Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

Accelerating the Hydrogen Production via Modifying the Fermi Surface.

The design of catalysts has attracted a great deal of attention in the field of electrocatalysis. The accurate design of the catalysts can avoid an unnecessary process that occurs during the blind trial. Based on the interaction between different metal species, a metallic compound supported by the carbon nanotube was designed. Among these compounds, RhFeP2CX (R-RhFeP2CX-CNT) was found to be in a rich-electron environment at the Fermi level (denoted as a flat Fermi surface), beneficial to the hydrogen evolution reaction (HER). R-RhFeP2CX-CNT exhibits a small overpotential of 15 mV at the current density of 10 mA·cm-2 in acidic media. Moreover, the mass activity of R-RhFeP2CX-CNT is 21597 A·g-1, which also demonstrates the advance of the active sites on R-RhFeP2CX-CNT. Therefore, R-RhFeP2CX-CNT can be an alternative catalyst applied in practical production, and the strategies of a flat Fermi surface will be a reliable strategy for catalyst designing.

PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.

The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility.

BACKGROUND: Both genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD. METHODS: We utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models. RESULTS: The hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx). CONCLUSION: Exposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

Background and aims: The key role of tissue-resident memory T (TRM) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on TRM cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on TRM cells in HCC. Methods: The function and phenotype of intrahepatic CD8+ TRM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8+ TRM cells both in in vitro induction model and in vivo orthotopic HCC mouse model. Results: There was an increase in LAG3 expression in CD8+ TRM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8+ TRM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8+ TRM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8+ TRM cell exhaustion, causing tumor immune escape. Conclusions: We identified CD8+TRM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8+ TRM cell function in HCC.

MUC1 promotes lung metastases of liver cancer by impairing anti-tumor immunity.

PURPOSE: MUC1 is a membrane bound protein that can regulate tumor progression but its role in tumor metastasis and the metastatic microenvironment remains unclear. METHODS: We performed differential gene analysis for primary liver cancer (n = 31) and lung metastases (n = 31) using the Gene Expression Omnibus (GEO) dataset (GSE141016) and obtained RNA sequencing data from 374 liver cancer and 50 normal tissues from The Cancer Genome Atlas (TCGA). We analyzed the prognostic value of MUC1 and the relationship between MUC1 and the TME using online databases and a clinical cohort. Immunohistochemistry detected MUC1 in normal liver, liver cancer, and lung metastases. Multiplex immunohistochemistry staining detected immune cells in the metastatic microenvironment. RESULTS: High MUC1 expression levels in hepatocellular carcinoma are associated with worse clinical prognosis and higher rates of lung metastasis. In addition, we observed a correlation between MUC1 and multiple immune cells in the metastatic microenvironment. In paired primary liver cancer and lung metastatic tumor tissues from the same patient, we observed higher MUC1 protein levels in lung metastases than in primary liver cancer. Furthermore, MUC1 was negatively correlated with CD8+T and Treg cells in the metastatic tumor microenvironment and positively correlated with DC. In addition, we found that MUC1 was associated with CD8+T cell activation and function using flow cytometry in another cohort of patients with liver cancer. CONCLUSION: These data confirm the potential of MUC1 as a prognostic marker and therapeutic target.

Efficacy of Pneumatophorus japonicus meat as an iron fortificant in whole-wheat flour in preventing iron deficiency.

