Impact of Low-Dose Ionizing Radiation on Cognitive Abilities in the Mouse : Assessment of Radiation Sensitivity during Pre- and Postnatal Brain Development

In our modern society various sources of radiation are omnipresent. Sectors like nuclear power generation, long distance air travel and medical radiation diagnostics rank among the most prominent. Especially, the amount of medically necessary radiation is increasing and represents a major source of exposure in the general population. Therefore, radiation protection and the epidemiology of radiation have gained in importance. The risk possibly arising from exposure to low-dose radiation is still part of intensive and ongoing debates, demonstrating that current results are still controversial. Consequently, further studies on the effects of low-dose radiation are of great social relevance. Systemic studies within animals could provide additional information about radiation impact on behaviour and neurogenesis within the hippocampus, thus contributing to a better understanding of radiation induced sequelae and improving current risk assessment. This thesis evaluates the effects of low-dose ionizing radiation (LDIR, defined as ≤ 0.5 Gy) on murine behaviour and neurogenesis. Chapter I and II deal with irradiations at specific time points during prenatal (E14.5) and early postnatal (P10) brain development and provide results on the long-term sensitivity to low-dose radiation. Chapter III deals with low-dose irradiation during different learning phases at an early adult stage (two months) and provides results on the short-term sensitivity to low-dose radiation. Chapter IV deals with the long-term effects of low-dose irradiation at E14.5 or P10 on neurogenesis. Chapter V provides an overarching comparison of all time points of irradiation. Mice performed a set of behavioural tasks including the Rotarod performance test for the analysis of motor function and coordination, the Elevated-Zero-Maze for evaluation of anxiety and exploration, and the Morris Water Maze for the analysis of spatial learning and memory abilities. Furthermore, naïve mice were irradiated at E14.5 or P10 and analyzed immunohistologically at the age of two months. Here, the focus was on quantification of DCX+ neural progenitor cells in the neurogenic niche of the dentate gyrus. Substantial dose-dependent effects during MWM testing were detected after irradiation at the time points E14.5 and P10, but not after irradiations in two months old mice compared to Sham controls. Impairment of MWM performance was characterized by decreasing efficiencies in spatial searching and disturbed reference memory with increasing irradiation dose. The comparison of E14.5 and P10 revealed only slight differences, so that a similar sensitivity to low-dose irradiation was ascribed to both time points. Immunohistological analysis revealed that irradiation with 0.5 Gy reduced the number of DCX+ progenitor cells in the adult dentate gyrus of naïve mice after both the embryonic and the early postnatal irradiation. However, a significant cell loss was only observed in mice irradiated at E14.5 compared to the P10. My data show that the neurogenic niche in the dentate gyrus reacts very sensitive to radiation exposure, even if doses are low. The alterations in neurogenesis are certainly associated with learning and memory deficits. As the observed impact on neurogenesis was differently pronounced in naïve animals irradiated at E14.5 or P10, whereas the observed cognitive effects were quite similar, the reduced number of progenitor cells within the hippocampal network was probably not the only relevant trigger for cognitive impairment. It is conceivable that migration of progenitor cells and synaptogenesis which are crucial steps during murine brain development at E14.5 and P10, respectively, add an extra layer of complexity to radiation-induced sequelae that should be also taken into consideration in the human brain

New insight into the dynamic properties and the active site architecture of H-Ras p21 revealed by X-ray crystallography at very high resolution

<p>Abstract</p> <p>Background</p> <p>In kinetic crystallography, the usually static method of X-ray diffraction is expanded to allow time-resolved analysis of conformational rearrangements in protein structures. To achieve this, reactions have to be triggered within the protein crystals of interest, and optical spectroscopy can be used to monitor the reaction state. For this approach, a modified form of H-Ras p21 was designed which allows reaction initiation and fluorescence readout of the initiated GTPase reaction within the crystalline state. Rearrangements within the crystallized protein due to the progressing reaction and associated heterogeneity in the protein conformations have to be considered in the subsequent refinement processes.</p> <p>Results</p> <p>X-ray diffraction experiments on H-Ras p21 in different states along the reaction pathway provide detailed information about the kinetics and mechanism of the GTPase reaction. In addition, a very high data quality of up to 1.0 Å resolution allowed distinguishing two discrete subconformations of H-Ras p21, expanding the knowledge about the intrinsic flexibility of Ras-like proteins, which is important for their function. In a complex of H-Ras•GppNHp (guanosine-5'-(β,γ-imido)-triphosphate), a second Mg²⁺ion was found to be coordinated to the γ-phosphate group of GppNHp, which positions the hydrolytically active water molecule very close to the attacked γ-phosphorous atom.</p> <p>Conclusion</p> <p>For the structural analysis of very high-resolution data we have used a new 'two-chain-isotropic-refinement' strategy. This refinement provides an alternative and easy to interpret strategy to reflect the conformational variability within crystal structures of biological macromolecules. The presented fluorescent form of H-Ras p21 will be advantageous for fluorescence studies on H-Ras p21 in which the use of fluorescent nucleotides is not feasible.</p

