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Abstract Background The Yangtze River Economic Belt, as a core economic region in China, is facing the dual challenges of an aging population and growing healthcare demand, and the balanced development and optimal allocation of nursing human resources is crucial to the region’s healthcare system. An in-depth study of the regional differences and convergence of nursing human resources in the region will provide a key basis for policy makers to achieve equity and efficiency in healthcare services and meet the growing demand for healthcare. Aim To analyze the regional differences and convergence characteristics of nursing human resource levels in the Yangtze River Economic Belt, and to provide scientific references for optimizing regional nursing human resource allocation. Methods Based on the panel data of 107 cities in the Yangtze River Economic Belt from 2010 to 2020, the regional differences and their sources were analyzed by using Dagum’s Gini coefficient, and the convergence characteristics were examined by the coefficient of variation and spatial convergence model. Results The average value of the number of nursing human resources in the Yangtze River Economic Belt is 2,132,300 people, with obvious regional differences, and the hypervariable density difference (53.01%) is the main source of the regional differences; there are obvious trends of σ-convergence and conditional β-convergence of the level of nursing human resources in the overall and the three major regions of the upstream, midstream, and downstream, and different factors have different moderating effects on the speed of spatial convergence in the other areas. Conclusion The implementation of precise policies for nursing human resources in different regions of the Yangtze River Economic Belt steadily reduces the regional differences between the upper, middle, and lower reaches and enhances the spatial linkage between regions of nursing human resources to improve the quality of nursing human resources.

Abstract RNA-binding proteins (RBPs) are a class of proteins that primarily function by interacting with different types of RNAs and play a critical role in regulating the transcription and translation of cancer-related genes. However, their role in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed RNA sequencing data and the corresponding clinical information of patients with HCC to screen for prognostic RBPs. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was identified as an independent prognostic factor for liver cancer. It is upregulated in HCC and is associated with a poor prognosis. Elevated IGF2BP3 expression was validated via immunohistochemical analysis using a tissue microarray of patients with HCC. IGF2BP3 knockdown inhibited the proliferation of Hep3B and HepG2 cells, whereas IGF2BP3 overexpression promoted the expansion of HuH-7 and MHCC97H cells. Mechanistically, IGF2BP3 modulates cell proliferation by regulating E2F1 expression. DNA hypomethylation of the IGF2BP3 gene may increase the expression of IGF2BP3, thereby enhancing cell proliferation in HCC. Therefore, IGF2BP3 may act as a novel prognostic biomarker and a potential therapeutic target for HCC.

With the continuous application of new agricultural chemicals in agricultural systems, it is imperative to study the environmental fate and potential transformation products (TPs) of these chemicals to better assess their ecological and health risks, as well as guide scientific application. The dissipation of fluchloraminopyr was firstly evaluated under aerobic/anaerobic condition in four representative soils, with Dissipation Time 50 (DT50) values ranging from 0.107 to 4.76 days. Eight TPs generated by soil degradation were identified via Ultra-High Performance Liquid Chromatography coupled with Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-QTOF/MS) and Density Functional Theory (DFT) calculations. The predominant transformation reactions of fluchloraminopyr in soil include oxidation, dechlorination, hydroxylation, and acetylation. The predictions from toxicological software indicated that the acute and chronic toxicity of TPs to aquatic organisms was significantly lower than that of fluchloraminopyr. Moreover, both M267 and M221 exhibited higher acute oral toxicity to terrestrial organisms compared to the parent compound. Consequently, these findings offer essential ecological risk evaluation data for the judicious application of fluchloraminopyr.

Plant growth regulators (PGRs) play an important role in increasing crop yield, and quality, and enhancing crop stress resistance in agricultural production, especially for important crops. PGRs can affect the transport and distribution of assimilates by changing the content and distribution of endogenous hormones in plants. Numerous empirical research results have proven that PGRs have an important impact on the growth, development, and yield composition of wheat. Taking wheat plants as an example, this study reviews the application of PGRs in wheat production and explores their impact on wheat growth and yield. Furthermore, residues and microbial degradation of PGRs are summarized in detail. Finally, future research directions on PGR application in wheat production are proposed. This summary is of great significance for understanding the role of PGRs in wheat production.

Diazinon, an organophosphorus insecticide, is predominantly removed through photodegradation and biodegradation in the environment. However, photodegradation can generate diazoxon, a highly toxic oxidation byproduct, while biodegradation is hard to complete mineralize diazinon, showing limitations in both methods. In this study, we provided an efficient strategy for the complete and harmless removal of diazinon by synergistically employing biodegradation and photodegradation. The diazinon-degrading strain X1 was capable of completely degrading 200 μM of diazinon into 2-isopropyl-6-methyl-4-pyrimidinol (IMP) within 6 h without producing the highly toxic diazoxon. IMP was the only intermediate metabolite in biodegradation process, which cannot be further degraded by strain X1. Through RT-qPCR and prokaryotic expression analyses, the hydrolase OpdB was pinpointed as the key enzyme for diazinon degradation in strain X1. Photodegradation was further used to degrade IMP and a pyridazine ring-opening product of IMP was identified via high resolution mass spectrometry. The acute toxicity of this product to aquatic organisms were 123 times and 6630 times lower than that of diazinon and IMP, respectively. The stepwise application of biodegradation and photodegradation was proved to be a successful approach for the remediation of diazinon and its metabolite IMP. This integrated method ensures the harmless and complete elimination of diazinon and IMP within only 6 h. The research provides a theoretical basis for the efficient and harmless remediation of organophosphorus insecticide residuals in the environment.

Abstract Ubiquitination, catalyzed usually by a three-enzyme cascade (E1, E2, E3), regulates various eukaryotic cellular processes. E3 ligases are the most critical components of this catalytic cascade, determining both substrate specificity and polyubiquitination linkage specificity. Here, we reveal the mechanism of a naturally occurring E3-independent ubiquitination reaction of a unique human E2 enzyme UBE2E1 by solving the structure of UBE2E1 in complex with substrate SETDB1-derived peptide. Guided by this peptide sequence-dependent ubiquitination mechanism, we developed an E3-free enzymatic strategy SUE1 (sequence-dependent ubiquitination using UBE2E1) to efficiently generate ubiquitinated proteins with customized ubiquitinated sites, ubiquitin chain linkages and lengths. Notably, this strategy can also be used to generate site-specific branched ubiquitin chains or even NEDD8-modified proteins. Our work not only deepens the understanding of how an E3-free substrate ubiquitination reaction occurs in human cells, but also provides a practical approach for obtaining ubiquitinated proteins to dissect the biochemical functions of ubiquitination.

Abstract Background Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear. Methods The in vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor A (VEGFA) levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the expression of pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and transwell assays. Results In vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12–0.5 μM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 μM SU11248 completely inhibited EPC migration to the supernatants of liver cell and protoscolex co-cultures. Conclusions SU11248 is a potential candidate drug for the treatment of AE, which predominantly inhibits parasite-induced angiogenesis. Host-targeted anti-angiogenesis treatment strategies constitute a new avenue for the treatment of AE. Graphical Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is a heterogeneity pathological malignant cancer with leading causes of morbidity and mortality. EGFR inhibitors, immune checkpoint inhibitors have become novel treatments. However, the mechanism still remained uncertain. Several studies have confirmed that the circadian rhythms induce multiple malignancies developing. We utilized multi-omics analysis to demonstrate the crosstalk between circadian clock genes and tumor microenvironment in HNSCC. Firstly, we performed the LASSO Cox regression analysis based on the 16 important clock genes. A 7-gene risk model was successfully established in TCGA and validated in GEO datasets. Next, CIBERSORT and ESTIMATE methods were performed to display the immune landscape of high risk and low risk groups, and the results showed that high abundance of mast cells activated, dendritic cells activated and neutrophils were positively correlated with poor OS. To further identify hub genes, Kaplan Meier plot was applied in all TCGA and GEO datasets and two hub genes (PER2, and PER3) were identified, especially PER3, which was found strongly associated with immune score, PDCD1, CD4 + and CD8 + T cells in HNSCCC. Moreover, to explore the innate mechanism of circadian-induced pathway, we constructed a circadian-related ceRNA regulatory network containing 34 lncRNAs, 3 miRNAs and 4 core circadian genes. In-vitro experiments also verified that Per2 or Per3 could suppressed the proliferation, migration and invasion of HNSC. This study unraveled the association between PER3 and prognosis in patients with HNSC and the innate mechanism remains to be elucidated.

