Subcellular compartmentalized localization of transmembrane proteins essential for production of fungal cyclic peptide cyclochlorotine.

Fungal biosynthetic gene clusters often include genes encoding transmembrane proteins, which have been mostly thought to be transporters exporting the products. However, there is little knowledge about subcellular compartmentalization of transmembrane proteins essential for biosynthesis. Fungal mycotoxin cyclochlorotine is synthesized by non-ribosomal peptide synthetase, which is followed by modifications with three transmembrane UstYa-family proteins. Heterologous expression in Aspergillus oryzae revealed that total biosynthesis of cyclochlorotine requires additional two transporter proteins. Here, we investigated subcellular localizations of the five transmembrane proteins under heterologous expression in A. oryzae. Enhanced green fluorescent protein (EGFP) fusions to the transmembrane proteins, which were confirmed to normally function in cyclochlorotine production, were expressed together with organellar markers. All the transmembrane proteins exhibited localizations commonly in line of the trans-Golgi, endosomes, and vacuoles. This study suggests that subcellular compartmentalization of UstYa family proteins and transporters allows corporative functions of delivering intermediates and subsequent modifications, completing cyclochlorotine biosynthesis.

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To explore the temporal and spatial variations in phytoplankton community in small estuaries, we collected surface water samples from Yongjiang River estuary during wet, normal, and dry seasons and determined the main driving factors of phytoplankton community. A total of 358 species belonging to nine phyla and 123 genera were identified in all seasons. During wet, normal, and dry seasons, species number was 276, 154 and 151, and the abundance was (170.45±225.43)×103, (51.92±30.28)×103 and (31.65±12.79)×103 cells·L-1, respectively. Diatoms dominated the phytoplankton community, and the main dominant species were Cyclotella meneghiniana, Skeletonema costatum, and Paralia sulcata. Shannon diversity and Pielou evenness indices decreased from inside mouth to outside mouth in wet season, but there was no obvious spatial difference in normal season or dry season. Results of non-metric multidimensional scaling analysis and analysis of similarities showed that phytoplankton community composition differed significantly among different regions (inside, at and outside mouth) and different seasons. In wet season, phytoplankton abundance was significantly positively correlated with temperature, dissolved inorganic nitrogen, and dissolved reactive phosphorus, but significantly negatively correlated with salinity. In normal season, phytoplankton abundance was significantly negatively correlated with temperature. In dry season, it was not significantly correlated with environmental factors. Results of redundancy analysis showed that temperature, salinity, ammonium and dissolved reactive phosphorus explained the variations in phytoplankton community by 19.5%, 11.9%, 9.4% and 8.2%, respectively. These results revealed high dominance of diatoms and the main driving factors (temperature, salinity and nutrients) of phytoplankton community in Yongjiang River estuary.

Tumescenamide C, a cyclic lipodepsipeptide from Streptomyces sp. KUSC_F05, exerts antimicrobial activity against the scab-forming actinomycete Streptomyces scabiei.

The antimicrobial activity of tumescenamide C against the scab-forming S. scabiei NBRC13768 was confirmed with a potent IC50 value (1.5 µg/mL). Three tumescenamide C-resistant S. scabiei strains were generated to compare their gene variants. All three resistant strains contained nonsynonymous variants in genes related to cellobiose/cellotriose transport system components; cebF1, cebF2, and cebG2, which are responsible for the production of the phytotoxin thaxtomin A. Decrease in thaxtomin A production and the virulence of the three resistant strains were revealed by the LC/MS analysis and necrosis assay, respectively. Although the nonsynonymous variants were insufficient for identifying the molecular target of tumescenamide C, the cell wall component wall teichoic acid (WTA) was observed to bind significantly to tumescenamide C. Moreover, changes in the WTA contents were detected in the tumescenamide C-resistant strains. These results imply that tumescenamide C targets the cell wall system to exert antimicrobial effects on S. scabiei.

Adaptive Changes in Detoxification Metabolism and Transmembrane Transport of Bombyx mori Malpighian Tubules to Artificial Diet.