Size Dependent Transport of Floating Plastics Modeled in the Global Ocean

Plastic has been detected in the ocean in most locations where scientists have looked for it. While ubiquitous in the environment, plastic pollution is heterogeneous, and plastics of varying composition, shape, and size accumulate differently in the global ocean. Many physical and biological processes influence the transport of plastics in the marine environment. Here we focus on physical processes and how they can naturally sort floating plastics at the ocean surface and within its interior. We introduce a new open-source GPU-accelerated numerical model, ADVECT, which simulates the three-dimensional dispersal of large arrays of modelled ocean plastics with varying size, shape, and density. We use this model to run a global simulation and find that buoyant particles are sorted in the ocean according to their size, both at the surface due to wind-driven drift and in the water column due to their rising velocity. Finally, we compare our findings with recent literature reporting the size distribution of plastics in the ocean and discuss which observations can and cannot be explained by the physical processes encoded in our model

Nutzerintegration bei der Produktentwicklung am Beispiel der Medizintechnik

Aus der Einführung: "Eine systematische Vorgehensweise entsprechend der Konstruktionsmethodik gilt als zielführender Ansatz bei der Findung von technischen Lösungen und der Entwicklung von Produkten. In der Literatur finden sich dazu zahlreiche Veröffentlichungen z. B. Feldhusen & Grote 2013; Ehrlenspiel 2014; Ehrlenspiel 2009; Roth 1994 und Livotov 2013. Die VDI Richtlinie 2221 „Methodik zum Entwickeln und Konstruieren technischer Systeme und Produkte“ (VDI 1993) beschreibt ebenfalls allgemeingültige Regeln bei der systematischen Lösungsfindung. Iterativ wird in mehreren Teilschritten eine zuvor definierte Aufgabe in eine Lösung überführt. Dabei werden die Phasen der Planung, der Konzeption, des Entwurfes und der Ausarbeitung durchschritten. In der Literatur und den Richtlinien ist jedoch keine explizite Rückkopplung mit dem Nutzer gefordert oder angedacht. Gerade vor dem Hintergrund der voranschreitenden Individualisierung der Produkte und kann hierin ein entscheidender Vorteil liegen. Entwicklungszyklen und die Zeit bis zur Markteinführung von Produkten können reduziert werden. Zudem ist von einer höheren Akzeptanz durch den Kunden auszugehen. ...

In situ observations of the atomistic mechanisms of Ni catalyzed low temperature graphene growth.

The key atomistic mechanisms of graphene formation on Ni for technologically relevant hydrocarbon exposures below 600 °C are directly revealed via complementary in situ scanning tunneling microscopy and X-ray photoelectron spectroscopy. For clean Ni(111) below 500 °C, two different surface carbide (Ni2C) conversion mechanisms are dominant which both yield epitaxial graphene, whereas above 500 °C, graphene predominantly grows directly on Ni(111) via replacement mechanisms leading to embedded epitaxial and/or rotated graphene domains. Upon cooling, additional carbon structures form exclusively underneath rotated graphene domains. The dominant graphene growth mechanism also critically depends on the near-surface carbon concentration and hence is intimately linked to the full history of the catalyst and all possible sources of contamination. The detailed XPS fingerprinting of these processes allows a direct link to high pressure XPS measurements of a wide range of growth conditions, including polycrystalline Ni catalysts and recipes commonly used in industrial reactors for graphene and carbon nanotube CVD. This enables an unambiguous and consistent interpretation of prior literature and an assessment of how the quality/structure of as-grown carbon nanostructures relates to the growth modes.L.L.P. acknowledges funding from Area di Ricerca Scientifica e Tecnologica of Trieste and from MIUR through Progetto Strategico NFFA. C.A. acknowledges support from CNR through the ESF FANAS project NOMCIS. C.A. and C.C. acknowledge financial support from MIUR (PRIN 2010-2011 nº 2010N3T9M4). S.B. acknowledges funding from ICTP TRIL program. S.H. acknowledges funding from ERC grant InsituNANO (n°279342). R.S.W. acknowledges funding from EPSRC (Doctoral training award), and the Nano Science & Technology Doctoral Training Centre Cambridge (NanoDTC). The help of C. Dri and F. Esch (design) and P. Bertoch and F. Salvador (manufacturing) in the realization of the high temperature STM sample holder is gratefully acknowledged. We acknowledge the Helmholtz-Zentrum-Berlin Electron storage ring BESSY II for provision of synchrotron radiation at the ISISS beamline and we thank the BESSY staff for continuous support of our experiments.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/nn402927q

