Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH‐102

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH‐101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg^?1) of the closely related analogue UCPH‐102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH‐102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH‐102 (10 μm ) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH‐102 (20 mg kg^?1) did not induce acute effects or any visible changes in behavior.     

Scatter correction of transmission near-infrared spectra by photon migration data: quantitative analysis of solids

The scope of this work is a new methodology to correct conventional near-infrared (NIR) data for scattering effects. The technique aims at measuring the absorption coefficient of the samples rather than the total attenuation measured in conventional NIR spectroscopy. The main advantage of this is that the absorption coefficient is independent of the path length of the light inside the sample and therefore independent of the scattering effects. The method is based on time-resolved spectroscopy and modeling of light transport by diffusion theory. This provides an independent measure of the scattering properties of the samples and therefore of the path length of light. This yields a clear advantage over other preprocessing techniques, where scattering effects are estimated and corrected for by using the shape of the measured spectrum only. Partial least squares (PLS) calibration models show that, by using the proposed evaluation scheme, the predictive ability is improved by 50% as compared to a model based on conventional NIR data alone. The method also makes it possible to predict the concentration of active substance in samples with other physical properties than the samples included in the calibration model.     

Least-squares support vector machines modelization for time-resolved spectroscopy

By use of time-resolved spectroscopy it is possible to separate light scattering effects from chemical absorption effects in samples. In the study of propagation of short light pulses in turbid samples the reduced scattering coefficient and the absorption coefficient are usually obtained by fitting diffusion or Monte Carlo models to the measured data by use of numerical optimization techniques. In this study we propose a prediction model obtained with a semiparametric modeling technique: the least-squares support vector machines. The main advantage of this technique is that it uses theoretical time dispersion curves during the calibration step. Predictions can then be performed by use of data measured on different kinds of sample, such as apples.     

The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients’ asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.     

Radiation doses to Norwegian heart-transplanted patients undergoing annual coronary angiography

Heart-transplanted patients in Norway undergo annual coronary angiography (CA). The aims of this study were to establish a conversion factor between dose-area product and effective dose for these examinations and to use this to evaluate the accumulated radiation dose and risks associated with annual CA. An experienced cardiac interventionist performed a simulated examination on an Alderson phantom loaded with thermoluminescence dosemeters. The simulated CA examination yielded a dose-area product of 17 Gy cm(2) and an effective dose of 3.4 mSv: the conversion factor between dose-area product and effective dose was 0.20 mSv Gy cm(-2). Dose-area product values from 200 heart-transplanted patients that had undergone 906 CA examinations between 2001 and 2008 were retrieved from the institutional database. Mean dose-area product from annual CA was 25 Gy cm(2), ranging from 2 to 140 Gy cm(2). Mean number of CA procedure was 8 (range, 1-23). Mean accumulated effective dose for Norwegian heart-transplanted patients between 2001 and 2008 was 34 mSv (range, 5-113 mSv). Doses and radiation risks for heart-transplanted patients are generally low, because most heart transplantations are performed on middle-aged patients with limited life expectancy. Special concern should however be taken to reduce doses for young heart-transplanted patients who are committed to lifelong follow-up of their transplanted heart.     

Organising for infrastructure development programmes: Governing internal logic multiplicity across organisational spaces

Programme organisations operate in complex environments under the influence of multiple institutional logics. Previous studies have focused on how these kinds of organisations respond to external demands by implementing appropriate governance structures. This, however, produces an understanding of programme organisations as being unitary and working to integrate programme activities and practices under one dominant internal institutional logic. In this paper, we study the consequences of internal logic multiplicity for the governance of programme organisations. Drawing on data from a major Danish construction programme we show how, in order to achieve its mission, the programme organisation incorporates three distinct logics into its daily activities and practices. The findings illustrate how a compartmentalised structural approach is applied to differentiate and independently deal with the three logics in structurally distinct organisational spaces. To avoid fragmentation and ensure coordination, governance mechanisms are put in place that coordinate activities and practices across the organisational spaces whilst maintaining their compartmentalisation. The paper thus contributes to the literature on programme management with insights on how the institutional context influences programme structures and operations, and how governance mechanisms are implemented to manage activities and practices across organisational spaces guided by different logics.     

Visualisation Techniques for Using Spatial Augmented Reality in the Design Process of a Car

If spatial augmented reality is used in the design process of a car, then one of the most important issues is that the virtual content is projected with a very high visual quality onto the real object, because based on this projection design decisions are made. Especially, the visualised colours on the real object should not be distinguishable from corresponding real reference colours. In this paper, we introduce a new approach for the augmentation of real objects which is able to match the requirements of a design process. We present a new rendering method with ray tracing which increases the visual quality of the projection images in comparison to existing methods. The desired values of these images have further to be adjusted according to the material, the ambient light and the local orientation of the projector. For this purpose, we develop a physically based computation which exactly determines the corresponding projection intensities for these values by using three‐dimensional lookup tables at every projector pixel. Since not all of the desired values can be represented with an intensity of the projector, an adjustment has to be computed for these values. Therefore, we conduct a user study with design experts who work in the automotive industry and use the results to propose a new adjustment method for such values. Finally, we compare our methods to existing procedures and conclude which ones are suitable for the design process of a car.     

Verification of continuous dynamical systems by timed automata

This paper presents a method for abstracting continuous dynamical systems by timed automata. The abstraction is based on partitioning the state space of a dynamical system using positive invariant sets, which form cells that represent locations of a timed automaton. The abstraction is intended to enable formal verification of temporal properties of dynamical systems without simulating any system trajectory, which is currently not possible. Therefore, conditions for obtaining sound, complete, and refinable abstractions are set up.     

Development of a microfabricated electrochemical-cantilever hybrid platform

The design and fabrication of a combined electrochemical-cantilever microfluidic system is described. A chip integrating cantilevers with electrodes into a microchannel is presented with the accompanying polymer flow cell. Issues such as electrical and fluid connections are addressed, electromechanical behavior in ionic solution is investigated, and two uses of the system are demonstrated. First, all cantilevers are functionalized with cysteine, to facilitate detection of Cu²⁺ ions, then one cantilever is electrochemically cleaned in situ to generate a reference cantilever for differential measurements. Two concentrations of Cu²⁺ ions are successfully measured in this way. Clean cantilevers are used to probe a solution with and without [Fe(CN)₆]^3−/4− redox couple present, demonstrating the combined voltammetric and deflection readout.     

DisCoveR: accurate and efficient discovery of declarative process models

International Journal on Software Tools for Technology Transfer - Declarative process modeling formalisms—which capture high-level process constraints—have seen growing interest,...