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Abstract Background Myocardial infarction (MI) is a major disease with high morbidity and mortality worldwide. However, existing treatments are far from satisfactory, making the exploration of potent molecular targets more imperative. The E3 ubiquitin ligase RING finger protein 5 (RNF5) has been previously reported to be involved in several diseases by regulating ubiquitination-mediated protein degradation. Nevertheless, few reports have focused on its function in cardiovascular diseases, including MI. Methods In this study, we established RNF5 knockout mice through precise CRISPR-mediated genome editing and utilized left anterior descending coronary artery ligation in 9-11-week-old male C57BL/6 mice. Subsequently, serum biochemical analysis and histopathological examination of heart tissues were performed. Furthermore, we engineered adenoviruses for modulating RNF5 expression and subjected neonatal rat cardiomyocytes to oxygen-glucose deprivation (OGD) to mimic ischemic conditions, demonstrating the impact of RNF5 manipulation on cellular viability. Gene and protein expression analysis provided insights into the molecular mechanisms. Statistical methods were rigorously employed to assess the significance of experimental findings. Results We found RNF5 was downregulated in infarcted heart tissue of mice and NRCMs subjected to OGD treatment. RNF5 knockout in mice resulted in exacerbated heart dysfunction, more severe inflammatory responses, and increased apoptosis after MI surgery. In vitro, RNF5 knockdown exacerbated the OGD-induced decline in cell activity, increased apoptosis, while RNF5 overexpression had the opposite effect. Mechanistically, it was proven that the kinase cascade initiated by apoptosis signal-regulating kinase 1 (ASK1) activation was closely regulated by RNF5 and mediated RNF5’s protective function during MI. Conclusions We demonstrated the protective effect of RNF5 on myocardial infarction and its function was dependent on inhibiting the activation of ASK1, which adds a new regulatory component to the myocardial infarction associated network and promises to enable new therapeutic strategy.

Abstract Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. Here, we identified the first evidence that TNFAIP3 interacting protein 3 (TNIP3) was a negative regulator of pathological cardiac hypertrophy. We observed a significant upregulation of TNIP3 in mouse hearts subjected to transverse aortic constriction (TAC) surgery and in primary neonatal rat cardiomyocytes stimulated by phenylephrine (PE). In Tnip3-deficient mice, cardiac hypertrophy was aggravated after TAC surgery. Conversely, cardiac-specific Tnip3 transgenic (TG) mice showed a notable reversal of the same phenotype. Accordingly, TNIP3 alleviated PE-induced cardiomyocyte enlargement in vitro. Mechanistically, RNA-sequencing and interactome analysis were combined to identify the signal transducer and activator of transcription 1 (STAT1) as a potential target to clarify the molecular mechanism of TNIP3 in pathological cardiac hypertrophy. Via immunoprecipitation and Glutathione S-transferase assay, we found that TNIP3 could interact with STAT1 directly and suppress its degradation by suppressing K48-type ubiquitination in response to hypertrophic stimulation. Remarkably, preservation effect of TNIP3 on cardiac hypertrophy was blocked by STAT1 inhibitor Fludaradbine or STAT1 knockdown. Our study found that TNIP3 serves as a novel suppressor of pathological cardiac hypertrophy by promoting STAT1 stability, which suggests that TNIP3 could be a promising therapeutic target of pathological cardiac hypertrophy and heart failure.

BackgroundWe attempted to develop a progression prediction model for local advanced rectal cancer(LARC) patients who received preoperative neoadjuvant chemoradiotherapy(NCRT) and operative treatment to identify high-risk patients in advance.MethodsData from 272 LARC patients who received NCRT and total mesorectal excision(TME) from 2011 to 2018 at the Fourth Hospital of Hebei Medical University were collected. Data from 161 patients with rectal cancer (each sample with one target variable (progression) and 145 characteristic variables) were included. One Hot Encoding was applied to numerically represent some characteristics. The K-Nearest Neighbor (KNN) filling method was used to determine the missing values, and SmoteTomek comprehensive sampling was used to solve the data imbalance. Eventually, data from 135 patients with 45 characteristic clinical variables were obtained. Random forest, decision tree, support vector machine (SVM), and XGBoost were used to predict whether patients with rectal cancer will exhibit progression. LASSO regression was used to further filter the variables and narrow down the list of variables using a Venn diagram. Eventually, the prediction model was constructed by multivariate logistic regression, and the performance of the model was confirmed in the validation set.ResultsEventually, data from 135 patients including 45 clinical characteristic variables were included in the study. Data were randomly divided in an 8:2 ratio into a data set and a validation set, respectively. Area Under Curve (AUC) values of 0.72 for the decision tree, 0.97 for the random forest, 0.89 for SVM, and 0.94 for XGBoost were obtained from the data set. Similar results were obtained from the validation set. Twenty-three variables were obtained from LASSO regression, and eight variables were obtained by considering the intersection of the variables obtained using the previous four machine learning methods. Furthermore, a multivariate logistic regression model was constructed using the data set; the ROC indicated its good performance. The ROC curve also verified the good predictive performance in the validation set.ConclusionsWe constructed a logistic regression model with good predictive performance, which allowed us to accurately predict whether patients who received NCRT and TME will exhibit disease progression.

