TY - JOUR A1 - Zoltner, Martin A1 - Krienitz, Nina A1 - Field, Mark C. A1 - Kramer, Susanne T1 - Comparative proteomics of the two T. brucei PABPs suggests that PABP2 controls bulk mRNA JF - PLoS Neglected Tropical Diseases N2 - Poly(A)-binding proteins (PABPs) regulate mRNA fate by controlling stability and translation through interactions with both the poly(A) tail and eIF4F complex. Many organisms have several paralogs of PABPs and eIF4F complex components and it is likely that different eIF4F/PABP complex combinations regulate distinct sets of mRNAs. Trypanosomes have five eIF4G paralogs, six of eIF4E and two PABPs, PABP1 and PABP2. Under starvation, polysomes dissociate and the majority of mRNAs, most translation initiation factors and PABP2 reversibly localise to starvation stress granules. To understand this more broadly we identified a protein interaction cohort for both T. brucei PABPs by cryo-mill/affinity purification-mass spectrometry. PABP1 very specifically interacts with the previously identified interactors eIF4E4 and eIF4G3 and few others. In contrast PABP2 is promiscuous, with a larger set of interactors including most translation initiation factors and most prominently eIF4G1, with its two partners TbG1-IP and TbG1-IP2. Only RBP23 was specific to PABP1, whilst 14 RNA-binding proteins were exclusively immunoprecipitated with PABP2. Significantly, PABP1 and associated proteins are largely excluded from starvation stress granules, but PABP2 and most interactors translocate to granules on starvation. We suggest that PABP1 regulates a small subpopulation of mainly small-sized mRNAs, as it interacts with a small and distinct set of proteins unable to enter the dominant pathway into starvation stress granules and localises preferentially to a subfraction of small polysomes. By contrast PABP2 likely regulates bulk mRNA translation, as it interacts with a wide range of proteins, enters stress granules and distributes over the full range of polysomes. KW - Trypanosoma KW - mRNA KW - T. brucei KW - PABPs Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177126 VL - 12 IS - 7 ER - TY - JOUR A1 - Zimmerer, Chris A1 - Fischbach, Martin A1 - Latoschik, Marc Erich T1 - Semantic Fusion for Natural Multimodal Interfaces using Concurrent Augmented Transition Networks JF - Multimodal Technologies and Interaction N2 - Semantic fusion is a central requirement of many multimodal interfaces. Procedural methods like finite-state transducers and augmented transition networks have proven to be beneficial to implement semantic fusion. They are compliant with rapid development cycles that are common for the development of user interfaces, in contrast to machine-learning approaches that require time-costly training and optimization. We identify seven fundamental requirements for the implementation of semantic fusion: Action derivation, continuous feedback, context-sensitivity, temporal relation support, access to the interaction context, as well as the support of chronologically unsorted and probabilistic input. A subsequent analysis reveals, however, that there is currently no solution for fulfilling the latter two requirements. As the main contribution of this article, we thus present the Concurrent Cursor concept to compensate these shortcomings. In addition, we showcase a reference implementation, the Concurrent Augmented Transition Network (cATN), that validates the concept’s feasibility in a series of proof of concept demonstrations as well as through a comparative benchmark. The cATN fulfills all identified requirements and fills the lack amongst previous solutions. It supports the rapid prototyping of multimodal interfaces by means of five concrete traits: Its declarative nature, the recursiveness of the underlying transition network, the network abstraction constructs of its description language, the utilized semantic queries, and an abstraction layer for lexical information. Our reference implementation was and is used in various student projects, theses, as well as master-level courses. It is openly available and showcases that non-experts can effectively implement multimodal interfaces, even for non-trivial applications in mixed and virtual reality. KW - multimodal fusion KW - multimodal interface KW - semantic fusion KW - procedural fusion methods KW - natural interfaces KW - human-computer interaction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197573 SN - 2414-4088 VL - 2 IS - 4 ER - TY - JOUR A1 - Zielewska-Büttner, Katarzyna A1 - Heurich, Marco A1 - Müller, Jörg A1 - Braunisch, Veronika T1 - Remotely Sensed Single Tree Data Enable the Determination of Habitat Thresholds for the Three-Toed Woodpecker (Picoides tridactylus) JF - Remote Sensing N2 - Forest biodiversity conservation requires precise, area-wide information on the abundance and distribution of key habitat structures at multiple spatial scales. We combined airborne laser scanning (ALS) data with color-infrared (CIR) aerial imagery for identifying individual tree characteristics and quantifying multi-scale habitat requirements using the example of the three-toed woodpecker (Picoides tridactylus) (TTW) in the Bavarian Forest National Park (Germany). This bird, a keystone species of boreal and mountainous forests, is highly reliant on bark beetles dwelling in dead or dying trees. While previous studies showed a positive relationship between the TTW presence and the amount of deadwood as a limiting resource, we hypothesized a unimodal response with a negative effect of very high deadwood amounts and tested for effects of substrate quality. Based on 104 woodpecker presence or absence locations, habitat selection was modelled at four spatial scales reflecting different woodpecker home range sizes. The abundance of standing dead trees was the most important predictor, with an increase in the probability of TTW occurrence up to a threshold of 44–50 dead trees per hectare, followed by a decrease in the probability of occurrence. A positive relationship with the deadwood crown size indicated the importance of fresh deadwood. Remote sensing data allowed both an area-wide prediction of species occurrence and the derivation of ecological threshold values for deadwood quality and quantity for more informed conservation management. KW - deadwood KW - standing deadwood KW - dead tree KW - snags KW - three-toed woodpecker (Picoides tridactylus) KW - habitat suitability model (HSM) KW - habitat requirements KW - airborne laser scanning (ALS) KW - CIR aerial imagery Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197565 SN - 2072-4292 VL - 10 IS - 12 ER - TY - THES A1 - Ziegenhals, Thomas T1 - The role of the miR-26 family in neurogenesis T1 - Die Rolle der miR-26 Familie in der Neurogenese N2 - For the differentiation of a embryonic stem cells (ESCs) to neuronal cells (NCs) a complex and coordinated gene regulation program is needed. One important control element for neuronal differentiation is the repressor element 1 silencing transcription factor (REST) complex, which represses neuronal gene expression in non-neuronal cells. Crucial effector proteins of the REST complex are small phosphatases such as the CTDSPs (C-terminal domain small phosphatases) that regulate polymerase II activity by dephosphorylating the C-terminal domain of the polymerase, thereby repressing target genes. The stepwise inactivation of REST, including the CTDSPs, leads to the induction of a neuron-specific gene program, which ultimately induces the formation of neurons. The spatio-temporal control of REST and its effector components is therefore a crucial step for neurogenesis. In zebrafish it was shown that the REST-associated CTDSP2 is negatively regulated by the micro RNA (miR) -26b. Interestingly, the miR-26b is encoded in an intron of the primary transcript of CTDSP2. This gives the fundament of an intrinsic regulatory negative feedback loop, which is essential for the proceeding of neurogenesis. This feedback loop is active during neurogenesis, but inactive in non-neuronal cells. The reason for this is that the maturation of the precursor miR (pre-miR) to the mature miR-26 is arrested in non neuronal cells, but not in neurons. As only mature miRs are actively repressing genes, the regulation of miR-26 processing is an essential step in neurogenesis. In this study, the molecular basis of miR-26 processing regulation in the context of neurogenesis was addressed. The mature miR is processed from two larger precursors: First the primary transcript is cleaved by the enzyme DROSHA in the nucleus to form the pre-miR. The pre-miR is exported from the nucleus and processed further through the enzyme DICER to yield the mature miR. The mature miR can regulate gene expression in association with the RNA-induced silencing complex (RISC). Multiple different scenarios in which miR processing was regulated were proposed and experimentally tested. Microinjection studies using Xenopus leavis oocytes showed that slowdown or blockage of the nucleo-cytoplasmic transport are not the reason for delayed pre-miR-26 processing. Moreover, in vitro and in vivo miR-processing assays showed that maturation is most likely regulated through a in trans acting factor, which blocks processing in non neuronal cells. Through RNA affinity chromatographic assays using zebrafish and murine lysates I was able to isolate and identify proteins that interact specifically with pre-miR-26 and could by this influence its biogenesis. Potential candidates are FMRP/FXR1/2, ZNF346 and Eral1, whose functional characterisation in the context of miR-biogenesis could now be addressed. The second part of my thesis was executed in close colaboration with the laboratory of Prof. Albrecht Müller. The principal question was addressed how miR-26 influences neuronal gene expression and which genes are primarily affected. This research question could be addressed by using a cell culture model system, which mimics ex vivo the differentiation of ESCs to NCs via neuronal progenitor. For the functional analysis of miR-26 knock out cell lines were generated by the CRISPR/Cas9 technology. miR-26 deficient ESC keep their pluripotent state and are able to develop NPC, but show major impairment in differentiating to NCs. Through RNA deep sequencing the miR-26 induced transcriptome differences could be analysed. On the level of mRNAs it could be shown, that the expression of neuronal gene is downregulated in miR-26 deficient NCs. Interestingly, the deletion of miR-26 leads to selectively decreased levels of miRs, which on one hand regulate the REST complex and on the other hand are under transcriptional control by REST themself. This data and the discovery that induction of miR-26 leads to enrichment of other REST regulating miRs indicates that miR-26 initiates neurogenesis through stepwise inactivation of the REST complex. N2 - Für die Differenzierung von embryonalen Stammzellen (ESCs) zu Neuronen (NCs) bedarf es eines komplexen Genregulationsprogramms, welches sowohl zeitlich als auch räumlich reguliert werden muss. Ein wichtiger Faktor während der neuronalen Differenzierung ist der sogenannte „repressor element 1 silencing transcription factor“ (REST)-Komplex, welcher die Expression neuronaler Gene in nicht neuralen Zellen unterdrückt. Wichtige Effektorproteine im REST-Komplex sind kleine Phosphatasen (sog. CTDSPs), welche durch die Dephosphorylierung der C-terminalen Domäne der RNA-Polymerase II deren Aktivität an Zielgenen reprimiert. Die schrittweise Inaktivierung von REST, einschließlich der CTDSPs, führt hingegen zur Einleitung des neuronalen Genprogramms und damit zur Entwicklung von neuronalen Zellen. Die zeitliche Regulierung des REST-Komplexes und seiner assoziierten Effektor-Komponenten ist daher auf molekularer Ebene das entscheidende Ereignis in der Neurogenese. Studien in Zebrafisch haben gezeigt, dass die REST-assoziierte Phosphatase CTDSP2 von der micro-RNA (miR) -26b negativ reguliert wird, was zu einer reduzierten REST Aktivität führt. Interessanterweise liegt diese miR in einem Intron von CTDSP2, also dem Gen, welches sie selbst repremiert. Diese Konstellation stellt die Basis für eine intrinsische negative Rückkopplungsschleife dar und ist essentiell für das Voranschreiten der Neurogenese. Diese Schleife ist aktiv während der Neurogenese, jedoch inaktiv in neuronalen Stammzellen. Der Grund hierfür ist, dass die Reifung der miR-26b auf der Stufe der Prozessierung des miR-Vorläufers (pre-miR) zur reifen miR in Stammzellen, nicht aber in Neuronen, angehalten ist. Da nur reife miR funktionell aktiv sein können, ist die Regulation der miR-26 Reifung ein essentieller Schritt im Rahmen der Neurogenese. In dieser Dissertation sollte der Frage nach der molekularen Basis der regulierten Prozessierung der miR-26 im Rahmen der Neurogenese nachgegangen werden. Die Prozessierung von miR erfolgt über zwei Intermediate: Zunächst wird aus dem primären Transkript im Zellkern die pre-miR durch das Enzym DROSHA gebildet. Diese wird dann aus dem Kern exportiert und durch das Enzym DICER zur reifen miR weiterverarbeitet, die im Kontext des „RNA-Induced Silencing Complex“ (RISC) die post-transkriptionale Genexpression reguliert. Mirkoinjektionsstudien an Xenopus leavis Oocyten zeigten, dass eine Verlangsamung bzw. Blockade des nukleo-zytoplasmatischen Transports nicht Ursache für die verzögerte Prozessierung der pre-miR-26 sein kann. Stattdessen haben in vitro und in vivo Prozessierungsexperimente gezeigt, dass die Reifung der miR-26 sehr wahrscheinlich durch einen in trans agierenden Faktor gesteuert wird, der die Prozessierung in nicht-neuronalen Zellen blockiert. Durch RNA affinitätschromatographische Versuche gelang es, Proteine aus Maus- und Zebrafischlysaten zu isolieren und diese zu identifizieren, die spezifisch mit der pre-miR-26b interagieren und deren Biogenese beeinflussen könnten. Vielversprechende Kandidaten sind die Proteine FMRP/FXR1/2, ZNF346 und Eral1, deren funktionelle Charakterisierung im Kontext der miR-Biogenese nun möglich ist. In einer Kooperation mit der Arbeitsgruppe von Prof. Albrecht Müller wurde im zweiten Teil der Arbeit der prinzipiellen Frage nachgegangen, wie die miR-26 die neuronale Genexpression steuert und welche Gene hiervon primär betroffen sind. Diese Untersuchungen wurden durch die Etablierung eines Zellkultur-Protokolls ermöglicht, welches ex vivo die Differenzierung von ESC über neuronal Vorläufer Zellen (NPC) zu NCs erlaubte und so eine systematische Analyse dieses Prozess erlaubte. Für die Funktionsanalyse von miR-26 wurden über die CRISPR/Cas9 Technologie Zelllinien hergestellt, welche keine miR-26 mehr im Genom haben. miR-26 defiziente ESCs behalten ihren pluripotenten Status und ließen sich zu NPCs entwickeln. Die Weiterentwicklung von NPCs zu NCs war