Search

Supplementary Table 3 from Identification of Biomarkers for Predicting Nasopharyngeal Carcinoma Response to Radiotherapy by Proteomics

Supplementary Table 1 from Identification of Biomarkers for Predicting Nasopharyngeal Carcinoma Response to Radiotherapy by Proteomics

Supplementary Table 4 from Identification of Biomarkers for Predicting Nasopharyngeal Carcinoma Response to Radiotherapy by Proteomics

Supplementary Table 2 from Identification of Biomarkers for Predicting Nasopharyngeal Carcinoma Response to Radiotherapy by Proteomics

ObjectivesIdiopathic pulmonary artery hypertension (IPAH) is a rare but life-threaten disease. However, the mechanism underlying IPAH is unclear. In this study, underlying mechanism, infiltration of immune cells, and immune-related hub genes of IPAH were analyzed via bioinformatics.MethodsGSE15197, GSE48149, GSE113439, and GSE117261 were merged as lung dataset. Weighted gene correlation network analysis (WGCNA) was used to construct the co-expression gene networks of IPAH. Gene Ontology and pathway enrichment analysis were performed using DAVID, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA). Infiltration of immune cells in lung samples was analyzed using CIBERSORT. GSE22356 and GSE33463 were merged as peripheral blood mononuclear cells (PBMCs) dataset. Immune-related differentially expressed genes (IRDEGs) of lung and PBMCs dataset were analyzed. Based on the intersection between two sets of IRDEGs, hub genes were screened using machine learning algorithms and validated by RT-qPCR. Finally, competing endogenous RNA (ceRNA) networks of hub genes were constructed.ResultsThe gray module was the most relevant module and genes in the module enriched in terms like inflammatory and immune responses. The results of GSEA and GSVA indicated that increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. The proportions of T cells CD4 memory resting and macrophage M1 were significantly greater in IPAH group, while the proportions of monocytes and neutrophils were significantly lower in IPAH group. IRDEGs of two datasets were analyzed and the intersection between two set of IRDEGs were identified as candidate hub genes. Predictive models for IPAH were constructed using data from PBMCs dataset with candidate hub genes as potential features via LASSO regression and XGBoost algorithm, respectively. CXCL10 and VIPR1 were identified as hub genes and ceRNA networks of CXCL10 was constructed.ConclusionInflammatory response, increasement in cytosolic calcium ion, and metabolism dysregulation play important roles in IPAH. T cells CD4 memory resting and macrophage M1 were significantly infiltrated in lung samples from patients with IPAH. IRDEGs of lung dataset and PBMCs dataset were analyzed, and CXCL10 and VIPR1 were identified as hub genes.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

Background: Atrial fibrillation (AF) increases the risk of stroke and heart failure. Postoperative AF (POAF) increases the risk of mortality after cardiac surgery. This study aims to explore mechanisms underlying AF, analyze infiltration of immune cells in left atrium (LA) from patients with AF, and identify potential circular RNA (circRNA) biomarkers for POAF.Methods: Raw data of GSE797689, GSE115574, and GSE97455 were downloaded and processed. AF-related gene co-expression network was constructed using weighted gene correlation network analysis and enrichment analysis of genes in relevant module was conducted. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to investigate pathways significantly enriched in AF group. Infiltration of immune cells was analyzed using single-sample GSEA. Differentially expressed genes (DEGs) between patients with or without AF were identified and competing endogenous RNA (ceRNA) networks of DEGs were constructed. To screen biomarkers for POAF, differentially expressed circRNAs (DEcircRNAs) between patients with or without POAF were identified. Intersection between DEcircRNAs and circRNAs in ceRNA networks of DEGs were extracted and circRNAs in the intersection were further screened using support vector machine, random forest, and neural network to identify biomarkers for POAF.Results: Three modules were found to be relevant with AF and enrichment analysis indicated that genes in these modules were enriched in synthesis of extracellular matrix and inflammatory response. The results of GSEA and GSVA suggested that inflammatory response-related pathways were significantly enriched in AF group. Immune cells like macrophages, mast cells, and neutrophils were significantly infiltrated in LA tissues from patients with AF. The expression levels of immune genes such as CHGB, HLA-DRA, LYZ, IGKV1-17 and TYROBP were significantly upregulated in patients with AF, which were correlated with infiltration of immune cells. ceRNA networks of DEGs were constructed and has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF.Conclusion: Synthesis of extracellular matrix and inflammatory response were main processes involved in development and progression of AF. Infiltration of immune cells was significantly different between patients with or without AF. Has_circ_0006314 and hsa_circ_0055387 were found to have potential predictive values for POAF.