Abstract Background Echinococcus granulosus can manipulate its host's immune response to ensure its own survival. However, the effect of histone modifications on the regulation of the NOD-like receptor protein 3 (NLRP3) inflammasome and downstream interleukin-1β (IL-1β) production in response to the parasite is not fully understood. Methods We evaluated IL-1β secretion through enzyme-linked immunosorbent assay and assessed reactive oxygen species levels using the dichlorodihydrofluorescein diacetate probe. Western blotting and quantitative real-time polymerase chain reaction were performed to examine the expression of NLRP3 and IL-1β in mouse peritoneal macrophages and Tohoku Hospital Pediatrics-1 cells, a human macrophage cell line. The presence of trimethylated histone H3 lysine 27 (H3K27me3) modification on NLRP3 and IL-1β promoters was studied by chromatin immunoprecipitation. Results Treatment with E. granulosus cyst fluid (EgCF) considerably reduced IL-1β secretion in mouse and human macrophages, although reactive oxygen species production increased. EgCF also suppressed the expression of NLRP3 and IL-1β. Mechanistically, EgCF prompted the enrichment of repressive H3K27me3 modification on the promoters of both NLRP3 and IL-1β in macrophages. Notably, the presence of EgCF led to a significant reduction in the expression of the H3K27me3 demethylase KDM6B. Conclusions Our study revealed that EgCF inhibits KDM6B expression and H3K27me3 demethylation, resulting in the transcriptional inhibition of NLRP3 and IL-1β. These results provide new insights into the immune evasion mechanisms of E. granulosus. Graphical Abstract

Abstract Background Echinococcus granulosus cyst fluid (EgCF) weakens macrophage inflammatory responses, thereby enabling the parasite to evade the immune system. However, the role of histone modification in this process remains to be explored. Methods The levels of IL-6, TNF-α, IL-10, H3K4me3, and KDM5B were detected using quantitative real-time PCR, ELISA, and Western blotting. The enrichment of H3K4me3 and KDM5B at the promoter of inflammatory factors was detected by chromatin immunoprecipitation. Results Based on EgCF-stimulated macrophage models, we found that EgCF significantly inhibited mRNA expression and protein secretion of IL-6 and TNF-α and upregulated mRNA expression of IL-10 under the influence of TLR4. EgCF lowered the level of H3K4me3 and promoted the transcription and protein stability of histone demethylase KDM5B. Chromatin immunoprecipitation analysis revealed that EgCF suppressed the enrichment of H3K4me3 modification at the promoters of TNF-α and IL-6 and downregulated their expression in macrophages. Additionally, the inhibition of KDM5B activity by CPI-455 weakened the anti-inflammatory effect of EgCF. Conclusions Our findings demonstrate a novel mechanism through which EgCF promotes KDM5B expression and inhibits the enrichment of H3K4me3 at the promoters of inflammatory cytokines to suppress the inflammatory response. Graphical Abstract

Abstract Background Circular RNAs (circRNAs), which are involved in various human malignancies, have emerged as promising biomarkers. The present study aimed to investigate unique expression profiles of circRNAs in hepatocellular carcinoma (HCC) and identify novel biomarkers associated with HCC development and progression. Methods CircRNA expression profiles of HCC tissues were jointly analyzed to identify differentially expressed circRNAs. Overexpression plasmid and siRNA targeting candidate circRNAs were used in functional assays in vitro. CircRNA-miRNA interactions were predicted using miRNAs expressed in the miRNA-seq dataset GSE76903. To further screen downstream genes targeted by the miRNAs, survival analysis and qRT-PCR were conducted to evaluate their prognostic role in HCC and construct a ceRNA regulatory network. Results Three significantly upregulated circRNAs, hsa_circ_0002003, hsa_circ_0002454, and hsa_circ_0001394, and one significantly downregulated circRNA, hsa_circ_0003239, were identified and validated by qRT-PCR. Our in vitro data indicated that upregulation of hsa_circ_0002003 accelerated cell growth and metastasis. Mechanistically, DTYMK, DAP3, and STMN1, which were targeted by hsa-miR-1343-3p, were significantly downregulated in HCC cells when hsa_circ_0002003 was silenced and were significantly correlated with poor prognosis in patients with HCC. Conclusion Hsa_circ_0002003 may play critical roles in HCC pathogenesis and serve as a potential prognostic biomarker for HCC. Targeting the hsa_circ_0002003/hsa-miR-1343-3p/STMN1 regulatory axis could be an effective therapeutic strategy in patients with HCC.

We report a case of a male patient who presented with multiple abdominal and pelvic echinococcosis. The patient had been diagnosed with hepatic echinococcosis for 7 years and developed intermittent distension and discomfort in the upper abdomen after an accidental fall. In recent years, the patient’s abdominal distention increased gradually. Computed tomography revealed multiple hydatid cysts in the liver, spleen, abdominal cavity, and pelvic cavity. Abdominal organs were severely compressed, such that he could not eat normally except for a liquid diet. The patient underwent radical surgical resection based on the multi-disciplinary treatment (MDT) and the operation lasted 10 h, nearly 100 hydatid cysts were excised, about 18 liters of cyst fluid and cyst contents were removed, and the patient lost 20 kg of weight after surgery. The operation was successful, but there were still some postoperative complications such as hypovolemic shock, postoperative ascites, postoperative bile leakage. Treatment measures for the patient were anti-infection, antishock, clamping the abdominal drainage tube, and negative pressure abdominal puncture drainage. At follow up the patient’s quality of life had been significantly improved with 15 kg weight gain compared to before.

Coiled-coil domain-containing (CCDC)family proteins play an important role in tumour progression, however, the role of CCDC167 in hepatocellular carcinoma remains unclear. To investigate the role of coiled-coil structural domain 167 (CCDC167) in hepatocellular carcinoma progression, we downloaded three hepatocellular carcinoma datasets (TCGA-LIHC, ICGC-LIRI and GSE76427) and analysed the mechanisms by which CCDC167 regulates hepatocellular carcinoma progression using MetaScape, CPTAC, HPA, TISCH and TISIDB.“ pRRophetic” package predicted the chemotherapeutic agents associated with CCDC167. The results showed that CCDC167 was highly expressed in hepatocellular carcinoma tissues and was associated with poor prognosis in patients with hepatocellular carcinoma. Knockdown of CCDC167 inhibits the proliferative capacity of hepatocellular carcinoma cells. CCDC167 was involved in the regulation of cell cycle, DNA replication and oxidative phosphorylation. Hepatocellular carcinoma samples with high expression of CCDC167 showed higher immune scores and C4 (lymphocyte depleted) subtypes. CCDC167 was associated with a variety of immune molecules (CD274, IL6R, and KDR), not only that, but CCDC167 was positively correlated with Treg infiltration and negatively correlated with T cells CD4 memory resting. High expression of CCDC167 increased immune escape in hepatocellular carcinoma patients. CCDC167 was associated with sensitivity to cisplatin in hepatocellular carcinoma patients. CCDC167 promoted the proliferative capacity of hepatocellular carcinoma cells. Our study suggests that CCDC167 is a novel and potentially valuable prognostic marker for hepatocellular carcinoma, and that CCDC167 iCCDC167 not only promotes hepatocellular carcinoma cell proliferation but is also associated with immune function in hepatocellular carcinoma patients.