hingegen massiv eingeschränkt. Durch RNA Hochdurchsatzsequenzierung gelang es die miR-26 induzierten Genexpressionsunterschiede geanu zu identifizieren. Auf der Ebene der mRNA konnte gezeigt werden, dass die Expression von neuronalen Genen in miR-26 defizienten NCs herunterreguliert ist und dass unter diesen Bedingungen offensichtlich kein anderer Differenzierungsweg eingeschlagen werden konnte. Interessanterweise führte die Deletion von miR-26 zu einer selektiven Verminderung von miRs, die einerseits den REST Komplex regulieren, andererseits aber auch unter dessen transkriptionaler Kontrolle stehen. Diese Daten und die Entdeckung, dass die Induktion von miR-26 zur Anreicherung anderer REST regulierender miRs führt, lässt vermuten, dass miR-26 die Neurogenese durch die schrittweise Inaktivierung des REST Komplexe initiiert. KW - miRNS KW - Neurogenese KW - miR-26 KW - REST-Complex KW - miRNA Biogenesis KW - microrna KW - neurogenesis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156395 ER - TY - THES A1 - Zenk, Markus T1 - On Numerical Methods for Astrophysical Applications T1 - Über numerische Methoden für astrophysikalische Anwendungen N2 - Diese Arbeit befasst sich mit der Approximation der Lösungen von Modellen zur Beschreibung des Strömungsverhaltens in Atmosphären. Im Speziellen umfassen die hier behandelten Modelle die kompressiblen Euler Gleichungen der Gasdynamik mit einem Quellterm bezüglich der Gravitation und die Flachwassergleichungen mit einem nicht konstanten Bodenprofil. Verschiedene Methoden wurden bereits entwickelt um die Lösungen dieser Gleichungen zu approximieren. Im Speziellen geht diese Arbeit auf die Approximation von Lösungen nahe des Gleichgewichts und, im Falle der Euler Gleichungen, bei kleinen Mach Zahlen ein. Die meisten numerischen Methoden haben die Eigenschaft, dass die Qualität der Approximation sich mit der Anzahl der Freiheitsgrade verbessert. In der Praxis werden deswegen diese numerischen Methoden auf großen Computern implementiert um eine möglichst hohe Approximationsgüte zu erreichen. Jedoch sind auch manchmal diese großen Maschinen nicht ausreichend, um die gewünschte Qualität zu erreichen. Das Hauptaugenmerk dieser Arbeit ist darauf gerichtet, die Qualität der Approximation bei gleicher Anzahl von Freiheitsgrade zu verbessern. Diese Arbeit ist im Zusammenhang einer Kollaboration zwischen Prof. Klingenberg des Mathemaitschen Instituts in Würzburg und Prof. Röpke des Astrophysikalischen Instituts in Würzburg entstanden. Das Ziel dieser Kollaboration ist es, Methoden zur Berechnung von stellarer Atmosphären zu entwickeln. In dieser Arbeit werden vor allem zwei Problemstellungen behandelt. Die erste Problemstellung bezieht sich auf die akkurate Approximation des Quellterms, was zu den so genannten well-balanced Schemata führt. Diese erlauben genaue Approximationen von Lösungen nahe des Gleichgewichts. Die zweite Problemstellung bezieht sich auf die Approximation von Strömungen bei kleinen Mach Zahlen. Es ist bekannt, dass Lösungen der kompressiblen Euler Gleichungen zu Lösungen der inkompressiblen Euler Gleichungen konvergieren, wenn die Mach Zahl gegen null geht. Klassische numerische Schemata zeigen ein stark diffusives Verhalten bei kleinen Mach Zahlen. Das hier entwickelte Schema fällt in die Kategorie der asymptotic preserving Schematas, d.h. das numerische Schema ist auf einem diskrete Level kompatibel mit dem auf dem Kontinuum gezeigten verhalten. Zusätzlich wird gezeigt, dass die Diffusion des hier entwickelten Schemas unabhängig von der Mach Zahl ist. In Kapitel 3 wird ein HLL approximativer Riemann Löser für die Approximation der Lösungen der Flachwassergleichungen mit einem nicht konstanten Bodenprofil angewendet und ein well-balanced Schema entwickelt. Die meisten well-balanced Schemata für die Flachwassergleichungen behandeln nur den Fall eines Fluids im Ruhezustand, die so genannten Lake at Rest Lösungen. Hier wird ein Schema entwickelt, welches sich mit allen Gleichgewichten befasst. Zudem wird eine zweiter Ordnung Methode entwickelt, welche im Gegensatz zu anderen in der Literatur nicht auf einem iterativen Verfahren basiert. Numerische Experimente werden durchgeführt um die Vorteile des neuen Verfahrens zu zeigen. In Kapitel 4 wird ein Suliciu Relaxations Löser angepasst um die hydrostatischen Gleichgewichte der Euler Gleichungen mit einem Gravitationspotential aufzulösen. Die Gleichungen der hydrostatischen Gleichgewichte sind unterbestimmt und lassen deshalb keine Eindeutigen Lösungen zu. Es wird jedoch gezeigt, dass das neue Schema für eine große Klasse dieser Lösungen die well-balanced Eigenschaft besitzt. Für bestimmte Klassen werden Quadraturformeln zur Approximation des Quellterms entwickelt. Es wird auch gezeigt, dass das Schema robust, d.h. es erhält die Positivität der Masse und Energie, und stabil bezüglich der Entropieungleichung ist. Die numerischen Experimente konzentrieren sich vor allem auf den Einfluss der Quadraturformeln auf die well-balanced Eigenschaften. In Kapitel 5 wird ein Suliciu Relaxations Schema angepasst für Simulationen im Bereich kleiner Mach Zahlen. Es wird gezeigt, dass das neue Schema asymptotic preserving und die Diffusion kontrolliert ist. Zudem wird gezeigt, dass das Schema für bestimmte Parameter robust ist. Eine Stabilität wird aus einer Chapman-Enskog Analyse abgeleitet. Resultate numerische Experimente werden gezeigt um die Vorteile des neuen Verfahrens zu zeigen. In Kapitel 6 werden die Schemata aus den Kapiteln 4 und 5 kombiniert um das Verhalten des numerischen Schemas bei Flüssen mit kleiner Mach Zahl in durch die Gravitation geschichteten Atmosphären zu untersuchen. Es wird gezeigt, dass das Schema well-balanced ist. Die Robustheit und die Stabilität werden analog zu Kapitel 5 behandelt. Auch hier werden numerische Tests durchgeführt. Es zeigt sich, dass das neu entwickelte Schema in der Lage ist, die Dynamiken besser Aufzulösen als vor der Anpassung. Das Kapitel 7 beschäftigt sich mit der Entwicklung eines multidimensionalen Schemas basierend auf der Suliciu Relaxation. Jedoch ist die Arbeit an diesem Ansatz noch nicht beendet und numerische Resultate können nicht präsentiert werden. Es wird aufgezeigt, wo sich die Schwächen dieses Ansatzes befinden und weiterer Entwicklungsbedarf besteht. N2 - This work is concerned with the numerical approximation of solutions to models that are used to describe atmospheric or oceanographic flows. In particular, this work concen- trates on the approximation of the Shallow Water equations with bottom topography and the compressible Euler equations with a gravitational potential. Numerous methods have been developed to approximate solutions of these models. Of specific interest here are the approximations of near equilibrium solutions and, in the case of the Euler equations, the low Mach number flow regime. It is inherent in most of the numerical methods that the quality of the approximation increases with the number of degrees of freedom that are used. Therefore, these schemes are often run in parallel on big computers to achieve the best pos- sible approximation. However, even on those big machines, the desired accuracy can not be achieved by the given maximal number of degrees of freedom that these machines allow. The main focus in this work therefore lies in the development of numerical schemes that give better resolution of the resulting dynamics on the same number of degrees of freedom, compared to classical schemes. This work is the result of a cooperation of Prof. Klingenberg of the Institute of Mathe- matics in Wu¨rzburg and Prof. R¨opke of the Astrophysical Institute in Wu¨rzburg. The aim of this collaboration is the development of methods to compute stellar atmospheres. Two main challenges are tackled in this work. First, the accurate treatment of source terms in the numerical scheme. This leads to the so called well-balanced schemes. They allow for an accurate approximation of near equilibrium dynamics. The second challenge is the approx- imation of flows in the low Mach number regime. It is known that the compressible Euler equations tend towards the incompressible Euler equations when the Mach number tends to zero. Classical schemes often show excessive diffusion in that flow regime. The here devel- oped scheme falls into the category of an asymptotic preserving scheme, i.e. the numerical scheme reflects the behavior that is computed on the continuous equations. Moreover, it is shown that the diffusion of the numerical scheme is independent of the Mach number. In chapter 3, an HLL-type approximate Riemann solver is adapted for simulations of the Shallow Water equations with bottom topography to develop a well-balanced scheme. In the literature, most schemes only tackle the equilibria when the fluid is at rest, the so called Lake at rest solutions. Here a scheme is developed to accurately capture all the equilibria of the Shallow Water equations. Moreover, in contrast to other works, a second order extension is proposed, that does not rely on an iterative scheme inside the reconstruction procedure, leading to a more efficient scheme. In chapter 4, a Suliciu relaxation scheme is adapted for the resolution of hydrostatic equilibria of the Euler equations with a gravitational potential. The hydrostatic relations are underdetermined and therefore the solutions to that equations are not unique. However, the scheme is shown to be well-balanced for a wide class of hydrostatic equilibria. For specific classes, some quadrature rules are computed to ensure the exact well-balanced property. Moreover, the scheme is shown to be robust, i.e. it preserves the positivity of mass and energy, and stable with respect to the entropy. Numerical results are presented in order to investigate the impact of the different quadrature rules on the well-balanced property. In chapter 5, a Suliciu relaxation scheme is adapted for the simulations of low Mach number flows. The scheme is shown to be asymptotic preserving and not suffering from excessive diffusion in the low Mach number regime. Moreover, it is shown to be robust under certain parameter combinations and to be stable from an Chapman-Enskog analysis. Numerical results are presented in order to show the advantages of the new approach. In chapter 6, the schemes developed in the chapters 4 and 5 are combined in order to investigate the performance of the numerical scheme in the low Mach number regime in a gravitational stratified atmosphere. The scheme is shown the be well-balanced, robust and stable with respect to a Chapman-Enskog analysis. Numerical tests are presented to show the advantage of the newly proposed method over the classical scheme. In chapter 7, some remarks on an alternative way to tackle multidimensional simulations are presented. However no numerical simulations are performed and it is shown why further research on the suggested approach is necessary. KW - Strömung KW - Numerical Methods KW - Hyperbolic Partial Differential Equations KW - Well-Balanced KW - Asymptotic Preserving KW - Atmosphäre KW - Mathematisches Modell KW - PDE Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162669 ER - TY - JOUR A1 - Zeiner, P. S. A1 - Zinke, J. A1 - Kowalewski, D. J. A1 - Bernatz, S. A1 - Tichy, J. A1 - Ronellenfitsch, M. W. A1 - Thorsen, F. A1 - Berger, A. A1 - Forster, M. T. A1 - Muller, A. A1 - Steinbach, J. P. A1 - Beschorner, R. A1 - Wischhusen, J. A1 - Kvasnicka, H. M. A1 - Plate, K. H. A1 - Stefanović, S. A1 - Weide, B. A1 - Mittelbronn, M. A1 - Harter, P. N. T1 - CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival JF - Acta Neuropathologica Communications N2 - Abstract Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity. We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line. We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74\(^{high}\) and TIL\(^{high}\) tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected. In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis. KW - CD74 KW - HLA class II KW - brain metastasis KW - HLA peptidome KW - tumor infiltrating lymphocytes Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233882 VL - 6 ER - TY - JOUR A1 - Yu, Sung-Huan A1 - Vogel, Jörg A1 - Förstner, Konrad U. T1 - ANNOgesic: a Swiss army knife for the RNA-seq based annotation of bacterial/archaeal genomes JF - GigaScience N2 - To understand the gene regulation of an organism of interest, a comprehensive genome annotation is essential. While some features, such as coding sequences, can be computationally predicted with high accuracy based purely on the genomic sequence, others, such as promoter elements or noncoding RNAs, are harder to detect. RNA sequencing (RNA-seq) has proven to be an efficient method to identify these genomic features and to improve genome annotations. However, processing and integrating RNA-seq data in order to generate high-resolution annotations is challenging, time consuming, and requires numerous steps. We have constructed a powerful and modular tool called ANNOgesic that provides the required analyses and simplifies RNA-seq-based bacterial and archaeal genome annotation. It can integrate data from conventional RNA-seq and differential RNA-seq and predicts and annotates numerous features, including small noncoding RNAs, with high precision. The software is available under an open source license (ISCL) at https://pypi.org/project/ANNOgesic/. KW - genome annotation KW - RNA-seq KW - transcriptomics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178942 VL - 7 ER - TY - INPR A1 - Yin, Yafu A1 - Werner, Rudolf A. A1 - Higuchi, Takahiro A1 - Lapa, Constantin A1 - Pienta, Kenneth J. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Rowe, Steven P. T1 - Follow-Up of Lesions with Equivocal Radiotracer Uptake on PSMA-Targeted PET in Patients with Prostate Cancer: Predictive Values of the PSMA-RADS-3A and PSMARADS- 3B Categories T2 - Journal of Nuclear Medicine N2 - Purpose: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging has become commonly utilized in patients with prostate cancer (PCa). The PSMA reporting and data system version 1.0 (PSMA-RADS version 1.0) categorizes lesions on the basis of the likelihood of PCa involvement, with PSMA-RADS-3A (soft tissue) and PSMA-RADS-3B (bone) lesions being indeterminate for the presence of disease. We retrospectively reviewed the imaging follow-up of such lesions to determine the rate at which they underwent changes suggestive of underlying PCa. Methods: PET/CT imaging with \(^{18}\)F-DCFPyL was carried out in 110 patients with PCa and lesions were categorized according to PSMA-RADS Version 1.0. 