Dual action of macrophage miR-204 confines cyclosporine A-induced atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis induced by cyclosporine A (CsA), an inhibitor of the calcineurin/nuclear factor of activated T cells (NFAT) pathway, is a major concern after organ transplantation. However, the atherosclerotic mechanisms of CsA remain obscure. We previously demonstrated that calcineurin/NFAT signalling inhibition contributes to atherogenesis via suppressing microRNA-204 (miR-204) transcription. We therefore hypothesised that miR-204 is involved in the development of CsA-induced atherosclerosis. EXPERIMENTAL APPROACH: ApoE-/- mice with macrophage-miR-204 overexpression were generated to determine the effects of miR-204 on CsA-induced atherosclerosis. Luciferase reporter assays and chromatin immunoprecipitation sequencing were performed to explore the targets mediating miR-204 effects. KEY RESULTS: CsA alone did not significantly affect atherosclerotic lesions or serum lipid levels. However, it exacerbated high-fat diet-induced atherosclerosis and hyperlipidemia in C57BL/6J and ApoE-/- mice, respectively. miR-204 levels decreased in circulating monocytes and plaque lesions during CsA-induced atherosclerosis. The upregulation of miR-204 in macrophages inhibited CsA-induced atherosclerotic plaque formation but did not affect serum lipid levels. miR-204 limited the CsA-induced foam cell formation by reducing the expression of the scavenger receptors SR-BII and CD36. SR-BII was post-transcriptionally regulated by mature miR-204-5p via 3'-UTR targeting. Additionally, nuclear-localised miR-204-3p prevented the CsA-induced binding of Ago2 to the CD36 promoter, suppressing CD36 transcription. SR-BII or CD36 expression restoration dampened the beneficial effects of miR-204 on CsA-induced atherosclerosis. CONCLUSION AND IMPLICATIONS: Macrophage miR-204 ameliorates CsA-induced atherosclerosis, suggesting that miR-204 may be a potential target for the prevention and treatment of CsA-related atherosclerotic side effects.

Vinylene-Linked Emissive Covalent Organic Frameworks for White-Light-Emitting Diodes.

Covalent organic frameworks (COFs) have gained considerable attention due to their highly conjugated π-skeletons, rendering them promising candidates for the design of light-emitting materials. In this study, we present two vinylene-linked COFs, namely, VL-COF-1 and VL-COF-2, which were synthesized through the Knoevenagel condensation of 2,4,6-trimethyl-1,3,5-triazine with terephthalaldehyde or 4,4'-biphenyldicarboxaldehyde. Both VL-COF-1 and VL-COF-2 exhibited excellent chemical and thermal stability. The presence of vinylene linkages between the constituent building blocks in these COFs resulted in broad excitation and emission properties. Remarkably, the designed VL-COFs demonstrated bright emission, fast fluorescence decay, and high stability, making them highly attractive for optoelectronic applications. To assess the potential of these VL-COFs in practical devices, we fabricated white-light-emitting diodes (WLEDs) coated with VL-COF-1 and VL-COF-2. Notably, the WLEDs coated with VL-COF-1 achieved high-quality white light emission, closely approximating standard white light. The promising performance of VL-COF-coated WLEDs suggests the feasibility of utilizing COF materials for stable and efficient lighting applications.

Structural Change and Radical Generation of a Cadmium-Based Metal-Organic Framework Induced by an Electric Field.

Herein we report the structural change and radical generation of a cadmium-based metal-organic framework (Cd-MOF) induced by external electric fields. Under a weaker single electric field, different coordination modes of Cd-L lead to 3D → 2D structural change. Under stronger superposed electric fields, Cd-MOF was excited to produce a stable free radical. This study will provide a new avenue for the controlled assembly of MOFs.

Synthesis and Study of Crown Ether-Appended Tetraplatinum(II) Macrocylic Chemosensors for Cation Detection.

Two new functionalized platinum(II) rectangles, Pt1 and Pt2, were designed and synthesized from phenanthro crown ether- and biphenyl polyether-bridged bicarboxylate ligands, respectively. The fluorescence titration study of rectangles Pt1 and Pt2 with alkali- and alkaline-earth-metal cations indicated that Pt1 can selectively recognize Na+, while Pt2 has selective binding ability for Mg2+. These selectivity findings suggest that the comparative size and conformational nature of the polyether receptor cavity have a crucial influence on the cation selection.

Contributions of cognitive flexibility, inhibition and number label knowledge to numerical equivalence in 3- to 5-year-old children.

