High-Efficiency Effect-Directed Analysis Leveraging Five High Level Advancements: A Critical Review.

Organic contaminants are ubiquitous in the environment, with mounting evidence unequivocally connecting them to aquatic toxicity, illness, and increased mortality, underscoring their substantial impacts on ecological security and environmental health. The intricate composition of sample mixtures and uncertain physicochemical features of potential toxic substances pose challenges to identify key toxicants in environmental samples. Effect-directed analysis (EDA), establishing a connection between key toxicants found in environmental samples and associated hazards, enables the identification of toxicants that can streamline research efforts and inform management action. Nevertheless, the advancement of EDA is constrained by the following factors: inadequate extraction and fractionation of environmental samples, limited bioassay endpoints and unknown linkage to higher order impacts, limited coverage of chemical analysis (i.e., high-resolution mass spectrometry, HRMS), and lacking effective linkage between bioassays and chemical analysis. This review proposes five key advancements to enhance the efficiency of EDA in addressing these challenges: (1) multiple adsorbents for comprehensive coverage of chemical extraction, (2) high-resolution microfractionation and multidimensional fractionation for refined fractionation, (3) robust in vivo/vitro bioassays and omics, (4) high-performance configurations for HRMS analysis, and (5) chemical-, data-, and knowledge-driven approaches for streamlined toxicant identification and validation. We envision that future EDA will integrate big data and artificial intelligence based on the development of quantitative omics, cutting-edge multidimensional microfractionation, and ultraperformance MS to identify environmental hazard factors, serving for broader environmental governance.

Occurrence and Prioritization of Human Androgen Receptor Disruptors in Sewage Sludges Across China.

The global practice of reusing sewage sludge in agriculture and its landfill disposal reintroduces environmental contaminants, posing risks to human and ecological health. This study screened sewage sludge from 30 Chinese cities for androgen receptor (AR) disruptors, utilizing a disruptor list from the Toxicology in the 21st Century program (Tox21), and identified 25 agonists and 33 antagonists across diverse use categories. Predominantly, natural products 5α-dihydrotestosterone and thymidine emerged as agonists, whereas the industrial intermediate caprolactam was the principal antagonist. In-house bioassays for identified disruptors displayed good alignment with Tox21 potency data, validating employing Tox21 toxicity data for theoretical toxicity estimations. Potency calculations revealed 5α-dihydrotestosterone and two pharmaceuticals (17ß-trenbolone and testosterone isocaproate) as the most potent AR agonists and three dyes (rhodamine 6G, Victoria blue BO, and gentian violet) as antagonists. Theoretical effect contribution evaluations prioritized 5α-dihydrotestosterone and testosterone isocaproate as high-risk AR agonists and caprolactam, rhodamine 6G, and 8-hydroxyquinoline (as a biocide and a preservative) as key antagonists. Notably, 16 agonists and 20 antagonists were newly reported in the sludge, many exhibiting significant detection frequencies, concentrations, and/or toxicities, demanding future scrutiny. Our study presents an efficient strategy for estimating environmental sample toxicity and identifying key toxicants, thereby supporting the development of appropriate sludge management strategies.

Renaissance of elemental phosphorus materials: properties, synthesis, and applications in sustainable energy and environment.

The polymorphism of phosphorus-based materials has garnered much research interest, and the variable chemical bonding structures give rise to a variety of micro and nanostructures. Among the different types of materials containing phosphorus, elemental phosphorus materials (EPMs) constitute the foundation for the synthesis of related compounds. EPMs are experiencing a renaissance in the post-graphene era, thanks to recent advancements in the scaling-down of black phosphorus, amorphous red phosphorus, violet phosphorus, and fibrous phosphorus and consequently, diverse classes of low-dimensional sheets, ribbons, and dots of EPMs with intriguing properties have been produced. The nanostructured EPMs featuring tunable bandgaps, moderate carrier mobility, and excellent optical absorption have shown great potential in energy conversion, energy storage, and environmental remediation. It is thus important to have a good understanding of the differences and interrelationships among diverse EPMs, their intrinsic physical and chemical properties, the synthesis of specific structures, and the selection of suitable nanostructures of EPMs for particular applications. In this comprehensive review, we aim to provide an in-depth analysis and discussion of the fundamental physicochemical properties, synthesis, and applications of EPMs in the areas of energy conversion, energy storage, and environmental remediation. Our evaluations are based on recent literature on well-established phosphorus allotropes and theoretical predictions of new EPMs. The objective of this review is to enhance our comprehension of the characteristics of EPMs, keep abreast of recent advances, and provide guidance for future research of EPMs in the fields of chemistry and materials science.