The high adaptability of insects to food sources has contributed to their ranking among the most abundant and diverse species on Earth. However, the molecular mechanisms underlying the rapid adaptation of insects to different foods remain unclear. We explored the changes in gene expression and metabolic composition of the Malpighian tubules as an important metabolic excretion and detoxification organ in silkworms (Bombyx mori) fed mulberry leaf and artificial diets. A total of 2436 differentially expressed genes (DEGs) and 245 differential metabolites were identified between groups, with the majority of DEGs associated with metabolic detoxification, transmembrane transport, and mitochondrial function. Detoxification enzymes, such as cytochrome P450 (CYP), glutathione-S-transferase (GST), and UDP-glycosyltransferase, and ABC and SLC transporters of endogenous and exogenous solutes were more abundant in the artificial diet group. Enzyme activity assays confirmed increased CYP and GST activity in the Malpighian tubules of the artificial diet-fed group. Metabolome analysis showed increased contents of secondary metabolites, terpenoids, flavonoids, alkaloids, organic acids, lipids, and food additives in the artificial diet group. Our findings highlight the important role of the Malpighian tubules in adaptation to different foods and provide guidance for further optimization of artificial diets to improve silkworm breeding.

Intranasal Dexmedetomidine for the Treatment of Pre-operative Anxiety and Insomnia: A Prospective, Randomized, Controlled, and Clinical Trial.

Background and Objective: Several patients with pre-operative anxiety and insomnia refuse to take sleeping pills because of the side effects of sleeping pills. This study aimed to evaluate the applicability of intranasal dexmedetomidine (DEX) in the treatment of pre-operative anxiety and insomnia. Methods: A total of 72 patients with insomnia and anxiety were randomly divided into two groups of intranasal DEX (n = 36) and intranasal normal saline (NS, n = 36). The primary outcomes included patients' time to fall asleep, total sleep time, insomnia severity index (ISI) after treatment, and satisfaction with the treatment effect. The secondary outcomes were mean arterial pressure (MAP), oxygen saturation (SPO2), heart rate (HR), Narcotrend index (NI) in the first 2 h of treatment, and the incidence of adverse events within 12 h after treatment. Results: The time to fall asleep (22.08 ± 3.95 min) and total sleep time (400.06 ± 28.84 min) in the DEX group were significantly different from those in the NS group [time to fall asleep, 89.31 ± 54.56 min; total sleep time (295.19 ± 73.51 min; P < 0.001)]. ISI after treatment in the DEX group was lower than that in the NS group (P < 0.001). Satisfaction with the treatment effect was better in the DEX group than that in the NS group (P < 0.001). The general vital signs in the two groups were stable during the treatment. The drowsiness rate in the NS group was higher than that in the DEX group (P < 0.001). Conclusion: Intranasal DEX can significantly improve pre-operative anxiety and insomnia. Clinical Trial Registration: This study was registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn/searchproj.aspx, ChiCTR2100044747).

Selenite Reduction by Proteus sp. YS02: New Insights Revealed by Comparative Transcriptomics and Antibacterial Effectiveness of the Biogenic Se0 Nanoparticles.

Biotransformation of selenite by microorganisms is an effective detoxification (in cases of dissimilatory reduction, e.g., to Se0) and assimilation process (when Se is assimilated by cells). However, the current knowledge of the molecular mechanism of selenite reduction remains limited. In this study, a selenite-resistant bacterium was isolated and identified as Proteus sp. YS02. Strain YS02 reduced 93.2% of 5.0 mM selenite to selenium nanoparticles (SeNPs) within 24 h, and the produced SeNPs were spherical and localized intracellularly or extracellularly, with an average dimension of 140 ± 43 nm. The morphology and composition of the isolated and purified SeNPs were characterized using dynamic light scattering (DLS), scanning electron microscopy (SEM) with energy-dispersive X-ray (EDX) spectrometry, and Fourier transform infrared (FTIR) spectroscopy. FTIR spectroscopy indicated the presence of proteins, polysaccharides, and lipids on the surface of the isolated SeNPs. Furthermore, the SeNPs showed excellent antimicrobial activity against several Gram-positive and Gram-negative pathogenic bacteria. Comparative transcriptome analysis was performed to elucidate the selenite reduction mechanism and biosynthesis of SeNPs. It is revealed that 197 genes were significantly upregulated, and 276 genes were significantly downregulated under selenite treatment. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that genes associated with ABC transporters, sulfur metabolism, pentose phosphate pathway (PPP), and pyruvate dehydrogenase were significantly enhanced, indicating selenite is reduced by sulfite reductase with PPP and pyruvate dehydrogenase supplying reducing equivalents and energy. This work suggests numerous genes are involved in the response to selenite stress, providing new insights into the molecular mechanisms of selenite bioreduction with the formation of SeNPs.