The density of rockfill material is an important index to evaluate the quality of rockfill dams. It is of great significance to accurately obtain the densities and permeability coefficients of rockfill material dams quickly and accurately by scientific means. However, it takes a long time to measure the permeability coefficient of rockfill material in practice, which means that such measurements cannot fully reflect all the relevant properties. In this paper, using a convolutional neural network (CNN), a machine learning model was established to predict the permeability coefficient of rockfill material with the full scale (d10~d100), pore ratio, Cu, and Cc as the inputs and the permeability coefficient as the output. Through collecting the permeability coefficient and related data in the literature, the set samples were sorted for model training. The prediction results of the trained CNN model are compared with those of the back propagation (BP) model to verify the accuracy of the CNN model. Laboratory constant head penetration experiments were designed to verify the generalization performance of the model. The results show that compared with the BP model, the CNN model has better applicability to the prediction of the permeability coefficient of rockfill material and that the CNN can obtain better accuracy and meet the requirements of the rough estimation of rockfill materials’ permeability in engineering.

Objective(s): Calgranulins S100A8 and S100A9 are common in renal stones and they are up-regulated in both urinary exosomes and kidneys of stone patients. Renal sources and important regulators for S100A8 and S100A9 in nephrolithiasis were explored in this study.Materials and Methods: We identified S100A8 and S100A9 abundance in various renal cells by searching the Single Cell Type Atlas. Macrophages were polarized from human myeloid leukemia mononuclear cells. Human proximal renal tubular epithelial cells (HK-2) were stimulated with calcium oxalate monohydrate (COM). Coculture experiments involving HK-2 cells and macrophages were conducted. qPCR, Western blotting, ELISA, and immunofluorescence were used for detecting interleukin 6 (IL6), S100A8, and S100A9.Results: The Single Cell Type Atlas showed that S100A8 and S100A9 in human kidneys primarily originated from macrophages. M1 was the predominant macrophage type expressing S100A8 and S100A9. Direct culture with COM did not affect the expression of these two calgranulins in M1 macrophages but coculture with COM-treated HK-2 cells did. COM could promote HK-2 cells to secrete IL6. IL6 could up-regulate S100A8 and S100A9 expression in macrophages of M1 type. In addition, 0.5 μM SC144 (a kind of IL6 inhibitor) significantly prevented COM-treated HK-2 cells from up-regulating S100A8 and S100A9 expression in macrophages of M1 type.Conclusion: M1-polarized macrophages were the predominant cell type expressing S100A8 and S100A9 in the kidneys of nephrolithiasis patients. CaOx crystals can promote renal tubular epithelial cells to secrete IL6 to up-regulate S100A8 and S100A9 expression in macrophages of M1 type.

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) have been used for thousands of years as traditional Chinese medicine (TCM) with sedative effects. Modern studies have shown that Citrus plants also have protective effects on the nervous system. However, the effective substances and mechanisms of action in Citrus TCMs still remain unclear. In order to explore the pharmacodynamic profiles of identified substances and the action mechanism of these herbs, a comprehensive approach combining ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) analysis and network pharmacology was employed. Firstly, UNIFI 2.1.1 software was used to identify the chemical characteristics of AF and AFI. Secondly, the SwissTargetPrediction database was used to predict the targets of chemical components in AF and AFI. Targets for neuroprotection were also collected from GeneCards: The Human Gene Database (GeneCards-Human Genes|Gene Database|Gene Search). The networks between targets and compounds or diseases were then constructed using Cytoscape 3.9.1. Finally, the Annotation, Visualization and Integrated Discovery Database (DAVID) (DAVID Functional Annotation Bioinformatics Microarray Analysis) was used for GO and pathway enrichment analysis. The results showed that 50 of 188 compounds in AF and AFI may have neuroprotective biological activities. These activities are associated with the regulatory effects of related components on 146 important signaling pathways, derived from the KEGG (KEGG: Kyoto Encyclopedia of Genes and Genomes), such as neurodegeneration (hsa05022), the Alzheimer’s disease pathway (hsa05010), the NF-kappa B signaling pathway (hsa04064), the hypoxia-inducible factor (HIF)-1 signaling pathway (hsa04066), apoptosis (hsa04210), the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance signaling pathway (hsa01521), and others, by targeting 108 proteins, including xanthine dehydrogenase (XDH), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), and glucose-6-phosphate dehydrogenase (G6PD), among others. These targets are thought to be related to inflammation, neural function and cell growth.

