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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

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

To represent the plurality of methods used within the Critical Studies Security community, this chapter surveys discourse analysis, corporeal analysis, ethnographic research, new materialism, and field analysis. Separating these practical methods from their ontological stakes makes critical analysis mutually intelligible and fosters a collobarative and plural discussion that shies away from doctrinaire orthodoxy. As a guide for analysis, this chapter also sets out some consensus positions about basic methods that are used in this field that critical scholars share and use in different theoretical traditions for their research design: idetifying standards of clarity, fit, and reflexivity by which critical scholarship can be judged, not on its ethical claims or its take on criticality, but rather on grounds of rigor.

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.

Developments in the field of Information and Communication Technologies (ICT) will have a significant impact on the way we study international relations. Opportunities related to data processing and automated reasoning that emerge through developments in complex algorithms will inevitably generate a debate on research methods in social sciences. Algorithms provide novel and innovative ways to sort and make sense of digital data. Applications of ‘big data’ and its potential uses in the social sciences remain understudied in IR. The field has not fully picked up on the potential uses of algorithmic processing for research. This article looks at the ethical questions that arise from the use of algorithmic data processing and automated reasoning. In particular, the article asks whether there should be any ethical limitations on the ways we collect data to be processed by algorithms.

The question of research methods, and their role in the field, is a major source of contention for IR scholars. We can, however, discuss method, methodology, and innovation without revising or revisiting old debates. Methods do not have to be divisive, or disciplining. A frank discussion of research design, methods, and methodological preferences is essential to innovation and reproducibility. This intervention is a call for increased transparency in IR research outputs; IR theorists should not erase their own footprints from their publications and openly admit and discuss failures as productive moments in research. The act of disappearing, which has become the norm in the name of professionalised publications, robs the field of the productive pedagogical potential of research methods. The true impact of research rests in its pedagogical potential. As researchers, our job is thus to find a sensitive balance between not determining the outcome of the research from the get-go by making it all about our preferences and opinions, but also not making the impact of our preferences and opinions disappear completely. Building on this premise, this intervention discusses the significant pedagogical potential of research methods, reproducibility and discussion of failures in International Relations.

Metastasis in lung cancer portends a poor prognosis, and the epithelial-mesenchymal transition (EMT) in lung cancer cells is considered a prerequisite to achieve metastatic potential. Recent studies indicate that BTB/POZ domain-containing protein 7 (BTBD7) regulates EMT-associated proteins in human malignancies and however, the role of BTBD7 in lung cancer have not been identified. In present study, we examined BTBD7 expression status and its association with unfavorable clinical features in non-small-cell lung cancer (NSCLC). Firstly, we studied the fresh specimens, and found that both mRNA and protein expression levels of BTBD7 in NSCLC tissue were significantly increased compared with the adjacent nontumorous lung tissue. Then, we determined BTBD7 protein expressions in the paraffin-embedded samples from NSCLC patients, and analyzed the relations of BTBD7 expression with clinicopathologic features of the patients. The results showed that incidence of metastasis in patients with positive BTBD7 expression was significantly higher than that in those with negative BTBD7 expression, and the positive BTBD7 expression rate in metastatic cases was significantly higher than that in non-metastatic ones; furthermore, Cox regression analyses revealed that BTBD7 was an independent risk factor for either metastasis or survival in NSCLC patients. Thus, we conclude that BTBD7 contributes to metastasis of NSCLC and BTBD7-positive NSCLC may have a high potential for metastasis and thereby a poor prognosis.

Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide. Given that Hsp27 is a chaperone protein, we examined its role in regulating ceramide synthases (CerSs), an enzyme family responsible for catalyzing generation of the sphingolipid ceramide. We determined that CerSs colocalized with Hsp27, and upon the presence of S135F mutants, CerS1 lost its colocalization with mitochondria suggesting that decreased mitochondrial ceramides result from reduced mitochondrial CerS localization rather than decreased CerS activity. Mitochondria in mutant cells appeared larger with increased interconnectivity. Furthermore, mutant cell lines demonstrated decreased mitochondrial respiratory function and increased autophagic flux. Mitochondrial structural and functional changes were recapitulated by blocking ceramide generation pharmacologically. These results suggest that mutant Hsp27 decreases mitochondrial ceramide levels, producing structural and functional changes in mitochondria leading to neuronal degeneration.—Schwartz, N. U., Linzer, R. W., Truman, J.-P., Gurevich, M., Hannun, Y. A., Senkal, C. E., Obeid, L. M. Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F.

Signaling by the transforming growth factor–β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)–generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia. Expression of a mutant TβRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TβRI inhibitory complex and increased the association between TβRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala 31 Thr 32 Ala 33 Leu 34 Gln 35 ) in TβRI. Mutating the cilia-targeting signal abolished the trafficking of TβRI to the primary cilia. Localization of TβRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TβRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TβRI/II-Shh signaling selectively at the plasma membrane of the primary cilium.

Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion. We find the soluble catalytic domain interacts directly with the membrane-associated NTD, which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region, which links the NTD and the catalytic domain, is necessary and sufficient for activation. Furthermore, we provide a mechanistic basis for this phenomenon using the crystal structure of the human nSMase2 catalytic domain determined at 1.85-A resolution. The structure reveals a DNase-I–type fold with a hydrophobic track leading to the active site that is blocked by an evolutionarily conserved motif which we term the “DK switch.” Structural analysis of nSMase2 and the extended N-SMase family shows that the DK switch can adopt different conformations to reposition a universally conserved Asp (D) residue involved in catalysis. Mutation of this Asp residue in nSMase2 disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and pharmacological inhibition by the lipid-competitive inhibitor GW4869. Taken together, these results demonstrate that the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface.

Single relations that can be used to calculate both the terminal settling velocities of spheres and the equivalent diameter of particles from their settling velocities are developed. The literature going back to Newton is reviewed and the relations developed tabulated. It is shown how the standard drag curve has developed into the dimensionless velocity versus dimensionless diameter curve. No relations that cover the full range that can conveniently be used for both velocity and diameter calculation were found, however a relation by Concha and Almendra covers most of the range. The standard drag curve data are constructed by utilizing 535 data points available in the literature in a Reynolds number range of 2.4 × 10−5 to 2 × 105. The settling velocities are corrected for experiments in finite width columns that do not satisfy the infinite medium dimensions. The data are converted to the dimensionless diameter and dimensionless velocity terms, which is more convenient for calculation purposes. The data are...

A novel rectangular shape differential CMOS split-drain Hall Effect magnetic field-effect transistor (MAGFET) was designed and fabricated employing a CMOS 0.5 μm process. The detection and monitoring of single 2.8 μm diameter magnetic beads was successfully performed using this MAGFET design. Based on the device modeling, simulation and the signal to noise ratio analysis, it was found that the optimal sensitivity can be achieved when the MAGFET channel width to length ratio is equal to 1.3. Further, it is shown through that when the MAGFET is scaled down, its SNR performance can sustain its peak, while being more sensitive to the geometry variations.

To advance the on-going debate on Securitisation Theory (ST), we argue that the important questions of audience and attention can be addressed through careful historical study. In an analysis of the securitising moves concerning the American military base on Diego Garcia, we are able to demonstrate that the Copenhagen and Paris Schools are not methodologically incompatible, and empirically that public attention for security issues has a tendency to dissipate without continual discursive investment.

Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.—Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.

Mechanisms that alter protein phosphatase 2A (PP2A)-dependent lung tumour suppression via the I2PP2A/SET oncoprotein are unknown. We show here that the tumour suppressor ceramide binds I2PP2A/SET selectively in the nucleus and including its K209 and Y122 residues as determined by molecular modelling/simulations and site-directed mutagenesis. Because I2PP2A/SET was found overexpressed, whereas ceramide was downregulated in lung tumours, a sphingolipid analogue drug, FTY720, was identified to mimick ceramide for binding and targeting I2PP2A/SET, leading to PP2A reactivation, lung cancer cell death, and tumour suppression in vivo. Accordingly, while molecular targeting of I2PP2A/SET by stable knockdown prevented further tumour suppression by FTY720, reconstitution of WT-I2PP2A/SET expression restored this process. Mechanistically, targeting I2PP2A/SET by FTY720 mediated PP2A/RIPK1-dependent programmed necrosis (necroptosis), but not by apoptosis. The RIPK1 inhibitor necrostatin and knockdown or genetic loss of RIPK1 prevented growth inhibition by FTY720. Expression of WT- or death-domain-deleted (DDD)-RIPK1, but not the kinase-domain-deleted (KDD)-RIPK1, restored FTY720-mediated necroptosis in RIPK1(-/-) MEFs. Thus, these data suggest that targeting I2PP2A/SET by FTY720 suppresses lung tumour growth, at least in part, via PP2A activation and necroptosis mediated by the kinase domain of RIPK1.

A novel circular CMOS MAGFET (Magnetic Field Effect Transistor) design is introduced and a novel device geometry design methodology is proposed to optimize the magnetic particle detection sensitivity of such devices. In order to optimize the signal to noise ratio, it was determined that the geometry of the MAGFET is required to have specific ratios, where its sector angle θ and its inner and outer radii r1 and r2 are optimized when θ/ln(r2/r1) = 1.3 . Compared to the more traditional rectangular MAGFET, the circular MAGFET has compatible SNR peak performance with rectangular MAGET. However, when the size of the MAGFET is scaled down in order to detect smaller magnetic particles, the proposed circular MAGFET has more robust SNR performance, design flexibility and tolerance to processing variations.