56/110 (50.9%) patients were determined to have indeterminate PSMA-RADS-3A or PSMA-RADS-3B lesions and 22/56 (39.3%) patients had adequate follow-up to be included in the analysis. The maximum standardized uptake values (SUV\(_{max}\)) of the lesions were obtained and the ratios of SUV\(_{max}\) of the lesions to SUV\(_{mean}\) of blood pool (SUV\(_{max}\)-lesion/SUV\(_{mean}\)-bloodpool) were calculated. Pre-determined criteria were used to evaluate the PSMA-RADS-3A and PSMA-RADS-3B lesions on follow-up imaging to determine if they demonstrated evidence of underlying malignancy. Results: A total of 46 lesions in 22 patients were considered indeterminate for PCa (i.e. PSMA-RADS-3A (32 lesions) or PSMA-RADS-3B (14 lesions)) and were evaluable on follow-up imaging. 27/46 (58.7%) lesions demonstrated changes on follow-up imaging consistent with the presence of underlying PCa at baseline. These lesions included 24/32 (75.0%) PSMA-RADS-3A lesions and 3/14 (21.4%) lesions categorized as PSMA-RADS-3B. The ranges of SUVmax and SUVmax-lesion/SUVmean-bloodpool overlapped between those lesions demonstrating changes consistent with malignancy on follow-up imaging and those lesions that remained unchanged on follow-up. Conclusion: PSMA-RADS-3A and PSMA-RADS-3B lesions are truly indeterminate in that proportions of findings in both categories demonstrate evidence of malignancy on follow-up imaging. Overall, PSMA-RADS-3A lesions are more likely than PSMA-RADS-3B lesions to represent sites of PCa and this information should be taken into when guiding patient therapy. KW - PSMA-RADS-3B KW - Positronen-Emissions-Tomografie KW - prostate-specific membrane antigen KW - prostate cancer KW - PSMA-targeted PET KW - PSMA-RADS-3A Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167594 SN - 0161-5505 N1 - This research was originally published in JNM. Yafu Yin, Rudolf A. Werner, Takahiro Higuchi, Constantin Lapa, Kenneth J. Pienta, Martin G. Pomper, Michael A. Gorin, Steven P. Rowe. Follow-Up of Lesions with Equivocal Radiotracer Uptake on PSMA-Targeted PET in Patients with Prostate Cancer: Predictive Values of the PSMA-RADS-3A and PSMA-RADS-3B Categories. J Nucl Med. 2019;60:511-516 © SNMMI. ER - TY - JOUR A1 - Yanku, Yifat A1 - Bitman-Lotan, Eliya A1 - Zohar, Yaniv A1 - Kurant, Estee A1 - Zilke, Norman A1 - Eilers, Martin A1 - Orian, Amir T1 - Drosophila HUWE1 ubiquitin ligase regulates endoreplication and antagonizes JNK signaling during salivary gland development JF - Cells N2 - The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development. KW - HECT KW - HUWE1 KW - ubiquitin KW - salivary gland KW - endoreplication KW - JNK KW - dMyc KW - dmP53 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197630 SN - 2073-4409 VL - 7 IS - 10 ER - TY - JOUR A1 - Wurmb, T A1 - Schorscher, N A1 - Justice, P A1 - Dietz, S A1 - Schua, R A1 - Jarausch, T A1 - Kinstle, U A1 - Greiner, J A1 - Möldner, G A1 - Müller, J A1 - Kraus, M A1 - Simon, S A1 - Wagenhäuser, U A1 - Hemm, J A1 - Roewer, N A1 - Helm, M T1 - Structured analysis, evaluation and report of the emergency response to a terrorist attack in Wuerzburg, Germany using a new template of standardised quality indicators JF - Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine N2 - Background: Until now there has been a reported lack of systematic reports and scientific evaluations of rescue missions during terror attacks. This however is urgently required in order to improve the performance of emergency medical services and to be able to compare different missions with each other. Aim of the presented work was to report the systematic evaluation and the lessons learned from the response to a terror attack that happened in Wuerzburg, Germany in 2016. Methods: A team of 14 experts developed a template of quality indicators and operational characteristics, which allow for the description, assessment and comparison of civil emergency rescue missions during mass killing incidents. The entire systematic evaluation process consisted of three main steps. The first step was the systematic data collection according to the quality indicators and operational characteristics. Second was the systematic stratification and assessment of the data. The last step was the prioritisation of the identified weaknesses and the definition of the lessons learned. Results: Five important “lessons learned” have been defined. First of all, a comprehensive concept for rescue missions during terror attacks is essential. Furthermore, the establishment of a defined high priority communication infrastructure between the different dispatch centres (“red phone”) is vital. The goal is to secure the continuity of information between a few well-defined individuals. Thirdly, the organization of the incident scene needs to be commonly decided and communicated between police, medical services and fire services during the mission. A successful mission tactic requires continuous flux of reports to the on-site command post. Therefore, a predefined and common communication infrastructure for all operational forces is a crucial point. Finally, all strategies need to be extensively trained before the real life scenario hits. Conclusion: According to a systematic evaluation, we defined the lessons learned from a terror attack in 2016. Further systematic reports and academic work surrounding life threatening rescue missions and mass killing incidents are needed in order to ultimately improve such mission outcomes. In the future, a close international collaboration might help to find the best database to report and evaluate major incidents but also mass killing events. KW - terror attack KW - mass casualties KW - evaluation KW - quality indicators KW - rescue mission Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177054 VL - 26 IS - 87 ER - TY - JOUR A1 - Wolff, Hans-Georg A1 - Weikamp, Julia G. A1 - Batinic, Bernad T1 - Implicit Motives as Determinants of Networking Behaviors JF - Frontiers in Psychology N2 - In today’s world of work, networking behaviors are an important and viable strategy to enhance success in work and career domains. Concerning personality as an antecedent of networking behaviors, prior studies have exclusively relied on trait perspectives that focus on how people feel, think, and act. Adopting a motivational perspective on personality, we enlarge this focus and argue that beyond traits predominantly tapping social content, motives shed further light on instrumental aspects of networking – or why people network. We use McClelland’s implicit motives framework of need for power (nPow), need for achievement (nAch), and need for affiliation (nAff) to examine instrumental determinants of networking. Using a facet theoretical approach to networking behaviors, we predict differential relations of these three motives with facets of (1) internal vs. external networking and (2) building, maintaining, and using contacts. We conducted an online study, in which we temporally separate measures (N = 539 employed individuals) to examine our hypotheses. Using multivariate latent regression, we show that nAch is related to networking in general. In line with theoretical differences between networking facets, we find that nAff is positively related to building contacts, whereas nPow is positively related to using internal contacts. In sum, this study shows that networking is not only driven by social factors (i.e., nAff), but instead the achievement motive is the most important driver of networking behaviors. KW - networking KW - social capital KW - implicit motives KW - work behavior KW - social interaction KW - career self-management Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189954 SN - 1664-1078 VL - 9 IS - 411 ER - TY - THES A1 - Wohlfart, Christian T1 - The Yellow River Basin in Transition - Multi-faceted Land Cover Change Analysis in the Yellow River Basin in the Context of Global Change Using Multi-sensor Remote Sensing Imagery T1 - Der Gelbe Fluss im Wandel - Multisensorale und multitemporale Analyse des Einzugsgebietes des Gelben Flusses in China mittels Fernerkundungsdaten vor dem Hintergrund des Globalen Wandels N2 - As a cradle of ancient Chinese civilization, the Yellow River Basin has a very long human-environment interrelationship, where early anthropogenic activities re- sulted in large scale landscape modifications. Today, the impact of this relationship has intensified further as the basin plays a vital role for China’s continued economic development. It is one of the most densely-populated, fastest growing, and most dynamic regions of China with abundant natural and environmental resources providing a livelihood for almost 190 million people. Triggered by fundamental economic reforms, the basin has witnessed a spectacular economic boom during the last decades and can be considered as an exemplary blueprint region for contemporary dynamic Global Change processes occurring throughout the country, which is currently transitioning from an agrarian-dominated economy into a modern urbanized society. However, this resourcesdemanding growth has led to profound land use changes with adverse effects on the Yellow River social-ecological systems, where complex challenges arise threatening a long-term sustainable development. Consistent and continuous remote sensing-based monitoring of recent and past land cover and land use change is a fundamental requirement to mitigate the adverse impacts of Global Change processes. Nowadays, technical advancement and the multitude of available satellite sensors, in combination with the opening of data archives, allow the creation of new research perspectives in regional land cover applications over heterogeneous landscapes at large spatial scales. Despite the urgent need to better understand the prevailing dynamics and underlying factors influencing the current processes, detailed regional specific land cover data and change information are surprisingly absent for this region. In view of the noted research gaps and contemporary developments, three major objectives are defined in this thesis. First (i), the current and most pressing social-ecological challenges are elaborated and policy and management instruments towards more sustainability are discussed. Second (ii), this thesis provides new and improved insights on the current land cover state and dynamics of the entire Yellow River Basin. Finally (iii), the most dominant processes related to mining, agriculture, forest, and urban dynamics are determined on finer spatial and temporal scales. The complex and manifold problems and challenges that result from long-term abuse of the water and land resources in the basin have been underpinned by policy choices, cultural attitude, and institutions that have evolved over centuries in China. The tremendous economic growth that has been mainly achieved by extracting water and exploiting land resources in a rigorous, but unsustainable manner, might not only offset the economic benefits, but could also foster social unrest. Since the early emergence of the first Chinese dynasties, flooding was considered historically as a primary issue in river management and major achievements have been made to tame the wild nature of the Yellow River. Whereas flooding is therefore largely now under control, new environmental and social problems have evolved, including soil and water pollution, ecological degradation, biodiversity decline, and food security, all being further aggravated by anthropogenic climate change. To resolve the contemporary and complex challenges, many individual environmental laws and regulations have been enacted by various Chinese ministries. However, these policies often pursue different, often contradictory goals, are too general to tackle specific problems and are usually implemented by a strong top-down approach. Recently, more flexible economic and market-based incentives (pricing, tradable permits, investments) have been successfully adopted, which are specifically tailored to the respective needs, shifting now away from the pure command and regulating instruments. One way towards a more holistic and integrated river basin management could be the establishment of a common platform (e.g. a Geographical Information System) for data handling and sharing, possibly operated by the Yellow River Basin Conservancy Commission (YRCC), where available spatial data, statistical information and in-situ measures are coalesced, on which sustainable decision-making could be based. So far, the collected data is hardly accessible, fragmented, inconsistent, or outdated. The first step to address the absence and lack of consistent and spatially up-to-date information for the entire basin capturing the heterogeneous landscape conditions was taken up in this thesis. Land cover characteristics and dynamics were derived from the last decade for the years 2003 and 2013, based on optical medium-resolution hightemporal MODIS Normalized Differenced Vegetation Index (NDVI) time series at 250 m. To minimize the inherent influence of atmospheric and geometric interferences found in raw high temporal data, the applied adaptive Savitzky-Golay filter successfully smoothed the time series and substantially reduced noise. Based on the smoothed time series data, a large variety of intra-annual phenology metrics as well as spectral and multispectral annual statistics were derived, which served as input variables for random forest (RF) classifiers. High quality reference data sets were derived from very high resolution imagery for each year independently of which 70 % trained the RF models. The accuracy assessments for all regionally specific defined thematic classes were based on the remaining 30 % reference data split and yielded overall accuracies of 87 % and 84 % for 2003 and 2013, respectively. The first regional adapted Yellow River Land Cover Products (YRB LC) depict the detail spatial extent and distribution of the current land cover status and dynamics. The novel products overall differentiate overall 18 land cover and use classes, including classes of natural vegetation (terrestrial and aquatic), cultivated classes, mosaic classes, non-vegetated, and artificial classes, which are not presented in previous land cover studies so far. Building on this, an extended multi-faceted land cover analysis on the most prominent land cover change types at finer spatial and temporal scales provides a better and more detailed picture of the Yellow River Basin dynamics. Precise spatio-temporal products about mining, agriculture, forest, and urban areas were examined from long-trem Landsat satellite time series monitored at annual scales to capture the rapid rate of change in four selected focus regions. All archived Landsat images between 2000 and 2015 were used to derive spatially continuous spectral-temporal, multi-spectral, and textural metrics. For each thematic region and year RF models were built, trained and tested based on a stablepixels reference data set. The automated adaptive signature (AASG) algorithm identifies those pixels that did not change between the investigated time periods to generate a mono-temporal reference stable-pixels data set to keep manual sampling requirements to a minimum level. Derived results gained high accuracies ranging from 88 % to 98 %. Throughout the basin, afforestation on the Central Loess Plateau and urban sprawl are identified as most prominent drivers of land cover change, whereas agricultural land remained stable, only showing local small-scale dynamics. Mining operations started in 2004 on the Qinghai-Tibet Plateau, which resulted in a substantial loss of pristine alpine meadows and wetlands. In this thesis, a novel and unique regional specific view of current and past land cover characteristics in a complex and heterogeneous landscape was presented by using a multi-source remote sensing approach. The delineated products hold great potential for various model and management applications. They could serve as valuable components for effective and sustainable land and water management to adapt and mitigate the predicted consequences of Global Change processes. N2 - Der Gelbe Fluss - in der Landessprache Huange He genannt - ist für die Ausprägung und Entwicklung der chinesischen Kultur von großer Bedeutung. Aufgrund der frühen Einflussnahme auf die natürlichen Ökosysteme in dieser Region durch den Menschen, entwickelte sich dort eine ausgeprägte Interaktion zwischen Mensch und Umwelt. Diese Wechselbeziehung hat sich infolge der gegenwärtigen rapiden sozioökonomischen Veränderungen in den letzten Jahrzehnten weiter intensiviert. Das Einzugsgebiet des Gelben Flusses bildet die Lebensgrundlage für fast 190 Millionen Menschen, die zum Großteil von natürlichen Ressourcen abhängig sind. Zudem gehört es zu den wirtschaftlich bedeutendsten und am schnellsten wachsenden Regionen in ganz China. Durch weitreichende Reformen wurde ein wirtschaftlicher Aufstieg forciert, um den Agrarstaat China zu einem modernen Industrie- und Dienstleistungsstaat weiterzuentwickeln. Ein derartiges rasantes wie auch ressourcenintensives Wirtschaftswachstum führte schließlich zu einem enormen Wandel in den Bereichen der Landbedeckung und Landnutzung. Hinzu kamen neue und komplexere wirtschafts-, sozial- und umweltpolitische Herausforderungen, die bis heute eine langfristige und nachhaltige Entwicklung der Region gefährden. Aus diesem Blickwinkel kann das Becken des Gelben Flusses als regionales Spiegelbild der durch den Globalen Wandel bedingten, gegenwärtigen Veränderungsprozesse in ganz China gelten. Eine wichtige Voraussetzung für den adäquaten Umgang mit den Herausforderungen des Globalen Wandels sind kontinuierliche Informationen über aktuelle sowie historische Veränderungen von Landbedeckung und Landnutzung. Infolge der technologischen Entwicklung steht heute eine Vielfalt an Satellitenbildsystemen mit immer höherer zeitlicher und räumlicher Auflösung zur Verfügung. In Verbindung mit kostenfreien und offenen Datenzugriffen ist es möglich, daraus neue Forschungsperspektiven im Bereich der Landoberflächenkartierung - insbesondere für heterogene Landschaften - zu entwickeln. Zur Generierung thematischer Karten werden häufig Klassifikationen entlang verschiedener räumlicher und zeitlicher Skalen vollzogen. Daraus können zusätzlich die nötigen Informationen für lokale wie auch regionale Entscheidungsträger abgeleitet werden. Trotz dieser neuen Möglichkeiten sind regionalspezifische Informationen, die einem besseren Verständnis der Dynamiken von Landoberflächen im Bereich des Gelben-Fluss-Beckens dienen, noch rar. Dieses Forschungsdesiderat wurde im Rahmen dieser Arbeit aufgegriffen, wobei folgende Schwerpunkte gesetzt werden: (i) Zunächst werden die vorherrschenden sozioökologischen Herausforderungen für das gesamte Einzugsgebiet des Gelben Flusses dargestellt sowie verschiedene Management- sowie Politikmodelle für eine nachhaltigere Ressourcennutzung diskutiert. (ii) Darauf aufbauend wird die fernerkundliche Ableitung von Landbedeckungs- und Landnutzungsveränderungen der letzten Dekade im Gebiet des gesamten Gelben Flusses flächendeckend durchgeführt und anschließend interpretiert. (iii) Im letzten Schritt werden basierend auf den zuvor abgeleiteten Informationsprodukten die dominierenden Landoberflächendynamiken in höherer zeitlicher und räumlicher Auflösung detailliert untersucht. Insbesondere die dynamischen Prozesse der Minenausbreitung, Landwirtschaft, Waldgebiete und der urbanen Räume rücken in den Fokus. Aufgrund jahrzehntelanger Übernutzung der natürlichen Ressourcen im Gebiet des Gelben Flusses in Verbindung mit politischen Entscheidungen, der vorherrschenden kulturellen Prägung wie auch der Entwicklung der dort ansässigen Institutionen ist eine vielschichtige Problematik entstanden, die für die gesamte Region eine große Herausforderung darstellt. Durch frühzeitige Maßnahmen der Flutbekämpfung und Flussregulierung konnte den zahlreichen Überflutungen der Vergangenheit entgegengewirkt und das Risiko großflächiger Überschwemmungen minimiert werden. Trotz dieser Erfolge ergeben sich laufend neue, komplexere Herausforderungen mit verheerenden Auswirkungen auf Ökologie und Gesellschaft, wie zum Beispiel Boden- und Wasserdegradation, Entwaldung, Rückgang der Artenvielfalt, Ernährungsunsicherheiten und ein steigendes soziales Ungleichgewicht. Durch den anthropogenen Klimawandel werden diese negativen Probleme noch weiter verstärkt. Zwar wurden sie von der chinesischen Regierung als solche erkannt, dennoch scheiterten die Versuche, mit zahlreichen Gesetzen und Verordnungen die genannten Folgen einzudämmen, an unkonkreten Formulierungen, so dass diese der Komplexität der Herausforderungen nicht gerecht wurden. Die in jüngster Zeit verfolgten modernen und deutlich flexibleren, marktorientierten Ansätze (z.B. Subventionen, Wasserzertifikate), die speziell an die lokalen Gegebenheiten angepasst wurden, zeigen bereits Erfolge. Mit Hilfe einer gemeinsamen Daten- und Informationsplattform, beispielsweise in Form eines Geographischen Informationssystems (GIS), wäre eine integrierte und holistische Flussmanagementstrategie für den Gelben Fluss leichter realisierbar. Auf diese Weise könnten alle verfügbaren statistischen-, räumlichen- und Feldaufnahmen gespeichert, harmonisiert und geteilt und so die bisher noch unvollständigen und veralteten Daten laufend aktualisiert werden. Die Flussbehörde des Gelben Flusses (Yellow River Conservancy Commission) böte sich an, ein solches System zu verwalten. In dieser Arbeit wird die heterogene Landbedeckungsstruktur für das gesamte Einzugsgebiet des Gelben Flusses für die Jahre 2003 und 2013 erfasst und interpretiert. Die fernerkundlichen Eingangsdaten für die einzelnen Klassifikationen bestehen aus optischen MODIS NDVI-Zeitserien, aus denen jährlich phänologische Parameter berechnet werden. Da die Qualität optischer Satellitenbilder häufig durch Wolken und Schatten beeinträchtigt ist, müssen die betroffenen Flächen maskiert und entfernt werden. Die so entstandenen Lücken in der Zeitserie werden durch einen Filteralgorithmus (SavitskyGolay) aufgefüllt und geglättet. Die verwendeten RandomForest-Klassifikationsverfahren ermöglichen die Ableitung von Landbedeckungen und -dynamiken. Diese neuen und räumlich detaillierten Produkte unterscheiden insgesamt 18 verschiedene Landbedeckungsund Landnutzungsklassen. Erstmals liefern diese eine regional spezifische Charakterisierung der vorherrschenden Landbedeckung im Gebiet des Gelben Flusses. Darauf aufbauend erfolgt eine sowohl zeitlich als auch räumlich detailliertere Untersuchung der wichtigsten Veränderungen im Bereich der Landbedeckung, die auf dichten Landsat-Zeitserien basiert. Jährliche Informationen über Dynamiken von Minenabbaugebieten, Landwirtschaft, Waldgebieten und urbanen Räumen zeigen präzise lokale Veränderungen im Einzugsgebiet des Gelben Flusses. Die daraus abgeleiteten Ergebnisse lassen insbesondere auf dem Lössplateau die Auswirkungen ökologischer Restorationsmaßnahmen erkennen, bei denen degradierte Flächen in Waldsysteme umgewandelt wurden. Auf dem Qinghai-Tibet-Plateau zeigt sich eine dramatische Ausbreitung von Kohletagebau zu Lasten der besonders anfälligen alpinen Matten und Feuchtgebiete. Auch der anhaltende Trend zur Urbanisierung spiegelt sich in den hier gewonnenen Ergebnissen deutlich wider. Durch die Kombination von Fernerkundungsdaten unterschiedlicher räumlicher und zeitlicher Auflösungen liefert diese Arbeit neue und bisher einzigartige Einblicke in historische und aktuelle Landbedeckungsdynamiken einer heterogenen Landschaft. Die regionalen Analysen wie auch die thematischen Informationsprodukte besitzen somit großes Potential zur Verbesserung der Informationsgrundlage. Die Ergebnisse dienen außerdem als aussagekräftige Entscheidungsgrundlage mit dem Ziel eines angemessenen und nachhaltigen Land- und Wassermanagements für die natürlichen Ökosysteme im Becken des Gelben Flusses. KW - Fernerkundung KW - Remote Sensing KW - Geografie KW - Globaler Wandel KW - Global Change KW - River Basins KW - China KW - Time Series Analyses KW - Sustainability Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163724 ER - TY - THES A1 - Wiedenmann, Jonas T1 - Induced topological superconductivity in HgTe based nanostructures T1 - Induzierte topologische Supraleitung in HgTe basierten Nanostrukturen N2 - This thesis describes the studies of topological superconductivity, which is predicted to emerge when pair correlations are induced into the surface states of 2D and 3D topolog- ical insulators (TIs). In this regard, experiments have been designed to investigate the theoretical ideas first pioneered by Fu and Kane that in such system Majorana bound states occur at vortices or edges of the system [Phys. Rev. Lett. 100, 096407 (2008), Phys. Rev. B 79, 161408 (2009)]. These states are of great interest as they constitute a new quasiparticle which is its own antiparticle and can be used as building blocks for fault tolerant topological quantum computing. After an introduction in chapter 1, chapter 2 of the thesis lays the foundation for the understanding of the field of topology in the context of condensed matter physics with a focus on topological band insulators and topological superconductors. Starting from a Chern insulator, the concepts of topological band theory and the bulk boundary corre- spondence are explained. It is then shown that the low energy Hamiltonian of mercury telluride (HgTe) quantum wells of an appropriate thickness can be written as two time reversal symmetric copies of a Chern insulator. This leads to the quantum spin Hall effect. In such a system, spin-polarized one dimensional conducting states form at the edges of the material, while the bulk is insulating. This concept is extended to 3D topological insulators with conducting 2D surface states. As a preliminary step to treating topological superconductivity, a short review of the microscopic theory of superconductivity, i.e. the theory of Bardeen, Cooper, and Shrieffer (BCS theory) is presented. The presence of Majorana end modes in a one dimensional superconducting chain is explained using the Kitaev model. Finally, topological band insulators and conventional superconductivity are combined to effectively engineer p-wave superconductivity. One way to investigate these states is by measuring the periodicity of the phase of the Josephson supercurrent in a topological Josephson junction. The signature is a 4π-periodicity compared to the 2π-periodicity in conventional Josephson junctions. The proof of the presence of this effect in HgTe based Josephson junction is the main goal of this thesis and is discussed in chapters 3 to 6. Chapter 3 describes in detail the transport of a 3D topological insulator based weak link under radio-frequency radiation. The chapter starts with a review of the state of research of (i) strained HgTe as 3D topological insulator and (ii) the progress of induc- ing superconducting correlations into the topological surface states and the theoretical predictions of 3D TI based Josephson junctions. Josephson junctions based on strained HgTe are successfully fabricated. Before studying the ac driven Josephson junctions, the dc transport of the devices is analysed. The critical current as a function of temperature is measured and it is possible to determine the induced superconducting gap. Under rf illumination Shapiro steps form in the current voltage characteristic. A missing first step at low frequencies and low powers is found in our devices. This is a signature of a 4π-periodic supercurrent. By studying the device in a wide parameter range - as a 147148 SUMMARY function of frequency, power, device geometry and magnetic field - it is shown that the results are in agreement with the presence of a single gapless Andreev doublet and several conventional modes. Chapter 4 gives results of the numerical modelling of the I −V dynamics in a Josephson junction where both a 2π- and a 4π-periodic supercurrents are present. This is done in the framework of an equivalent circuit representation, namely the resistively shunted Josephson junction model (RSJ-model). The numerical modelling is in agreement with the experimental results in chapter 3. First, the missing of odd Shapiro steps can be understood by a small 4π-periodic supercurrent contribution and a large number of modes which have a conventional 2π-periodicity. Second, the missing of odd Shapiro steps occurs at low frequency and low rf power. Third, it is shown that stochastic processes like Landau Zener tunnelling are most probably not responsible for the 4π contribution. In a next step the periodicity of Josephson junctions based on quantum spin Hall insulators using are investigated in chapter 5. A fabrication process of Josephson junctions based on inverted HgTe quantum wells was successfully developed. In order to achieve a good proximity effect the barrier material was removed and the superconductor deposited without exposing the structure to air. In a next step a gate electrode was fabricated which allows the chemical potential of the quantum well to be tuned. The measurement of the diffraction pattern of the critical current Ic due to a magnetic field applied perpendicular to the sample plane was conducted. In the vicinity to the expected quantum spin Hall phase, the pattern resembles that of a superconducting quantum interference device (SQUID). This shows that the current flows predominantly on the edges of the mesa. This observation is taken as a proof of the presence of edge currents. By irradiating the sample with rf, missing odd Shapiro steps up to step index n = 9 have been observed. This evidences the presence of a 4π-periodic contribution to