Biosynthesis of Cyclochlorotine: Identification of the Genes Involved in Oxidative Transformations and Intramolecular O,N-Transacylation.

Mycotoxin cyclochlorotine (1) and structurally related astins are cyclic pentapeptides containing unique nonproteinogenic amino acids, such as ß-phenylalanine, l-allo-threonine, and 3,4-dichloroproline. Herein, we report the biosynthetic pathway for 1, which involves intriguing tailoring processes mediated by DUF3328 proteins, including stereo- and regiospecific chlorination and hydroxylation and intramolecular O,N-transacylation. Our findings demonstrate that DUF3328 proteins, which are known to be involved in oxidative cyclization of fungal ribosomal peptides, have much higher functional diversity than previously expected.

Microplastic pollution in wild commercial nekton from the South China Sea and Indian Ocean, and its implication to human health.

Marine biota, especially commercially important species, serves as a basis for human nutrition. However, millions of tons of plastic litter are produced and enter the marine environment every year, with potential adverse impacts on marine organisms. In the present study, we investigated the occurrence and characteristics of microplastic (MP) pollution in the digestive tracts of 13 species of wild nektons from 20 stations sampled in the South China Sea (SCS) and the Indian Ocean (IO), and assessed the human health risks of MPs. The detection rate of MPs ranged from 0.00% to 50.00% from the SCS, which was dramatically lower than that from the IO (10.00-80.00%). The average abundance of MP was 0.18 ± 0.06 items g wet weight-1 (ww-1) in the SCS, which was significantly lower than that in the IO with a concentration of 0.70 ± 0.16 items g ww-1. Most MPs were fibers in type, black in color, and polyester (PES) in polymer composition in both the SCS and IO. Interestingly, distinct profiles of MP pollution were found between the benthic and pelagic nektons: 1) The predominant MP composition was PES in the benthic nektons, whereas polyamide (PA) accounted for a larger part of the total MP count in the pelagic nektons within the SCS; 2) The abundance of MP in the benthic nektons (0.52 ± 0.24 items individual-1) was higher than that in the pelagic nektons (0.30 ± 0.11 items individual-1). Accordingly, the mean hazard score of MPs detected in the benthic nektons (220.66 ± 210.75) was higher than that in the pelagic nektons (49.53 ± 22.87); 3) The mean size of the MP in the pelagic nektons (0.84 ± 0.17 mm) was larger than that in the benthic nektons (0.49 ± 0.09 mm). Our findings highlight the need to further investigate the ecological impacts of MPs on wild nekton, especially commercially important species, and its potential implications for human health.

Longicatenamides A-D, Two Diastereomeric Pairs of Cyclic Hexapeptides Produced by Combined-culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596.

Longicatenamides A-D, two diastereomeric pairs of new cyclic hexapeptides, were isolated from the combined-culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596. Their planar structures were determined by spectroscopic analysis including extensive 2D NMR and MS analysis. The absolute configurations of their component amino acids were determined by the use of highly sensitive reagents we recently developed; the highly sensitive-advanced Marfey's method (HS-advanced Marfey's method), which led us to reduce the sample loss and prevent incorrect structural determination. Particularly, the Cß-stereochemistry of hyGlu in longicatenamides A and C was assigned without any use of Cß-Marfey's methods. Longicatenamide A exhibited weak but preferential antimicrobial activity against Bacillus subtilis.