Agrochemicals are emergingly being implicated in the widespread dissemination of antibiotic resistance genes (ARGs) in agroecosystems. However, minimal research exists on the disturbance of fumigant on soil ARGs. Focusing on a typical fumigant dazomet in a simulated soil microcosm, we characterized the dazomet-triggered timely response and longstanding dynamic of ARGs at one-fold and two-fold field recommended doses using metagenome and quantitative PCR. Dazomet treatments reduced 13.17%-69.98% of absolute abundance of 16S rRNA gene and targeted ARGs, but, awfully, boosted diversity and relative abundance of ARGs up to 1.33–1.60 and 1.62–1.90 folds, respectively. Approximately 77.28% of changes in relative abundance of ARGs could be explained by bacterial community and mobile genetic elements (MGEs). Mechanistically, primary hosts of ARGs shifted from Proteobacteria (control) to Firmicutes and Actinobacteria (treatments) accompanied with corresponding changes in their abundance by combining community analysis, host tracking analysis and antibiotic resistant bacteria assay. Meanwhile, dazomet exposure significantly increased the incidence of MGEs and stimulated the conjugation of antibiotic-resistant plasmid. In addition, absolute abundance of targeted ARGs gradually recovered in the post-fumigation stage. Collectively, our results elucidate the dazomet-triggered emergence and spread of soil ARGs and highlight the importance of navigating toward rational use of fumigant in agricultural fields.

Abstract Background Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is an aminoacyl-tRNA synthase involved in the pathology of cancer and other diseases. In this study, we investigated the carcinogenic function, potential mechanism, and clinical significance of EPRS1 in human hepatocellular carcinoma (HCC). Methods The expression, clinical significance, and prognostic value of EPRS1 in HCC were assessed using the TCGA and GEO databases. The function of EPRS1 in HCC cells was detected by CCK-8, Transwell, and hepatosphere formation assays. Immunohistochemistry was used to explore the difference in EPRS1 levels in HCC tissues and peri-cancerous tissues. The mechanism of EPRS1 was studied using a proteomics method. Finally, cBioportal and MEXEPRSS were used to analyze the variations involved in the differential expression of EPRS1. Results EPRS1 was frequently upregulated at the mRNA and protein levels in liver cancer. Increased EPRS1 correlated with shortened patient survival. EPRS1 could promote cancer cell proliferation, characteristics of cell stemness, and mobility. Mechanistically, EPRS1 played a carcinogenic role by upregulating several downstream proline-rich proteins, primarily LAMC1 and CCNB1. In addition, copy number variation could contribute to the high expression of EPRS1 in liver cancer. Conclusion Together, our data imply that enhanced EPRS1 contributes to the development of HCC by increasing the expression of oncogenes in the tumor microenvironment. EPRS1 may be a successful treatment target.

Co-existence of NO3--N, antibiotics, phosphorus (P), and Cu2+ in aquaculture wastewater has been frequently detected, but simultaneous removal and relationship between enzyme and pollutants removal are far from satisfactory. In this study, simultaneous removal of NO3--N, P, antibiotics, and Cu2+ by moving bed biofilm reactor (MBBR) was established. About 95.51 ± 3.40% of NO3--N, 61.24 ± 3.51% of COD, 18.74 ± 1.05% of TP, 88% of Cu2+ were removed synchronously in stage I, and antibiotics removal in stages I-IV was 73.00 ± 1.32%, 79.53 ± 0.88%, 51.07 ± 3.99%, and 33.59 ± 2.73% for tetracycline (TEC), oxytetracycline (OTC), chlortetracycline hydrochloride (CTC), sulfamethoxazole (SMX), respectively. The removal kinetics and toxicity of MBBR effluent were examined, indicating that the first order kinetic model could better reflect the removal of NO3--N, TN, and antibiotics. Co-existence of multiple antibiotics and Cu2+ was the most toxicity to E. coli growth. Key enzyme activity, reactive oxygen species (ROS) level, and its relationship with TN removal were investigated. The results showed that enzymes activities were significantly different under the co-existence of antibiotics and Cu2+. Meanwhile, different components of biofilm were extracted and separated, and enzymatic and non-enzymatic effects of biofilm were evaluated. The results showed that 70.00%− 94.73% of Cu2+ was removed by extracellular enzyme in stages I-V, and Cu2+ removal was mainly due to the action of extracellular enzyme. Additionally, microbial community of biofilm was assessed, showing that Proteobacteria, Bacteroidetes, and Gemmatimonadetes played an important role in the removal of NO3--N, Cu2+, and antibiotics at the phylum level. Finally, chemical bonds of attached and detached biofilm were characterized by X-ray photoelectron spectroscopy (XPS), and effect of nitrogen (N) and P was proposed under the co-existence of antibiotics and Cu2+. This study provides a theoretical basis for further exploring the bioremediation of NO3--N, Cu2+, and antibiotics in aquaculture wastewater.

Abstract Background Gallbladder disease (GBD) can increase the risk of cardiovascular disease (CVD). However, GBD has rarely been reported in the less developed, rural areas of Xinjiang. This study aimed to determine the prevalence of GBD and incidence of CVD in a prospective cohort study in rural Xinjiang. Moreover, the study aimed to explore the association between GBD and CVD within this cohort. Methods The study cohort included 11,444 Uyghur adults in Xinjiang, 3rd division, from the 51st Mission. Study groups were classified according to whether GBD was present or absent at baseline. The occurrence of CVD was the end event. Demographic, anthropometric, and biochemical data were recorded, and the incidence of CVD in the GBD and non-GBD groups analysed. Cox proportional hazards regression models were used to assess the association between GBD and CVD and factors associated with their incidence. Several subgroup analyses were performed to assess CVD incidence in different subgroups. The interaction between GBD and cardiometabolic risk factors, and subsequent risk of developing CVD, was evaluated. Results Prevalence of GBD in the study cohort was 10.29%. After a median follow-up of 4.92 years, the cumulative incidence of CVD in the study cohort was 10.49%, 8.43% in males and 12.65% in females. CVD incidence was higher in the GBD group (34.04% vs. 7.78%, HR = 4.96, 95% CI: 4.40–5.59). After multivariate adjustment, the risk of CVD remained higher in the GBD group (HR = 2.89, 95% CI: 2.54–3.29). Subgroup analyses showed male sex, smoking, alcohol consumption, lack of exercise, and abnormal renal function were all associated with increased risk of CVD. Moreover, the risk of CVD was markedly higher in GBD combined with cardiometabolic risk factors (hypertension, T2DM, dyslipidaemia, overweight, and abdominal obesity), than in cardiometabolic risk factors alone and this was higher in the GBD group than in the non-GBD group regardless of whether cardiometabolic risk factors were combined. Conclusion GBD is an important independent risk factor for CVD development. Awareness of these associations will raise concerns among clinicians about the risk of cardiovascular disease in patients with GBD.