Dynamic viral integration patterns actively participate in the progression of BK polyomavirus-associated diseases after renal transplantation.

The classical lytic infection theory along with large T antigen-mediated oncogenesis cannot explain the BK polyomavirus (BKPyV)-associated tumor secondary to BKPyV-associated nephropathy (BKVAN), viremia/DNAemia, and viruria after renal transplantation. This study performed virome capture sequencing and pathological examination on regularly collected urine sediment and peripheral blood samples, and BKVAN and tumor biopsy tissues of 20 patients with BKPyV-associated diseases of different stages. In the early noncancerous stages, well-amplified integration sites were visualized by in situ polymerase chain reaction, simultaneously with BKPyV inclusion bodies and capsid protein expression. The integration intensity, the proportion of microhomology-mediated end-joining integration, and host PARP-1 and POLQ gene expression levels increased with disease progression. Furthermore, multiomics analysis was performed on BKPyV-associated urothelial carcinoma tissues, identifying tandem-like structures of BKPyV integration using long-read genome sequencing. The carcinogenicity of BKPyV integration was proven to disturb host gene expression and increase viral oncoprotein expression. Fallible DNA double-strand break repair pathways were significantly activated in the parenchyma of BKPyV-associated tumors. Olaparib showed an antitumor activity dose-response effect in the tumor organoids without BRCA1/2 genes mutation. In conclusion, the dynamic viral integration patterns actively participate in the progression of BKPyV-associated diseases and thus could be a potential target for disease monitoring and intervention.

Diagnosis of Clinically Significant Portal Hypertension Using CT- and MRI-based Vascular Model.

Background Currently, the hepatic venous pressure gradient (HVPG) remains the reference standard for diagnosis of clinically significant portal hypertension (CSPH) but is limited by its invasiveness and availability. Purpose To investigate a vascular geometric model for noninvasive diagnosis of CSPH (HVPG ≥10 mm Hg) in patients with liver cirrhosis for both contrast-enhanced CT and MRI. Materials and Methods In this retrospective study, consecutive patients with liver cirrhosis who underwent HVPG measurement from August 2016 to April 2019 were included. Patients without hepatic diseases were included and marked as non-CSPH to balance the ratio of CSPH 1:1. A variety of vascular parameters were extracted from the portal vein, hepatic vein, aorta, and inferior vena cava and then entered into a vascular geometric model for identification of CSPH. Diagnostic performance was assessed with the area under the receiver operating characteristic curve (AUC). Results The model was developed and tested with retrospective data from 250 patients with liver cirrhosis and 273 patients without clinical evidence of hepatic disease at contrast-enhanced CT examination, including 213 patients with CSPH (mean age, 49 years ± 12 [SD]; 138 women) and 310 patients without CSPH (mean age, 50 years ± 9; 177 women). For external validation, an MRI data set with 224 patients with cirrhosis (mean age, 49 years ± 10; 158 women) and a CT data set with 106 patients with cirrhosis (mean age, 53 years ± 12; 71 women) were analyzed. Significant reductions in mean whole-vessel volumes were observed in the portal vein (ranging from 36.9 cm3 ± 16.0 to 29.6 cm3 ± 11.1; P < .05) and hepatic vein (ranging from 35.3 cm3 ± 21.5 to 22.4 cm3 ± 15.7; P < .05) when CSPH occurred. Similarly, the mean whole-vessel lengths were shorter in patients with CSPH (portal vein: 1.7 m ± 1.2 vs 3.0 m ± 2.4, P < .05; hepatic vein: 0.9 m ± 1.5 vs 1.8 m ± 1.5, P < .05) than in those without CSPH. The proposed vascular model performed well in the internal test set (mean AUC, 0.90 ± 0.02) and external test sets (mean AUCs, 0.84 ± 0.12 and 0.87 ± 0.11). Conclusion A contrast-enhanced CT- and MRI-based vascular model was proposed with good diagnostic consistency for hepatic venous pressure gradient measurement. ClinicalTrials.gov registration nos. NCT03138915 and NCT03766880 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Roldán-Alzate and Reeder in this issue.

Development and validation of a machine learning-based model for varices screening in compensated cirrhosis (CHESS2001): an international multicenter study.

BACKGROUND AND AIMS: The prevalence of high-risk varices (HRV) is low among compensated cirrhotic patients undergoing EGD. Our study aimed to identify a novel machine learning (ML)-based model, named ML EGD, for ruling out HRV and avoiding unnecessary EGDs in patients with compensated cirrhosis. METHODS: An international cohort from 17 institutions from China, Singapore, and India were enrolled (CHESS2001). The variables with the top 3 importance scores (liver stiffness, platelet count, and total bilirubin) were selected by the Shapley additive explanation and input into a light gradient-boosting machine algorithm to develop ML EGD for identification of HRV. Furthermore, we built a web-based calculator for ML EGD, which is free with open access (http://www.pan-chess.cn/calculator/MLEGD_score). Unnecessary EGDs that were not performed and the rates of missed HRV were used to assess the efficacy and safety for varices screening. RESULTS: Of 2794 enrolled patients, 1283 patients formed a real-world cohort from 1 university hospital in China used to develop and internally validate the performance of ML EGD for varices screening. They were randomly assigned into the training (n = 1154) and validation (n = 129) cohorts with a ratio of 9:1. In the training cohort, ML EGD spared 607 (52.6%) unnecessary EGDs with a missed HRV rate of 3.6%. In the validation cohort, ML EGD spared 75 (58.1%) EGDs with a missed HRV rate of 1.4%. To externally test the performance of ML EGD, 966 patients from 14 university hospitals in China (test cohort 1) and 545 from 2 hospitals in Singapore and India (test cohort 2) comprised the 2 test cohorts. In test cohort 1, ML EGD spared 506 (52.4%) EGDs with a missed HRV rate of 2.8%. In test cohort 2, ML EGD spared 224 (41.1%) EGDs with a missed HRV rate of 3.1%. When compared with the Baveno VI criteria, ML EGD spared more screening EGDs in all cohorts (training cohort, 52.6% vs 29.4%; validation cohort, 58.1% vs 44.2%; test cohort 1, 52.4% vs 26.5%; test cohort 2, 41.1% vs 21.1%, respectively; P < .001). CONCLUSIONS: We identified a novel model based on liver stiffness, platelet count, and total bilirubin, named ML EGD, as a free web-based calculator. ML EGD could efficiently help rule out HRV and avoid unnecessary EGDs in patients with compensated cirrhosis. (Clinical trial registration number: NCT04307264.).

Identification and Coexposure of Neonicotinoid Insecticides and Their Transformation Products in Retail Cowpea (Vigna unguiculata).

There is growing evidence that the transformation products of emerging contaminants in foodstuffs may pose a health risk to humans. However, the exact identities, levels, and estimated dietary intake (EDI) of neonicotinoid transformation products in crops remain poorly understood. We established an extended suspect screening strategy to investigate neonicotinoid insecticides and their transformation products in retail cowpea from 11 cities in Hainan Province, China. Forty-nine transformation products were identified in retail cowpea, of which 22-36 were found in 98.6% of the samples. Notably, 31 new transformation products were derived from new processes or a combination of different transformation processes. The mean concentrations of neonicotinoids and nine of the transformation products (with authentic standards) were in the ranges of 0.0824-5.34 and 0.0636-1.50 ng/g, respectively. The cumulative EDIs of the quantified transformation products were lower than those of parent neonicotinoids with the exception of clothianidin desmethyl, which had a ratio of 1157%. However, the coexistence of the other 40 transformation products (without authentic standards) in cowpea suggested that the exposure risk from all of the transformation products might be higher. This study demonstrated that pesticide transformation products should be considered in food chain risk assessments and included in future regulatory management.

Disposable Polypropylene Face Masks: A Potential Source of Micro/Nanoparticles and Organic Contaminates in Humans.