Iron deficiency anemia (IDA) is a global health concern affecting one-third of the world's population, particularly those dominated by plant-based food. Fortifying staple foods with iron has been an effective strategy for preventing IDA. Pneumatophorus japonicus is an essential economic fish in China. Pneumatophorus japonicus dark meat is usually underutilized as a byproduct, though it contains bounteous nutrients, including heme iron (10.50 mg/100 g). This study aimed to investigate the iron bioavailability of P. japonicus dark meat and to evaluate its potential as an iron fortifier for whole-wheat flour, a typical staple food, using an in vitro digestion/Caco-2 cell culture system. Our results suggested the excellent iron bioavailability of P. japonicus dark meat in comparison with beef (a heme dietary iron reference), whole-wheat flour (a non-heme dietary iron reference), and FeSO4 (a conventional iron supplement). The addition of P. japonicus dark meat notably enhanced iron solubility, bioavailability, and protein digestibility of whole-wheat flour. The flour-dark meat mixture yielded 1.96 times the iron bioavailability compared to beef per gram. The iron bioavailability was further improved by adding vitamin C, a commonly used dietary factor, at the Vc/iron mass ratio of 2:100-5:100. Our findings reveal the promise of P. japonicus dark meat as a significant source of bioavailable iron, providing a basis for developing fish byproducts as alternatives for iron supplementation. PRACTICAL APPLICATION: This study investigated the iron bioavailability of Pneumatophorus japonicus meat using in vitro digestion/Caco-2 cell culture system. These results could be used to improve the utilization of Pneumatophorus japonicus byproduct (dark meat) and develop the potential of the byproduct as an iron fortifier for whole-wheat flour.

Effect of two-stage heating treatment on physicochemical properties of shrimp (Penaeus vannamei) meat.

BACKGROUND: Changes in the physicochemical properties of shrimp meat treated with two-stage heating were investigated. Currently, shrimp products in the processing process are susceptible to uneven dehydration, shrimp meat shrinkage, which results in rough and hard texture, poor chewiness, and seriously affects the edible quality as well as economic benefits. Improving the utilization value of shrimp resources, expanding its market shares, optimizing the tenderness of shrimp is the key to developing new types of fresh and ready-to-eat shrimp products. RESULTS: The results indicated that preheating at 30 °C could not affect the quality of shrimp meat significantly (P > 0.05). As the preheating temperature increased from 40 °C to 50 °C, the hardness and shear force of shrimp meat decreased due to the exposure of protein hydrophobic groups, protein aggregation and degradation, muscle fraction broken, and weight loss increase. Further increase in preheating temperature would lead to further aggregation and gelation of proteins, causing hardness and shear force increase. Besides, the results of microstructure showed that preheating at 40 °C and 50 °C could cause the shrimp muscles to become loose. CONCLUSION: This study showed that the preheating temperature ranging from 40 °C to 50 °C could effectively improve the tenderness of shrimp meat. This study might be useful for developing tenderized shrimp products in the future. © 2022 Society of Chemical Industry.

Characterization of intrahepatic B cells in acute-on-chronic liver failure.

Background and objectives: Acute on chronic liver failure (ACLF) is characterized by the immunologic dissonance during the prolonged pathogenic development. Both abnormal innate immune response and adaptive T-cell response have been reported in patients with ACLF; however, less is known regarding B cells in ACLF pathogenesis. Previous reports were only based on immunophenotyping of peripheral blood samples. Here, we aim to dissect liver-infiltrating B-cell subpopulation in ACLF. Methods: Paired liver perfusate and peripheral blood were freshly collected from healthy living donors and recipients during liver transplantation. Liver tissues were obtained from patients with ACLF, cirrhosis, and healthy controls. Flow cytometry was used to characterize the phenotypic and functional alterations in intrahepatic and circulating B-cell populations from ACLF, cirrhosis, and healthy controls. The expression of CD19+ and CD138+ on liver tissues was examined by immunohistochemistry staining. Results: In this study, we first deciphered the intrahepatic B cells subsets of patients with ACLF. We found that the ACLF liver harbored reduced fraction of naïve B cells and elevated percentage of CD27+CD21- activated memory B cells (AM), CD27-CD21- atypical memory B cells (atMBC), CD27+IgD-IgM+(IgM+ memory B cells), and CD27+CD38++ plasma cells than cirrhosis and healthy controls. Moreover, these B subpopulations demonstrated enhanced activation and altered effector functions. Specifically, the ACLF liver was abundant in atMBC expressing higher CD11c and lower CD80 molecule, which was significantly correlated to alanine aminotransferase and aspartate aminotransferase. In addition, we found that intrahepatic CD27+CD38++plasma cells were preferentially accumulated in ACLF, which expressed more CD273 (PD-L2) and secreted higher granzyme B and IL-10. Finally, the enriched hepatic plasma B cells were in positive association with disease severity indices including alkaline phosphatase and gamma-glutamyl transferase. Conclusions: In this pilot study, we showed an intrahepatic B-cell landscape shaped by the ACLF liver environment, which was distinct from paired circulating B-cell subsets. The phenotypic and functional perturbation in atMBC and plasma cells highlighted the unique properties of infiltrating B cells during ACLF progression, thereby denoting the potential of B-cell intervention in ACLF therapy.

A Single-Atom Cobalt Catalyst for the Fluorination of Acyl Chlorides at Parts-per-Million Catalyst Loading.

Improving the stability of sensitive catalytic systems is an emerging research topic in the catalysis field. However, the current design of heterogeneous catalysts mainly improves their catalytic performance. This paper presents a single-atom catalyst (SAC) strategy to improve the cobalt-catalysed fluorination of acyl chlorides. A stable Co-F intermediate can be formed through the oxidative fluorination of Co1 -N4 @NC SAC, which can replace the unstable high-valent cobalt catalytic system and avoid the use of phosphine ligands. In the SAC system, KF can be employed as a fluorinating reagent to replace the AgF, which can be applied to various substrates and scale-up conversion with high turnover numbers (TON=1.58×106 ). This work also shows that inorganic SACs have tremendous potential for organofluorine chemistry, and it provides a good reference for follow-up studies on the structure-activity relationship between catalyst design and chemical reaction mechanisms.

Localization and diagnosis of abnormal channels in children with ASD based on WMSSE and ASI.

BACKGROUND: The purpose of this study is to explore the differences of resting EEG in children with autism spectrum disorders and then analyze the sensitive channels with significant differences, to provide support for the accurate differential diagnosis of autism spectrum disorder (ASD). NEW METHOD: Based on the weighted multi-scale sample entropy (WMSSE) algorithm and amplitude synchronization index (ASI) algorithm of EEG, this paper comprehensively evaluates the brain state of ASD children from the two aspects of brain function complexity and brain function synchronization connectivity. Further, by combining the support vector machine (SVM) classification model to explore the location of abnormal channels of ASD children and realize the diagnosis of ASD children. RESULTS: The WMSSE of the ASD group was lower than that of the healthy group. Furthermore, there was a significant difference in the F3/F4 channels and F7/F8 channels (P < 0.05), and the synchronization of the brain in the ASD group was also lower than that of the healthy group in Delta, Theta, Alpha, Beta band. Finally, combined with the WMSSE and ASI features of the F3/F4 channels (posterior frontal lobe) and F7/F8 channels (anterior temporal lobe), the classification accuracy and AUC value of ASD patients calculated by the SVM classification model were 82.7 ± 3.2%/ 0.795 (F3 / F4 channels), 89.8 ± 1.7%/ 0.812 (F7 / F8 channels). COMPARISON WITH EXISTING METHODS: It avoids the one-sided problem of single analysis complexity and synchronous connectivity, and provides a research basis for the comprehensive evaluation of ASD brain function. CONCLUSION: WMSSE and ASI can be used as effective potential biomarkers for ASD diagnosis, and F7 and F8 channels can be preliminarily located as abnormal sensitive channels for ASD brain regulation. It also proves that the feature analysis of comprehensive complexity and synchronous connectivity is more conducive to the abnormal diagnosis of ASD patients.

