albicans infection, which sheds light on the application of antioxidants in the suppression of tissue damage caused by fungal infection.

The TRP Ca2+ channel Yvc1 regulates hyphal reactive oxygen species gradient for maintenance of polarized growth in Candida albicans.

Candida albicans is an important opportunistic fungal pathogen, and hyphal polarized growth is critical for its invasive infection to the host. Both the vacuolar transient receptor potential (TRP) Ca2+ channel Yvc1 and the NADPH oxidase Fre8-governed reactive oxygen species (ROS) gradient are involved in hyphal development, but the relationship between Yvc1 and Fre8 during hyphal polarized growth remains to be investigated. Herein, we found that deletion of YVC1 led to dispersed distribution of ROS along the germ tube, while it was concentrated at the hyphal tip in WT cells. Moreover, Fre8 localization was altered as YVC1 was disrupted. Besides, similar to deletion of YVC1, addition of the Ca2+ chelating agent EGTA caused depolarization of Fre8-GFP in the wild-type cells, indicating the critical role of Yvc1-maintained Ca2+ gradient in polarized distribution of Fre8-GFP and consequent disruption of tip ROS gradient. By constructing a series of GFP-tagged polarized growth-related proteins, including Bud6, Exo70 and Lifeact, we found that these proteins, similar to Fre8 and ROS, had depolarized localization in yvc1Δ/Δ. Thus, our work provides a mechanic explanation of Yvc1-governed and ROS-related hyphal polarized growth, and shed a novel light on the role of Ca2+ signaling in maintenance of redox homeostasis and morphogenesis in the fungal pathogens.

Xuebijing Injection Maintains GRP78 Expression to Prevent Candida albicans-Induced Epithelial Death in the Kidney.

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.

Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase.

Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (Ki) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5-10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best Ki of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target.

Co3O4 nanoparticles at sublethal concentrations inhibit cell growth by impairing mitochondrial function.

Co3O4 nanoparticles (NPs) are one kind of the important nanomaterials that have the application potential in catalyst, electrochromic devices, sensors, etc. However, their biological effect remains to be detailed. In this study, we investigated the effect of the as-synthesized Co3O4 NPs (15-30 nm) on the growth of mammalian cells, and found that the NPs severely inhibited cell growth at the sublethal concentrations from 12.5 to 200 mg/L. Interestingly, the NPs did not cause obvious cell death and ROS accumulation, indicating that their inhibitory effect was not attributed to both apoptosis- or necrosis-related cell death and ROS accumulation. Transcription profiling analysis revealed that the NPs caused remarkable down regulation of the genes involved in mitochondrial functions. Transmission electron microscopy (TEM) and biochemical analysis further showed that the NPs might interact with the mitochondria, impairing the mitochondrial membrane potential (MMP) and ATP production. This study uncovers a mitochondrial respiratory chain-related and ROS-independent toxicity mechanism of Co3O4 NPs in eukaryotic cells.

[Effects of mercury concentration on life table demography of Moina macrocopa under different Scenedesmus obliquus densities].

In order to compare the chronic toxicity of pollutants to organisms in an aquatic environment under different food densities, the cladoceran Moina macrocopa was used as test animal to investigate the effects of Hg²âº concentrations (0, 0.4, 1.1, 1.8, 2.5, 3.2 and 3.9 µg · L⁻¹) on its life table demography under low (0.5 x 106 cells · mL⁻¹), medium (1.0 x 106 cells · mL⁻¹) and high (2.0 x 106 cells · mL⁻¹) densities of Scenedesmus obliquus. The results showed that at low and high food levels, certain concentrations of Hg²âº had inhibitory effects on survival, reproduction and population growth of M. macrocopa. However, at the medium food level, the inhibitory effects disappeared. Compared with the control, at the low food level, Hg²âº at 0.4-2.5 and 3.9 µg · L⁻¹ significantly decreased the life expectancy at hatching, Hg²âº at 0.4, 1.1, 2.5 and 3.9 µg · L⁻¹ decreased the generation time, Hg²âº at 1.1, 2.5 and 3.9 µg · L⁻¹ decreased the net reproduction rate, and Hg²âº at 3.9 µg · L⁻¹ decreased the gross reproduction rate of M. macrocopa. At the high food level, Hg²âº at 1.1 µg · L⁻¹ decreased the intrinsic rate of population increase, and Hg²âº at 3.9 µg · L⁻¹ decreased the life expectancy at hatching and the net reproduction rate of M. macrocopa. However, at the medium food level, Hg²âº at 3.2 µg · L⁻¹ increased the life expectancy at hatching of M. macrocopa. When S. obliquus density was 0.5 x 106 cells · mL⁻¹, there were significant dose-effect relationships between Hg²âº concentration and the life expectancy at hatching, the generation time as well as the cross reproduction rate of M. macrocopa. However, when S. obliquus density was 1.0 x 106 or 2.0 x 106 cells · mL⁻¹, there were no any significant dose-effect relationships between Hg²âº concentration and each of the life table demographic parameters of M. macrocopa.