Abstract Artificial neural networks (ANNs) can understand the behavior of a given system from the historical measurements of its associated variables. Adjusting the weight and bias of the ANN model using an optimization algorithm is known as the training process. The ANN reliability is directly related to the success of the training process. Therefore, this study investigates the effect of optimization algorithms on the prediction accuracy of the multilayer perceptron neural networks (MLPNNs). The complex gas hydrate prevention unit is simulated using the MLPNN model trained by 20 different optimization algorithms. This study investigates the gradient‐based, evolutionary, and Bayesian‐based optimization algorithms. Combining statistical and ranking analyses confirms that the Levenberg–Marquardt (LM) is the most efficient optimization technique for training the MLPNN model. This training algorithm adjusts the weight and bis parameters of the MLPNN so that the highest accurate predictions have been achieved. On the other hand, the trained MLPNN by imperialist competitive algorithm shows the lowest accuracy for the considered task. The trained MLPNN by the LM algorithm predicts 239 laboratory‐measured data sets about the methanol (MeOH) loss with the absolute average relative deviation of 6.4% and regression coefficient of 0.9643. Coupling the developed MLPNN and differential evolution optimization algorithm shows that temperature = 263 K and pressure = 6.92 MPa are the optimum condition for minimizing the MeOH loss in the gas hydrate prevention unit. Economic analysis confirms that the annual cost of methanol loss for the daily processing of 100 × 106 m3 of gas is ~17 million US dollars.

PurposeRadiotherapy is one of the most important treatments for high-grade glioma (HGG), but the best way to delineate the target areas for radiotherapy remains controversial, so our aim was to compare the dosimetric differences in radiation treatment plans generated based on the European Organization for Research and Treatment of Cancer (EORTC) and National Research Group (NRG) consensus to provide evidence for optimal target delineation for HGG.MethodsWe prospectively enrolled 13 patients with a confirmed HGG from our hospital and assessed dosimetric differences in radiotherapy treatment plans generated according to the EORTC and NRG-2019 guidelines. For each patient, two treatment plans were generated. Dosimetric parameters were compared by dose–volume histograms for each plan.ResultsThe median volume for planning target volume (PTV) of EORTC plans, PTV1 of NRG-2019 plans, and PTV2 of NRG-2019 plans were 336.6 cm3 (range, 161.1–511.5 cm3), 365.3 cm3 (range, 123.4–535.0 cm3), and 263.2 cm3 (range, 116.8–497.7 cm3), respectively. Both treatment plans were found to have similar efficiency and evaluated as acceptable for patient treatment. Both treatment plans showed well conformal index and homogeneity index and were not statistically significantly different (P = 0.397 and P = 0.427, respectively). There was no significant difference in the volume percent of brain irradiated to 30, 46, and 60 Gy according to different target delineations (P = 0.397, P = 0.590, and P = 0.739, respectively). These two plans also showed no significant differences in the doses to the brain stem, optic chiasm, left and right optic nerves, left and right lens, left and right eyes, pituitary, and left and right temporal lobes (P = 0.858, P = 0.858, P = 0.701 and P = 0.794, P = 0.701 and P = 0.427, P = 0.489 and P = 0.898, P = 0.626, and P = 0.942 and P = 0.161, respectively).ConclusionThe NRG-2019 project did not increase the dose of organs at risk (OARs) radiation. This is a significant finding that further lays the groundwork for the application of the NRG-2019 consensus in the treatment of patients with HGGs.Clinical trial registrationThe effect of radiotherapy target area and glial fibrillary acidic protein (GFAP) on the prognosis of high-grade glioma and its mechanism, number ChiCTR2100046667. Registered 26 May 2021.

BackgroundHepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Lysosomes are organelles that play an important role in cancer progression by breaking down biomolecules. However, the molecular mechanisms of lysosome-related genes in HCC are not fully understood.MethodsWe downloaded HCC datasets from TCGA and GEO as well as lysosome-related gene sets from AIMGO. After univariate Cox screening of the set of lysosome-associated genes differentially expressed in HCC and normal tissues, risk models were built by machine learning. Model effects were assessed using the concordance index (C-index), Kaplan-Meier (K-M) and receiver operating characteristic curves (ROC). Additionally, we explored the biological function and immune microenvironment between the high- and low-risk groups, and analyzed the response of the high- and low-risk groups to immunotherapy responsiveness and chemotherapeutic agents. Finally, we explored the function of a key gene (RAMP3) at the cellular level.ResultsUnivariate Cox yielded 46 differentially and prognostically significant lysosome-related genes, and risk models were constructed using eight genes (RAMP3, GPLD1, FABP5, CD68, CSPG4, SORT1, CSPG5, CSF3R) derived from machine learning. The risk model was a better predictor of clinical outcomes, with the higher risk group having worse clinical outcomes. There were significant differences in biological function, immune microenvironment, and responsiveness to immunotherapy and drug sensitivity between the high and low-risk groups. Finally, we found that RAMP3 inhibited the proliferation, migration, and invasion of HCC cells and correlated with the sensitivity of HCC cells to Idarubicin.ConclusionLysosome-associated gene risk models built by machine learning can effectively predict patient prognosis and offer new prospects for chemotherapy and immunotherapy in HCC. In addition, cellular-level experiments suggest that RAMP3 may be a new target for the treatment of HCC.

Abstract Growing evidence has demonstrated the functional relevance of long intergenic noncoding RNAs (lincRNAs) to tumorigenesis and immune response. However, immune-related lincRNAs and their value in predicting the clinical outcomes of patients with liver cancer remain largely unexplored. Herein, we utilized the strategy of iterative gene pairing to construct a tumor-specific immune-related lincRNA pairs signature (IRLPS), which did not require specific expression levels, as an indicator of patient outcomes. The 18-IRLPS we developed was associated with overall survival, tumor progression, and recurrence in liver cancer patients. Multivariate analysis revealed that the risk model was an independent predictive factor. A high IRLPS risk was correlated suppressive immune microenvironment, and IRLPS-high patients might benefit more from CD276 blockade or TMIGD2 agonist. Patients in the high-risk group were associated with elevated tumor mutation, increased sensitivity to dopamine receptor antagonists, cisplatin, doxorubicin, and mitomycin but more resistance to vinblastine. Mechanistically, IRLPS high scores might lead to poor prognosis by promoting cell proliferation and metabolic reprogramming. The prognostic significance of the 18-IRLPS was confirmed in independent cancer datasets. These findings highlighted the robust predictive performances of the 18-IRLPS for prognosis and personalized treatment.

Solid-state sodium-ion batteries with sodium metal anodes possess high safety and reliability, which are considered as a promising candidate for the next generation of energy storage technology. However, poor electronic and ionic conductivities at the interface between electrodes and solid-state electrolytes restrict its practical application. Herein, we demonstrate a β″-Al2O3 electrolyte with a vertically porous-dense bilayer structure to solve this problem. The carbon-coated vertically porous layer serves as a high mass-loading host for Na3V2(PO4)3 cathode and provides fast electronically and ionically conductive pathways. In addition, the dense layer is produced to prevent sodium dendrite growth and improve mechanical strength of β″-Al2O3 electrolyte. Experimental results show that the cathode loading in vertically porous layer can reach to 8 mg cm−2, and the porous-dense bilayer β″-Al2O3 electrolyte-based battery exhibits a reversible specific capacity of 87 mAh g−1 and a capacity retention of 95.5% over 100 cycles at a current density of 0.1 C, which is superior to that of the traditional dense β″-Al2O3 electrolyte-based battery. This work based on electrolyte structure design represents an efficient strategy for the development of solid-state sodium-ion batteries with high mass-loading cathode.

