Duramycin-induced calcium release in cancer cells

Introduction: Duramycin through binding with phosphatidylethanolamine (PE) has shown potential to be an effective anti-tumour agent. However its mode of action in relation to tumour cells is not fully understood. Methods: PE expression on the surface of a panel of cancer cell lines was analysed using duramycin and subsequent antibody labelling then analysed by flow cytometry. Cell viability was also assessed via flow cytometry using annexin V and propidium iodide (PI). Calcium ion (Ca²⁺) release by tumour cells in response to duramycin was determined by spectrofluorometry following incubation with Fluo-3, AM. Confocal microscopy was performed on the cancer cell line AsPC-1 to assess real time cell response to duramycin treatment. Results: Duramycin was able to detect cell surface PE expression on all 15 cancer cell lines screened, which was shown to be duramycin concentration dependent. However higher concentrations induced necrotic cell death. Duramycin induced calcium ion (Ca²⁺) release from the cancer cell lines also in a concentration and time dependent manner. Confocal microscopy showed an influx of PI into the cells over time and induced morphological changes. Conclusion: Duramycin induces Ca²⁺ release from cancer cell lines in a time and concentration dependent relationship

Effect of distortion on the buckling strength of stiffened panels

This paper predicts the behaviour of stiffened plates with different distortion levels in order to address a rational structural design procedure as pre-existing and fabricationrelated (like weld-induced) initial geometrical distortion is of great importance in structural design point of view. The considered range of scantlings, the distortion typesand levels were chosen, based on panels used at BVT Surface Fleet Ltd., where the type 45 destroyer were under construction. An analytical relation is presented based on Perry's column approach to establish the variation of buckling strength against the geometrical distortion. A parametric form of non linear finite element analysis using ABAQUS has been carried out under axial loading condition to predict the behaviour and the buckling strength. The effect of residual stress is not considered in this study. A new strength parameter is proposed to represent buckling strength which takes into account the inelastic post-buckling behaviour of the structure. The results from FE analysis are plotted in non-dimensional terms and arrived at some important conclusions

Unternehmenskultur und Customer Relationship Management in Bezug auf Kundenzufriedenheit und Kundenloyalität anhand einer empirischen Studie

Auf den theoretischen Teil mit grundsätzlichen Faktoren und Erläuterungen zu Franchising, Customer Relationship Management, der Reputation eines Unternehmens und Kultur als allgemeinem Begriff folgte eine deskriptive Analyse der ausgewerteten Fragebögen, welche einleitend Alter, Geschlecht, Herkunftsland sowie Ausbildung der befragten Testpersonen beschreibt. In weiterer Folge dieser ersten Analyse der empirischen Auswertung wurde die Beschwerdebereitschaft der Befragten und ihre Kundenzufriedenheit verglichen und mit den Standorten der beiden Restaurants TGI Friday’s und Salud näher analysiert. Auf Grund der übersichtlichen Gliederung sowie Darstellung in Form von Tabellen, Grafiken und Abbildungen kann die Arbeit einen guten Überblick der beschriebenen Themen bieten und eine interessante Einleitung für die folgenden empirisch analysierten Themen darstellen. Des Weiteren wurde das aufgestellte Modell (Kapitel 6.2.3) mittels linearer Regressionsanalyse ausführlich getestet. Vorbereitend wurde einerseits eine Reliabilitätsanalyse, andererseits eine Faktorenanalyse der einzelnen Variablen durchgeführt, um die Modelltauglichkeit zu gewährleisten. Alles in allem zeigte das Modell einen guten „Fit“. Dies hat zur Bedeutung, dass sich die Basiskomponenten des Modells Kundenzufriedenheit sowie Kundenloyalität eindeutig erklären lassen und die theoretischen Aspekte der Arbeit durch die empirische Analyse bewiesen werden konnten. Diese Masterarbeit zeigt deutlich auf, dass die Beschäftigung mit Kundenzufriedenheit und Kundenloyalität vor Gründung mittels Franchising unumgänglich ist. In dem Potential dieser beiden Faktoren liegen Möglichkeiten zur erfolgreichen Führung unter anderem des Restaurants- Franchisings. Prinzipiell ist es möglich, dass Modell als Ausgangspunkt für weitere Studien heranzuziehen. Es wurde zwar an zwei Franchise- Restaurants geprüft, allerdings ist es vorstellbar das Modell auf andere Branchen auszuweiten um dessen praktische Relevanz erneut zu analysieren. Die Erweiterung des Modells mit zusätzlichen Faktoren könnte sich außerdem als hilfreich erweisen um die Möglichkeit zu schaffen, eine verstärkte Aussage über die Kundenzufriedenheit und Kundenloyalität zu erlangen

The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.