Natural peptides (NPs) are ubiquitous throughout the organism with diversified structures and wide dynamic concentration range, which leads to serious challenge for their comprehensive analysis. Herein, a pseudotargeted peptidomics strategy based on dynamic multiple reaction monitoring (DMRM) with high-throughput data acquisition and accurate quantification was established. Specifically, an in-house software Pep-MRMer was developed for extraction of ions information of peptides, followed by de-redundancy and fusion to construct a transition list. Additionally, retention time (RT) calibration method was optimized by using high content components for effective transference of ion pairs between different detection conditions (e.g., instruments, chromatographic gradients). This strategy was applied for profiling NPs and screening signature peptides for species authentication of Pheretima, a multi-source animal-derived drug widely used in Asian countries. In all, a total of 3307 peptides had excellent quantitative detection after transference. Subsequently, nine signature peptides with extraordinary specificity were screened, identified, and confirmed by comparing with the synthetic standards. Ultimately, a 10 min specific chromatogram based on signature peptides was developed, which realized rapid and accurate identification of Pheretima. Taken together, this research provides a robust strategy for species discrimination of animal-derived drugs without adequate quality control measures.

Fluoride is an essential micronutrient for humans. Nonetheless, when the amount of fluoride ion is greater than required, it will cause skeletal fluorosis and dental fluorosis to threaten human health. In this paper, a series of sodium alginate (SA)-based foam materials are prepared by freeze-drying technique and anchored with the nano-activated alumina (nAl2O3) in the SA to obtain a novel adsorbent of SA-nAl2O3 foam used for fluoride ions removal. The SA-nAl2O3 foam morphology was further explored and confirmed that nAl2O3 existed stably in the SA. The adsorption results showed that the maximal fluoride ion adsorption capacity was 5.09 mg/g with 20 mg/L fluorine solutions at a pH of 3. The adsorption isotherm fitted adequately to the Langmuir isotherm model, which demonstrated that the adsorption process is closer to monolayer adsorption. The adsorption kinetics behavior of SA-nAl2O3 foam was described by a pseudo-second-order model, and the adsorption process occurred by chemisorption. Adsorption thermodynamics analysis emphasized that the adsorption process was spontaneous and endothermic. The main mechanism of the foam is ion exchange. The SA-nAl2O3 foam exhibited excellent regeneration performance and stability after three cycles. HIGHLIGHTS A novel adsorption material of SA-nAl2O3 foam was obtained for fluoride ion removal.; SA-nAl2O3 foam exhibited steady fluoride ion adsorption capacity.; SA-nAl2O3 foam has excellent regenerability after three cycles;

IntroductionChlamydia trachomatis is the etiological agent of the commonest sexually transmitted bacterial infection. This study aimed to examine the prevalence of genital chlamydia and associated risk factors in Chinese female outpatients with genital tract infections.MethodsA prospective, multicenter epidemiological study of genital chlamydia prevalence in 3008 patients with genital tract infections in 13 hospitals in 12 provinces of China was performed between May 2017 and November 2018. Vaginal secretion specimens were collected for the clinical diagnosis of vaginitis, whereas cervical secretion specimens were tested for Chlamydia trachomatis and Neisseria gonorrhoeae. All patients participated in a one-on-one cross-sectional questionnaire interview. ResultsTotally 2,908 participants were included. The prevalence rates of chlamydia and gonococcal infections in women with genital tract infections were 6.33% (184/2908) and 0.01% (20/2908), respectively. Multivariate analysis showed high risk factors for chlamydia were premarital sex behavior, first sexual intercourse before the age of 20 and bacterial vaginosis.DiscussionGiven that most chlamydia cases are asymptomatic and no vaccine is currently available, chlamydia prevention strategies should include behavioral interventions as well as early screening programs to identify and treat individuals with genital tract infections, especially those with the above identified risk factors.