Developing and applying a classification system for ranking the biological effects of endocrine disrupting chemicals on male rockfish Sebastiscus marmoratus in the Maowei Sea, China.

Endocrine disrupting compounds (EDCs) in marine environments has become a major environmental concern. Nonetheless, the biological effects of EDCs on organisms in coastal environments remain poorly characterized. In this study, biomonitoring of EDCs in male fish Sebastiscus marmoratus was carried out in the Maowei Sea, China. The results showed that the concentration of 4-nonylphenol (4-NP) was below the detection limit, the concentrations of 4-tert-octylphenol (4-t-OP) and bisphenol A (BPA) in seawater were moderate compared with those in other global regions, and the possible sources are the municipal wastewater discharge. Nested ANOVA analyses suggest significant differences of the brain aromatase activities and plasma vitellogenin (VTG) expression between the port area and the oyster farming area. A new fish expert system (FES) was developed for evaluating the biological effects of EDCs on fish. Our findings show that the FES is a potential tool to evaluate the biological effects of marine pollutants.

Chronotype and depressive symptoms: A moderated mediation model of sleep quality and resilience in the 1st-year college students.

OBJECTIVE: Depression is highly prevalent among 1st-year college students, and evening chronotype is an important risk factor associated with depression. This study investigates the mediating role of sleep quality and the moderating role of resilience between chronotype and depressive symptoms. METHODS: A total of 4531 students were included in this cross-sectional study. Mediation and moderated mediation models were applied. RESULTS: The association between chronotype and depressive symptoms was partially mediated by sleep quality, and the direct and indirect effects were moderated by resilience. The negative correlation between chronotype and depressive symptoms was significant in students with low levels of resilience compared with moderate/high levels. The positive correlation between sleep quality and depressive symptoms was strongest in low-level resilience students. CONCLUSION: This study reveals that greater eveningness is associated with poorer sleep quality among 1st-year college students, which may lead to severer depression, and highlights the importance of resilience training in reducing depressive symptoms.

Microplastics in three typical benthic species from the Arctic: Occurrence, characteristics, sources, and environmental implications.

Microplastics (MPs) in the Arctic have raised increasing concern, but knowledge on MP contamination in benthic organisms from Arctic shelf regions, e.g., the Chukchi Sea is still limited. Therefore, the present study investigated the occurrence, characteristics, sources, and environmental implications of MPs in the three most common benthic species, namely sea anemone (Actiniidae und.), deposit-feeding starfish (Ctenodiscus crispatus), and snow crab (Chionoecetes opilio), from the Chukchi Sea. The abundances of MPs in the three benthic species were significantly greater than those from the Bering Sea, but lower than those from other regions globally. The top three compositions of MPs in the three species were polyester, nylon, and polyethylene terephthalate. The detection limit for MP size in the present study was 0.03 mm and the mean size of MP in the three species was 0.89 ± 0.06 mm. The surfaces of MPs found in the starfish and crabs were covered with many attachments, cracks, and hollows, while the surfaces of MPs found in the sea anemones were smooth, which was likely a consequence of different feeding behaviors. There was a significantly positive correlation between the abundances of MPs and other anthropogenic substances. The mean MP abundances in the sea anemones ranged from 0.2 items/individual to 1.7 items/individual, which was significantly higher than that in the deposit-feeding starfish (0.1-1.4 items/individual) and snow crabs (0.0-0.6 items/individual). Sea anemones inhabiting lower latitudes ingested relatively higher levels of MPs than those inhabiting higher latitudes. The MP abundances in the sea anemones are significantly and positively correlated with the seasonal reduced ratio of sea ice coverage from August to September. Our findings indicate that sea anemones could function as a bioindicator of MP pollution, and that the MPs in the benthos from the Chukchi Sea might originate from the melting sea ice, fishery activities and ocean currents.

Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton.

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome-editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical-induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.

Microplastics negatively impact embryogenesis and modulate the immune response of the marine medaka Oryzias melastigma.

