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Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid‐gestational age—the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case–control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis. Synopsis Mass spectrometry‐based proteomics for plasma proteome profiling were performed on early gestational pregnant women with or without congenital heart disease (CHD) offspring. In‐depth analysis revealed a potential pathogenic mechanism and identified a set of biomarkers in early gestational plasma predicting fetal CHD. A total of 104 early gestational pregnant women with CHD offspring and 103 controls with healthy offspring were included. A total of 264 proteins were found significantly upregulated and 358 proteins downregulated in the plasma of early gestational pregnant women with CHD offspring. Dyslipidemia and CD4 + might be involved in the occurrence of CHD. Nine CHD‐related biomarkers had been identified. Graphical Abstract Mass spectrometry‐based proteomics for plasma proteome profiling was performed on early gestational pregnant women with or without congenital heart disease (CHD) offspring. In‐depth analysis revealed a potential pathogenic mechanism and identified a set of biomarkers in early gestational plasma predicting fetal CHD.

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism. Notch signaling activation drives an endothelial-to-mesenchymal transition critical for heart development. Here, the authors investigate the role of NOTCH1 intracellular domain (NICD1) in the mitochondria of developing mouse fetal hearts.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched‐chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high‐fat diet/low‐dose streptozotocin (HFD/STZ)‐induced T2DM and leptin receptor‐deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label‐free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L‐type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA‐deficiency‐induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP. Treatment of diabetic neuropathic pain remains a major challenge due to its unclear mechanisms. This paper describes an observation that branched‐chain amino acids (BCAA) abundance is correlated with diabetic neuropathic pain in patients, and offers new perspectives on the metabolic regulation of diabetic neuropathic pain beyond traditional glucose‐centric approaches.

In this work, the effect of heat flux on pitting corrosion behaviors and passive film properties of 304 stainless steel in 3.5 wt.% NaCl solution were investigated by the self-developed metal heat transfer surface testing system using electrochemical methods and surface analysis techniques. The results show that positive heat flux reduces the corrosion current density, inhibits the occurrence and growth of metastable and steady-state pitting corrosion, while the effect of negative heat flux is the opposite. The effects of heat flux on the semiconductor carrier concentration and the contents of Cr 2 O 3 and NiO are not significant, but the effects on the contents of Fe (III) and Fe (II) in the outer layer of passive film are obvious. The positive heat flux increases the ratio of Fe (III) /Fe (II), thereby increasing the corrosion resistance of passive film, while the negative heat flux does the opposite.

The microstructure, texture distribution, tensile property and fracture toughness of 7A36 aluminum alloy profile were investigated by optical microscopy (OM), scanning electron microscopy (SEM), electron back scattered diffraction (EBSD), tensile and toughness tests, respectively. The results show that when extrusion temperature increased from 410 °C to 430 °C, the second phase grew and the intensity of aging state alloy increased. With the extrusion temperature increased, the fracture toughness and elongation increased firstly and the decreased. The fracture toughness KIC can reach to 46.47 MPa·m1/2 at 420 °C. The extruded and final state of the 7A36 profile was dominated by the textured texture (Brass, S, and Copper), accompanied by a small amount of recrystallized type texture (Cube and Goss). As the extrusion temperature increased, the hard deformation texture increased, resulting in an increase in strength. The increase of extrusion temperature led to the increase of dynamic recrystallization fraction. The dynamic recrystallization fraction of the extruded state was 2.26 % when extrusion temperature was 430 °C. The change in KIC performance is the combined result of re-crystallization, second phase and texture.