The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5-6-wk-old female mice from the HMDP (4-5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a "genetical genomics" approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL

Differential tangential expansion as a mechanism for cortical gyrification.

Gyrification, the developmental buckling of the cortex, is not a random process-the forces that mediate expansion do so in such a way as to generate consistent patterns of folds across individuals and even species. Although the origin of these forces is unknown, some theories have suggested that they may be related to external cortical factors such as axonal tension. Here, we investigate an alternative hypothesis, namely, whether the differential tangential expansion of the cortex alone can account for the degree and pattern-specificity of gyrification. Using intrinsic curvature as a measure of differential expansion, we initially explored whether this parameter and the local gyrification index (used to quantify the degree of gyrification) varied in a regional-specific pattern across the cortical surface in a manner that was replicable across independent datasets of neurotypicals. Having confirmed this consistency, we further demonstrated that within each dataset, the degree of intrinsic curvature of the cortex was predictive of the degree of cortical folding at a global and regional level. We conclude that differential expansion is a plausible primary mechanism for gyrification, and propose that this perspective offers a compelling mechanistic account of the co-localization of cytoarchitecture and cortical folds

Research protocol – Assessing Post-Stroke Psychology Longitudinal Evaluation (APPLE) study : A prospective cohort study in stroke

Acknowledgements The following experts provided advice on the design and conduct of the APPLE study: Prof Jonathan Evans (University of Glasgow); Prof Gillian Mead (University of Edinburgh); Prof Sarah T Pendlebury (University of Oxford) Funding This work was supported by the Chief Scientist Office and Stroke Association (funders reference PPA 2015/01_CSO).Peer reviewedPublisher PD

Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

International audiencePURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of \textgreater2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy

Enrichment of Sialylated IgG by Lectin Fractionation Does Not Enhance the Efficacy of Immunoglobulin G in a Murine Model of Immune Thrombocytopenia

Intravenous immunoglobulin G (IVIg) is widely used against a range of clinical symptoms. For its use in immune modulating therapies such as treatment of immune thrombocytopenic purpura high doses of IVIg are required. It has been suggested that only a fraction of IVIg causes this anti immune modulating effect. Recent studies indicated that this fraction is the Fc-sialylated IgG fraction. The aim of our study was to determine the efficacy of IVIg enriched for sialylated IgG (IVIg-SA (+)) in a murine model of passive immune thrombocytopenia (PIT). We enriched IVIg for sialylated IgG by Sambucus nigra agglutinin (SNA) lectin fractionation and determined the degree of sialylation. Analysis of IVIg-SA (+) using a lectin-based ELISA revealed that we enriched predominantly for Fab-sialylated IgG, whereas we did not find an increase in Fc-sialylated IgG. Mass spectrometric analysis confirmed that Fc sialylation did not change after SNA lectin fractionation. The efficacy of sialylated IgG was measured by administering IVIg or IVIg-SA (+) 24 hours prior to an injection of a rat anti-mouse platelet mAb. We found an 85% decrease in platelet count after injection of an anti-platelet mAb, which was reduced to a 70% decrease by injecting IVIg (p<0.01). In contrast, IVIg-SA (+) had no effect on the platelet count. Serum levels of IVIg and IVIg-SA (+) were similar, ruling out enhanced IgG clearance as a possible explanation. Our results indicate that SNA lectin fractionation is not a suitable method to enrich IVIg for Fc-sialylated IgG. The use of IVIg enriched for Fab-sialylated IgG abolishes the efficacy of IVIg in the murine PIT model

Funny walking : the rise, fall and rise of the Anglo-American comic eccentric dancer

This article will attempt to reposition comic eccentric dance as a metamorphic form that still, surprisingly, exists, and is to be found with reasonable ubiquity, in renewed incarna-tions within twenty first century media. Tracing the origins of comic eccentric dance through examples of earlier comedy performance, and drawing from Bergson’s comic theory of body misalliance, this article will dis-cuss this particularly ludic fusion of music and comedy. Further changes to the form affected by modernist preoccupations during the new Jazz Age at the turn of the twentieth century will be suggested. Finally, ways in which the formulation lives on in twenty-first century in-carnations in the comedy work of, for instance, Jimmy Fallon and Ricky Gervase, and in popular television shows such as Strictly Come Dancing (BBC 2004 - ) and Britain’s Got Talent (ITV 2006 - ) will be posited