the supercurrent. The experiment is repeated using a weak link based on a non-inverted HgTe quantum well. This material is expected to be a normal band insulator without helical edge channels. In this device, all the expected Shapiro steps are observed even at low frequencies and over the whole gate voltage range. This shows that the observed phenomena are directly connected to the topological band structure. Both features, namely the missing of odd Shapiro steps and the SQUID like diffraction pattern, appear strongest towards the quantum spin Hall regime, and thus provide evidence for induced topological superconductivity in the helical edge states. A more direct way to probe the periodicity of the Josephson supercurrent than using Shapiro steps is the measurement of the emitted radiation of a weak link. This experiment is presented in chapter 6. A conventional Josephson junction converts a dc bias V to an ac current with a characteristic Josephson frequency fJ = eV /h. In a topological Josephson junction a frequency at half the Josephson frequency fJ /2 is expected. A new measurement setup was developed in order to measure the emitted spectrum of a single Josephson junction. With this setup the spectrum of a HgTe quantum well based Josephson junction was measured and the emission at half the Josephson frequency fJ /2 was detected. In addition, fJ emission is also detected depending on the gate voltage and detection frequency. The spectrum is again dominated by half the Josephson emission at low voltages while the conventional emission is determines the spectrum at high voltages. A non-inverted quantum well shows only conventional emission over the whole gateSUMMARY 149 voltage and frequency range. The linewidth of the detected frequencies gives a measure on the lifetime of the bound states: From there, a coherence time of 0.3–4ns for the fJ /2 line has been deduced. This is generally shorter than for the fJ line (3–4ns). The last part of the thesis, chapter 7, reports on the induced superconducting state in a strained HgTe layer investigated by point-contact Andreev reflection spectroscopy. For the experiment, a HgTe mesa was fabricated with a small constriction. The diameter of the orifice was chosen to be smaller than the mean free path estimated from magne- totransport measurements. Thus one gets a ballistic point-contact which allows energy resolved spectroscopy. One part of the mesa is covered with a superconductor which induces superconducting correlations into the surface states of the topological insulator. This experiment therefore probes a single superconductor normal interface. In contrast to the Josephson junctions studied previously, the geometry allows the acquisition of energy resolved information of the induced superconducting state through the measurement of the differential conductance dI/dV as a function of applied dc bias for various gate voltages, temperatures and magnetic fields. An induced superconducting order parame- ter of about 70µeV was extracted but also signatures of the niobium gap at the expected value around Δ Nb ≈ 1.1meV have been found. Simulations using the theory developed by Blonder, Tinkham and Klapwijk and an extended model taking the topological surface states into account were used to fit the data. The simulations are in agreement with a small barrier at the topological insulator-induced topological superconductor interface and a high barrier at the Nb to topological insulator interface. To understand the full con- ductance curve as a function of applied voltage, a non-equilibrium driven transformation is suggested. The induced superconductivity is suppressed at a certain bias value due to local electron population. In accordance with this suppression, the relevant scattering regions change spatially as a function of applied bias. To conclude, it is emphasized that the experiments conducted in this thesis found clear signatures of induced topological superconductivity in HgTe based quantum well and bulk devices and opens up the avenue to many experiments. It would be interesting to apply the developed concepts to other topological matter-superconductor hybrid systems. The direct spectroscopy and manipulation of the Andreev bound states using circuit quantum electrodynamic techniques should be the next steps for HgTe based samples. This was already achieved in superconducting atomic break junctions by the group in Saclay [Science 2015, 349, 1199-1202 (2015)]. Another possible development would be the on-chip detection of the emitted spectrum as a function of the phase φ through the junction. In this connection, the topological junction needs to be shunted by a parallel ancillary junction. Such a setup would allow the current phase relation I(φ) directly and the lifetime of the bound states to be measured directly. By coupling this system to a spectrometer, which can be another Josephson junction, the energy dependence of the Andreev bound states E(φ) could be obtained. The experiments on the Andreev reflection spectroscopy described in this thesis could easily be extended to two dimensional topological insulators and to more complex geometries, like a phase bias loop or a tunable barrier at the point-contact. This work might also be useful for answering the question how and why Majorana bound states can be localized in quantum spin Hall systems. N2 - Die vorliegende Dissertation befasst sich mit der experimentellen Untersuchung von topologischer Supraleitung, die durch die Kombination von konventionellen Supraleitern mit 2D- und 3D- topologischen Isolatoren (TI) entsteht. Diesbezüglich wurden Experi- mente durchgeführt, die auf zwei bahnbrechenden Arbeiten von Fu und Kane [Phys. Rev. Lett. 100, 096407 (2008), Phys. Rev. B 79, 161408 (2009)] aufbauen. Diesen zufolge wird in supraleitenden topologischen Isolatoren ein neuartiges Quasiteilchen, ein sogenanntes Majorana-Fermion, vorhergesagt. Das große Interesse an diesem Teilchen beruht auf des- sen besonderen Eigenschaften. Es sind Fermionen mit halbzahligen Spin, jedoch besitzen sie keine Ladung und es ist gleichzeitig sein eigenes Antiteilchen. Darüber hinaus besitzt das Teilchen im Vergleich zu konventionellen Fermionen eine andere Austauschstatistik und zählt daher zu den sogenannten nicht-abelschen Anyonen. Aufgrund dieser Eigen- schaften wurde vorhergesagt, dass sie für weniger fehleranfällige Quantenbits als Bauteile für einen Quantencomputer verwendet werden können. Nach einer Einleitung in Kapitel 1 folgt in Kapitel 2 eine Einführung in das Konzept von Topologie in der Festkörperphysik. Der Schwerpunkt liegt dabei auf zwei Materialklassen, topologischen Isolatoren und topologische Supraleiter. Zunächst wird ein Zweibandmo- dell, der Chern-Isolator, beschrieben, um das Konzept von topologischen Isolatoren und die Entstehung von Oberflächenzuständen darzulegen. Es ist möglich die Bandstruktur von Quecksilbertellurid- (HgTe-) Quantentrögen als zwei zeitumkehrinvariante Kopien des Chern-Isolators zu interpretieren, was zu einem 2D topologischen Isolator führt. Das Konzept von 2D-TIs wird auf drei Dimensionen erweitert. Eine Einführung in konventio- nelle Supraleitung und insbesondere die mikroskopische Theorie von Bardeen, Cooper und Schrieffer dient einem pädagogischen Zugang zur topologischen Supraleitung. Eine eindimensionale supraleitenden Kette, entwickelt von Alexei Kitaev, dient der Erklärung für die Entstehung von Majorana-Fermionen in p-Wellen Supraleitern. Es ist möglich diesen Zustand durch die Kombination von konventionellen Supraleitern und topologi- schen Isolatoren zu verwirklichen. In dieser Dissertation wird die erwartet topologische Supraleitung in einem sogenannten Josephson-Kontakt untersucht. Dabei wurde vorher- gesagt, dass in einem “topologischen Josephson-Kontakt”die Phase des Suprastromes eine 4π-Periodizität besitzt, während ein normaler Josephson-Kontakt 2π-periodisch ist. Ziel dieser Arbeit ist der experimentelle Nachweis der 4π-Periodizität des Suprastroms in Josephson-Kontakten, die auf HgTe-Bauelementen beruhen. Als Methodik eignet sich die Messung der Shapiro-Plateaus und der Emission des Josephson-Kontaktes an, die ausführlich in den Kapiteln 3 bis 6 werden. In Kapitel 3 wird der Transport in Josephson-Kontakten, die auf dem dreidimensio- nalen topologischen Isolator HgTe beruhen unter Einfluss von Mikrowellenstrahlung detailliert ausgeführt. Dieser Teil beginnt mit einem Überblick über die Eigenschaften von HgTe als dreidimensionaler topologischer Isolator und zeigt insbesondere den Nachweis der Oberfächenleitung von relativistischen Elektronen auf. Des Weiteren wird der Stand der Forschung von Josephson-Kontakten auf diesem Materialsystem dargelegt. In solchen Strukturen werden nämlich aufgrund von Majorana-Fermionen gebundene Andreev- Zustände erwartet, welche sich in der Mitte der supraleitenden Bandlücke (bei null Energie) kreuzen. Sie werden als “gapless Andreev Bound States”bezeichnet. Die Existenz dieser Zustände kann durch den Nachweis einer 4π-Periodizität der Phase des Supra- stroms bewiesen werden. Da die endliche Lebensdauer dieser Zustände “langsamen”dc- Messungen den Nachweis der Periodizität nicht erlauben, wird Strahlung im Gigahertz Frequenzbereich verwendet. Josephson-Kontakte aus 3D-HgTe-Heterostrukturen werden erfolgreich lithografiert. Zunächst werden die Strukturen mit dc-Messungen charakte- risiert und es wird gezeigt, dass der Suprastrom einen Josephson-Effekt aufweist. Die Temperaturabhängigkeit des kritischen Stroms wird simuliert, wodurch die Bestimmung der Größe der induzierten supraleitenden Bandlücke ermöglicht wird. Durch Mikrowel- lenstrahlung entstehen Shapiro-Plateaus in der Strom-Spannungskennlinie I −V -Kurve. Der Spannungsabstand von zwei aufeinander folgenden Plateaus spiegelt die Periodizität des Josephsonstroms wider. Zu erwarten wäre, dass der Abstand in einem topologischen Josephson-Kontakt im Vergleich zu einem konventionellen Josephson-Kontakt doppelt so groß ist (oder anders formuliert: die ungeradzahligen Plateau-Indizes fehlen). In den Strom-Spannungskennlinien wird jedoch beobachtet, dass der erste erwartete Schritt ausbleibt. Alle höheren ungeradzahligen Schritte sind sichtbar. Durch die Untersuchung des Phänomens als Funktion von Mikrowellenfrequenz, Mikrowellenamplitude, Magnet- feldstärke und Probengeometrie wird argumentiert, dass die Ergebnisse der Experimente mit einem topologischen Andreev-Zustand und einer großen Zahl konventioneller Moden vereinbar sind. Um die experimentellen Ergebnisse aus Kapitel 3 nachzuvollziehen, werden in Kapitel 4 die I −V -Kennlinie eines Josephson-Kontaktes mit einer linearen Kombination eines 2π- und eines 4π-periodischen Suprastroms unter Mikrowellenstrahlung numerisch simuliert. Dies erfolgt durch ein Netzwerkmodell, welches aus einem Josephson-Kontakt in Parallelschaltung zu einem ohmschen Widerstand besteht (RSJ-Modell). Die Ergebnisse aus Kapitel 3 können nur durch das Vorhandensein eines 4π-periodischem Suprastroms I4π eindeutig numerisch simuliert werden. Darüber hinaus wird herausgestellt, dass eine Kopplung des Systems an die 4π-periodische Komponente möglich ist, obwohl der Beitrag zum Gesamtstrom Ic sehr klein ist (I4π « Ic ). Die Grundlage für die Experimente in Kapitel 5 bildet ein Josephson-Kontakt, der auf einem invertierten HgTe-Quantentrog basiert. Dieser besitzt helikale Randkanäle, welche mit Supraleitern topologisch geschützte Andreev-Zustände formen. Hierfür ist zuerst ein neuer Lithographieprozess zur Herstellung der Proben entwickelt worden. Da sich der HgTe-Quantentrog unter einer Hg0.3Cd0.7Te-Barriere befindet, muss diese für eine gute induzierte Supraleitung lokal entfernt und der Supraleiter aufgetragen werden, ohne das Vakuum zu brechen. Zur Variation der Ladungsträgerdichte im Josephson-Kontakt wird eine Feldeffektelektrode auf der Struktur platziert. Die Messung des Beugungsmusters des kritischen Stroms als Funktion des Magnetfeldes erlaubt es, die Stromverteilung in der Probe zu untersuchen. Das Beugungsmuster ähnelt dem eines supraleitenden Quanteninterferenzbauelement [engl. Superconducting Quantum Interference Device: (SQUID)] und zeigt, dass der Strom vorwiegend am Rand der Probe fließt. Durch die Bestrahlung mit Mikrowellen werden fehlende ungeradzahlige Shapiro-Plateaus bis zum Stufenindex n = 9 beobachtet. Dies verdeutlicht, dass der Strom eine 4π-periodischen Beitrag aufweist. Das Experiment wird mit einem nicht-invertierten HgTe-Quantentrog wiederholt. Dieser ist nicht in der Quanten-Spin-Hall-Phase und zeigt über den gesamten Parameterbereich alle erwarteten Shapiro-Plateaus, was beweist, dass die Topologie der Probe eine wichtige Eigenschaft ist, um die 4π-Periodizität zu beobachten. Beide Effekte, das SQUID-Beugungsmuster und die verschwindenden ungeradzahligen Shapiro- Plateaus, sind in der Nähe der Quanten-Spin-Phase am sichtbarsten und können daher als Beweis für induzierte topologische Supraleitung in spinpolarisierten Randkanälen interpretiert werden. Eine Messmethode zur direkten Bestimmung der Periodizität des Suprastromes, an- ders als die Verwendung von Shapiro-Plateaus, ist die Messung der Josephson-Emission, was in Kapitel 6 beschrieben wird. Ein topologischer Josephson-Kontakt emittiert Strah- lung bei der halben Josephsonfrequenz f J /2 aufgrund der 4π-Periodizität des Joseph- sonstromes. Hierfür wird ein neuer experimenteller Aufbau entwickelt, um das kleine Emissionssignal eines einzelnen Josephson-Kontaktes zu verstärken. Dieser neue Aufbau erlaubt es, das Spektrum eines invertierten HgTe-Quantentrog zu messen und eine Emis- sion bei f J /2 zu detektieren. Je nach Ladungsträgerdichte und Detektionfrequenz wird auch gewöhnliche Emission bei f J im Spektrum beobachtet. Generell dominiert aber bei niedriger Spannung die f J /2-Emission und bei höheren Spannungen die f J . Da Spannung und ac-Frequenz durch die zweite Josephson-Gleichung proportional zueinander lässt sich das Verhalten mit den Ergebnissen der Shapiro-Plateau-Messungen vereinbaren. Darüber hinaus ist aus der Linienbreite der Emissionssignale eine Lebensdauer für die ABS in der Größenordnung von 0.3 − 4 ns für die f J /2-Emission und 3 − 4 ns für die f J - Emission abgeschätzt worden. Ein nicht-invertierter Quantentrog zeigt im Vergleich zum invertierten nur gewöhnliche Emission bei f J über den gesamten zugänglichen Frequenz- und Ladungsträgerbereich. Im letzten Teil der Arbeit, in Kapitel 7, wird die in den 3D-topologischen Isolator HgTe induzierte Supraleitung mit Hilfe von Andreev-Punktkontaktspektroskopie unter- sucht. Hierfür wird eine HgTe-Struktur mit einer Verengung fabriziert, deren Durchmesser kleiner als die mittlere freie Weglänge der topologischen Oberflächenzustände ist und somit eine energieabhängige Spektroskopie des