To investigate the contributions of cognitive flexibility, inhibition and number label knowledge to children's numerical equivalence, one hundred and one 3- to 5-year-olds were administered the dimensional change card sorting task, the day-night task and the give-a-number task. The numerical equivalence was assessed with the numerical matching task in three surface similarity conditions. Results showed that, in the high surface similarity condition, cognitive flexibility and label knowledge, rather than inhibition, were significant predictors of children's performance in numerical equivalence. In the low surface similarity and the cross-mapping conditions, only cognitive flexibility, rather than number label knowledge and inhibition, significantly explained the unique variance in numerical equivalence. Besides, cognitive flexibility explained more variation in numerical equivalence in the cross-mapping condition compared with the low surface similarity condition. These findings highlight different roles of cognitive flexibility, inhibition and number label knowledge in numerical equivalence in the three surface similarity conditions.

Ponatinib modulates the metabolic profile of obese mice by inhibiting adipose tissue macrophage inflammation.

Obesity-induced metabolic syndrome is a rapidly growing conundrum, reaching epidemic proportions globally. Chronic inflammation in obese adipose tissue plays a key role in metabolic syndrome with a series of local and systemic effects such as inflammatory cell infiltration and inflammatory cytokine secretion. Adipose tissue macrophages (ATM), as one of the main regulators in this process, are particularly crucial for pharmacological studies on obesity-related metabolic syndrome. Ponatinib, a multi-targeted tyrosine kinase inhibitor originally used to treat leukemia, has recently been found to improve dyslipidemia and atherosclerosis, suggesting that it may have profound effect on metabolic syndrome, although the mechanisms underlying have not yet been revealed. Here we discovered that ponatinib significantly improved insulin sensitivity in leptin deficient obese mice. In addition to that, ponatinib treatment remarkably ameliorated high fat diet-induced hyperlipidemia and inhibited ectopic lipid deposition in the liver. Interestingly, although ponatinib did not reduce but increase the weight of white adipose tissue (WAT), it remarkably suppressed the inflammatory response in WAT and preserved its function. Mechanistically, we showed that ponatinib had no direct effect on hepatocyte or adipocyte but attenuated free fatty acid (FFA) induced macrophage transformation from pro-inflammatory to anti-inflammatory phenotype. Moreover, adipocytes co-cultured with FFA-treated macrophages exhibited insulin resistance, while pre-treat these macrophages with ponatinib can ameliorate this process. These results suggested that the beneficial effects of ponatinib on metabolic disorders are achieved by inhibiting the inflammatory phenotypic transformation of ATMs, thereby maintaining the physiological function of adipose tissue under excessive obesity. The data here not only revealed the novel therapeutic function of ponatinib, but also provided a theoretical basis for the application of multi-target tyrosine kinase inhibitors in metabolic diseases.

[Fe2S2-Agx]-Hydrogenase Active-Site-Containing Coordination Polymers and Their Photocatalytic H2 Evolution Reaction Properties.

Three [Fe2S2-Agx]-hydrogenase active-site-containing coordination polymers (CPs), {[Fe2S2-Ag1](4-cpmt)2(CO)6(ClO4-)}n (1), {[Fe2S2-Ag2](4-cpmt)2(CO)6(OTf-)2(benzene)}n (2), and {[Fe2S2-Ag2](3-cpmt)2(CO)6(ClO4-)2}n (3), were obtained by a direct synthesis method from ligands [FeFe](4-cpmt)2(CO)6 [L1; 4-cpmt = (4-cyanophenyl)methanethiolate] and [FeFe](3-cpmt)2(CO)6 [L2; 3-cpmt = (3-cyanophenyl)methanethiolate] with silver salts. 1-3 represent the first examples of [FeFe]-hydrogenase-based CPs. It was worth noting that the Ag-S bonding between the Ag centers and S atoms of a [Fe2S2] cluster produced a novel [Fe2S2-Agx] (x = 1 or 2) catalytic site in all three polymers. The results of photochemical H2 generation experiments indicated that 2 and 3 containing [Fe2S2-Ag2] active sites showed obviously improved catalytic performances compared with ligands L1 and L2 and [Fe2S2-Ag1]-containing 1. This work provides a pioneering strategy for the direct synthesis of [Fe2S2]-based CPs or metal-organic frameworks.

Esophageal peripheral T-cell lymphoma treated with radiotherapy: A case report.