Antibiotic resistance genes (ARGs) are important biological contamination factors in soil systems, posing direct or indirect threats to soil health, food safety and human health. The ubiquitous pollution of ARGs is usually implicated with the application of organic manures in agricultural soil ecosystem. However, little is known about the transmission and fate of ARGs after manure input concerning different soils. Herein, the transmission potential and temporal dynamics of manure-associated ARGs was characterized with three different agricultural soils collected from Jiangxi (JX), Zhejiang (ZJ), and Jilin (JL), respectively. The results show that manure input did not affect the total abundance of ARGs in the receiving soils, but remarkedly alter the compositions of ARGs in soils. The manure-associated ARGs were significantly enriched in the manure-amended soils, including genes conferring resistance to sulfonamide, aminoglycoside, tetracycline, chloramphenicol, and trimethoprim with the fold of 1.97 − 27.86. Variance partitioning analysis showed that the major variances of ARG community was explained by mobile genetic elements and bacterial profile (> 76%) but not the concentrations of heavy metals and antibiotics. Furthermore, 31, 37, and 38 ARG subtypes were identified as the potential extrinsic ARGs derived from manures in the JX, ZJ, and JL soils, respectively, including 13 shared ARG subtypes. It was also found that the manure-associated ARGs (aadA, sul1, sul2, tetC, and tetG) declined with the incubation time in the JX and ZJ soils, whereas they firstly decreased and then increased in the JL soil. The abundance of these five ARGs in the JL soil was significantly higher than that in the JX and ZJ soils. Collectively, this finding revealed that soil type was responsible for the transmission and fate of manure-associated ARGs in agroecosystem.

Nanotechnology has been widely used in the field of pesticides. Integration of nano-pesticides and carbon dot fluorescence can fully utilize the potential for high admission of pesticides on leaves and convenience observation of its distribution and transport in the tissues. In the present study, a fluorescent mesoporous nanosilica with double hollow shells for loading imidacloprid (Im@FL-MSNs) was designed and synthesized. The physical and chemical properties of the imidacloprid nanocarriers were characterized by transmission electron microscopy (TEM), FT-IR spectroscopy, thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS) and N2 adsorption/desorption. When the mass ratio of FL MSNs to imidacloprid is 6:5, Im@FL-MSNs exhibits good fluorescence properties, high loading efficiency (∼30%), great slow-release performance as well as pH controllability. Besides, Im@FL-MSNs can improve the ability of imidacloprid to adhere on the leaf surface of bok choy (Initial contact angled is greater than 80°）. Importantly, Im@FL-MSNs did not reduce the biological activity of imidacloprid (LC50 (95% CI) = 1.43 mg/L). It was able to visually study the absorption and distribution of imidacloprid in bok choy plants, and provide theoretical and technical guidance for pesticide reduction.

Tongue squamous cell carcinoma (TSCC) is a prevalent cancer of the oral cavity. Survival metrics are usually unsatisfactory, even using combined treatment with surgery, radiation, and chemotherapy. Immune checkpoint inhibitors can prolong survival, especially in patients with recurrent or metastatic disease. However, there are few effective biomarkers to provide prognosis and guide immunotherapy. Here, we utilized weighted gene co-expression network analysis to identify the co-expression module and selected the turquoise module for further scrutiny. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed the innate pathways. The findings indicated that cell junction organization, response to topologically incorrect protein, and regulation of cell adhesion pathways may be essential. Eleven crucial predictive genes (PLXNB1, N4BP3, KDELR2, INTS8, PLAU, PPFIBP2, OAF, LMF1, IL34, ZFP3, and MAP7D3) were used to establish a risk model based on Cox and LASSO analyses of The Cancer Genome Atlas and GSE65858 databases (regarding overall survival). Kaplan–Meier analysis and receiver operating characteristic curve suggested that the risk model had better prognostic effectiveness than other clinical traits. Consensus clustering was used to classify TSCC samples into two groups with significantly different survival rates. ESTIMATE and CIBERSORT were used to display the immune landscape of TSCC and indicate the stromal score; specific types of immune cells, including naïve B cells, plasma cells, CD8 T cells, CD4 memory resting and memory activated T cells, follicular helper T cells, and T regulatory cells, may influence the heterogeneous immune microenvironment in TSCC. To further identify hub genes, we downloaded GEO datasets (GSE41613 and GSE31056) and successfully validated the risk model. Two hub genes (PLAU and PPFIBP2) were strongly associated with CD4+ and CD8+ T cells and programmed cell death protein 1 (PD1) and PD-ligand 1.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor is one of the important herbicides to solve the problem of weed control. With the widespread and continued use of HPPD inhibitor (HPPDi) herbicides, it may inevitably put pressure on the environment. Humic acid (HA) can effectively interact with pesticides through sorption or covalent bond formation and promote the degradation of pesticides, which can reduce the risk of pesticides in the environment. In the present study, the interactions of four HPPDi herbicides (sulcotrione, tembotrione, topramezone and mesotrione) with HA were reported and comparative assessment of the binding using multispectral technology, density functional theory (DFT) calculation and two-dimensional correlation spectroscopy (2D-COS). Time-resolved measurements and the Stern-Volmer constant at different temperature verified that HPPDi can bind with HA through the static quenching mechanism. From the thermodynamic parameters, the interaction force between HA and sulcotrione, tembotrione, topramezone and mesotrione was provided by electrostatic force. DFT, binding constant and three-dimensional (3D) fluorescence peak variation all indicated that the order of the binding ability of the four HPPDi and HA was mesotrione > tembotrione > sulcotrione > topramezone. According to dynamic light scattering (DLS), pH 7 is most conducive to the formation of HA-HPPDi complexes. Fourier transform infrared spectroscopy (FTIR) and 2D-COS showed that HA combined with HPPDi through aromatic C-H, CO and C-X, and the first binding group to HA was almost all CO. Sulcotrione, tembotrione, topramezone and mesotrione quench the endogenous fluorescence of HA by a static quenching mechanism and bind to HA through electrostatic interaction to form a complex. These results provide important insights into the combination of environmental pollutants with HA.

[This corrects the article DOI: 10.1371/journal.pntd.0008023.].

Abstract Background The regulatory roles of circular RNAs (circRNAs) in tumorigenesis have attracted increasing attention. However, novel circRNAs with the potential to be used as serum/plasma biomarkers and their regulatory mechanism in the pathogenesis of hepatocellular carcinoma (HCC) remain explored. Methods CircRNA expression profiles of tumor tissues and plasma samples from HCC patients were compiled and jointly analyzed. CircRNA–miRNA–mRNA interactions were predicted by bioinformatics tools. The expression of interacting miRNAs and mRNA was verified in independent datasets. Survival analysis and pathway enrichment analysis were conducted on hub genes. Results We identified three significantly up-regulated circRNAs (hsa_circ_0009910, hsa_circ_0049783, and hsa_circ_0089172) both in HCC tissues and plasma samples. Two of them were validated to be indeed circular and could be excreted from hepatoma cells. We further revealed four miRNAs (hsa-miR-455-5p, hsa-miR-615-3p, hsa-miR-18a-3p, hsa-miR-4524a-3p) that targeting circRNAs and expressed in human HCC samples, and 95 mRNAs targeted by miRNAs and significantly up-regulated in two HCC cohorts. A protein-protein interaction network revealed 19 hub genes, 12 of them (MCM6, CCNB1, CDC20, NDC80, ZWINT, ASPM, CENPU, MCM3, MCM5, ECT2, CDC7, and DLGAP5) were associated with reduced survival in two HCC cohorts. KEGG, Reactome, and Wikipathway enrichment analysis indicated that the hub genes mainly functioned in DNA replication and cell cycle. Conclusions Our study uncovers three novel deregulated circRNAs in tumor and plasma from HCC patients and provides an insight into the pathogenesis from the circRNA–miRNA–mRNA regulatory network.