The diagnosis of amnestic mild cognitive impairment by combining the characteristics of brain functional network and support vector machine classifier.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is an essential stage of early detection and potential intervention for Alzheimer's disease (AD). Patients with aMCI exhibit partially abnormal functional brain connectivity and it is suggested that these features may represent a new diagnostic marker of early AD. NEW METHOD: In this paper, we constructed two brain network models, a phase synchronization index (PSI) undirected network and a directed transfer function (DTF) directed network, to evaluate the cognitive function in patients with aMCI. We then built SVM classification models using the network clustering coefficient, global efficiency and average node degree as features to distinguish between aMCI patients and controls. RESULTS: Our results reveal a classification accuracy and AUC of 66.6 ± 1.7% and 0.7475 and 80.0 ± 2.2% and 0.7825, respectively, for the two network models (PSI and DTF). As the directed network model performed better than the undirected model, we introduced an improved graph theory feature, efficiency density, which resulted in an increased classification accuracy and AUC value 86.6 ± 2.6% and 0.8295, respectively. COMPARISON WITH EXISTING METHODS: The analysis of network models and the directionality of information flow is suitable for analysis of nonlinear EEG signals for assessment of the functional state of the brain. Compared with traditional network features, our proposed improved features more comprehensively evaluate transmission efficiency and density of the brain. CONCLUSION: In this study, we demonstrate that an improved efficiency density feature is helpful for enhancing classification the accuracy of aMCI. Moreover, directed brain network models exhibit better classification for aMCI diagnosis than undirected networks.

Qualitative Transcriptional Signature for the Pathological Diagnosis of Pancreatic Cancer.

It is currently difficult for pathologists to diagnose pancreatic cancer (PC) using biopsy specimens because samples may have been from an incorrect site or contain an insufficient amount of tissue. Thus, there is a need to develop a platform-independent molecular classifier that accurately distinguishes benign pancreatic lesions from PC. Here, we developed a robust qualitative messenger RNA signature based on within-sample relative expression orderings (REOs) of genes to discriminate both PC tissues and cancer-adjacent normal tissues from non-PC pancreatitis and healthy pancreatic tissues. A signature comprising 12 gene pairs and 17 genes was built in the training datasets and validated in microarray and RNA-sequencing datasets from biopsy samples and surgically resected samples. Analysis of 1,007 PC tissues and 257 non-tumor samples from nine databases indicated that the geometric mean of sensitivity and specificity was 96.7%, and the area under receiver operating characteristic curve was 0.978 (95% confidence interval, 0.947-0.994). For 20 specimens obtained from endoscopic biopsy, the signature had a diagnostic accuracy of 100%. The REO-based signature described here can aid in the molecular diagnosis of PC and may facilitate objective differentiation between benign and malignant pancreatic lesions.

[Treatment of the postoperative infection of limbs fracture after internal fixation with vacuum sealing drainage (VSD) combined with continual irrigation].

OBJECTIVE: To explore the clinical effects of VSD combined with continual irrigation in treating the infection of limbs fracture after internal fixation. METHODS: From March 2010 to June 2015, 10 patients with infection of limbs fracture after internal fixation were treated with VSD combined with continual irrigation. There were 7 males and 3 females, aged from 11 to 58 years with an average of 34.4 years. Course of disease was from 1 to 8 months with an average of 4.8 months. Postoperative infection occurred in fractures of ulna and radius of 4 cases, tibiofibular fractures of 3 cases, calcaneal fractures of 2 cases, femoral fractures of 1 case. Eight infections were open fracture and 2 infections were close fracture. In additon to above treatment, antibiotics, dressing changing or skingrafting were used in the patients. Informations of wound surface healing, change dressings, original infection focus were observed. RESULTS: All infections got control, the wound healing after change dressings or skingrafting, and no complications such as osteomyelitis were found. The mean treatment time was 38.4 days(ranged, 29 to 45 days) and replacement times was 2.2 times(ranged, 1 to 4 times). All patients were followed up, no recurrent infections were found at 1 year after fracture healing. CONCLUSIONS: VSD combined with continual irrigation can effectively decrease the incidence of complications and promote the wound growth, healing and considerably shorten the healing time. It is an effective method for the treatment of infection of limbs fracture after internal fixation.