ObjectivesThe mortality rate of abdominal aortic aneurysm (AAA) is extremely high in the older population. This study aimed to identify potential biomarkers of AAA and aortic rupture and analyze infiltration of immune cells in stable and ruptured AAA samples.MethodsRaw data of GSE47472, GSE57691, and GSE98278 were downloaded. After data processing, the co-expression gene networks were constructed. Gene Ontology and pathway enrichment analysis of AAA- and aortic rupture-related gene modules were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used for further enrichment analysis. The CIBERSORT tool was used to analyze the relative abundance of immune cells in samples. Differentially expressed immune-related genes were analyzed between different samples. Predictive models were constructed via extreme gradient boosting, and hub genes were identified according to feature importance.ResultsBlue and yellow modules were significantly related to AAA, and genes in these modules were associated with the aortic wall and immune response, respectively. In terms of aortic rupture, the most relevant module was significantly enriched in the inflammatory response. The results of GSEA and GSVA suggested that immune cells and the inflammatory response were involved in the development of AAA and aortic rupture. There were significant differences in the infiltration of immune cells and expression levels of immune-related genes among different samples. NFKB1 might be an important transcription factor mediating the inflammatory response of AAA and aortic rupture. After the construction of a predictive model, CD19, SELL, and CCR7 were selected as hub genes for AAA whereas OAS3, IFIT1, and IFI44L were identified as hub genes for aortic rupture.ConclusionWeakening of the aortic wall and the immune response both contributed to the development of AAA, and the inflammatory response was closely associated with aortic rupture. The infiltration of immune cells was significantly different between different samples. NFKB1 might be an important transcription factor in AAA and aortic rupture. CD19, SELL, and CCR7 had potential diagnostic value for AAA. OAS3, IFIT1, and IFI44L might be predictive factors for aortic rupture.

OBJECTIVE: To investigate alterations in the mechanical properties of in-house three-dimensional (3D) printed orthodontic aligners after intraoral ageing. MATERIALS AND METHODS: Sixteen 3D-printed aligners (TC-85DAC resin, Graphy, Seoul, Korea) were used for the purpose of the study, which were divided into 10 control (not used) aligners and 6 materials retrieved from 4 patients after 1-week service (retrieved group). Samples from the control group were analysed by attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. Samples from control/retrieved groups were embedded resin and subjected to instrumented indentation testing (IIT) to record force-indentation depth curves, calculating the following (as per ISO 14577-1, 2002 standard): Martens hardness (HM), indentation modulus (EIT), and elastic index (ηIT), and the indentation relaxation index (RIT). Differences between control and retrieved 3D-printed aligners were checked with Mann-Whitney/t-tests at an alpha = 5%. RESULTS: ATR-FTIR analysis showed that aligners were made of a vinyl ester-urethane material. The results of the IIT testing were: HM (control: median 91.5 N/mm2, interquartile range [IQR] 88.0-93.0/as-retrieved: median 90.5 N/mm2, IQR 89.0-93.0); EIT (control, mean 2616.3 MPa, standard deviation [SD] 107.0 MPa/retrieved, mean 2673.2 MPa, SD 149.4 MPa); ηIT (control: median 28.6%, IQR 28.2-30.9%/as-retrieved: median 29.0%, IQR 28.7-29.2%); and RIT (control: median 45.5%, IQR 43.0-47.0%/as-retrieved: median 45.1%, IQR 45.0-45.3%). No differences between as-retrieved and control aligners were found for any of the mechanical properties tested (P > 0.05 in all instances). CONCLUSION: The mechanical properties of the in-house 3D-printed aligners tested were not affected after 1 week in service period. © The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Hysteresis is treated as a history dependent branching, and the use of the classical Preisach model for the analysis of macroeconomic hysteresis is first discussed. Then, a new Preisach-type model is introduced as a macroeconomic aggregation of more realistic microeconomic hysteresis than in the case of the classical Preisach model. It is demonstrated that this model is endowed with a more general mechanism of branching and may account for the continuous evolution of the economy and its effect on hysteresis. Furthermore, it is shown that the sluggishness of economic recovery is an intrinsic manifestation of hysteresis branching., 13 pages, 19 figures

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

Angiogenesis is critical for re‐establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR‐185‐5p were differently expressed in plasma from patients with ACS by high‐throughput RNA sequencing. The expressional levels of miR‐185‐5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT‐PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR‐185‐5p. In HUVECs, miR‐185‐5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR‐185‐5p inhibitors performed the opposites. Further, the inhibitory effects of miR‐185‐5p up‐regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus‐mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain‐function of miR‐185‐5p by agomir infusion down‐regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR‐185‐5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR‐185‐5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

Nasopharyngeal carcinoma (NPC) is an epithelial carcinoma originating from the nasopharyngeal mucosal tissue and is highly prevalent in southeast Asia. Galectin‑3 (gal‑3) serves crucial roles in many cancers but its role in NPC remains to be elucidated. The aim of the present study was to investigate the role of gal‑3 in NPC. Immunohistochemistry and ELISA were used to determine the expression level of gal‑3 in patients with NPC or chronic rhinitis (CR). Gal‑3 short hairpin (sh)RNA was established to knockdown gal‑3 in 5‑8F and 6‑10B cells, allowing for the evaluation of the roles of gal‑3 in proliferation, migration and apoptosis in NPC cell lines. Immunohistochemistry staining of IL‑6 and IL‑8 was applied to access the inflammatory state of tumor tissues, and the correlation between the inflammatory state and gal‑3 was analyzed. The results demonstrated that gal‑3 was upregulated in patients with NPC compared with patients with CR. Knockdown of gal‑3 inhibited proliferation and migration in 5‑8F and 6‑10B cells, as well as promoted apoptosis in these cells. The expression levels of MMP‑9 and IL‑8 were also decreased in 5‑8F and 6‑10B cells after transfection with gal‑3 shRNA. A positive correlation was identified between the expression level of gal‑3 and the inflammatory state of NPC. The phosphorylation levels of ERK1/2 and Akt were downregulated after knockdown of gal‑3 in 5‑8F and 6‑10B cells. In conclusion, the expression level of gal‑3 was upregulated in patients with NPC and was positively correlated with the inflammatory state of NPC. The results suggested that gal‑3 promoted the proliferation and migration of 5‑8F and 6‑10B cells, while inhibiting the apoptosis of these cells. Moreover, activation of ERK1/2 and Akt may be the underlying mechanism of the effects of gal‑3 on NPC.

PURPOSE Laparoscopic total extraperitoneal repair (TEP) is one of the most preferred minimally invasive methods for inguinal hernia repair. In our study, we aimed to compare the advantages and disadvantages of general anesthesia (GA), spinal anesthesia (SA), and epidural anesthesia (EA) for TEP operations. MATERIALS AND METHODS This is a retrospective study involving 221 patients who underwent TEP surgery for inguinal hernia between January 2018 and July 2020. Patients were divided into 3 groups as GA (n=77), SA (n=70), and EA (n=74). Demographic data of the patients, duration of anesthesia and surgery, perioperative and postoperative complications, postoperative pain, anatomical delineation, hospital stay and quality of life were evaluated. RESULTS Anesthesia time was the longest in the EA group (23.1±2.32 min) and significantly prolonged the operation time (P

Hysteresis is treated as a history dependent branching, and the use of the classical Preisach model for the analysis of macroeconomic hysteresis is first discussed. Then, a new Preisach-type model is introduced as a macroeconomic aggregation of more realistic microeconomic hysteresis than in the case of the classical Preisach model. It is demonstrated that this model is endowed with a more general mechanism of branching and may account for the continuous evolution of the economy and its effect on hysteresis. Furthermore, it is shown that the sluggishness of economic recovery is an intrinsic manifestation of hysteresis branching.

Diabetes-related macrovascular and microvascular complications lead to poor prognosis. Insulin receptor substrate p53 (IRSp53) is known to act as a substrate for the insulin receptor tyrosine kinase, but its role in endothelial dysfunction remains unclear. Human umbilical vein endothelial cells (HUVECs) treated with D-glucose at different concentrations and a streptozocin-induced rat diabetes mellitus (DM) model were used to investigate the effects of hyperglycemia on the expression levels of IRSp53 and galectin-3 (gal-3) and the inflammatory state and mobility of HUVECs. Thereafter, IRSp53-overexpressing HUVECs and IRSp53-knockdown HUVECs were established using IRSp53-overexpressing lentivirus or IRSp53-siRNA to explore the role of IRSp53 in the HUVEC inflammatory state and HUVEC mobility. D-glucose at high concentration (HG) and hyperglycemia were found to induce downregulation of IRSp53 and upregulation of gal-3 in vitro and in vivo. Treatment with HG resulted in activation of NF-κB in HUVECs and impaired HUVEC mobility. Insulin restored HG-induced changes in the expression levels of IRSp53 and gal-3 in HUVECs and protected the cells from NF-κB activation and impaired mobility. Overexpression of IRSp53 inhibited the activation of NF-κB in HUVECs and strengthened HUVEC migration. Knockdown of IRSp53 facilitated the activation of NF-κB in HUVECs and decreased HUVEC migration. However, neither overexpression nor knockdown of IRSp53 altered the effects of insulin on HG-induced detrimental changes in HUVECs. HG and hyperglycemia resulted in downregulation of IRSp53 in vitro and in vivo. IRSp53 is concluded to inhibit the activation of NF-κB in HUVECs and to strengthen HUVEC migration.

BACKGROUND: Atrial fibrillation (AF) is related to structural and electrical atria remodeling. Atrial fibrosis development and progression is characteristic of structural remodeling and is taken as the AF perpetuation substrate. Increasing evidence has confirmed that microRNAs (miRNAs) are associated with AF, including cardiac fibrosis. METHODS: Pericardial fluid (PF) samples were collected from nine adult patients who had congenital heart disease with persistent AF or sinus rhythm (SR) undergoing surgery. Abnormally expressed miRNAs were acquired, and P2 were taken as the thresholds of differentially expressed miRNAs (DE-miRNAs). The predicted target genes were obtained by miRTarBase. The Database for Annotation, Visualization and Integrated Discovery was used to annotate functions and analyze pathway abundance for latent targets of DE-miRNAs. STRING database was applied to construct a protein–protein interplay (PPI) network, and Cytoscape software was used to visualize the miRNA-hub gene-Kyoto Encyclopedia of Genes and Genomes (KEGG) network. DE-miRNA expressions were evaluated by quantitative polymerase chain reaction (qPCR). RESULTS: Fifty-five exosomal DE-miRNAs were found between the AF and SR samples; these included 24 miRNAs that were upregulated and 31 that were downregulated. For the top 3 downregulated miRNAs (miR-382-3p, miR-3126-5p, and miR-450a-2-3p) 283 predicted target genes were identified, and were implicated in cardiac fibrosis-related pathways, including the hypoxia-inducible factor-1 (HIF1), mitogen-activated protein kinase (MAPK), and adrenergic and insulin pathways. The top 10 hub genes in the PPI network, including mitogen-activated protein kinase 1 (MAPK1) and AKT serine/threonine kinase 1 (AKT1), were identified as hub genes. By establishing the miRNA-hub gene-KEGG network, we observed that these hub genes, which were regulated by miR-382-3p, miR-3126-5p, and miR-450a-2-3p, were involved in many KEGG pathways associated with cardiac fibrosis, such as the AKT1/glycogen synthase kinsase-3β (GSK-3β) and transforming growth factor-β (TGF-β)/MAPK1 pathways. CONCLUSIONS: The findings of the present study suggest that miR-382-3p, miR-450a-2-3p, and miR-3126-5p contained in exosomes in human PF are pivotal in the progression of AF. The results of qPCR showed that miR-382-3p was consistent with our sequencing data, which indicates its potential value as a therapeutic target for AF.

Niemann–Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism. Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Gräler, Markus H.. Universitätsklinikum Jena; Alemania Fil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Marvanova, Pavlina. Veterinární univerzita Brno; República Checa Fil: Jampilek, Josef. Univerzita Komenského v Bratislave; Eslovaquia Fil: Lima, Santiago. Virginia Commonwealth University; Estados Unidos Fil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados Unidos Fil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unidos

Regulation of sphingolipid metabolism plays a role in cellular homeostasis, and dysregulation of these pathways is involved in cancer progression. Previously, our reports identified ceramide as an anti-metastatic lipid. In the present study, we investigated the biochemical alterations in ceramide-centered metabolism of sphingolipids that were associated with metastatic potential. We established metastasis-prone sublines of SKOV3 ovarian cancer cells using an in vivo selection method. These cells showed decreases in ceramide levels and ceramide synthase (CerS) 2 expression. Moreover, CerS2 down regulation in ovarian cancer cells promoted metastasis in vivo and potentiated cell motility and invasiveness. Moreover, CerS2 knock-in suppressed the formation of lamellipodia required for cell motility in this cell line. In order to define specific roles of ceramide species in cell motility controlled by CerS2, the effect of exogenous long- and very long- chain ceramide species on the formation of lamellipodia was evaluated. Treatment with distinct ceramides increased cellular ceramides and had inhibitory effects on the formation of lamellipodia. Interestingly, blocking the recycling pathway of ceramides by a CerS inhibitor was ineffective in the suppression of exogenous C(24:1)-ceramide for the formation of lamellipodia. These results suggested that C(24:1)-ceramide, a CerS2 metabolite, predominantly suppresses the formation of lamellipodia without the requirement for deacylation/reacylation. Moreover, knock-down of neutral ceramidase suppressed the formation of lamellipodia concomitant with up-regulation of C(24:1)-ceramide. Collectively, the CerS2-C(24:1)-ceramide axis, which may be countered by neutral ceramidase, is suggested to limit cell motility and metastatic potential. These findings may provide insights that lead to further development of ceramide-based therapy and biomarkers for metastatic ovarian cancer.

Background Epicardial adipose tissue (EAT) remodeling and adipocytokines are associated with structural remodeling in atrial fibrillation (AF). However, the role of omentin-1, a novel adipocytokine, in structural remodeling remains unknown. Methods Hematoxylin and eosin (H&E) and Masson’s trichrome stains were used to investigate the histology of EAT and right atrial appendages. The expression levels of adipocytokines in these human samples were determined by immunohistochemical assay and western blotting. Models of transforming growth factor (TGF)-β1-induced activation of cardiac fibroblasts (CFs) and TGF-β1-induced endothelial-mesenchymal transition (EndMT) of human umbilical vein endothelial cell (HUVEC) were established to explore roles of omentin-1 in these processes. To determine changes in adipocytokines secretion under hypoxia conditions, adipocytes were treated with 5% O2 and 95% N2, and then CFs and HUVECs were co-cultured with the conditioned medium of adipocytes to determine the effects of hypoxia-treated adipocytes on these cells. Results Expression of omentin-1 was downregulated in the EAT and right atrial appendages from patients with AF compared to samples from patients without AF, while the TGF-β1 level was upregulated in EAT from patients with AF. EAT from patients with AF exhibited adipocyte hypertrophy and severe interstitial fibrosis. Omentin-1 inhibited TGF-β1-induced CF activation and reversed TGF-β1-induced HUVEC EndMT. Adipocytes treated with hypoxia exhibited downregulation of omentin-1 and partly activated CFs. Conclusions This study demonstrated that omentin-1 was an antifibrotic adipocytokine and was downregulated in patients with AF, which was partly mediated by hypoxia.

Objectives. Endothelial cell injury is a critical pathological change during the development of atherosclerosis. Here, we explored the effect of omentin-1 on free fatty acid- (FFA-) induced endothelial cell injury. Methods. An FFA-induced endothelial cell injury model was established to investigate the role of omentin-1 in this process. Cell proliferation was analyzed with the Cell Counting Kit assay and flow cytometry. Scratch and transwell assays were used to evaluate cell migration. Factors secreted by endothelial cells after injury were detected by western blotting, reverse-transcription quantitative polymerase chain reaction, and cellular fluorescence assay. Results. Omentin-1 rescued the FFA-induced impaired proliferation and migration capabilities of human umbilical vein endothelial cells (HUVECs). It decreased the number of THP-1 cells attached to HUVECs in response to injury and inhibited the FFA-induced proinflammatory state of HUVECs. Conclusion. Omentin-1 could partly ameliorate FFA-induced endothelial cell injury.

Additional file 1: Table S1. Primes used in the article.

Frequency combs have triggered an impressive evolution of optical metrology across diverse regions of the electromagnetic spectrum, from the ultraviolet to the terahertz frequencies. An unexplored territory, however, remains in the region of vibrational bending modes, mostly due to the lack of single-mode lasers in the long-wavelength (LW) part of the mid-infrared (MIR) spectrum. We fill this gap through a purely MIR-based nonlinear laser source with tunability from 12.1 to 14.8 $��$m, optical power up to 110 $��$W, MHz-level linewidth and comb calibration. This enables the first example of bending modes metrology in this region, with the assessment of several CO$_2$-based frequency benchmarks with uncertainties down to 30 kHz, and the accurate study of the $��_{11}$ band of benzene, which is a significant testbed for the resolution of the spectrometer. These achievements pave the way for LW-MIR metrology, rotationally-resolved studies and astronomic observations of large molecules, such as aromatic hydrocarbons., 36 pages including Supplementary Materials, 4 figures (paper), 3 figures (SM)

Additional file 2: Figure S1. The p-SMAD3 and t-SMAD3 protein levels in HUVECs treated with the CM of adipocytes were detected via western blotting (A) (n=3). TGF-β1, COL1, and COL3 protein levels in adipocytes treated with normoxia or hypoxia were detected via western blotting (B) (n=3). α-SMA, COL1, and COL3 protein levels in CFs treated with the CM of adipocytes were detected via western blotting (C) (n=3). Vimentin and VE-Cad protein levels in HUVECs treated with the CM of adipocytes were detected via western blotting (D) (n=3). (E) Representative scratch assay images of HUVECs treated with the CM of adipocytes (×100 magnification).

Fatty acid channeling into oxidation or storage modes depends on physiological conditions and hormonal signaling. However, the directionality of this channeling may also depend on the association of each of the five acyl-CoA synthetase isoforms with specific protein partners. Long-chain acyl-CoA synthetases (ACSLs) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs, which are then either oxidized or used in esterification reactions. In highly oxidative tissues, ACSL1 is located on the outer mitochondrial membrane (OMM) and directs fatty acids into mitochondria for β-oxidation. In the liver, however, about 50% of ACSL1 is located on the endoplasmic reticulum (ER) where its metabolic function is unclear. Because hepatic fatty acid partitioning is likely to require the interaction of ACSL1 with other specific proteins, we used an unbiased protein interaction technique, BioID, to discover ACSL1-binding partners in hepatocytes. We targeted ACSL1 either to the ER or to the OMM of Hepa 1–6 cells as a fusion protein with the Escherichia coli biotin ligase, BirA*. Proteomic analysis identified 98 proteins that specifically interacted with ACSL1 at the ER, 55 at the OMM, and 43 common to both subcellular locations. We found subsets of peroxisomal and lipid droplet proteins, tethering proteins, and vesicle proteins, uncovering a dynamic role for ACSL1 in organelle and lipid droplet interactions. Proteins involved in lipid metabolism were also identified, including acyl-CoA–binding proteins and ceramide synthase isoforms 2 and 5. Our results provide fundamental and detailed insights into protein interaction networks that control fatty acid metabolism.

Chemoresistance is a major barrier to successful cisplatinbased chemotherapy for epithelial ovarian cancer (EOC), and emerging evidences suggest that microRNAs (miRNAs) are involved in the resistance. In this study, it was indicated that miR-363 downregulation was significantly correlated with EOC carcinogenesis and cisplatin resistance. Moreover, miR-363 overexpression could resensitise cisplatin-resistant EOC cells to cisplatin treatment both in vitro and in vivo. In addition, data revealed that EMT inducer Snail was significantly upregulated in cisplatin-resistant EOC cell lines and EOC patients and was a functional target of miR-363 in EOC cells. Furthermore, snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells. Taken together, findings suggest that miR-363 may be a biomarker for predicting responsiveness to cisplatin-based chemotherapy and a potential therapeutic target in EOC. [BMB Reports 2018; 51(9): 456-461].

High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.

Abstract Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of ‘stemness’ genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKα directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance.

Foot ulcers affect 15% of patients with diabetes, resulting in a great health burden. The occurrence and development of diabetic foot ulcers is associated with neuropathy, peripheral arterial disease, and infection. Several growth factors are involved in these processes, including epidermal growth factor, vascular endothelial growth factor, transforming growth factor-beta, fibroblast growth factor, and erythropoietin, which could promote wound healing of patients with diabetes. Thus, this review discusses the role of these growth factors in the pathogenesis of diabetic foot ulcers, aiming to achieve novel insights into the management of diabetic foot ulcers.

Data presented in European Union documents have a social life of their own; they are collected, analyzed, disseminated, used, and reused. Along the way, data interact with different external elements—economic, social, and political actors, positions, and preferences—transforming their potential for different contexts and meanings. The Directorates-General are significant data actors, involved in both data-gathering and fact dissemination stages of data's social life and controlling the flows of data through the EU. This article focuses on the social life of two sets of data, tracing the evolution of these datasets into political discourses about disaster response and migration, and arguing that data never speak for themselves but rather evolve into facts through networks, which shape official policy discourses.

The Preisach model of hysteresis admits simple device realizations. It is suggested in the paper that these realizations can be utilized as unique data storage devices as well as analog global optimizers.

In this chapter Mark B. Salter, current editor of Security Dialogue, discusses with Can E. Mutlu the meaning and significance of technology for International Relations in light of his eclectic work. Salter, perhaps best-known for his dynamic presentations and engaging intellectual approach and recently for the two-volume project Making Things International, traces his engagement with technology across a vast field of contributions ranging from civilization in international politics, the genealogy of the modern passport, and critical security studies, touching on Foucauldian and Bourdieusian notions. In the conversation, Salter reflects on the recent material turn in IR and the expansion of this as a significant research area within critical consciousness in IR, with more and more people working on materiality, science and technology studies, actor-network theory. He points to the importance of remembering that we are not the first generation to experience this kind of epochal change, and that emancipatory change happens through engagement, and how technology is shaping the encounter with the Other—reminding us that scholarship can and should start with curiosity and intuition.

…

…

BACKGROUND Convex hemiepiphysiodesis has been reported to have mixed results in the treatment of congenital spine deformities. Multiple modifications of the original technique were suggested to improve the results. The purpose of this study is to report the results and complications of an instrumented convex growth arrest procedure modified with concave distraction. METHODS The records of 11 patients with long sweeping congenital curves (involving multiple anomalous vertebrae) who underwent convex instrumented hemiepiphysiodesis with concave distraction were evaluated. Mean age at index operation was 58 months (range, 29 to 101 mo). Lengthening of the concave distraction rod was done every 6 months. The magnitude of coronal/sagittal deformity and T1-T12 height were measured on the preoperative, postoperative, and latest follow-up radiographs. Average follow-up was 44.9 months (range, 24 to 89 mo). RESULTS In the coronal plane, the convex hemiepiphysiodesis segment was corrected from an average of 60.5 to 40.4 degrees postoperatively and further improved to 35.5 degrees at the latest follow-up. The distracted segment was corrected from 33.4 to 15.2 degrees postoperatively and to 12.7 degrees at the latest follow-up. Sagittal plane alignment was minimally affected. The average T1-T12 height was 157.1 mm in the early postoperative period and 181.1 mm at last follow-up. During follow-up, we identified partial pull-out of screws on the distraction side in 5 of the 11 patients and rod breakages in 3 patients. These were revised during planned lengthenings. There were no unplanned surgeries, deep wound infections, nor neurological complications. CONCLUSIONS Convex instrumented hemiepiphysiodesis with concave distraction resulted in good curve correction while maintaining the growth of thorax. The correction of the anomalous segment improved over time, proving the effectiveness of the hemiepiphysiodesis. Addition of a concave distraction construct appears to enhance spinal growth, thereby augmenting the hemiepiphysiodesis effect.