Nutzerintegration bei der Produktentwicklung am Beispiel der Medizintechnik

Aus der Einführung: "Eine systematische Vorgehensweise entsprechend der Konstruktionsmethodik gilt als zielführender Ansatz bei der Findung von technischen Lösungen und der Entwicklung von Produkten. In der Literatur finden sich dazu zahlreiche Veröffentlichungen z. B. Feldhusen & Grote 2013; Ehrlenspiel 2014; Ehrlenspiel 2009; Roth 1994 und Livotov 2013. Die VDI Richtlinie 2221 „Methodik zum Entwickeln und Konstruieren technischer Systeme und Produkte“ (VDI 1993) beschreibt ebenfalls allgemeingültige Regeln bei der systematischen Lösungsfindung. Iterativ wird in mehreren Teilschritten eine zuvor definierte Aufgabe in eine Lösung überführt. Dabei werden die Phasen der Planung, der Konzeption, des Entwurfes und der Ausarbeitung durchschritten. In der Literatur und den Richtlinien ist jedoch keine explizite Rückkopplung mit dem Nutzer gefordert oder angedacht. Gerade vor dem Hintergrund der voranschreitenden Individualisierung der Produkte und kann hierin ein entscheidender Vorteil liegen. Entwicklungszyklen und die Zeit bis zur Markteinführung von Produkten können reduziert werden. Zudem ist von einer höheren Akzeptanz durch den Kunden auszugehen. ...

Development of a skull phantom for the assessment of implant X-ray visibility

The paper presents the development and test of a skull phantom, which can be used for the assessment of the radiographic visibility of neurovascular implants. State of the art methods are based on specimens of the human skull. These are highly individual and not suitable for comparison of different radiographic data sets. The development process of the skull phantom is described from data generation to image processing, design and manufacturing using 3D printing. An experimental setup is recommended to generate reproducible data sets for implant visibility assessment with bone mimicking structures of the phantom. The model is evaluated by qualitative comparison with equivalent data sets of the original human skull model. The results show, that contrast characteristics of the phantom and the human skull model are similar. X-ray attenuation of the human bone is higher than the polymeric phantom material. The introduced phantom allows the determination of X-ray attenuation characteristics of different neurovascular implants for medical approval and testing processes

Nutzerintegration bei der Produktentwicklung am Beispiel der Medizintechnik

Aus der Einführung: "Eine systematische Vorgehensweise entsprechend der Konstruktionsmethodik gilt als zielführender Ansatz bei der Findung von technischen Lösungen und der Entwicklung von Produkten. In der Literatur finden sich dazu zahlreiche Veröffentlichungen z. B. Feldhusen & Grote 2013; Ehrlenspiel 2014; Ehrlenspiel 2009; Roth 1994 und Livotov 2013. Die VDI Richtlinie 2221 „Methodik zum Entwickeln und Konstruieren technischer Systeme und Produkte“ (VDI 1993) beschreibt ebenfalls allgemeingültige Regeln bei der systematischen Lösungsfindung. Iterativ wird in mehreren Teilschritten eine zuvor definierte Aufgabe in eine Lösung überführt. Dabei werden die Phasen der Planung, der Konzeption, des Entwurfes und der Ausarbeitung durchschritten. In der Literatur und den Richtlinien ist jedoch keine explizite Rückkopplung mit dem Nutzer gefordert oder angedacht. Gerade vor dem Hintergrund der voranschreitenden Individualisierung der Produkte und kann hierin ein entscheidender Vorteil liegen. Entwicklungszyklen und die Zeit bis zur Markteinführung von Produkten können reduziert werden. Zudem ist von einer höheren Akzeptanz durch den Kunden auszugehen. ...