Fluorescence-labeling technology has been widely used for rapid detection of pesticides in agricultural production. However, there are few studies on the use of this technology to investigate pesticide uptake and transport in plants with fluorescent nanoparticle formulations. Here, we investigated uptake, transport, accumulation and metabolism of imidacloprid loaded in fluorescent mesoporous SiO2 nanoparticles (Im@FL-MSNs) in tomato plants, and compared the results with the pesticide application in granular formulation. The results revealed that Im@FL-MSNs applied via root uptake and foliar spray both could effectively transport in tomato plants and carry the imidacloprid to plant tissues. Neither Im@FL-MSNs nor imidacloprid was detected inside of tomato fruits from root uptake or foliar spray applications. Compared with the foliar application of granular formulation, imidacloprid in Im@FL-MSNs demonstrated a higher concentration in leaves (1.14 ± 0.07 mg/kg > 1.08 ± 0.04 mg/kg, 1.13 ± 0.09 mg/kg > 1.11 ± 0.02 mg/kg), longer half-life (0.84 d < 1.31 d, 0.90 d < 1.36 d) and small numbers of metabolites formed. These results suggest that mesoporous silica nanoparticles could serve as an effective and efficient pesticide carrier for achieving the high use efficiency in plant protection. The information is also helpful to guide the pesticide applications and assess the risks associated with environmental quality and dietary consumption of vegetables.

Recently, attention has been focused on the central role of TREM2 in diverse pathologies. However, the role of TREM2 signaling in the tumor microenvironment of hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically investigated the single-cell transcriptomes of human HCC tissues and found that TREM2 was predominantly expressed by a macrophage subpopulation enriched in tumor tissues that resemble lipid-associated macrophages (LAMs). The accumulation of TREM2+ LAM-like cells in HCC was confirmed in two additional cohorts using scRNA-seq analysis and immunohistochemistry. High expression of TREM2 correlated with high infiltrating macrophage abundance and poor prognosis. Based on systematic interrogations of transcriptional profiles and cellular interactions, TREM2+ LAM-like cells were identified to mainly originate from S100A8+ monocytes and represented an immunosuppressive state. TREM2+ LAM-like cells recruited suppressive Treg cells, facilitating microenvironment remodeling. Furthermore, gene regulatory analysis and in vitro functional assays indicated that activation of LXR signaling could promote the reprogramming of TREM2+ LAM-like cells. Correlation analysis of bulk RNA-sequencing data demonstrated that the enrichment of TREM2+ LAM-like cells was an independent indicator of adverse clinical outcomes in HCC patients. Our comprehensive analyses provide deeper insights into the immunosuppressive role of TREM2+ LAM-like cells in HCC.

Abstract Background China carried out a comprehensive drug price reform (CDPR) in 2017 to control the growing expense of drug effectively and reduce the financial burden of inpatients. However, early studies in pilot regions found the heterogeneity in the effectiveness of CDPR from different regions and other negative effects. This study aimed to evaluate the effects of the reform on medical expenses, medical service utilisation and government financial reimbursement for inpatients in economically weaker regions. Methods Shihezi was selected as the sample city, and 238,620 inpatients, who were covered by basic medical insurance (BMI) and had complete information from September 2016 to August 2018 in public hospitals, were extracted by cluster sampling. An interrupted series design was used to compare the changing trends in medical expenses, medical service utilisation and reimbursement of BMI for inpatients before and after the reform. Results Compared with the baseline trends before the CDPR, those after the CDPR were observed with decreased per capita hospitalisation expenses (HE) by ¥301.9 per month (p

5-Substituted benzylidene 3-acylthiotetronic acids are antifungal. A series of 3-acylthiotetronic acid derivatives with varying substitutions at the 5-position were designed, synthesized, and characterized, based on the binding pose of 3-acyl thiolactone with the protein C171Q KasA. Fungicidal activities of these compounds were screened against Valsa Mali, Curvularia lunata, Fusarium graminearum, and Fusarium oxysporum f. sp. lycopersici. Most target compounds exhibited excellent fungicidal activities against target fungi at the concentration of 50 μg·mL−1. Compounds 11c and 11i displayed the highest activity with a broad spectrum. The median effective concentration (EC50) values of 11c and 11i were 1.9–10.7 and 3.1–7.8 μg·mL−1, respectively, against the tested fungi, while the EC50 values of the fungicides azoxystrobin, carbendazim, and fluopyram were respectively 0.30, 4.22, and > 50 μg·mL−1 against V. Mali; 6.7, 41.7, and 0.18 μg·mL−1 against C. lunata; 22.4, 0.42, and 0.43 μg·mL−1 against F. graminearum; and 4.3, 0.12, and > 50 μg·mL−1 against F. oxysporum f. sp. lycopersici. The structures and activities of the target compounds against C. lunata were analyzed to obtain a statistically significant comparative molecular field analysis (CoMFA) model with high prediction abilities (q2 = 0.9816, r2 = 0.8060), and its reliability was verified. The different substituents on the benzylidene at the 5-position had significant effects on the activity, while the introduction of a halogen atom at the benzene ring of benzylidene was able to improve the activity against the tested fungi.

Alternaria alternata is a pathogen in a wide range of agriculture crops and causes significant economic losses. A strain of A. alternata (Y784-BC03) was isolated and identified from “Hongyang” kiwifruit and demonstrated to cause black spot infections on fruits. The genome sequence of Y784-BC03 was obtained using Nanopore MinION technology. The assembled genome is composed of 33,869,130bp (32.30Mb) comprising 10 chromosomes and 11,954 genes. A total of 2,180 virulence factors were predicted to be present in the obtained genome sequence. The virulence factors comprised genes encoding secondary metabolites, including non-host-specific toxins, cell wall-degrading enzymes, and major transcriptional regulators. The predicted gene clusters encoding genes for the biosynthesis and export of secondary metabolites in the genome of Y784-BC03 were associated with non-host-specific toxins, including cercosporin, dothistromin, and versicolorin B. Major transcriptional regulators of different mycotoxin biosynthesis pathways were identified, including the transcriptional regulators, polyketide synthase, P450 monooxygenase, and major facilitator superfamily transporters.

Due to the prevalence of the order production mode, multi-variety, small-batch manufacturing enterprises frequently delay deliveries to downstream customers. To date, most existing studies on delayed delivery risk have focused on the response to the risk after it occurs, ignoring how the risk arises. For multi-variety, low-volume production companies, any part of the production process could lead to the ultimate risk of delayed delivery, and the risk is transmissible. Therefore, the path of risk transmission needs to be identified to effectively control the risk of late delivery at key production stages. In this paper, from the perspective of risk transmission, a recognition method based on association rules and the Bayesian network was proposed to identify the risk conduction path. This method firstly determined the strong association rules among the risk factors based on historical data stored in the ERP system and determined the Bayesian network topology structures of the risk transmission path by combining the business process and expert experience. Secondly, the prior and conditional probabilities of each node were determined using data statistics, and the risk transmission path of delayed delivery was identified using the forward and backward reasoning of the Bayesian network. Finally, this paper provided a case study to verify the method, and the following conclusions were obtained: (1) the delay in delivery to downstream customers is mainly due to the delayed delivery of upstream suppliers and the sudden change in customer demand, and (2) the adjustment of enterprise production plans is the key node of the delayed delivery risk transmission path. Through the research in this paper, production companies can identify the target of risk management more scientifically and mitigate the risk through the adjustment of key links.

Since the 2019-nCoV outbreak was first reported, hundreds of millions of people all over the world have been infected. There is no doubt that improving the cure rate of 2019-nCoV is one of the most effective means to deal with the current serious epidemic. At present, Remdesivir (RDV) has been clinically proven to be effective in the treatment of SARS-CoV-2. However, the uncertain side effects make it important to reduce the use of drugs while ensuring the self-healing effect. We report an approach here with targeted therapy for the treatment of SARS-CoV-2 and other coronaviruses illness. In this study, mesoporous silica was used as the carrier of RDV, the nucleocapsid protein (N protein) aptamer was hybridized with the complementary chain, and the double-stranded DNA was combined with gold nanoparticles as the gates of mesoporous silica pores. When the RDV-loaded mesoporous silica is incubated with the N protein, aptamer with gold nanoparticles dissociate from the complementary DNA oligonucleotide on the mesoporous silica surface and bind to the N protein. The releasing of RDV was determined by detecting the UV-vis absorption peak of RDV in the solution. These results show that the RDV delivery system designed in this work has potential clinical application for the treatment of 2019-nCoV.

Fungicides, including thiophanate-methyl, tebuconazole, pyraclostrobin, and difenoconazole, have been widely used as preservatives to control fungal diseases during pear storage. However, the metabolic capability of pear for exogenous compounds decreases at lower storage temperatures, leading to an increase in the risk of exposure to chemical preservatives. In this work, a sensitive and stable ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) analytical method was established to investigate the dissipation dynamics and dietary intake risk of four chemical preservatives in pears under different conditions. The mean recoveries of the preservatives in pear samples ranged from 73.2% to 117.1%, with relative standard deviations of 0.5–7.2%. The dissipation half-lives (T1/2) of thiophanate-methyl, tebuconazole, pyraclostrobin, and difenoconazole in pears were 7.2–21.1 d and 31.6–173.3 d at storage temperatures of 25 °C and 4 °C, respectively. The results of dietary risk evaluation showed that the intake risk of preservatives in commercial pears was acceptable. However, some pears from commercial supermarkets still contained preservatives at amounts that exceeded the maximum residue limit (MRL) set by the Chinese government. This work provides a guideline for the risk evaluation of fruit preservatives on human health.

Orphan genes are associated with regulatory patterns, but experimental methods for identifying orphan genes are both time-consuming and expensive. Designing an accurate and robust classification model to detect orphan and non-orphan genes in unbalanced distribution datasets poses a particularly huge challenge. Synthetic minority over-sampling algorithms (SMOTE) are selected in a preliminary step to deal with unbalanced gene datasets. To identify orphan genes in balanced and unbalanced Arabidopsis thaliana gene datasets, SMOTE algorithms were then combined with traditional and advanced ensemble classified algorithms respectively, using Support Vector Machine, Random Forest (RF), AdaBoost (adaptive boosting), GBDT (gradient boosting decision tree), and XGBoost (extreme gradient boosting). After comparing the performance of these ensemble models, SMOTE algorithms with XGBoost achieved an F1 score of 0.94 with the balanced A. thaliana gene datasets, but a lower score with the unbalanced datasets. The proposed ensemble method combines different balanced data algorithms including Borderline SMOTE (BSMOTE), Adaptive Synthetic Sampling (ADSYN), SMOTE-Tomek, and SMOTE-ENN with the XGBoost model separately. The performances of the SMOTE-ENN-XGBoost model, which combined over-sampling and under-sampling algorithms with XGBoost, achieved higher predictive accuracy than the other balanced algorithms with XGBoost models. Thus, SMOTE-ENN-XGBoost provides a theoretical basis for developing evaluation criteria for identifying orphan genes in unbalanced and biological datasets.

BACKGROUND:Human cystic echinococcosis (CE) is one of the commonest zoonoses, and it is endemic in many parts of the world including China. Complications and recurrences after the surgical treatment of hepatic CE (HCE) incur a large personal, healthcare, and societal burden. There has been some progress in HCE prevention, diagnosis, and treatment, but there is no "one size fits all" approach, and surgery still remains the cornerstone of treatment for some cyst stages and locations or in areas with little knowledge or access to other treatment modalities. In 2009 we designed and implemented a program to improve surgical outcomes from HCE in Xinjiang province, China. METHODOLOGY/PRINCIPAL FINDINGS:A multimodal HCE training program was implemented in eleven primary hospitals in Xinjiang province, China, which provided education and training on HCE clinical knowledge and practice, the application of diagnostic and treatment options, and optimal surgery. The management of HCE cases was analyzed before and after program implementation. Contrast enhanced CT use, application of scoloicidal agents, removal of necrotic cyst wall remnants, appropriate perioperative drug use, and the use of optimal surgical approach increased after program implementation. Further, postoperative recurrences and residual cavity complications creased from 7.4% to 1.3% and 15.2% to 9.0% after program implementation, respectively. CONCLUSIONS/SIGNIFICANCE:Tis integrated surgical training program is useful for improving outcomes of patients with HCE and can be used in institutions in other endemic areas.

The Heat shock proteins (HSPs) are a group of molecular chaperones that play a crucial role in cell response to various stresses. A full-length cDNA of the heat shock protein 90 (PuHsp90) was cloned and sequenced from the clam Paphia undulata. Phylogenetic analysis revealed that PuHsp90 grouped with the Hsp90 from other metazoan species. Expression of PuHsp90 was highly detected in the gonad, followed by digest gland, gills and heart but was found poorly expressed in mantle, adductor muscle and hemocytes. After a heat shock stress at 32 °C up-regulation of PuHsp90 was detected in the mantle, adductor muscle, gills and hemocytes. Maximal expression levels occurred at 4 h after the heat shock and up-regulation is indicative of protein denaturation and of an increase in energy consumption. In contrast after the heat shock, PuHsp90 was continuously down-regulated in the digestive gland and in the gonad suggesting modifications of the biochemical pathways and energy budgets involved in the synthesis of other protein, such as catalase and of other Hsp proteins. These results reveal that PuHsp90 may play an important role in the clam response to a temperature stress.

Avian influenza A viruses (IAV) can cross the species barrier and cause disease in humans. Understanding the pathogenesis of avian IAV remains a challenge. Interferon-mediated antiviral responses and multiple cytokines production are important host cellular antiviral immunity against IAV infection. To elucidate the pathogenicity of avian IAV, a system approach was adopted to investigate dysregulation of the two host cellular antiviral immune responses in contrast with human IAV. As a result, we revealed that avian IAV not only disrupted normal early host cellular interferon-mediated antiviral responses, but also caused abnormal cytokines production through different pathways. For avian IAV infection, dysregulation of STAT2 was mainly responsible for abnormal cellular interferon-mediated antiviral responses, and IRF5 and NFKB1 played crucial roles in unusual cytokines production. In contrast, for human IAV infection, IRF1, IRF7, and STAT1 contributed to cellular cytokines production. Furthermore, differential activation of pattern recognition receptors (PRRs) likely led to avian IAV-related abnormal early host cellular antiviral immunity, where TLR7 and RIG-I were activated by avian and human IAV, respectively. Finally, a pathogenesis model was proposed that combined of early host cellular interferon-mediated antiviral responses with cytokines production could partly explain the pathogenicity of avian IAV. In conclusion, our study provides a new perspective of the pathogenesis of avian IAV, which will be helpful in preventing their infections in the future.

Influenza A virus (IAV) is a worldwide ongoing health threat causing diseases in both humans and animals. The interaction between IAV and host is a dynamic and evolving process that influences the pathogenicity and host specificity of the virus. TRIM14, a member of tripartite motif (TRIM) family, has been demonstrated to possess a strong capability of regulating type I interferon and NF-κB induction in host defense against viral infection. In this study, we found that TRIM14 could restrict the replication of IAV in a type I interferon and NF-κB independent manner. Mechanistically, different domains of TRIM14 could selectively interact with the viral nucleoprotein (NP), resulting in disparate influences on the RNP formation and viral replication. In particular, the PRYSPRY domain of TRIM14 exhibited a potent inhibitory activity on NP protein stability and IAV replication. On the contrary, the ΔS2 domain could rather antagonize the function of PRYSPRY domain and promote the IAV RNP formation by stabilizing NP. At the biochemical level, TRIM14-NP interaction could induce the K48-linked ubiquitination and proteasomal degradation of NP. Moreover, due to the rapid degradation of newly synthesized NP, TRIM14 could effectively block the translocation of NP from cytoplasm to nucleus thus further restrain the propagation of IAV in host cells. Taken together, our study has unraveled a previously unknown mechanism of TRIM14 mediated inhibition on RNP formation and influenza virus replication, and provides a new paradigm of complex and multifaceted host–pathogen interaction between ISG and viral protein.