The coal fired power plants are one of the oldest, most common and wide spread generators of electricity. They utilise heat generated by burning coal, that is pulverised in different type of grinding machines selected based on the coal type that is being processed, to produce steam power. For bituminous coal, vertical spindle pulverisers are the preferred and most common equipment for pulverisation. In this thesis, the vertical spindle pulverisers were of interest and their operation is modelled. In order to achieve this goal, a sampling procedure was developed to collect samples from these pulverisers. A standard procedure for sample analyses was followed; and when required, new experimental and sampling tools were developed and manufactured. A multi-component data set of five industrial scale surveys was produced for the pulveriser operating at different coal and air flow conditions. The multi-component data are based on size and ash content as well as density for one test and the feed samples. The selected samples were classified into size-by-size density bins by float/sink density analysis. One of the general outcomes of using multi-component data was confirmation of the mineral matter accumulation in the mill showing its dependency on size. Moreover, the multi-component data were utilised to calculate the flow rates and unknown particle size distributions of the mill interior streams by mass balancing. Hence, the mill interior streams particle size distributions and flow rates, as well as size-by-size ash content distributions were obtained; thus the circulating loads that develop in the pulveriser were calculated. This information was used in constructing the ball feed stream via combining the reject streams with the coal fed to the pulveriser, which is the key stream to compute comminution information and model parameters. The mass balanced streams information were utilised to evaluate the classifications that occur in the pulveriser. The model parameters describing the classification curves that correspond to the two different zones in the pulveriser were found to be closely related to the operational conditions. A 3D multi-component breakage function was developed with the results obtained from compressive breakage tests. It is observed that the coal and mineral matter differ in breakage behaviour. This difference was incorporated into the 3D breakage model in order to be able to predict the breakage of these component particles and their composites. The mass balanced stream information together with the multi-component breakage function was utilised to successfully determine the rate of breakage of particles in the grinding zone. The model parameters describing the rate of breakage of the particles were found to be related to the operational variables. A demonstration of the developed approach was done using a simulator which linked comminution and classification models based on size and density components, to work in closed circuit operation. The classification function used in the overall simulation model was changed to an efficiency curve model based on settling velocities of particles to enable integration of both density and size of particles into the model; rather than employing empirical relations developed based only on particle size. Similarly, parameters for rate of breakage of particles have differed from that of parameters calculated during the computations for open circuit grinding conditions. The results obtained from the simulation studies were satisfactory in describing the existing conditions that occur in the pulveriser at all the sampled conditions. In conclusion, a mathematical model of an industrial scale ball-and-race pulveriser was developed by determining the effect of operational variables on the comminution and classification operations within the pulveriser.

The authors in this collective discussion engage, disaggregate and unpack the triangulation of security, technology and architecture, across a range of contemporary spaces/places. Reflecting diverse interdisciplinary commitments and perspectives, the collective discussion considers security, technology and architecture in urban environments and global/local interfaces, borders, borderlands and ports of entry, and even the sensorium, from soundscapes of the airport to teargas laden environments. From quotidian to high-tech, these interventions tease out the increasing ferocity of architecture and/in its relationship with technology and security. © The Authors 2016.

A new hysteresis-based technique for random number generation is presented which can be efficiently implemented by using modern spintronics based nano-technology. Thermal fluctuation induced random switchings of rectangular hysteresis loops are utilized whose outputs result in the generation of random binary numbers. Mathematically, the random switching is treated as a repeated sequence of two exit problems for stationary stochastic processes, which are shown to be reduced to the solution of initial boundary value problems for the appropriate backward Kolmogorov equations. Analytical solution of these boundary value problems are carried out for the stationary Gaussian Markov Ornstein-Uhlenbeck process. An alternative approach to the analysis of the random switching based on stochastic processes on graphs is also discussed with special attention paid to the trade-offs between the strength of thermal noise and the widths of the hysteresis loops.

Endothelial progenitor cells (EPCs) are a group of circulating cells with important functions in vascular repair and treatment of cardiovascular diseases. However, in patients with atrial fibrillation (AF), the number and function of EPCs reportedly are decreased. TGF-β is highly expressed in AF patients. In this study, we examined the effect of TGF-β1 on EPCs and the therapeutic outcome of metformin treatment on TGF-β1-induced EPCs. EPCs were induced with TGF-β1 at different concentrations (5 ng/ml, 10 ng/ml, and 20 ng/ml) for 48 h followed by western blot, qPCR, and immunofluorescence analyses to investigate changes in the levels of the fibrosis-related proteins, α-SMA, Col I, Col III, CTGF, and MMP-1. Live-dead cell staining was used to evaluate cell apoptosis. Compared with the control, TGF-β1 treatment significantly (p<0.05) enhanced the levels of α-SMA, Col I, Col III, CTGF, and MMP-1 in a dose-dependent manner. The most effective concentration of TGF-β1 (20 ng/ml) was then used to induce fibrosis biomarker expression in EPCs, followed by treatment with metformin at different concentrations (0.5, 1, and 2 mmol/l). Metformin treatment suppressed TGF-β-induced expression of all above factors, with the effect at 2 mmol/l being significant (p<0.05). Live-dead cell staining showed no difference among the control, TGF-β1-treated, and metformin-treated groups. In conclusion, our study showed that TGF-β1 induces the expression of fibrosis biomarkers in EPCs, which is attenuated by treatment with metformin. Thus, metformin may have therapeutic potential for improving EPC function in cardiovascular diseases.