Fluorine is one of the essential trace elements for human life activities, but excessive intake of fluoride poses a great risk to people's health. In this paper, a series of mixed matrix membrane (MMM)-based polysulfone for removing fluoride were prepared by phase inversion, and their properties, adsorption capacity, adsorption isotherms, adsorption kinetics of fluoride ions, and mechanism were all investigated. The results confirmed that the MMM contained a large number of hydroxyl and aluminum functional groups due to resin being added. The MMM exhibited the best fluorine ion adsorption capacity of 2.502 mg/g at a pH of 6 with the initial concentration of 6 mg/L. As well, adsorption kinetics of fluorine ion on MMM followed the pseudo-second-order model, while the adsorption behavior of fluorine ion on MMM was well simulated by the Langmuir isotherm model. The adsorption capacity of MMM remained stable after six cycles and the regeneration efficiency was still above 80%, resulting in a long-term stability adequate for fluorine ion removal. Complexation and ion exchange played a key role in the fluorine ion adsorption of MMM. These results indicated the MMM as novel type of absorbent had an excellent capacity for removing fluoride. HIGHLIGHTS MMM was prepared via phase inversion for removing fluoride.; The addition of resin significantly enhanced fluoride removal via the membrane.; The MMM exhibited the maximum fluoride adsorption capacity of 2.502 mg/g.; Fluoride adsorption by MMM depended on ion-exchange and complexation.; MMM retained stable fluoride adsorption capacity after six cycles.;

Cordyceps sinensis (C. sinensis) is a widely used and highly valuable traditional Chinese medicine. Several dipeptides have been detected in C. sinensis, but current scientific knowledge of its chemical makeup remains limited. In this study, an improved approach that integrates offline two-dimensional liquid chromatography (2D LC) separation, precursor ion list, library screening, and diagnostic ion filtering was established to systematically screen and characterize dipeptides in C. sinensis. Offline 2D LC integrating hydrophilic interaction LC and reverse phase separations was established to eliminate interference and identify the target dipeptides. A library containing the potential 400 dipeptides was created, and a precursor ion list with all theoretical precursor ions was adopted to trigger the MS/MS scan with high sensitivity. To identify dipeptides, the type and connection sequence of amino acids were determined according to the product ions. Ile and Leu residues were differentiated for the first time according to the characteristic ion at m/z 69.07. Ultimately, 170 dipeptides were identified or tentatively characterized from C. sinensis, and most are reported for the first time in this species herein. In addition, the identified dipeptides were also applied for discrimination among the three Cordyceps species, and 11 markers were identified. The obtained results provide a deeper understanding of the chemical basis of C. sinensis.

Highlights Patients with thyroid tumor have higher perchlorate exposure than control. Perchlorate can increase the risk of papillary thyroid carcinoma. Perchlorate can disturb the homeostasis of thyroid function. Perchlorate was positively correlated with thyroglobulin antibody.

Abstract Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.

The differential diagnosis of renal tumors and abscesses is crucial owing to their different treatments. Although antibacterial administration and radiological examination are excellent means for distinction, misdiagnosis is common and may lead to severe consequences, such as the need for nephrectomy. Here, we report a case involving a 52-year-old Asian woman with a renal mass for which a differential diagnosis was challenging. The mass persisted after administration of intravenous antibiotic therapy for 1 month. A computed tomography scan indicated an inflammatory lesion, whereas magnetic resonance imaging suggested a diagnosis of a tumor. Despite these indications, a right renal abscess was suspected during robot-assisted laparoscopic surgery, and nephron-sparing surgery was performed, which allowed confirmation of the final pathological result by biopsy specimen. Postoperatively, the mass gradually decreased in size after antibiotic therapy for a further month. This case, in which a renal abscess mimicked a tumor and the patient almost underwent a nephrectomy, highlights the need for caution in establishing therapeutic schedules for patients with inaccurate diagnoses. The management strategies for such patients must be reviewed and improved.

Accurate identification of the botanical origins of Rhizoma Alismatis (RA) is pivotal to its precise clinical usage. We herein present a strategy, by integrating untargeted metabolomics, data cross validation, absolute quantification, and vector machine model, for species discrimination and source recognition of Rhizoma Alismatis for the first time. An ultra-high-performance liquid chromatography/LTQ-Orbitrap mass spectrometry with precursor ions list-including data-dependent acquisition approach was developed for metabolite profiling. Holistic, continuous, and pattern recognition chemometrics could make it feasible to unveil forty-one markers, with “multi-duplicated and traceability samples comparison” cross validation to narrow down to twelve robust markers, some of which were further validated by absolute quantification. A support vector machine model was eventually developed to distinguish these two species and predict origins of commercially available varieties. This was the first report on systematic comparison and discrimination of two original species of RA. This integral strategy, in contrast to conventional approaches, renders more convincing data supporting for the discovery of multi-source chemical makers of traditional Chinese medicines (TCM).

Urachal signet ring cell carcinoma is a kind of rare but aggressive tumor, and a few cases have been reported previously. A 49-year-old male patient with primary complaints of increased frequency of urination, urodynia, and hematuria was diagnosed to have primary urachal signet ring cell carcinoma by our department. Multiple metastases were found in the sigmoid colon, terminal ileum, mesentery, and peritoneum during the operation, and palliative surgery involving partial cystectomy with en bloc resection of the urachus was then performed. A chemotherapy regimen of fluorouracil combined with cisplatin was made for this case. In addition, this patient also received anlotinib for targeted therapy. So far, this patient has done well on regular follow-up for 6 months and is in stable condition. We reported this additional urachal signet ring cell carcinoma case and conducted a literature review to strengthen our cognition of this disease.

Jujube fruit was well-loved and praised by the broad masses due to its delicious taste, abundant nutritional value, and medicinal properties. Few studies reported the quality evaluation and gut microbiota regulation effect of polysaccharides of jujube fruits from different producing areas. In the present study, multi-level fingerprint profiling, including polysaccharides, oligosaccharides, and monosaccharides, was established for the quality evaluation of polysaccharides from jujube fruits. For polysaccharides, the total content in jujube fruits ranged from 1.31% to 2.22%, and the molecular weight distribution (MWD) ranged from 1.14 × 105 to 1.73 × 106 Da. The MWD fingerprint profiling of polysaccharides from eight producing areas was similar, but the profile of infrared spectroscopy (IR) showed differentiation. The characteristic signals were screened and used to establish a discrimination model for the identification of jujube fruits from different areas, and the accuracy of identification reached 100.00%. For oligosaccharides, the main components were galacturonic acid polymers (DP, 2–4), and the profile of oligosaccharides exhibited high similarity. The monosaccharides, GalA, Glc, and Ara, were the primary monosaccharides. Although the fingerprint of monosaccharides was semblable, the composing proportion of monosaccharides revealed significant differences. In addition, the polysaccharides of jujube fruits could regulate the gut microbiota composition and possess potential therapeutic effects on dysentery and nervous system diseases.

This study was aimed at estimating the intake of lead and cadmium by the Belgian consumers due to the use of ceramic ware. We adopted refined exposure scenarios with respect to migrant concentration, ceramic ware usage, and metal release characteristics. A deterministic estimation was initially performed, followed by probabilistic estimation, if the deterministic estimate exceeds toxicological reference values. Based on the reference doses established by the European Food Safety Authority (EFSA), the risk of lead and cadmium exposure was characterized by the margin of exposure (MOE) and the tolerable weekly intake (TWI), respectively. The probabilistic median and 95th percentile intake of lead were 0.02 and 5.77 μg/kg b.w. per day for adults, and 0.07 and 17.3 μg/kg b.w. per day for children. The MOEs for neurotoxicity, nephrotoxicity and cardiovascular effects were 7.1, 27 and 64 for average consumers, and 0.02, 0.1 and 0.3 for high consumers. The deterministic mean and 95th percentile intake of cadmium were 0.026 (7% TWI) and 0.03 (8% TWI) μg/kg b.w. per day for adults, and 0.08 (22 % TWI) and 0.09 (25 % TWI) μg/kg b.w. per day for children. Considering the exposure of the Belgian population from foodstuffs resulted in the exceedance of the TWI by as much as 20-fold. The risk of exposure to lead and cadmium of the Belgian consumers suggests measures, such as lowering the migration limits for ceramic ware, should be taken to minimize the risk.

Flavonoids derived from citrus plants are favored by phytomedicinal researchers due to their wide range of biological activities, and relevant studies have been sustained for 67 years (since the first paper published in 1955). In terms of a scientometric and critical review, the scientometrics of related papers, chemical structures, and pharmacological action of citrus flavonoids were comprehensively summarized. The modern pharmacological effects of citrus flavonoids are primarily focused on their anticancer activities (such as breast cancer, gastric cancer, lung cancer, and liver cancer), neuroprotective effects (such as anti-Alzheimer’s disease, Parkinson’s disease), and metabolic diseases. Furthermore, the therapeutic mechanism of cancers (including inducing apoptosis, inhibiting cell proliferation, and inhibiting cancer metastasis), neuroprotective effects (including antioxidant and anti-inflammatory), and metabolic diseases (such as non-alcoholic fatty liver disease, type 2 diabetes mellitus) were summarized and discussed. We anticipate that this review could provide an essential reference for anti-cancer and neuroprotective research of citrus flavonoids and provide researchers with a comprehensive understanding of citrus flavonoids.

Dioxins, environmentally stable and ubiquitous, have been found to induce metabolic changes especially in lipids and be related to multiple diseases. However, limited study is available on lipid alternations related to human exposure to dioxins. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of adverse health risks associated with dioxin exposure. A lipidomic study integrating nontargeted lipidomics, and targeted free fatty acid (FFA) and acyl-coenzyme A (acyl-CoA) analyses were conducted to investigate the 94 serum samples from two groups of male workers with remarkably different dioxin concentrations. The obtained results exhibited distinct lipidomic signatures between the high and low exposed groups. A total of 37 lipids were identified with the significant changes. The results revealed that dioxin exposure caused accumulations of triglyceride (TG), ceramide (Cer) and sphingoid (So), remodeling of glycerophospholipid (GP), imbalanced FFA metabolism, as well as upregulation of platelet-activating factor (PAF). These findings implied the associations between dioxin exposure and potential adverse health risks including inflammation, apoptosis, cardiovascular diseases (CVDs), and liver diseases. This study is the first to explain the associations between dioxin exposure and health effects at the level of lipid metabolism.

Solid-free drilling fluid has more advantages as a new type of drilling fluid compared with traditional drilling fluid, such as improving drilling efficiency, protecting oil and not having clay particles clog the oil and gas layer. In this study, Zn/Cu/Fe-doped magnesium–aluminum hydroxide (Mg-Al MMH) was prepared using the co-precipitation method and evaluated in solid-free drilling fluid. The inhibition mechanism of synthesized hydroxide was analyzed by X-ray diffraction, laser particle-size analysis and thermogravimetric analysis. The samples were directly used as drilling fluid base muds for performance evaluation. The results showed that the linear expansion rate of 4% M6-Fe was only 12.32% at room temperature within 2 h, that the linear expansion rate was 20.28% at 90 °C and that the anti-swelling rate was 81.16% at room temperature, indicating that it has a strong inhibition ability at both room temperature and at high temperatures. Meanwhile, the possibility of multi-mixed metal hydroxide as a drilling fluid base mud is discussed in this study. We found that 4% M6-Fe exhibited low viscosity, a high YP/PV ratio and high temperature resistance, and its apparent viscosity retention rate reached 100% rolled at 200 °C for 16 h, with a YP/PV ratio of 2.33.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

Twenty-one protostane-type triterpenoids with diverse structures, including nine new compounds (1–9), were isolated from the of Alisma plantago-aquatica Linn. Structurally, alisolides A‒F (1–6), composed of an oxole group coupled to a five-membered ring, represent unusual C-17 spirost protostane-type triterpenoids. Alisolide H (8) is a novel triterpenoid with an unreported endoperoxide bridge. Alisolide I (9) represents the first example of 23,24-acetal triterpenoid. Their structures were elucidated based on spectroscopic analysis, wherein the absolute configurations of 4‒6, 8 were further confirmed by the Mo2(OAc)4-induced ECD method. Furthermore, all isolates were evaluated for their inhibitory effects on LPS-induced NO production in Caco-2 cells, and all the compounds showed remarkable inhibitory activities, with IC50 values in the range of 0.76–38.20 μmol/L. Key words: Alisma plantago-aquatica Linn., Protostane-type triterpenoids, Caco-2 cells, LPS-induced NO production

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting chemicals that possess neuroendocrine and reproductive toxicity to humans and disturb thyroid hormone homeostasis, neurobehavior, and development. The most predominant congener of PBDEs in humans and other organisms is 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47); however, the molecular mechanisms underlying its cytotoxicity remain largely unknown. Here, we evaluated the toxic effect and underlying mechanism of nuclear receptors (NRs) induced by BDE-47 in SK-N-SH human neuroblastoma cells. The CCK-8 cell viability assay showed that the proliferation of human SK-N-SH cells exposed to BDE-47 was significantly inhibited in time- and dose-dependent manners, and flow cytometry showed that cell cycle was arrested at the S phase after BDE-47 exposure. Moreover, compared with the control group, the expression of retinoic acid receptor alpha (RXRα), pregnane X receptor (PXR), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) at the mRNA and protein levels was significantly increased, as determined by quantitative PCR and western blot analysis, demonstrating that BDE-47 activated the NRs in vitro. Moreover, BDE-47 could bind to all four NRs in the affinity order of PPARγ > PXR > TRβ > RXRα under molecular dynamics. Because RXR is the promiscuous dimerization partner for a large number of NRs, ZDock was used to calculate its interaction with other three NRs. Taking the number of hydrogen bonds and ZDock scores into account, the rank of docking ability between RXRα and the NRs was PXR > TRβ > PPARγ. Further analysis of the interaction between BDE-47 and dimerized-NRs, the affinity order was RXRα > TRβ > PXR > PPARγ via Glide. The results of this study demonstrated that BDE-47 interfered the cross-talk among NRs, especially the promiscuous RXRα, which might be critical for the harmonized re-adjustment of cytotoxicity and biological regulation. Our findings provide a better understanding of the mechanisms underlying toxic effects and intermolecular interaction induced by BDE-47.