In the process of cardiac fibrosis, the balance between the Wnt/β-catenin signalling pathway and Wnt inhibitory factor genes plays an important role. Secreted frizzled-related protein 3 (sFRP3), a Wnt inhibitory factor, has been linked to epigenetic mechanisms. However, the underlying role of epigenetic regulation of sFRP3, which is crucial in fibroblast proliferation and migration, in cardiac fibrosis have not been elucidated. Therefore, we aimed to investigate epigenetic and transcription of sFRP3 in cardiac fibrosis. Using clinical samples and animal models, we investigated the role of sFRP3 promoter methylation in potentially enhancing cardiac fibrosis. We also attempted to characterize the underlying mechanisms using an isoprenaline-induced cardiac fibrosis mouse model and cultured primary cardiac fibroblasts. Hypermethylation of sFRP3 was associated with perpetuation of fibroblast activation and cardiac fibrosis. Additionally, mitochondrial fission, regulated by the Drp1 protein, was found to be significantly altered in fibrotic hearts, contributing to fibroblast proliferation and cardiac fibrosis. Epigenetic modification of sFRP3 promoter methylation also influenced mitochondrial dynamics, linking sFRP3 repression to excessive mitochondrial fission. Moreover, sFRP3 hypermethylation was mediated by DNA methyltransferase 3A (DNMT3A) in cardiac fibrosis and fibroblasts, and DNMT3A knockdown demethylated the sFRP3 promoter, rescued sFRP3 loss, and ameliorated the isoprenaline-induced cardiac fibrosis and cardiac fibroblast proliferation, migration and mitochondrial fission. Mechanistically, DNMT3A was shown to epigenetically repress sFRP3 expression via promoter methylation. We describe a novel epigenetic mechanism wherein DNMT3A represses sFRP3 through promoter methylation, which is a critical mediator of cardiac fibrosis and mitochondrial fission. Our findings provide new insights for the development of preventive measures for cardiac fibrosis. Graphical Abstract DNA methyltransferase DNMT3A causes upregulation of sFRP3 methylation levels in cardiac fibrosis and cardiac fibroblasts. Subsequently, sFRP3 downregulation promotes cardiac fibroblast proliferation, migration and mitochondrial fission. DNA methyltransferase DNMT3A repressed sFRP3 to facilitate cardiac fibroblast activation and cardiac fibrosis.

More than half of the patients with type II diabetes mellitus (T2D) develop diabetic cardiomyopathy (DCM). Glycemic control alone cannot effectively prevent or alleviate DCM. Herein, we concentrated on the variations in levels of metabolites between DCM and T2D patients without cardiomyopathy phenotype. In high-fat diet/low-dose streptozotocin-induced T2D and leptin receptor-deficient diabetic mouse models, we investigated the effect of altering branched-chain amino acids (BCAAs) levels on DCM. We discovered that the levels of plasma BCAAs are notably lower in 15 DCM patients compared to 19 T2D patients who do not exhibit cardiomyopathy phenotype, using nuclear magnetic resonance analysis. This finding was further validated in two additional batches of samples, 123 DCM patients and 129 T2D patients based on the BCAA assay kit, and 30 DCM patients and 30 T2D patients based on the LC-MS/MS method, respectively. Moreover, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated cardiomyopathy phenotypes in diabetic mice. Furthermore, BCAA deficiency promoted cardiac fibroblast activation by stimulating autophagy in DCM mice. Mechanistically, BCAA deficiency activated autophagy via the AMPK-ULK1 signaling pathway in cardiac fibroblasts. Using pharmacological approaches, we validated our findings that autophagy inhibition relieved, whereas autophagy activation aggravated, DCM phenotypes. Taken together, we describe a novel perspective wherein BCAA supplementation may serve as a potential therapeutic agent to mitigate DCM and fibrosis. Our findings provide insights for the development of preventive measures for DCM.

Purpose – This paper aims to present a different cooling method (water cooling) to protect all the mechanical/electrical components for Tokamak in-vessel inspection manipulator. The method is demonstrated effective through high temperature experiment, which provides an economical and robust approach for manipulators to work normally under high temperature. Design/methodology/approach – The design of cooling system uses spiral copper tube structure, which is versatile for all types of key components of manipulator, including motors, encoders, drives and vision systems. Besides, temperature sensors are set at different positions of the manipulator to display temperature data to construct a close-loop feedback control system with cooling components. Findings – The cooling system for the whole inspection manipulator working under high temperature is effective. Using insulation material such as rubber foam as component coating can significantly reduce the environmental heat transferred to cooling system. Originality/value – Compared with nitrogen gas cooling applied in robotic protection design, although it is of less interest in prior research, water cooling method proves to be effective and economical through our high temperature experiment. This paper also presents an energetic analysis method to probe into the global process of water cooling and to evaluate the cooling system.

A series of xanthene derivatives were prepared from cyclohexane-1,3-dione and aromatic aldehydes through Knoevenagel–Michael and cyclisation reactions in methanol:ethanol mixture (1:1), catalysed by a very small amount of l-proline at room temperature. Isomeric tetraketones were synthesised from dimedone and aromatic aldehydes under the same condition. Condensation of them with amines gave acridione derivatives. The crystal structure of an acridione was obtained and determined by X-ray single-crystal diffraction.

A series of novel 10-substituted 3,6-diphenyl-9-aryl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione derivatives synthesised by condensation of different amines with xanthenes, was prepared from 5-phenylcyclohexane-1,3-dione and aromatic aldehydes by a Knoevenagel and Michael reaction and cyclisation catalysed by a trace of l-proline at room temperature. In addition, the molecular structure of a xanthene was determined by single-crystal X-ray diffraction analysis.