We have been effectively protected by disposable propylene face masks during the COVID-19 pandemic; however, they may pose health risks due to the release of fine particles and chemicals. We measured micro/nanoparticles and organic chemicals in disposable medical masks, surgical masks, and (K)N95 respirators. In the breathing-simulation experiment, no notable differences were found in the total number of particles among mask types or between breathing intensities. However, when considering subranges, <2.5 µm particles accounted for ∼90% of the total number of micro/nanoparticles. GC-HRMS-based suspect screening tentatively revealed 79 (semi)volatile organic compounds in masks, with 18 being detected in ≥80% of samples and 44 in ≤20% of samples. Three synthetic phenolic antioxidants were quantified, and AO168 reached a median concentration of 2968 ng/g. By screening particles collected from bulk mask fabrics, we detected 18 chemicals, including four commonly detected in masks, suggesting chemical partition between the particles and the fabric fibers and chemical exposure via particle inhalation. These particles and chemicals are believed to originate from raw materials, intentionally and nonintentionally added substances in mask production, and their transformation products. This study highlights the need to study the long-term health risks associated with mask wearing and raises concerns over mask quality control.

Microbiota of long-term indwelling hemodialysis catheters during renal transplantation perioperative period: a cross-sectional metagenomic microbial community analysis.

Background: Catheter-related infection (CRI) is a major complication in patients undergoing hemodialysis. The lack of high-throughput research on catheter-related microbiota makes it difficult to predict the occurrence of CRI. Thus, this study aimed to delineate the microbial structure and diversity landscape of hemodialysis catheter tips among patients during the perioperative period of kidney transplantation (KTx) and provide insights into predicting the occurrence of CRI.Methods: Forty patients at the Department of Transplantation undergoing hemodialysis catheter removal were prospectively included. Samples, including catheter tip, catheter outlet skin swab, catheter blood, peripheral blood, oropharynx swab, and midstream urine, from the separate pre- and post-KTx groups were collected and analyzed using metagenomic next-generation sequencing (mNGS). All the catheter tips and blood samples were cultured conventionally.Results: The positive detection rates for bacteria using mNGS and traditional culture were 97.09% (200/206) and 2.65% (3/113), respectively. Low antibiotic-sensitivity biofilms with colonized bacteria were detected at the catheter tip. In asymptomatic patients, no statistically significant difference was observed in the catheter tip microbial composition and diversity between the pre- and post-KTx group. The catheter tip microbial composition and diversity were associated with fasting blood glucose levels. Microorganisms at the catheter tip most likely originated from catheter outlet skin and peripheral blood.Conclusions: The long-term colonization microbiota at the catheter tip is in a relatively stable state and is not readily influenced by KTx. It does not act as the source of infection in all CRIs, but could reflect hematogenous infection to some extent.

In Silico Discovery of Small-Molecule Inhibitors Targeting SARS-CoV-2 Main Protease.

The COVID-19 pandemic has caused severe health threat globally, and novel SARS-Cov-2 inhibitors are urgently needed for antiviral treatment. The main protease (Mpro) of the virus is one of the most effective and conserved targets for anti-SARS-CoV-2 drug development. In this study, we utilized a molecular docking-based virtual screening approach against the conserved catalytic site to identify small-molecule inhibitors of SARS-CoV-2 Mpro. Further biological evaluation helped us identify two compounds, AF-399/40713777 and AI-942/42301830, with moderate inhibitory activity. Besides that, the in silico data, including molecular dynamics (MD) simulation, binding free energy calculations, and AMDET profiles, suggested that these two hits could serve as the starting point for the future development of COVID-19 intervention treatments.

A Novel SAVE Score to Stratify Decompensation Risk in Compensated Advanced Chronic Liver Disease (CHESS2102): An International Multicenter Cohort Study.

INTRODUCTION: In patients with compensated advanced chronic liver disease (cACLD), the invasive measurement of hepatic venous pressure gradient is the best predictor of hepatic decompensation. This study aimed at developing an alternative risk prediction model to provide a decompensation risk assessment in cACLD. METHODS: Patients with cACLD were retrospectively included from 9 international centers within the Portal Hypertension Alliance in China (CHESS) network. Baseline variables from a Japanese cohort of 197 patients with cACLD were examined and fitted a Cox hazard regression model to develop a specific score for predicting hepatic decompensation. The novel score was validated in an external cohort (n = 770) from 5 centers in China, Singapore, Korea, and Egypt, and was further assessed for the ability of predicting clinically significant portal hypertension in a hepatic venous pressure gradient cohort (n = 285). RESULTS: In the derivation cohort, independent predictors of hepatic decompensation were identified including Stiffness of liver, Albumin, Varices, and platElets and fitted to develop the novel score, termed "SAVE" score. This score performed significantly better (all P < 0.05) than other assessed methods with a time-dependent receiver operating characteristic curve of 0.89 (95% confidence interval [CI]: 0.83-0.94) and 0.83 (95% CI: 0.73-0.92) in the derivation and validation cohorts, respectively. The decompensation risk was best stratified by the cutoff values at -6 and -4.5. The 5-year cumulative incidences of decompensation were 0%, 24.9%, and 69.0% in the low-risk, middle-risk, and high-risk groups, respectively ( P < 0.001). The SAVE score also accurately predicted clinically significant portal hypertension (AUC, 0.85 95% CI: 0.80-0.90). DISCUSSION: The SAVE score can be readily incorporated into clinical practice to accurately predict the individual risk of hepatic decompensation in cACLD.

Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues.

This study evaluated the predictive value of serum HBV DNA, HBV RNA, HBcrAg, HBsAg, intrahepatic HBV DNA and cccDNA for HBeAg clearance and seroconversion during long-term treatment with nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A single centre, prospective cohort of CHB patients was used for this study. Serum HBV RNA levels were retrospectively measured at baseline, 6, 12, 24, 36, 48, 60, 72 and 84 months post-NAs treatment. Serum HBsAg and HBcrAg levels were quantified at baseline, month 6, 60 and 72. Histological samples from liver biopsy at baseline and month 60 were analysed for intrahepatic HBV DNA and cccDNA. Eighty-three HBeAg-positive patients were enrolled with a median follow-up time of 108 months (range 18-138 months). Of them, 53 (63.86%) patients achieved HBeAg clearance, and 37 (44.58%) achieved HBeAg seroconversion. Cox multivariate analysis showed that only baseline HBV RNA was independently associated with HBeAg clearance and seroconversion (<5.45 log10 copies/mL, HR = 5.06, 95% CI: 1.87-13.71, p = .001; HR = 3.38, 95% CI: 1.28-8.91, p = .01). The independent association with HBeAg clearance and seroconversion remained for HBV RNA levels at month 6 (<4.72 log10 copies/mL, HR = 4.16, 95% CI: 1.61-10.72, p = .003; HR = 6.52, 95% CI: 1.85-22.94, p = .003) and month 12 (<4.08 log10 copies/mL, HR = 3.68, 95% CI: 1.96-6.90, p < .001; HR = 2.79, 95% CI: 1.31-5.94, p = .008). The AUCs of baseline HBV RNA for predicting the HBeAg clearance (0.83, 95% CI: 0.70-0.96, 0.83, 95% CI: 0.70-0.96 and 0.82, 95% CI: 0.69-0.95 respectively) and seroconversion (0.89, 95% CI: 0.77-1.00; 0.81, 95% CI: 0.66-0.95 and 0.84, 95% CI: 0.71-0.98 respectively) at month 36, 60 and 84 were higher than those of HBV DNA, HBsAg and HBcrAg. In conclusion, lower serum HBV RNA at baseline, month 6 and 12 post-NAs treatment could predict HBeAg clearance and seroconversion during long-term NAs treatment.

Safety and immunogenicity of COVID-19 vaccination in patients with hepatocellular carcinoma (CHESS-NMCID 2101): A multicenter prospective study.

Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received two doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, where pain at the injection site (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequent local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/ml at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower γ-glutamyl transpeptidase level was related to positive neutralizing antibody (odds ratio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.

Serum HBV DNA plus RNA reflecting cccDNA level before and during NAs treatment in HBeAg positive CHB patients.

