Background: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans... Show moreBackground: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of C-14-labeled ACT-541468 to investigate its absorption, distribution, metabolism, and excretion (ADME).Methods: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry.Results: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine.Conclusion: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations. Show less
Scattering of light in the presence of nano-structured materials, i.e. with features in the order of the wavelength of the light or smaller, reveals details of how light interacts with matter at... Show moreScattering of light in the presence of nano-structured materials, i.e. with features in the order of the wavelength of the light or smaller, reveals details of how light interacts with matter at the nanoscale. In this dissertation we present four cases of light scattering on nano-structures. First we describe how light confined in 2D structures, namely a dielectric membrane and a metal layer, interacts with either a single nano-hole or a hole-array. Then, we study two cases of light propagating in random scattering media: we show how phase modulation can be used to measure scattering properties in a volume scatterer (e.g. white paint), and we investigate light transport in a rough thin-film silicon solar cell. Show less
'Bewegend lezen' stelt een cinematografische leeshouding voor en doet dit via Thomas Rosenbooms roman 'Gewassen vlees'(1994), door velen beschouwd als historische roman. Dit proefschrift verkent... Show more'Bewegend lezen' stelt een cinematografische leeshouding voor en doet dit via Thomas Rosenbooms roman 'Gewassen vlees'(1994), door velen beschouwd als historische roman. Dit proefschrift verkent wat het kan betekenen wanneer analytische instrumenten uit de narratologie en de filmanalyse gezamenlijk worden ingezet. Zo laat het zien dat de roman juist deze leeshouding uitlokt wat leidt tot verbindingen met filmgenres en specifieke filmfragmenten. Via analyses van diverse fragmenten wordt helder op welke wijze de roman omgaat met 'het verleden', namelijk: ambigue. Enerzijds speelt de roman in op een dominante fictie en gaat daarbij pornografisch om met ons verleden: het verleden is een lustobject. Anderzijds verstoort de roman ook, evenzo pornografisch, de dominante fictie van de historische roman, bijvoorbeeld door het introduceren van een beeldtaal die nauw aansluit bij animatie-, slapstick- en griezelaspecten. de inzichten die deze dissertatie biedt door deze cinematografische leeshouding aan te nemen hebben consequenties voor onze visie op en omgang met het verleden, onze leeservaring en ons literatuuronderwijs. Show less
Meer, B.J. van; Vries, H. de; Firth, K.S.A.; Weerd, J. van; Tertoolen, L.G.J.; Karperien, H.B.J.; ... ; Mummery, C.L. 2017
The polymer polydimethylsiloxane (PDMS) is widely used to build microfluidic devices compatible with cell culture. Whilst convenient in manufacture, PDMS has the disadvantage that it can absorb... Show moreThe polymer polydimethylsiloxane (PDMS) is widely used to build microfluidic devices compatible with cell culture. Whilst convenient in manufacture, PDMS has the disadvantage that it can absorb small molecules such as drugs. In microfluidic devices like "Organs-on-Chip", designed to examine cell behavior and test the effects of drugs, this might impact drug bioavailability. Here we developed an assay to compare the absorption of a test set of four cardiac drugs by PDMS based on measuring the residual non-absorbed compound by High Pressure Liquid Chromatography (HPLC). We showed that absorption was variable and time dependent and not determined exclusively by hydrophobicity as claimed previously. We demonstrated that two commercially available lipophilic coatings and the presence of cells affected absorption. The use of lipophilic coatings may be useful in preventing small molecule absorption by PDMS. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. Show less
This thesis describes coupling of light to periodic structures. A material is patterned with a regular pattern on a length scale comparable to the wavelength of light. With these structures, light... Show moreThis thesis describes coupling of light to periodic structures. A material is patterned with a regular pattern on a length scale comparable to the wavelength of light. With these structures, light can be manipulated very precisely. The structures find applications in semiconductor lasers, light emitting diodes (LEDs), photovoltaic cells, and detectors of light. A periodic array of holes in a layer of semiconductor or in a thin metal film causes a coupling between the incident light and light that is trapped inside the layer. This coupling can be studied by measuring the reflection and transmission. The environment has an important role here; e.g. placing glass antennas in the holes can increase the coupling between light and plasmons. A thin, superconducting wire can be used as a detector of light. To increase the surface area, the wire is folded into a meander. The optical properties of this detector are very dependent on the polarization, due to the regular periodic structure of the meander. Moreover, we found that the absorption of a very thin absorbing layer can be almost 100%, when it is illuminated under the right angle, from the substrate. This can be used to increase the efficiency of the detectors. Show less
In the present we focus on the optical properties of the Green Fluorescent Protein (GFP), which are modelled using the state-of-the-art computational tools availeable up to date: the Density... Show moreIn the present we focus on the optical properties of the Green Fluorescent Protein (GFP), which are modelled using the state-of-the-art computational tools availeable up to date: the Density Functional Theory (DFT) in the Hybrid QM/MM approach is employed to access the ground state configuration of the chromphore in the protein environment, while Time-Dependent DFT and quantum Monte Carlo (QMC) relate the geometry to the abserved absorption spectra. Show less