An amendment to this paper has been published and can be accessed via the original article.

This study is the first systematic comparison of the biochemical composition and nutritional quality between diploid and triploid Hong Kong oysters, Crassostrea hongkongensis. Results showed that in the reproductive season, the glycogen content in five tissues (gill, mantle, adductor muscle, labial palps and gonad) was significantly higher (P < 0.05) in triploids than in diploids, with odds ratios (ORs) of 96.26, 60.17, 72.59, 53.56, and 128.52%, respectively. In the non-reproductive phase, significant differences in glycogen content (P < 0.05) between diploid and triploid oysters existed only in gill and gonad. In both diploid and triploid Hong Kong oysters, quantitative real-time PCR analysis of the glycogen synthesis gene (ChGS) and glycogen phosphorylase gene (ChGP) showed that the gene expression patterns matched the pattern of variation in glycogen content. Moreover, in both the reproductive and the non-reproductive phases, triploid Hong Kong oysters had a well balance of essential amino acids and were thus a well source of high-quality protein. Surprisingly, in both phases, significantly higher (P < 0.05) percentages of four essential fatty acids (α-linolenic acid, linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid) were observed in triploids than in diploids. Additionally, the ratio of n-3/n-6 polyunsaturated fatty acids (PUFAs) was much higher in triploids than that in diploids. Variations in Biochemical composition were consistent with the relative expression of the citrate synthase gene (ChCS) and the α-ketoglutarate dehydrogenase gene (ChKD), which are key enzyme genes of the tricarboxylic acid cycle. Overall, the triploid Hong Kong oyster has a better nutritional value and taste than the diploid in terms of glycogen content, protein quality and fatty acid content.

Mice are used for modelling the biology of many human diseases, including colorectal cancer (CRC). Mouse models recapitulate many aspects of human disease and are invaluable tools for studying the biology, treatment and prevention of CRC. Unlike humans, many mouse models develop lesions primarily in the small intestine, which necessitates removal and examination of this organ in order to evaluate treatment efficacy. Commonly, the small intestine is visually examined for gross lesions and then selectively embedded in paraffin blocks for further microscopic analysis. Unfortunately, this method suffers from inherent bias toward counting large lesions and simultaneously missing smaller lesions. Even more, this method leaves no permanent record of diagnosed and measured lesions. We evaluated inter-observer variability in a mouse model of CRC using visual examination, and directly compared the visual, gross examination with a histologic analytic method using digital slides of hematoxylin and eosin stained tissue sections.Using visual examination, there was a high degree of inter-observer variability. As this method does not provide a permanent record of measurements, there is no capability to arbitrate between differing observations. In contrast, histologic analysis allowed for the creation of a permanent record of lesion measurements taken. When compared directly, histologic analysis of annotated digital images has significantly improved accuracy. Using this method we were able to distinguish mutant mice from wild type littermates even at a very young age. With gross visual examination, this distinction was not possible.Histologic analysis of digital images of murine intestinal tissue provides a vital improvement over the commonly used visual, gross examination method. Unlike visual gross examination, histologic analysis is not biased by the size of intestinal adenoma, misdiagnosis of another lesion type, or presence of a Peyer's patch. It also provides accountability in the form of a permanent record of lesions counted. Histologic analysis using digital slides represents a critical improvement over the current, widely used method of visual gross examination and should be considered for future studies using mouse models of CRC.

The residue dynamics and risk assessment of prochloraz and its metabolite 2,4,6-trichlorophenol (2,4,6-TCP) in apple under different treatment concentrations were investigated using a GC-ECD method. The derivatization percent of prochloraz to 2,4,6-TCP was stable and complete. The recoveries of prochloraz and 2,4,6-TCP were 82.9%–114.4%, and the coefficients of variation (CV) were 0.7%–8.6% for the whole fruit, apple pulp, and apple peel samples. Under the application of 2 °C 2.0 g/L, 2 °C 1.0 g/L, 20 °C 2.0 g/L, and 20 °C 1.0 g/L treatment, the half-life for the degradation of prochloraz was 57.8–86.6 d in the whole fruit and apple peel, and the prochloraz concentration in the apple pulp increased gradually until a peak (0.72 mg·kg−1) was reached. The concentration of 2,4,6-TCP was below 0.1 mg·kg−1 in four treatment conditions and not detected (

The interactions of dihydroquinazolines with human serum albumin (HSA) were studied in pH 7.4 aqueous solution via fluorescence, circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopic techniques. In this work, 6-chloro-1-(3,3-dimethyl-butanoyl)-2(un)substitutedphenyl-2,3-dihydroquinazolin-4(1H)-one (PDQL) derivatives were designed and synthesized to study the impact of five similar substituents (methyl, methoxy, cyano, trifluoromethyl and isopropyl) on the interactions between PDQL and HSA using a comparative methodology. The results revealed that PDQL quenched the intrinsic fluorescence of HSA through a static quenching process. Displacement experiments with site-specific markers revealed that PDQL binds to HSA at site II (subdomain IIIA) and that there may be only one binding site for PDQL on HSA. The thermodynamic parameters indicated that hydrophobic interactions mainly drove the interactions between PDQL and HSA. The substitution using five similar groups in the benzene ring could increase the interactions between PDQL and HSA to some extent through the van der Waals force or hydrogen bond effects in the proper temperature range. Isopropyl substitution could particularly enhance the binding affinity, as observed via comparative studies

In the present study, 3-(fluorobenzylideneamino)-6-chloro-1-(3,3-dimethylbutanoyl)-phenyl-2,3-dihydroquinazolin-4(1H)-one (FDQL) derivatives have been designed and synthesized to study the interaction between fluorine substituted dihydroquinazoline derivatives with human serum albumin (HSA) using fluorescence, circular dichroism and Fourier transform infrared spectroscopy. The results indicated that the FDQL could bind to HSA, induce conformation and the secondary structure changes of HSA, and quench the intrinsic fluorescence of HSA through a static quenching mechanism. The thermodynamic parameters, ΔH, ΔS, and ΔG, calculated at different temperatures, revealed that the binding was through spontaneous and hydrophobic forces and thus played major roles in the association. Based on the number of binding sites, it was considered that one molecule of FDQL could bind to a single site of HSA. Site marker competition experiments indicated that the reactive site of HSA to FDQL mainly located in site II (subdomain IIIA). The substitution by fluorine in the benzene ring could increase the interactions between FDQL and HSA to some extent in the proper temperature range through hydrophobic effect, and the substitution at meta-position enhanced the affinity greater than that at para- and ortho-positions.

Biothiols such as cysteine (Cys) and homocysteine (Hcy) are essential biomolecules participating in molecular and physiological processes in an organism. However, their selective detection remains challenging. In this study, ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (NL) was synthesized as a ratiometric fluorescent probe for the rapid and selective detection of Cys and Hcy over glutathione (GSH) and other amino acids. The fluorescence intensity of the probe in the presence of Cys/Hcy increased about 3-fold at a concentration of 20 equiv. of the probe, compared with that in the absence of these chemicals in aqueous media. The limits of detection of the fluorescent assay were 0.911 μM and 0.828 μM of Cys and Hcy, respectively. 1H-NMR and MS analyses indicated that an excited-state intramolecular proton transfer is the mechanism of fluorescence sensing. This ratiometric probe is structurally simple and highly selective. The results suggest that it has useful applications in analytical chemistry and diagnostics.