Zustandes erlaubt. Auf einer Seite der Verengung werden supraleitende Paarkorrelationen durch einen gewöhnlichen Supralei- ter Niob induziert. Diese Struktur ermöglicht daher die Untersuchung der Grenzfläche zwischen einem Supraleiter und einem Normalleiter (topologischer Isolator). Durch die Messung der differentiellen Leitfähigkeit d I /dV als Funktion der dc-Spannung ist es möglich die Energieabhängigkeit der Supraleitung zu untersuchen. Eine induzierte supraleitenden Bandlücke von 70 µeV wird gefunden. Die Leitfähigkeit zeigt Signatu- ren einer weiteren supraleitende Bandlücke des konventionellen Supraleiters Niob von ∆Nb ≈ 1.1 meV. Die Leitfähigkeit wird zum einen mit der Theorie von Blonder, Tinkham und Klapwijk modelliert und zum anderen mit einem erweiterten Modell, welches die 2D Oberflächenzustände des topologischen Isolators berücksichtigt simuliert. Für die Grenzfläche topologischer Isolator mit topologischem Supraleiter wird eine hohe Trans- missionswahrscheinlichkeit (niedrige Barriere) festgestellt, während an der Grenzfläche zwischen dem konventionellen Supraleiter und dem topologischen Isolator eine hohe Barriere in Übereinstimmung mit dem Modell war. Der Transportmechanismus wird durch eine Unterdrückung der induzierten Supraleitung durch eine Nichtgleichgewichts- verteilung der Zustände als Funktion der Spannung erklärt. Die vorliegende Dissertation konnte klare Signaturen von induzierter topologischer Supraleitung in Josephson-Kontakten auf Basis von HgTe-Quantentrögen und Volumen- material aufzeigen. Sie kann auch als Ausgangspunkt für eine große Anzahl von weiter- führenden Experimenten dienen. Die hier entwickelte Technik und auch Theorie kann auf andere topologische Zustände in Verbindung mit Supraleitern angewandt werden. Ein weiteres Experiment für HgTe-Strukturen ließe sich beispielsweise mit Hilfe von su- praleitenden Resonatoren die Spektroskopie und Manipulation der mikroskopischen topologischen Andreev-Zustände durchführen. Diese Technik wurde schon erfolgreich von Janvier et al . auf mechanisch kontrollierten supraleitenden Bruchkontakten ange- wandt [Science 2015, 349, 1199-1202 (2015)]. Eine alternative Technik zur Spektroskopie der Andreev Zustände benötigt konventionelle Josephson-Kontakte in Kombination mit topologischen Kontakten. Die konventionellen Kontakte erlauben die Kontrolle der supra- leitenden Phase und dienen als Spektrometer. Die Andreev-Punktkontaktspektroskopie kann auf zweidimensionale topologische Isolatoren erweitert werden. Auch kann ei- ne supraleitende Schleife, welche die Kontrolle über die Phase und eine veränderbare Barriere ermöglicht, neue Einblicke in die Transportmechanismen geben. Solche Un- tersuchungen bieten Ansatzpunkte für die Lokalisierung von Majorana-Zuständen in Quanten-Spin-Hall-Systemen. KW - Quecksilbertellurid KW - Supraleitung KW - Topologischer Isolator KW - topological insulators KW - Majorana bound state KW - topological superconductor KW - HgTe KW - Josephson junction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162782 ER - TY - JOUR A1 - Wevrett, Jill A1 - Fenwick, Andrew A1 - Scuffham, James A1 - Johansson, Lena A1 - Gear, Jonathan A1 - Schlögl, Susanne A1 - Segbers, Marcel A1 - Sjögreen-Gleisner, Katarina A1 - Solný, Pavel A1 - Lassmann, Michael A1 - Tipping, Jill A1 - Nisbet, Andrew T1 - Inter-comparison of quantitative imaging of lutetium-177 (\(^{177}\)Lu) in European hospitals JF - EJNMMI Physics N2 - Background This inter-comparison exercise was performed to demonstrate the variability of quantitative SPECT/CT imaging for lutetium-177 (\(^{177}\)Lu) in current clinical practice. Our aim was to assess the feasibility of using international inter-comparison exercises as a means to ensure consistency between clinical sites whilst enabling the sites to use their own choice of quantitative imaging protocols, specific to their systems. Dual-compartment concentric spherical sources of accurately known activity concentrations were prepared and sent to seven European clinical sites. The site staff were not aware of the true volumes or activity within the sources—they performed SPECT/CT imaging of the source, positioned within a water-filled phantom, using their own choice of parameters and reported their estimate of the activities within the source. Results The volumes reported by the participants for the inner section of the source were all within 29% of the true value and within 60% of the true value for the outer section. The activities reported by the participants for the inner section of the source were all within 20% of the true value, whilst those reported for the outer section were up to 83% different to the true value. Conclusions A variety of calibration and segmentation methods were used by the participants for this exercise which demonstrated the variability of quantitative imaging across clinical sites. This paper presents a method to assess consistency between sites using different calibration and segmentation methods. KW - Lutetium KW - Lu-177 KW - SPECT/CT KW - quantitative imaging KW - PRRT KW - molecular radiotherapy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233658 VL - 5 ER - TY - JOUR A1 - Werner, Rudolf A1 - Wakabyashi, Hiroshi A1 - Chen, Xinyu A1 - Hirano, Mitsuru A1 - Shinaji, Tetsuya A1 - Lapa, Constantin A1 - Rowe, Steven A1 - Javadi, Mehrbod A1 - Higuchi, Takahiro T1 - Functional renal imaging with \(^{18}\)F-FDS PET in rat models of renal disorders JF - Journal of Nuclear Medicine N2 - Background: Precise regional quantitative assessment of renal function is limited with conventional \(^{99m}\)Tc-labeled renal radiotracers. A recent study reported that the positron emission tomography (PET) radiotracer 2-deoxy-2-(\(^{18}\)F-fluorosorbitol (\(^{18}\)F-FDS) has ideal pharmacokinetics for functional renal imaging. Furthermore, (\(^{18}\)F-FDS is available via simple reduction from routinely used 2-deoxy-2-(\(^{18}\)F-fluoro-D-glucose ((\(^{18}\)F-FDG). We aimed to further investigate the potential of (\(^{18}\)F-FDS PET as a functional renal imaging agent using rat models of kidney diseases. Methods: Two different rat models of renal impairment were investigated: Glycerol induced acute renal failure (ARF) by intramuscular administration of glycerol in hind legs and unilateral ureteral obstruction (UUO) by ligation of the left ureter. 24h after these treatments, dynamic 30 min 18F-FDS PET data were acquired using a dedicated small animal PET system. Urine 18F-FDS radioactivity 30 min after radiotracer injection was measured together with co-injected \(^{99m}\)Tc-diethylenetriaminepentaacetic acid (\(^{99m}\)Tc-DTPA) urine activity. Results: Dynamic PET imaging demonstrated rapid (\(^{18}\)F-FDS accumulation in the renal cortex and rapid radiotracer excretion via kidneys in control healthy rats. On the other hand, significantly delayed renal radiotracer uptake (continuous slow uptake) was observed in ARF rats and UUO-treated kidneys. Measured urine radiotracer concentrations of (\(^{18}\)F-FDS and \(^{99m}\)Tc-DTPA were well correlated (R=0.84, P<0.05). Conclusions: (\(^{18}\)F-FDS PET demonstrated favorable kinetics for functional renal imaging in rat models of kidney diseases. Advantages of high spatiotemporal resolution of PET imaging and simple tracer production could potentially complement or replace conventional renal scintigraphy in select cases and significantly improve the diagnostic performance of renal functional imaging. KW - unilateral ureteral obstruction KW - Nierenfunktionsstörung KW - Positronen-Emissions-Tomografie KW - 18F-FDS KW - 99mTc-DTPA KW - PET KW - renal failure KW - Glomerular filtration Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161279 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Hiroshi Wakabayashi, Xinyu Chen, Mitsuru Hirano, Tetsuya Shinaji, Constantin Lapa, Steven P. Rowe, Mehrbod S. Javadi and Takahiro Higuchi. Functional renal imaging with 18F-FDS PET in rat models of renal disorders. J Nucl Med. May 1, 2018;vol. 59 no. 5: 828-832. © SNMMI. ER - TY - JOUR A1 - Werner, Rudolf A1 - Wakabayashi, Hiroshi A1 - Bauer, Jochen A1 - Schütz, Claudia A1 - Zechmeister, Christina A1 - Hayakawa, Nobuyuki A1 - Javadi, Mehrbod S. A1 - Lapa, Constantin A1 - Jahns, Roland A1 - Ergün, Süleyman A1 - Jahns, Valerie A1 - Higuchi, Takahiro T1 - Longitudinal \(^{18}\)F-FDG PET imaging in a Rat Model of Autoimmune Myocarditis JF - European Heart Journal Cardiovascular Imaging N2 - Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund’s adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease). Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis. KW - positron emission tomography KW - Myokarditis KW - myocarditis KW - inflammation KW - 18F-FDG KW - PET KW - personalized treatment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165601 SN - 2047-2404 ER - TY - JOUR A1 - Werner, Rudolf A1 - Solnes, Lilja A1 - Javadi, Mehrbod A1 - Weich, Alexander A1 - Gorin, Michael A1 - Pienta, Kenneth A1 - Higuchi, Takahiro A1 - Buck, Andreas A1 - Pomper, Martin A1 - Rowe, Steven A1 - Lapa, Constantin T1 - SSTR-RADS Version 1.0 as a Reporting System for SSTR-PET Imaging and Selection of Potential PRRT Candidates: A Proposed Standardization Framework JF - Journal of Nuclear Medicine N2 - Reliable standards and criteria for somatostatin receptor (SSTR) positron emission tomography (PET) are still lacking. We herein propose a structured reporting system on a 5-point scale for SSTR-PET imaging, titled SSTR-RADS version 1.0, which might serve as a standardized assessment for both diagnosis and treatment planning in neuroendocrine tumors (NET). SSTR-RADS could guide the imaging specialist in interpreting SSTR-PET scans, facilitate communication with the referring clinician so that appropriate work-up for equivocal findings is pursued, and serve as a reliable tool for patient selection for planned Peptide Receptor Radionuclide Therapy. KW - Radionuclide Therapy KW - Standardisierung KW - Positronen-Emissions-Tomografie KW - 68Ga-DOTATATE/-TOC KW - Gastrointestinal KW - Neuroendocrine KW - Neuroendocrine Tumor KW - Oncology KW - GI KW - PET KW - PET/CT KW - PRRT KW - RADS KW - SSTR Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161298 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Lilja B. Solnes, Mehrbod Som Javadi, Alexander Weich, Michael A. Gorin, Kenneth J. Pienta, Takahiro Higuchi, Andreas K. Buck, Martin G. Pomper, Steven P. Rowe, Constantin Lapa. SSTR-RADS Version 1.0 as a Reporting System for SSTR-PET Imaging and Selection of Potential PRRT Candidates: A Proposed Standardization Framework. J. Nucl. Med. July 1, 2018, vol. 59, no. 7, 1085-1091. © SNMMI ER - TY - JOUR A1 - Werner, Rudolf A1 - Schmid, Jan-Stefan A1 - Higuchi, Takahiro A1 - Javadi, Mehrbod S. A1 - Rowe, Steven P. A1 - Märkl, Bruno A1 - Aulmann, Christoph A1 - Fassnacht, Martin A1 - Kroiß, Matthias A1 - Reiners, Christoph A1 - Buck, Andreas A1 - Kreissl, Michael A1 - Lapa, Constantin T1 - Predictive value of \(^{18}\)F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib JF - Journal of Nuclear Medicine N2 - Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We aimed to assess the role of metabolic imaging using 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after TKI treatment initiation. During follow-up, CT scans were performed every 3 months and analyzed according to Response Evaluation Criteria In Solid Tumors (RECIST). The predictive value for estimating progression-free (PFS) and overall survival (OS) was examined by investigating \(^{18}\)F-FDG mean/maximum standardized uptake values (SUVmean/max) of the metabolically most active lesion as well as by analyzing clinical parameters (tumor marker doubling times {calcitonin, carcinoembryonic antigen (CEA)}, prior therapies, RET (rearranged during transfection) mutational status, and disease type). Results: Within a median follow-up of 5.2 years, 9 patients experienced disease progression after a median time interval of 2.1y whereas the remainder had ongoing disease control (n=5 partial response and n=4 stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5y after TKI initiation. Pre-therapeutic SUVmean >4.0 predicted a significantly shorter PFS (PFS: 1.9y vs. 5.2y; p=0.04). Furthermore, sustained high 18F-FDG uptake at 3 months with a SUVmean>2.8 tended to portend an unfavorable prognosis with a PFS of 1.9y (vs. 3.5y; p=0.3). Prolonged CEA doubling times were significantly correlated with longer PFS (r=0.7) and OS (r=0.76, p<0.01, respectively). None of the other clinical parameters had prognostic significance. Conclusions: Pre-therapeutic \(^{18}\)F-FDG PET/CT holds prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. Low tumor metabolism of SUVmean < 4.0 prior to treatment predicts longer progression-free survival. KW - positron emission tomography KW - Medullärer Schilddrüsenkrebs KW - Positronen-Emissions-Tomografie KW - medullary thyroid carcinoma KW - tyrosine kinase inhibitor KW - vandetanib KW - 2- deoxy-2-(18F)fluoro-D-glucose KW - 18F-FDG Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161256 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Jan-Stefan Schmid, Takahiro Higuchi, Mehrbod S. Javadi, Steven P. Rowe, Bruno Märkl, Christoph Aulmann, Martin Fassnacht, Matthias Kroiss, Christoph Reiners, Andreas K. Buck, Michael C. Kreissl, Constantin Lapa. Predictive value of 18F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib. J Nucl Med. May 1, 2018;vol. 59 no. 5: 756-761. © SNMMI. ER - TY - JOUR A1 - Werner, Rudolf A1 - Hänscheid, Heribert A1 - Leal, Jeffrey P. A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro A1 - Lodge, Martin A. A1 - Buck, Andreas K. A1 - Pomper, Martin G. A1 - Lapa, Constantin A1 - Rowe, Steven P. T1 - Impact of Tumor Burden on Quantitative [\(^{68}\)Ga]DOTATOC Biodistribution JF - Molecular Imaging and Biology N2 - Purpose: As has been previously reported, the somatostatin receptor (SSTR) imaging agent [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotate ([\(^{68}\)Ga]DOTATATE) demonstrates lower uptake in normal organs in patients with a high neuroendocrine tumor (NET) burden. Given the higher SSTR affinity of [\(^{68}\)Ga]DOTATATE, we aimed to quantitatively investigate the biodistribution of [\(^{68}\)Ga]-labeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe(1)-Tyr(3)-octreotide ([68Ga]DOTATOC) to determine a potential correlation between uptake in normal organs and NET burden. Procedures: Of the 44 included patients, 36/44 (82%) patients demonstrated suspicious radiotracer uptake on [\(^{68}\)Ga]DOTATOC positron emission tomography (PET)/x-ray computed tomography (CT). Volumes of Interest (VOIs) were defined for tumor lesions and normal organs (spleen, liver, kidneys, adrenals). Mean body weight corrected standardized uptake