Thyroid tumor and thyroid goiter are prevalent disease around the world. In this case-control study, we investigated the association between exposure to a total of twelve mineral elements and thyroid disease as well as thyroid functions. Participants with thyroid tumor or goiter (N = 197) were matched with a healthy population (N = 197) by age (± 2 years old) and same sex. Questionnaires were used to collect data about the demographic characteristics and information of subjects. Serum and urine samples were collected simultaneously for each of the subjects. Mineral elements, iodine level of urine and levels of the total seven thyroid function indexes in serum were detected respectively. Conditional logistic regression was applied to estimate the associations between mineral elements and the risk of thyroid tumor and goiter through single-element models and multiple-element models. Multiple linear regression was used to evaluate relationships between mineral elements and percentage changes of thyroid functions. Higher concentrations of mineral elements in the recruited population were found in this study than other comparable studies, and the levels of chromium (Cr), manganese (Mn), nickel (Ni), arsenic (As), cadmium (Cd), selenium (Se), antimony (Sb), thallium (Tl) and lead (Pb) in the case group were lower than the control group. According to the single-element models, Cr, Mn, Ni, Sb and Tl showed significant negative associations with the risk of thyroid tumor and goiter, and, Cd showed nonmonotonic dose response. Cd and mercury (Hg) showed a nonmonotonic percentage change with T4, while Tl was associated with the increased FT4 in the control group. Therefore, Cd, Hg and Tl may disturb the balance of thyroid function to some extent, and Cr, Mn, Ni, Cd, Sb, and Tl may become potential influencing factors for the risk of thyroid tumor and goiter.

In this paper, a statistical analysis of the tensile strength of FRP composites is conducted. A relatively large experimental database including 58 datasets is first constructed, and the Normal, Lognormal, and Weibull distributions are fitted to the data using a tail-sensitive Anderson–Darling statistic as the measure of goodness of fit. Fitting results show that the Normal, Lognormal, and Weibull distributions can be used to model the tensile strength of FRP composites. Then, the characteristic value for the tensile strength of FRP composites at a fixed percentile is analyzed. It is found that the Weibull distribution results in a higher safety margin in comparison to either the Normal or the Lognormal distribution. When the experimental justification, the theoretical justification, as well as the design conservativeness are taken into consideration, the Weibull distribution is the most recommended distribution to model the tensile strength of FRP composites. Furthermore, a probabilistic model considering the statistical uncertainty for the tensile strength for FRP composites is proposed. It is believed that the statistical uncertainty can be modeled as a reduction factor, and the recommended value of such factor for engineering design practices is provided based on regression analysis.

Dioxins, a group of persistent organic pollutants, have been proved to correlate with ranges of diseases by activating the aryl hydrocarbon receptor (AhR). However, previous dioxin toxicity studies primarily focused on the activation of AhR with signaling pathways at gene and protein levels. The investigation of underlying mechanisms at the metabolic level is still necessary. In this study, serum samples of 48 and 47 healthy participants with the highest and lowest dioxin levels based on quartile distribution of the serum dioxin concentrations of 215 male adults were selected for metabolomics analysis by using liquid chromatography coupled with orbitrap high-resolution mass spectrometry to investigate dioxin-related metabolic responses. The identified potential biomarkers included acylcarnitines, fatty acids and derivatives, glycerophospholipids, etc. suggested that metabolic pathways such as fatty acid β-oxidation, essential fatty acid metabolism, arachidonic acid metabolism, glycerophospholipid and sphingolipid metabolism and purine metabolism were disturbed by dioxin exposure. The results indicated that people with high dioxin exposure levels were at the potential health risks of inflammation, liver and cardiovascular diseases. The metabolic findings may help understand the link between dioxin exposure and the diseases.

Cereal crops' grain yield and quality are traits that are usually considered to be negatively correlated. Here, the authors show that interaction of G-protein βγ subunits with an alternatively spliced MADS1lgy3 protein can increase rice grain yield and quality simultaneously in field conditions.