RATIONALE: The clinical prognosis of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) patients is poor. Therefore, effective treatment is still a challenge at present. Moreover, little is known about the value of radiotherapy in the treatment of PTCL-NOS. PATIENT CONCERNS: A 55-year-old male patient with eating difficulties and progressive exacerbation for 3 months was diagnosed as non-Hodgkin's lymphoma. Airway compression occurred after 2 cycles of first line treatment with cyclophosphamide-Adriamycin-vincristine-prednisone regimen, radiotherapy (48Gy/24f) was given as the second line therapy. DIAGNOSIS: After radiotherapy, the patient complained that mild intermittent dysphagia still existed. Endoscopic biopsy of the upper digestive tract confirmed necrotic material and superficial squamous epithelial mucosa, suggesting esophageal stricture after radiotherapy, which was indistinguishable from tumor residue. INTERVENTIONS: The patient received anti-inflammatory treatment outside the hospital and did not receive any other special treatment. OUTCOMES: The symptoms of dysphagia disappeared and the focus showed complete response (CR). As of October 1, 2020, the patient has been diagnosed with PTCL-NOS for more than 57 months and the overall survival (OS) have not been achieved. LESSONS: Radiotherapy has obvious and rapid anti-tumor effect on cyclophosphamide-Adriamycin-vincristine-prednisone refractory PTCL-NOS. At the same time, hollow organs after radiotherapy can lead to lumen stenosis and the symptoms of suspected recurrence which is difficult to distinguish only from the imaging findings.

Weighted correlation gene network analysis reveals a new stemness index-related survival model for prognostic prediction in hepatocellular carcinoma.

In this study, we constructed a new survival model using mRNA expression-based stemness index (mRNAsi) for prognostic prediction in hepatocellular carcinoma (HCC). Weighted correlation network analysis (WGCNA) of HCC transcriptome data (374 HCC and 50 normal liver tissue samples) from the TCGA database revealed 7498 differentially expressed genes (DEGs) that clustered into seven gene modules. LASSO regression analysis of the top two gene modules identified ANGPT2, EMCN, GLDN, USHBP1 and ZNF532 as the top five mRNAsi-related genes. We constructed our survival model with these five genes and tested its performance using 243 HCC and 202 normal liver samples from the ICGC database. Kaplan-Meier survival curve and receive operating characteristic curve analyses showed that the survival model accurately predicted the prognosis and survival of high- and low-risk HCC patients with high sensitivity and specificity. The expression of these five genes was significantly higher in the HCC tissues from the TCGA, ICGC, and GEO datasets (GSE25097 and GSE14520) than in normal liver tissues. These findings demonstrate that a new survival model derived from five strongly correlating mRNAsi-related genes provides highly accurate prognoses for HCC patients.

The Role of Perceptual Interference, Semantic Interference, and Relational Integration in the Development of Analogical Reasoning.

This study aimed to examine the role of perceptual interference, semantic interference, and relational integration (RI) in the development of analogical reasoning, and to compare the interactive pattern of interference and RI in children and adults. In Experiment 1, we tested 31 3- and 4-year-olds, 27 5- and 6-year-olds, and 40 adults for perceptual interference and RI in analogical reasoning. Perceptual interference emerged when proper mapping between analogically matching objects was incoherent with their perceptual features. RI was evaluated via manipulation of the number of objects in an analogical scene. Significant main effects of perceptual interference and RI were found in children and adults. In Experiment 2, we tested 30 3- and 4-year-olds, 27 5- and 6-year-olds, and 40 adults for semantic interference and RI in analogical reasoning. Semantic interference emerged when proper mapping between analogically matching objects was incoherent with their categorical features. Results showed significant main effects of semantic interference and RI in children and adults. The results of both experiments suggested different mechanisms of interference and RI in children and adults. For children, interference and RI depended on shared cognitive sources. If one factor (i.e., interference resolution) needed more cognitive demand, there would be limited resources available for another factor (i.e., RI). Furthermore, for adults, the increased load of RI and interference on adults' analogical reasoning exceeded the sum of their respective singular effects. For 3- and 4-year-olds, the degree of perceptual interference was larger than the degree of semantic interference in the Binary Relation condition, whereas there was no significant difference between the degree of two types of interference in the Quaternary Relation condition. Moreover, for 5- and 6-year-olds, the degree of semantic interference was larger than the degree of perceptual interference in both relation conditions. For adults, there was no difference between the degree of two types of interference in both relation conditions. The article also discusses the theoretical and practical implications of this research.

Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2.

Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ∼50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 µM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CLint, decreased by 18.5%-35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo.