3D Micro-PIXE at atmospheric pressure: A new tool for the investigation of art and archaeological objects

The paper describes a novel experiment characterized by the development of a confocal geometry in an external Micro-PIXE set-up. The position of X-ray optics in front of the X-ray detector and its proper alignment with respect to the proton micro-beam focus provided the possibility of carrying out 3D Micro-PIXE analysis. As a first application, depth intensity profiles of the major elements that compose the patina layer of a quaternary bronze alloy were measured. A simulation approach of the 3D Micro-PIXE data deduced elemental concentration profiles in rather good agreement with corresponding results obtained by electron probe micro-analysis from a cross-sectioned patina sample. With its non-destructive and depth-resolving properties, as well as its feasibility in atmospheric pressure, 3D Micro-PIXE seems especially suited for investigations in the field of cultural heritage.     

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGlo^TM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.     

In search of trustworthy information: a qualitative study of the search behavior of people with dyslexia in Norway

Universal Access in the Information Society - Access to trustworthy information is a premise for participation in a democratic society. However, locating useful and valid information may not be a...     

Digital Elevation Model generation for historical landscape analysis based on LiDAR data,a case study in Flanders (Belgium)

This paper discusses the generation of a high precision DEM (Digital Elevation Model) based on high density airborne LiDAR (Light Detection and Ranging) data for an interdisciplinary landscape archaeological study concerning the settlement history and environment in Sandy Flanders, a region to the north of Ghent (Belgium). The objective was to create a detailed topographical surface free of artificial features and topographical artefacts, in the form of a DEM, visualizing the natural and current topography through the implementation of true ground points only. The semi-automatical removal of these features and artefacts was based on topographical vector data, visual interpretations and slope analysis. Ultimately two DEM’s were constructed (1) a TIN (Triangulated Irregular Network) model, whereby the inherent large file format restricts the usability to large scale and (2) a grid model which can be used for small-, medium- and large-scale applications. Both datasets were used as an image that is interpreted using ancillary data from historical sources. Its usefulness is illustrated in a case of field pattern and microfield topography. Starting from this DEM, the approach of this landscape historical study is mainly retrogressive, i.e. starting from the landscape structures and elements that are still present in the contemporary landscape and moving into the past.     

Autonomic information flow improves prognostic impact of task force HRV monitoring

Heart rate variability (HRV) represents the cardiovascular control mediated by the autonomic nervous system and other mechanisms. In the established task force HRV monitoring different cardiovascular control mechanisms can approximately be identified at typical frequencies of heart rate oscillations by power spectral analysis. HRV measures assessing complex and fractal behavior partly improved clinical risk stratification. However, their relationship to (patho-)physiology is not sufficiently explored. Objective of the present work is the introduction of complexity measures of different physiologically relevant time scales. This is achieved by a new concept of the autonomic information flow (AIF) analysis which was designed according to task force HRV. First applications show that different time scales of AIF improve the risk stratification of patients with multiple organ dysfunction syndrome and cardiac arrest patients in comparison to standard HRV. Each group's significant time scales correspond to their respective pathomechanisms.     

Asymptotic statistical theory of overtraining and cross-validation

A statistical theory for overtraining is proposed. The analysis treats general realizable stochastic neural networks, trained with Kullback-Leibler divergence in the asymptotic case of a large number of training examples. It is shown that the asymptotic gain in the generalization error is small if we perform early stopping, even if we have access to the optimal stopping time. Based on the cross-validation stopping we consider the ratio the examples should be divided into training and cross-validation sets in order to obtain the optimum performance. Although cross-validated early stopping is useless in the asymptotic region, it surely decreases the generalization error in the nonasymptotic region. Our large scale simulations done on a CM5 are in good agreement with our analytical findings.     

SK119, a Novel Shikonin Derivative,Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC₅₀ values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.