Microplastic (MP) pollution is an emerging contaminant in aquatic environments worldwide. Nonetheless, the developmental toxicity of MPs in the early life stages of fish and the mechanisms involved are not yet fully understood. The present study investigated the effects of different concentrations of polystyrene (PS) MPs on the early development of the marine model fish the medaka Oryzias melastigma. Our results showed that waterborne exposure to PS MPs significantly delayed the hatching time, altered the heartbeat and decreased the hatching rate of embryos. Furthermore, the genes involved in cardiac development, encoding for embryo-hatching enzymes, as well as inflammatory responses were significantly upregulated. The transcriptome results showed that mainly the pathways involved in metabolism, immune response, genetic information processing and diseases were significantly enriched. These results demonstrate that PS MPs negatively impact embryogenesis and the immune response of O. melastigma.

Biomonitoring of aromatic hydrocarbons in clam Meretrix meretrix from an emerging urbanization area, and implications for human health.

Pollution with total petroleum hydrocarbons (TPHs) is a global concern and particularly in coastal environments. Polycyclic aromatic hydrocarbons (PAHs) are regarded as the most toxic components of TPHs and they can also be derived from other sources. Fangcheng Port is considered as a representative emerging coastal city in China, but the status, sources, and hazards to organisms and humans with respect to contamination with PAHs and TPHs are unknown in the coastal regions of this area. Therefore, in this study, we cloned cytochrome P450 family genes (CYP1A1, CYP3A, and CYP4) and heat shock protein 70 gene (HSP70) in the clam Meretrix meretrix as well as optimizing the method for measuring the 7-ethoxyresorufin O-deethylase activity. These molecular indicators and four specific physiological indexes were found to be appropriate biomarkers for indicating the harmful effects of PAHs and TPHs on clams after exposure to the crude oil water-soluble fraction. In field monitoring surveys, we found that the 2- and 3-ring PAHs were dominant in the clams whereas the 4- to 6-ring PAHs were dominant in the sediments at each site. The PAH levels (3.63-12.77 ng/g wet weight) in wild clams were lower, whereas the TPH levels (13.25-70.50 µg/g wet weight) were higher compared with those determined previous in China and elsewhere. The concentrations of PAHs and TPHs in the sediments (19.20-4215.76 ng/g and 3.65-866.40 µg/g dry weight) were moderate compared with those in other global regions. Diagnostic ratio analysis demonstrated that the PAHs were derived mainly from pyrogenic sources. The TPHs may have come primarily from industrial effluents, land and maritime transportation, or fishing activities. The Integrated Biomarker Response version 2 indexes indicated that the clams collected from site S5 exhibited the most harmful effects due to contamination by PAHs and TPHs. Human health risk assessments demonstrated that the risks due to PAHs and TPHs following the consumption of clams can be considered acceptable. Our results suggest that continuous monitoring of contamination by PAHs and TPHs is recommended in this emerging coastal city as well as assessing their human health risks.

Antimicrobial activity and mechanisms of multiple antimicrobial peptides isolated from rockfish Sebastiscus marmoratus.

Pathogenic disease is a major factor affecting the aquaculture of the rockfish Sebastiscus marmoratus, an important commercial species inhabiting the nearshore waters of the Western Pacific Ocean. Antimicrobial peptides (AMPs), as critical components of innate immunity, have been considered as promising antibiotic substitutes. The aims of this study were 1) to identify major AMPs in the rockfish, 2) to assess their antimicrobial activity and 3) to evaluate their potential therapeutic application. Six AMPs were identified, Hepcidin 1, liver-expressed antimicrobial peptide 2 (LEAP-2), Piscidin, Moronecidin, NK-lysin and ß-defensin through analysis of the liver transcriptome of S. marmoratus. The transcriptional expression profiles of these AMPs were investigated by real-time quantitative PCR (RT-qPCR). These AMPs showed tissue-specific distribution patterns, and S. marmoratus displays a time-, dose- and tissue-dependent expression of AMPs in response to lipopolysaccharide (LPS) challenge. While the synthetic peptides of LEAP-2 and Moronecidin exerted broad-spectrum antimicrobial activity against important aquatic pathogens in vitro by directly disrupting microbial membrane, and no cytotoxicity against murine hepatic cells was observed at the effective concentrations from 5 µM to 40 µM. The existence of multiple AMPs and their distinct tissue distribution patterns and inducible expression patterns suggests a sophisticated, highly redundant, and multilevel network of antimicrobial defensive mechanisms of S. marmoratus. Therefore, S. marmoratus-derived AMPs appear to be potential therapeutic applications against pathogen infections in aquaculture.