Cervical cancer tumors with undetectable HPV (HPVU) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPVU tumors to date (HPVU = 35, HPV+ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV+ and HPVU tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPVU cancer cell lines. Patients with HPVU CC tumors had worse progression-free and overall survival outcomes compared to HPV+ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPVU tumors, with converging functional roles in cell cycle progression. In vitro HPVU, but not HPV+, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPVU status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPVU CC patients.

Sweat glands (SGs) are spread over almost the entire surface of the human body and are essential for thermoregulation. Theoretically, tissue-specific stem cells (TSSCs) are excellent candidate cells for the regeneration of SGs due to their genetic stability and differentiation ability. Herein, we attempted to isolate TSSCs derived from adult human sweat glands (ahSGs). ahSGs were localized and identified by H&E staining, double immunofluorescence staining, transmission electron microscope (TEM), and immuno-TEM. We found a population of cells with stem cell characteristics (SGSCs), located in basal myoepithelial cells of the secretory portion of the solenoid bulb. The SGSCs expressed alpha-smooth muscle actin (α-SMA) and showed the typical characteristics of mesenchymal stem cells (MSCs), with a positive antigen profile for CD44, CD73, CD90, and CD105, and had the multilineage differentiation potential to osteoblasts and adipocytes. In addition, the isolated α-SMA positive cells remained stably phenotypic and proliferative cycles at passage 12. This is the first report of successful isolation of MSC-like cells from ahSGs, which may contribute to wound repair and SG regeneration.

Background: To investigate the association between the red cell distribution width (RDW) and mortality in patients with acute pancreatitis (AP), and to assess the ability of RDW to predict mortality in AP patients. Materials and Methods: This retrospective cohort study included 120 patients (50 males and 70 females) with AP who were admitted to the First Affiliated Hospital of Zhongshan Medical University from January 2011 to October 2013. Demographic data and laboratory measures including RDW were obtained from medical records of each patient. A receiver operating characteristic (ROC) curve analysis was used to assess RDW values to predict the death of AP patients. Results: The serum concentration levels of total Ca 2+ (P = 0.007) and albumin (P < 0.001), and the white blood cell counts (P = 0.005) were significantly lower, and the mortality rate (P < 0.001) and body mass index (P < 0.001) were significantly higher (P = 13.4% than in patients with RDW values of ≤13.4%. RDW values were negatively correlated with the serum concentration levels of albumin (r = −0.212, P = 0.012) and total Ca 2+ (r = −0.206, P = 0.033), and were positively correlated with the patient′s age (r = 0.201, P = 0.035). ROC analysis showed that the AUC for the RDW value was 0.894 (P < 0.001, 95% confidence interval = 0.823-0.966), and the optimal cut-off value to predict death was 14.35 (sensitivity = 88.2%, specificity = 91.8%). Conclusion: Red cell distribution width is a potentially new and sensitive predictor of mortality in patients with AP.

The mass spectrometry (MS) has been widely used for profiling chemical components of traditional Chinese medicine (TCM). However, there are few studies reporting quality control of TCM based on mass spectrometry fingerprint (MSF) due to its complicated operation and high cost. The aim of this study was to extend the application of MSF for quality evaluation of TCM. In this study, an MSF based on single quadrupole mass spectrometry method was established, and was successfully used for the quality control of Venenum bufonis (VB), a famous TCM which was used clinically for cancer treatment in China. The results showed that the superiority of MSF for more chemical information exposure and the finding of more potential chemical markers (eight versus four) compared with the traditional photo-diode array (a kind of ultra violet detector, PDA). Besides, the performance of MSF was also validated by similarity and principle component analysis (PCA) of MS data acquired on two other mass spectrometry (low-resolution, triple quadrupole, QQQ, and high-resolution, quadruple time-of-flight, Q-TOF), showing high consistency with QQQ and Q-TOF, but robustness with few parameters’ settings. Based on our study, MSF could be widely applied for the quality control of TCM.

Recent GWAS have identified several susceptibility loci for NHL. Despite these successes, much of the heritable variation in NHL risk remains to be explained. Common copy-number variants are important genomic sources of variability, and hence a potential source to explain part of this missing heritability. In this study, we carried out a CNV analysis using GWAS data from 681 NHL cases and 749 controls to explore the relationship between common structural variation and lymphoma susceptibility. Here we found a novel association with diffuse large B-cell lymphoma (DLBCL) risk involving a partial duplication of the C-terminus region of the LOC283177 long non-coding RNA that was further confirmed by quantitative PCR. For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), known somatic deletions were identified on chromosomes 13q14, 11q22-23, 14q32 and 22q11.22. Our study shows that GWAS data can be used to identify germline CNVs associated with disease risk for DLBCL and somatic CNVs for CLL/SLL.