Background & Aims: Correlations between serum viral markers and intrahepatic cccDNA in patients undergoing long-term nucleos(t)ide analogues (NAs) treatment haven't been fully explored. In this study, we evaluate the correlation between intrahepatic cccDNA and other serum viral markers and intrahepatic HBV DNA in HBeAg positive chronic hepatitis B (CHB) patients during 60-month treatment with NAs. Methods: Fifty-four HBeAg positive CHB patients received long-term NAs treatment were included in this study. Serial serum samples were regularly collected and quantitatively analyzed for HBsAg, HBV DNA, HBV RNA and HBcrAg. Histological samples from liver biopsy at baseline and month 60 were analyzed for intrahepatic HBV DNA and cccDNA. Results: At baseline, serum HBV DNA plus RNA was positively associated with intrahepatic cccDNA in multivariate regression analysis (ß=0.205, P<0.001). In the correlation analysis between cccDNA and serum viral markers, HBV DNA plus RNA had the highest correlation coefficient (r=0.698, P<0.001), followed by serum HBV DNA (r=0.641, P<0.001), HBV RNA (r=0.590, P<0.001), and HBcrAg (r=0.564, P<0.001). At month 60, correlations between these serum viral markers and cccDNA were not observed (P>0.05). Multivariate regression analysis showed that only the decreased HBV DNA plus RNA was positively associated with cccDNA decline (ß=0.172, P =0.006). Changes of HBV DNA plus RNA (r=0.525, P=0.001) was better correlated with cccDNA decline as compared to HBV RNA (r=0.384, P=0.008), HBV DNA (r=0.431, P=0.003), and HBsAg (r=0.342, P=0.029). Conclusions: Serum HBV DNA plus RNA better correlated with intrahepatic cccDNA than other viral makers before and during NAs treatment in HBeAg positive CHB patients.

Origins and Evolution of Cuticle Biosynthetic Machinery in Land Plants.

The aerial epidermis of land plants is covered with a hydrophobic cuticle that protects the plant against environmental stresses. Although the mechanisms of cuticle biosynthesis have been extensively studied in model plants, particularly in seed plants, the origins and evolution of cuticle biosynthesis are not well understood. In this study, we performed a comparative genomic analysis of core components that mediate cuticle biosynthesis and characterized the chemical compositions and physiological parameters of cuticles from a broad set of embryophytes. Phylogenomic analysis revealed that the cuticle biosynthetic machinery originated in the last common ancestor of embryophytes. Coexpansion and coordinated expression are evident in core genes involved in the biosynthesis of two major cuticle components: the polymer cutin and cuticular waxes. Multispecies analyses of cuticle chemistry and physiology further revealed higher loads of both cutin and cuticular waxes in seed plants than in bryophytes as well as greater proportions of dihydroxy and trihydroxy acids, dicarboxylic acids, very-long-chain alkanes, and >C28 lipophilic compounds. This can be associated with land colonization and the formation of cuticles with enhanced hydrophobicity and moisture retention capacity. These findings provide insights into the evolution of plant cuticle biosynthetic mechanisms.

Genome-wide hypermethylation is closely associated with abnormal expression of genes involved in neural development in induced pluripotent stem cells derived from a Down syndrome mouse model.

Mental retardation is the main clinical manifestation of Down syndrome (DS), and neural abnormalities occur during the early embryonic period and continue throughout life. Tc1, a model mouse for DS, carries the majority part of the human chromosome 21 and has multiple neuropathy phenotypes similar to patients with DS. To explore the mechanism of early neural abnormalities of Tc1 mouse, induced pluripotent stem (iPS) cells from Tc1 mice were obtained, and genome-wide gene expression and methylation analysis were performed for Tc1 and wild-type iPS cells. Our results showed hypermethylation profiles for Tc1 iPS cells, and the abnormal genes were shown to be related to neurodevelopment and distributed on multiple chromosomes. In addition, important genes involved in neurogenesis and neurodevelopment were shown to be downregulated in Tc1 iPS cells. In short, our study indicated that genome-wide hypermethylation leads to the disordered expression of genes associated with neurodevelopment in Tc1 mice during early development. Overall, our work provided a useful reference for the study of the molecular mechanism of nervous system abnormalities in DS.

Compartmentalization and Excretion of 2,4,6-Tribromophenol Sulfation and Glycosylation Conjugates in Rice Plants.