Cumulative score based on preoperative plasma fibrinogen and serum C-reactive protein could predict long-term survival for esophageal squamous cell carcinoma.

The present study was to establish a prognostic indicator based on preoperative fibrinogen and C-reactive protein (CRP) (FC score) in esophageal squamous cell carcinoma (ESCC). Clinicopathologic characteristics, preoperative plasma fibrinogen and serum CRP levels were reviewed in patients who underwent transthoracic esophagectomy. The optimal cut-off value for fibrinogen and CRP was defined as 4.0 g/dL and 10.0 mg/L according to previous reports. Patients with elevated fibrinogen and CRP levels were assigned a score of 2, those with only one of these two abnormalities were allocated a score of 1, and those with neither of the two abnormalities were assigned a score of 0. Preoperative FC score was significantly correlated with degree of differentiation, depth of invasion, tumor-node-metastasis (TNM) stage and modified Glasgow Prognostic Score (mGPS). No significant differences in age, gender, tumor length, tumor location, lymph node status or smoking were identified between groups. Univariate survival analysis demonstrated that high preoperative FC score (1/2) was significantly associated with impaired disease free survival (DFS) [hazard ratio (HR), 1.650; 95% confidence interval (CI), 1.181-2.303; P=0.003] and overall survival (OS) (HR, 1.879; 95% CI, 1.333-2.648; P<0.001), and it remained an independent predictor for both DFS (HR, 1.468; 95% CI, 1.043-2.067; P=0.028) and OS (HR, 2.070; 95% CI, 1.266-3.385; P=0.004) in multivariate Cox regression analysis. Preoperative FC score might represent a new potential marker of worst prognosis that warrants further evaluation in prospective and large cohort studies among ESCC patients who underwent transthoracic esophagectomy.

The preoperative sensitive-modified Glasgow prognostic score is superior to the modified Glasgow prognostic score in predicting long-term survival for esophageal squamous cell carcinoma.

The present study was designed to investigate the prognostic significance of the preoperative sensitive-modified Glasgow prognostic score (S-mGPS) and its superiority in esophageal squamous cell carcinoma (ESCC). Clinicopathologic characteristics, preoperative albumin and C-reactive protein (CRP) levels were retrospectively collected in 442 patients who underwent transthoracic esophagectomy. The S-mGPS was calculated before surgery based on optimal cutoff values of 45.6 g/L for albumin and 10.0 mg/L for CRP. 360, 74 and 8 cases were assigned an mGPS of 0, 1 and 2, respectively. In contrast, the S-mGPS was 0 in 114, 1 in 258 and 2 in 70 patients. Of the 360 patients with an mGPS of 0, 246 migrated to the S-mGPS-1 group. Both mGPS and S-mGPS were significantly correlated with tumor length, depth of invasion, pathological tumor-node-metastasis (pTNM) stage and adjuvant treatment. In addition, they were significantly associated with disease free survival (DFS) and overall survival (OS) in univariate analysis. Furthermore, multivariate Cox regression analysis identified S-mGPS as an independent prognostic indicator for both DFS [hazard ratio (HR), 1.577; 95% confidence interval (CI), 1.149-2.163; P = 0.005] and OS (HR, 1.762; 95% CI, 1.250-2.484; P = 0.001), but not mGPS (HR, 0.957; 95% CI, 0.692-1.323; P = 0.790 for DFS and HR, 1.089; 95% CI, 0.781-1.517; P = 0.615 for OS, respectively). Moreover, subgroup analysis revealed that the prognostic impact of the S-mGPS was especially striking in pTNM stage II patients. The preoperative S-mGPS is superior to the mGPS as a prognostic predictor in patients with resectable ESCC.