The most environmentally abundant bromophenol congener, 2,4,6-tribromophenol (2,4,6-TBP, 6.06 µmol/L), was exposed to rice for 5 d both in vivo (intact seedling) and in vitro (suspension cell) to systematically characterize the fate of its sulfation and glycosylation conjugates in rice. The 2,4,6-TBP was rapidly transformed to produce 6 [rice cells (3 h)] and 8 [rice seedlings (24 h)] sulfated and glycosylated conjugates. The predominant sulfation conjugate (TP408, 93.0-96.7%) and glycosylation conjugate (TP490, 77.1-90.2%) were excreted into the hydroponic solution after their formation in rice roots. However, the sulfation and glycosylation conjugates presented different translocation and compartmentalization behaviors during the subsequent Phase III metabolism. Specifically, the sulfated conjugate could be vertically transported into the leaf sheath and leaf, while the glycosylation conjugates were sequestered in cell vacuoles and walls, which resulted in exclusive compartmentalization within the rice roots. These results showed the micromechanisms of the different compartmentalization behaviors of 2,4,6-TBP conjugates in Phase III metabolism. Glycosylation and sulfation of the phenolic hydroxyl groups orchestrated by plant excretion and Phase III metabolism may reduce the accumulation of 2,4,6-TBP and its conjugates in rice plants.

Toxicity of Tetrabromobisphenol A and Its Derivative in the Mouse Liver Following Oral Exposure at Environmentally Relevant Levels.

As typical brominated flame retardants (BFRs), tetrabromobisphenol A (TBBPA) and its derivative TBBPA-bis(2,3-dibromopropyl ether) (TBBPA-BDBPE) are ubiquitous in various environmental compartments. However, the potential health risk posed by these compounds, especially at environmentally relevant levels, remains unclear. In this study, using adult male mice, we investigated the toxicity of orally administered TBBPA and TBBPA-BDBPE at an environmentally relevant dose (57 nmol/kg body weight). After a single exposure and daily exposure, we assessed lipid metabolism homeostasis, the transcriptome, and immune cell components in the liver. We found that the single exposure to TBBPA or TBBPA-BDBPE alone increased the number of hepatic macrophages, induced alterations in the levels of lipids, including triacylglycerol and free fatty acids, and caused transcriptome perturbation. The results from the daily administration groups showed that TBBPA and TBBPA-BDBPE both significantly increased the triacylglycerol content; however, the elevation of hepatic macrophages was observed only in the TBBPA-BDBPE treatment group. This study confirmed that environmentally relevant levels of TBBPA and TBBPA-BDBPE are toxic to the liver. Our findings revealed that dysfunction of the liver is a health concern, following exposure to BFRs, even at very low concentrations. The chronic effects induced by TBBPA and its derivatives should be further investigated.

Development and validation of a radiomics signature as a non-invasive complementary predictor of gastroesophageal varices and high-risk varices in compensated advanced chronic liver disease: A multicenter study.

BACKGROUND AND AIM: Gastroesophageal varices (GEV) present in compensated advanced chronic liver disease (cACLD) and can develop into high-risk varices (HRV). The gold standard for diagnosing GEV is esophagogastroduodenoscopy (EGD). However, EGD is invasive and less tolerant. This study aimed to develop and validate radiomics signatures based on noncontrast-enhanced computed tomography (CT) images for non-invasive diagnosis of GEV and HRV in patients with cACLD. METHODS: The multicenter trial enrolled 161 patients with cACLD from six university hospitals in China between January 2015 and September 2019, who underwent both EGD and noncontrast-enhanced CT examination within 14 days prior to the endoscopy. Two radiomics signatures, termed rGEV and rHRV, respectively, were built based on CT images in a training cohort of 129 patients and validated in a prospective validation cohort of 32 patients (ClinicalTrials. gov identifier: NCT03749954). RESULTS: In the training cohort, both rGEV and rHRV exhibited high discriminative abilities on determining the existence of GEV and HRV with the area under receiver operating characteristic curve (AUC) of 0.941 (95% confidence interval [CI] 0.904-0.978) and 0.836 (95% CI 0.766-0.905), respectively. In validation cohort, rGEV and rHRV showed high discriminative abilities with AUCs of 0.871 (95% CI 0.739-1.000) and 0.831 (95% CI 0.685-0.978), respectively. CONCLUSIONS: This study demonstrated that rGEV and rHRV could serve as the satisfying auxiliary parameters for detection of GEV and HRV with good diagnostic performance.

Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response.

BACKGROUND: Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. METHODS: The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. RESULTS: Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif-/- mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1ß were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1ß and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. CONCLUSIONS: In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.