value (SUV\(_{mean}\)) for normal organs was assessed and was used to calculate the corresponding mean specific activity uptake (Upt: fraction of injected activity per kg of tissue). For the entire tumor burden, SUV\(_{mean}\), maximum standardized uptake value (SUV\(_{max}\)), and the total mass (TBM) was calculated and the decay corrected tumor fractional uptake (TBU) was assessed. A Spearman’s rank correlation coefficient was used to determine the correlations between normal organ uptake and tumor burden. Results: The median SUV\(_{mean}\) was 18.7 for the spleen (kidneys, 9.2; adrenals, 6.8; liver, 5.6). For tumor burden, the median values were SUV\(_{mean}\) 6.9, SUV\(_{max}\) 35.5, TBM 42.6g, and TBU 1.2%. With increasing volume of distribution, represented by lean body mass and body surface area (BSA), Upt decreased in kidneys, liver, and adrenal glands and SUV\(_{mean}\) increased in the spleen. Correlation improved only for both kidneys and adrenals when the influence of the tumor uptake on the activity available for organ uptake was taken into account by the factor 1/(1-TBU). TBU was neither predictive for SUV\(_{mean}\) nor for Upt in any of the organs. The distribution of organ Upt vs. BSA/(1-TBU) were not different for patients with minor TBU (<3%) vs. higher TBU (>7%), indicating that the correlations observed in the present study are explainable by the body size effect. High tumor mass and uptake mitigated against G1 NET. Conclusions: There is no significant impact on normal organ biodistribution with increasing tumor burden on [\(^{68}\)Ga]DOTATOC PET/CT. Potential implications include increased normal organ dose with [\(^{177}\)Lu-DOTA]\(^0\)-D-Phe\(^1\)-Tyr\(^3\)-Octreotide and decreased absolute lesion detection with [\(^{68}\)Ga]DOTATOC in high NET burden. KW - somatostatin receptor KW - Positronen-Emissions-Tomografie KW - quantification KW - [68Ga]DOTATOC KW - neuroendocrine tumor KW - SSTR-PET KW - theranostics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170280 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Kircher, Malte A1 - Solnes, Lilja B. A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Pomper, Martin G. A1 - Rowe, Steven A1 - Lapa, Constantin T1 - The theranostic promise for neuroendocrine tumors in the late 2010s – Where do we stand, where do we go? JF - Theranostics N2 - More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context. KW - theranostics KW - Positronen-Emissions-Tomografie KW - PRRT KW - somatostatin receptor KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170264 VL - 8 IS - 22 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Marcus, Charles A1 - Sheikhbahaei, Sara A1 - Solnes, Lilja B. A1 - Leal, Jeffrey P. A1 - Du, Yong A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. T1 - Visual and Semiquantitative Accuracy in Clinical Baseline 123I-Ioflupane SPECT/CT Imaging JF - Clinical Nuclear Medicine N2 - PURPOSE: We aimed to (a) elucidate the concordance of visual assessment of an initial I-ioflupane scan by a human interpreter with comparison to results using a fully automatic semiquantitative method and (b) to assess the accuracy compared to follow-up (f/u) diagnosis established by movement disorder specialists. METHODS: An initial I-ioflupane scan was performed in 382 patients with clinically uncertain Parkinsonian syndrome. An experienced reader performed a visual evaluation of all scans independently. The findings of the visual read were compared with semiquantitative evaluation. In addition, available f/u clinical diagnosis (serving as a reference standard) was compared with results of the human read and the software. RESULTS: When comparing the semiquantitative method with the visual assessment, discordance could be found in 25 (6.5%) of 382 of the cases for the experienced reader (ĸ = 0.868). The human observer indicated region of interest misalignment as the main reason for discordance. With neurology f/u serving as reference, the results of the reader revealed a slightly higher accuracy rate (87.7%, ĸ = 0.75) compared to semiquantification (86.2%, ĸ = 0.719, P < 0.001, respectively). No significant difference in the diagnostic performance of the visual read versus software-based assessment was found. CONCLUSIONS: In comparison with a fully automatic semiquantitative method in I-ioflupane interpretation, human assessment obtained an almost perfect agreement rate. However, compared to clinical established diagnosis serving as a reference, visual read seemed to be slightly more accurate as a solely software-based quantitative assessment. KW - Single-Photon-Emissions-Computertomographie KW - SPECT KW - Parkinson’s disease KW - Parkinsonism KW - DaTscan KW - 123I-Ioflupane KW - SPECT KW - SPECT/CT Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168181 SN - 1536-0229 VL - 44 IS - 1 ER - TY - CHAP A1 - Werner, Rudolf A. A1 - Marcus, Charles A1 - Sheikhbahaei, Sara A1 - Higuchi, Takahiro A1 - Solnes, Lilja B. A1 - Rowe, Steven P. A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. T1 - Diagnostic Accuracy of Visual Assessment of an Initial DaT-Scan in Comparison to a Fully Automatic Semiquantitative Method T2 - Journal of Nuclear Medicine N2 - No abstract available. KW - Parkinson-Krankheit KW - SPECT KW - Parkinson KW - Parkinson Disease KW - DaTscan KW - Ioflupane KW - molecular imaging Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162208 UR - http://jnm.snmjournals.org/content/59/supplement_1/626.abstract SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Charles Marcus, Sara Sheikhbahaei, Takahiro Higuchi, Lilja B. Solnes, Steven P. Rowe, Andreas K. Buck, Constantin Lapa, Mehrbod S. Javadi. Diagnostic Accuracy of Visual Assessment of an Initial DaT-Scan in Comparison to a Fully Automatic Semiquantitative Method. J Nucl Med. May 1, 2018; vol. 59 no. supplement 1:626. © SNMMI. VL - 59 IS - Supplement No. 1 SP - 626 ER - TY - CHAP A1 - Werner, Rudolf A. A1 - Marcus, Charles A1 - Sheikhbahaei, Sara A1 - Higuchi, Takahiro A1 - Solnes, Lilja B. A1 - Rowe, Steven P. A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. T1 - The Impact of Ageing on Dopamine Transporter Imaging T2 - Journal of Nuclear Medicine N2 - No abstract available. KW - Parkinson-Krankheit KW - Parkinson KW - Parkinson Disease KW - DaTscan KW - Ioflupane KW - SPECT KW - molecular imaging KW - ageing Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162213 UR - http://jnm.snmjournals.org/content/59/supplement_1/1646.abstract SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Charles Marcus, Sara Sheikhbahaei, Takahiro Higuchi, Lilja B. Solnes, Steven P. Rowe, Andreas K. Buck, Constantin Lapa, Mehrbod S. Javadi. The Impact of Ageing on Dopamine Transporter Imaging. J Nucl Med. May 1, 2018; vol. 59 no. supplement 1:1646. © SNMMI. VL - 59 IS - Supplement No 1 SP - 1646 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Kobayashi, Ryohei A1 - Javadi, Mehrbod Som A1 - Köck, Zoe A1 - Wakabayashi, Hiroshi A1 - Unterecker, Stefan A1 - Nakajima, Kenichi A1 - Lapa, Constantin A1 - Menke, Andreas A1 - Higuchi, Takahiro T1 - Impact of Novel Antidepressants on Cardiac Metaiodobenzylguanidine (mIBG) Uptake: Experimental Studies in SK-N-SH Cells and Healthy Rabbits JF - Journal of Nuclear Medicine N2 - Background: \(^{123}\)I-metaiodobenzylguanidine (mIBG) provides independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not impact its quantitative information. We aimed to evaluate the four most-prescribed antidepressants currently used as a first‑line treatment for patients with major depressive disorder (MDD) and their potential on altering mIBG imaging results. Methods: The inhibition effect of four different types of antidepressants (desipramine, escitalopram, venlafaxine and bupropion) for MDD treatment on \(^{131}\)I-mIBG uptake was assessed by in-vitro cell uptake assays using human neuroblastoma SK-N-SH cells. The half maximal inhibitory concentration (IC50) of tracer uptake was determined from dose-response curves. To evaluate the effects of IV pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5, 15 mg/kg) on mIBG cardiac uptake, in-vivo planar 123I-mIBG scans in healthy New Zealand White Rabbits were conducted. Results: The IC50 values of desipramine, escitalopram, venlafaxine and bupropion on \(^{131}\)I-mIBG cellular uptake were 11.9 nM, 7.5 μM, 4.92 μM, and 12.9 μM, respectively. At the maximum serum concentration (Cmax, as derived by previous clinical trials), the inhibition rates of 131I-mIBG uptake were 90.6 % for desipramine, 25.5 % for venlafaxine, 11.7 % for bupropion and 0.72 % for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in-vivo rabbit model: with dosage considerably higher than clinical practice, the non-inhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine led to a marked reduction of cardiac 123I-mIBG uptake. Conclusions: In the present in-vitro binding assay and in-vivo rabbit study, the selective-serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac mIBG uptake within therapeutic dose ranges, while other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac mIBG imaging, in particular, if the patient’s neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine interfering antidepressant. KW - MDD KW - Antidepressants KW - depression KW - 123I-mIBG KW - antidepressant KW - cardiac sympathetic nerve system KW - major depressive disorder KW - myocardial sympathetic innervation imaging Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161280 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Ryohei Kobayashi, Mehrbod Som Javadi, Zoe Köck, Hiroshi Wakabayashi, Stefan Unterecker, Kenichi Nakajima, Constantin Lapa, Andreas Menke, Takahiro Higuchi. Impact of Novel Antidepressants on Cardiac Metaiodobenzylguanidine (mIBG) Uptake: Experimental Studies in SK-N-SH Cells and Healthy Rabbits. J. Nucl. Med. July 1, 2018, vol. 59, no. 7, 1099-1103. © SNMMI. ER - TY - INPR A1 - Werner, Rudolf A. A1 - Ilhan, Harun A1 - Lehner, Sebastian A1 - Papp, László A1 - Zsótér, Norbert A1 - Schatka, Imke A1 - Muegge, Dirk O. A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Bartenstein, Peter A1 - Bengel, Frank A1 - Essler, Markus A1 - Lapa, Constantin A1 - Bundschuh, Ralph A. T1 - Pre-therapy Somatostatin-Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy T2 - Molecular Imaging and Biology N2 - Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed. Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated. Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.). Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification. KW - Pancreas KW - Positronen-Emissions-Tomografie KW - PET KW - neuroendocrine tumor KW - tumor heterogeneity KW - [68Ga] KW - [177Lu]-DOTATATE/-DOTATOC KW - PET/CT KW - SSTR Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164624 UR - https://link.springer.com/article/10.1007/s11307-018-1252-5 SN - 1536-1632 N1 - This is a post-peer-review, pre-copyedit version of an article published in Molecular Imaging and Biology. The final authenticated version is available online at: http://dx.doi.org/s11307-018-1252-5 N1 - Die finale Version dieses Artikels steht unter https://doi.org/10.1007/s11307-018-1252-5 bzw. http://nbn-resolving.org/urn:nbn:de:bvb:20-opus-167168 open access zur Verfügung. ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Ilhan, Harun A1 - Lehner, Sebastian A1 - Papp, László A1 - Zsótér, Norbert A1 - Schatka, Imke A1 - Muegge, Dirk O. A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Bartenstein, Peter A1 - Bengel, Frank A1 - Essler, Markus A1 - Lapa, Constantin A1 - Bundschuh, Ralph A. T1 - Pre-therapy Somatostatin-Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy JF - Molecular Imaging and Biology N2 - Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed. Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated. Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.). Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification. KW - tumor heterogeneity KW - Positronen-Emissions-Tomografie KW - PET KW - PET/CT KW - pancreas KW - SSTR KW - [177Lu]-DOTATATE/-DOTATOC KW - [68Ga] KW - neuroendocrine tumor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167168 SN - 1536-1632 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Eissler, Christoph A1 - Hayakawa, Nobuyuki A1 - Arias-Loza, Paula A1 - Wakabayashi, Hiroshi A1 - Javadi, Mehrbod S. A1 - Chen, Xinyu A1 - Shinaji, Tetsuya A1 - Lapa, Constantin A1 - Pelzer, Theo A1 - Higuchi, Takahiro T1 - Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET JF - Scientific Reports N2 - In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent. KW - diabetic cardiomyopathy KW - personalized treatment KW - precision medicine KW - ZDF rats KW - ECG KW - PET KW - \(^{18}\)F-fluorodeoxyglucose KW - \(^{18}\)F-FDG KW - diabetes Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171765 VL - 8 IS - 17631 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Chen, Xinyu A1 - Rowe, Steven P. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro T1 - Moving into the Next Era of PET Myocardial Perfusion Imaging - Introduction of Novel \(^{18}\)F-labeled Tracers JF - The International Journal of Cardiovascular Imaging N2 - The heart failure (HF) epidemic continues to rise with coronary artery disease (CAD) as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 sec), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed. KW - heart failure with mid-range ejection fraction KW - Positronenemissionstomografie KW - coronary artery disease KW - precision medicine KW - positron emission tomography KW - PET KW - SPECT KW - myocardial perfusion imaging KW - MPI KW - 18F-flurpiridaz KW - 18FFBnTP KW - HFmrEF Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169134 SN - 1569-5794 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Chen, Xinyu A1 - Maya, Yoshifumi A1 - Eissler, Christoph A1 - Hirano, Mitsuru A1 - Nose, Naoko A1 - Wakabayashi, Hiroshi A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro T1 - The Impact of Ageing on 11C-Hydroxyephedrine Uptake in the Rat Heart JF - Scientific Reports N2 - We aimed to explore the impact of ageing on 11C-Hydroxyephedrine (11C-HED) uptake in the healthy rat heart in a longitudinal setting. To investigate a potential cold mass effect, the influence of specific activity on cardiac 11C-HED uptake was evaluated: 11C-HED was synthesized by N-methylation of (−)-metaraminol as the free base (radiochemical purity >95%) and a wide range of specific activities (0.2–141.9 GBq/μmol) were prepared. \(^{11}\)C-HED (48.7±9.7MBq, ranged 0.2–60.4μg/kg cold mass) was injected in healthy Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac 11C-HED retention index (%/min) was calculated as myocardial tissue activity at 20-30 min divided by the integral of the blood activity curves. Additionally, the impact of ageing on myocardial 11CHED uptake was investigated longitudinally by PET studies at different ages of healthy Wistar Rats. A dose-dependent reduction of cardiac 11C-HED uptake was observed: The estimated retention index as a marker of norepinephrine function decreased at a lower specific activity (higher amount of cold mass). This observed high affinity of 11C-HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the 11C-HED retention index decreased with increasing age. An age-related decline of cardiac sympathetic innervation could be demonstrated. The herein observed cold mass effect might increase in succeeding scans and therefore, 11C-HED microPET studies should be planned with extreme caution if one single radiosynthesis is scheduled for multiple animals. KW - ageing KW - Positronen-Emissions-Tomografie KW - 11C-HED KW - 11C-Hydroxyephedrine KW - cardiac sympathetic nervous system KW - myocardial sympathetic innervation imaging KW - PET Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164826 SN - 2281-5872 VL - 8 IS - 11120 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Chen, Xinyu A1 - Hirano, Mitsuru A1 - Rowe, Steven P. A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro T1 - SPECT vs. PET in Cardiac Innervation Imaging: Clash of the Titans JF - Clinical and Translational Imaging N2 - Purpose: We aim to provide an overview of the conventional single photon emission computed tomography (SPECT) and emerging positron emission tomography (PET) catecholamine analogue tracers for assessing myocardial nerve integrity, in particular focusing on \(^{18}\)F-labeled tracers. Results: Increasingly, the cardiac sympathetic nervous system (SNS) is being studied by non-invasive molecular imaging approaches. Forming the backbone of myocardial SNS imaging, the norepinephrine (NE) transporter at the sympathetic nerve terminal plays a crucial role for visualizing denervated myocardium: in particular, the single-photon-emitting NE analogue \(^{123}\)I-meta-Iodobenzylguanidine (\(^{123}\)I-mIBG) has demonstrated favorable results in the identification of patients at a high risk for cardiac death. However, cardiac neuronal PET agents offer several advantages inlcuding improved spatio-temporal resolution and intrinsic quantifiability. Compared to their \(^{11}\)C-labeled counterparts with a short half-life (20.4 min), novel \(^{18}\)F-labeled PET imaging agents to assess myocardial nerve integrity have the potential to revolutionize the field of SNS molecular imaging: The longer half-life of \(^{18}\)F (109.8 min) allows for more flexibility in the study design and delivery from central cyclotron facilities to smaller hospitals may lead to further cost reduction. A great deal of progress has been made by the first in-human studies of such \(^{18}\)F-labeled SNS imaging agents. Moreover, dedicated animal platforms open avenues for further insights into the handling of radiolabeled catecholamine analogues at the sympathetic nerve terminal. Conclusions: \(^{18}\)F-labeled imaging agents demonstrate key properties for mapping cardiac sympathetic nerve integrity and might outperform current SPECT-based or \(^{11}\)C-labeled tracers in the long run. KW - single photon emission computed tomography: sympathetic nerve KW - Positronen-Emissions-Tomografie KW - 18F-LMI1195 KW - 11C-hydroxyephedrine KW - 123I-metaiodobenzylguanidine KW - positron emission tomography Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163628 SN - 2281-5872 ER - TY - CHAP A1 - Werner, Rudolf A. A1 - Chen, Xinyu A1 - Hirano, Mitsuru A1 - Nose, Naoko A1 - Lapa, Constantin A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro T1 - The Impact of Ageing on [\(^{11}\)C]meta-Hydroxyephedrine Uptake in the Rat Heart T2 - Journal of Nuclear Medicine N2 - No abstract available. KW - Positronen-Emissions-Tomografie KW - moycardial sympathetic innervation KW - Positronen-Emissions-Tomografie KW - positron emission tomography KW - PET KW - 11C-HED KW - hydroxyephedrine KW - ageing Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162228 UR - http://jnm.snmjournals.org/content/59/supplement_1/100.abstract SN - 0161-5505 VL - 59 IS - Supplement No 1 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Bundschuh, Ralph A. A1 - Higuchi, Takahiro A1 - Javadi, Mehrbod S. A1 - Rowe, Steven P. A1 - Zsótér, Norbert A1 - Kroiss, Matthias A1 - Fassnacht, Martin A1 - Buck, Andreas K. A1 - Kreissl, Michael C. A1 - Lapa, Constantin T1 - Volumetric and Texture Analysis of Pretherapeutic \(^{18}\)F-FDG PET can Predict Overall Survival in Medullary Thyroid Cancer Patients Treated with Vandetanib JF - Endocrine N2 - Purpose: The metabolically most active lesion in 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic \(^{18}\)F-FDG PET. Methods: Eighteen patients with progressive MTC underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated. Results: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3y (vs. low-risk group, OS=5.3y, 8/18, AUC=0.78, P=0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS=3.5y vs. low-risk group, OS=5y, 7/18, AUC=0.83, P=0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P=0.02, OS, n.s.). Conclusions: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction. KW - personalized medicine KW - Positronen-Emissions-Tomografie KW - medullary thyroid carcinoma KW - tyrosine kinase inhibitor KW - TKI KW - vandetanib KW - 18F-FDG KW - positron emission tomography KW - 2-deoxy-2-(18F)fluoro-D-glucose KW - PET Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167910 SN - 1355-008X ER - TY - INPR A1 - Werner, Rudolf A. A1 - Bundschuh, Ralph A. A1 - Bundschuh, Lena A1 - Javadi, Mehrbod S. A1 - Leal, Jeffrey P. A1 - Higuchi, Takahiro A1 - Pienta, Kenneth J. A1 - Buck, Andreas K. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Lapa, Constantin A1 - Rowe, Steven P. T1 - Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on \(^{18}\)F-DCFPyL PET/CT Imaging T2 - Journal of Nuclear Medicine N2 - Objectives: Recently, the standardized reporting and data system for prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging studies, termed PSMA-RADS version 1.0, was introduced. We aimed to determine the interobserver agreement for applying PSMA-RADS to imaging interpretation of 18F-DCFPyL PET examinations in a prospective setting mimicking the typical clinical work-flow at a prostate cancer referral center. Methods: Four readers (two experienced readers (ER, > 3 years of PSMA-targeted PET interpretation experience) and two inexperienced readers (IR, < 1 year of experience)), who had all read the initial publication on PSMA-RADS 1.0, assessed 50 18F-DCFPyL PET/computed tomography (CT) studies independently. Per scan, a maximum of 5 target lesions were selected by the observers and a PSMA-RADS score for every target lesion was recorded. No specific pre-existing conditions were placed on the selection of the target lesions, although PSMA-RADS 1.0 suggests that readers focus on the most highly avid or largest lesions. An overall scan impression based on PSMA-RADS was indicated and interobserver agreement rates on a target lesion-based, on an organ-based, and on an overall PSMA-RADS score-based level were computed. Results: The number of target lesions identified by each observer were as follows: ER 1, 123; ER 2, 134; IR 1, 123; and IR 2, 120. Among those selected target lesions, 125 were chosen by at least two individual observers (all four readers selected the same target lesion in 58/125 (46.4%) instances, three readers in 40/125 (32%) and two observers in 27/125 (21.6%) instances). The interobserver agreement for PSMA-RADS scoring among identical target lesions was good (intraclass correlation coefficient (ICC) for four, three and two identical target lesions, ≥0.60, respectively). For lymph nodes, an excellent interobserver agreement was derived (ICC=0.79). The interobserver agreement for an overall scan impression based on PSMA-RADS was also excellent (ICC=0.84), with a significant difference for ER (ICC=0.97) vs. IR (ICC=0.74, P=0.005). Conclusions: PSMA-RADS demonstrates a high concordance rate in this study, even among readers with different levels of experience. This suggests that PSMA-RADS can be effectively used for communication with clinicians and can be implemented in the collection of data for large prospective trials. KW - 18F-DCFPyL KW - Positronen-Emissions-Tomografie KW - PSMA-RADS KW - interreader KW - interobserver KW - PSMA KW - prostate cancer KW - RADS KW - reporting and data system KW - PET Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167788 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Ralph A. Bundschuh, Lena Bundschuh, Mehrbod S. Javadi, Jeffrey P. Leal, Takahiro Higuchi, Kenneth J. Pienta, Andreas K. Buck, Martin G. Pomper, Michael A. Gorin, Constantin Lapa and Steven P. Rowe. Interobserver Agreement for the Standardized Reporting System PSMA-RADS 1.0 on 18F-DCFPyL PET/CT Imaging. J Nucl Med 2018;59:1857-1864 © SNMMI. ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Bundschuh, Ralph A. A1 - Bundschuh, Lena A1 - Javadi, Mehrbod S. A1 - Higuchi, Takahiro A1 - Weich, Alexander A1 - Sheikhbahaei, Sara A1 - Pienta, Kenneth J. A1 - Buck, Andreas K. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Lapa, Constantin A1 - Rowe, Steven P. T1 - MI-RADS: Molecular Imaging Reporting and Data Systems – A Generalizable Framework for Targeted Radiotracers with Theranostic Implications JF - Annals of Nuclear Medicine N2 - Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader’s confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems. KW - PET KW - Positronen-Emissions-Tomografie KW - prostate cancer KW - neuroendocrine tumor KW - prostate-specific membrane antigen (PSMA) KW - somatostatin receptor (SSTR) KW - positron emission tomography KW - theranostics KW - standardization KW - RADS KW - reporting and data systems KW - personalized medicine Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166995 SN - 0914-7187 ER - TY - INPR A1 - Werner, Rudolf A. A1 - Andree, Christian A1 - Javadi, Mehrbod S. A1 - Lapa, Constantin A1 - Buck, Andreas K. A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Rowe, Steven P. A1 - Pienta, Kenneth J. T1 - A Voice From the Past: Re-Discovering the Virchow Node with PSMA-targeted \(^{18}\)F-DCFPyL PET Imaging T2 - Urology - The Gold Journal N2 - No abstract available. KW - 18F-DCFPyL KW - Virchow Node KW - PSMA-PET KW - Virchow Node KW - Positron Emission Tomography KW - Prostate Cancer KW - PET Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161103 SN - 0090-4295 N1 - This is the accepted manuscript of Rudolf Werner, Christian Andree, Mehrbod S. Javadi, Constantin Lapa, Andreas K. Buck, Takahiro Higuchi, Martin G. Pomper, Michael A.Gorin, Steven P.Rowe, Kenneth J. Pienta: A Voice From the Past: Re-Discovering the Virchow Node with PSMA-Targeted 18F-DCFPyL PET Imaging. Published in Urology 117(2018), p. 18-21. https://doi.org/10.1016/j.urology.2018.03.030 N1 - Die finale Version dieses Artikels steht unter https://doi.org/10.1016/j.urology.2018.03.030 oder https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-164632 open access zur Verfügung. ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Andree, Christian A1 - Javadi, Mehrbod S. A1 - Lapa, Constantin A1 - Buck, Andreas K. A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Rowe, Steven P. A1 - Pienta, Kenneth J. T1 - A Voice From the Past: Re-Discovering the Virchow Node with PSMA-targeted \(^{18}\)F-DCFPyL PET Imaging JF - Urology - The Gold Journal N2 - No abstract available. KW - 18F-DCFPyL KW - PET KW - PSMA-PET KW - Positron Emission Tomography KW - Prostate Cancer KW - Virchow Node Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164632 SN - 0090-4295 VL - 117 ER - TY - JOUR A1 - Werner, Rudolf A. T1 - Editorial: Cardiac Innervation Imaging as a Risk Stratification Tool for Potential Device Therapy Candidates JF - Journal of Nuclear Cardiology N2 - As a scintigraphic approach evaluating cardiac nerve integrity, \(^{123}\)I-metaiodobenzylguanidine (123I-mIBG) has been recently Food and Drug Administration approved. A great deal of progress has been made by the prospective ADMIRE-HF trial, which primarily demonstrated the association of denervated myocardium assessed by \(^{123}\)I-mIBG and cardiac events. However, apart from risk stratification, myocardial nerve function evaluated by molecular imaging should also be expanded to other clinical contexts, in particular to guide the referring cardiologist in selecting appropriate candidates for specific therapeutic interventions. In the present issue of the Journal of Nuclear Cardiology, the use of 123I-mIBG for identifying cardiomyopathy patients, which would most likely not benefit from ICD due low risk of arrhythmias, is described. If we aim to deliver on the promise of cardiac innervation imaging as a powerful tool for risk stratification in a manner similar to nuclear oncology, studies such as the one reviewed here may imply an important step to lay the proper groundwork for a more widespread adoption in clinical practice. KW - SPECT KW - SPECT KW - myocardial nerve KW - 123I-metaiodobenzylguanidine KW - 123I-mIBG KW - cardiac nerve KW - ICD KW - arrhythmia KW - cardiac innervation imaging Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168465 UR - https://rdcu.be/970i SN - 1071-3581 N1 - SharedIt-Link zur Publikation: https://rdcu.be/970i N1 - This is a post-peer-review, pre-copyedit version of an article published in Journal of Nuclear Cardiology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s12350-018-01475-0 ER - TY - JOUR A1 - Weis, Matthias A1 - Shan, Junwen A1 - Kuhlmann, Matthias A1 - Jungst, Tomasz A1 - Tessmar, Jörg A1 - Groll, Jürgen T1 - Evaluation of hydrogels based on oxidized hyaluronic acid for bioprinting JF - Gels N2 - In this study, we evaluate hydrogels based on oxidized hyaluronic acid, cross-linked with adipic acid dihydrazide, for their suitability as bioinks for 3D bioprinting. Aldehyde containing hyaluronic acid (AHA) is synthesized and cross-linked via Schiff Base chemistry with bifunctional adipic acid dihydrazide (ADH) to form a mechanically stable hydrogel with good printability. Mechanical and rheological properties of the printed and casted hydrogels are tunable depending on the concentrations of AHA and ADH cross-linkers. KW - biofabrication KW - bioprinting KW - hyaluronic acid Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197600 SN - 2310-2861 VL - 4 IS - 4 ER - TY - JOUR A1 - Weigel, Tobias A1 - Schmitz, Tobias A1 - Pfister, Tobias A1 - Gaetzner, Sabine A1 - Jannasch, Maren A1 - Al-Hijailan, Reem A1 - Schürlein, Sebastian A1 - Suliman, Salwa A1 - Mustafa, Kamal A1 - Hansmann, Jan T1 - A three-dimensional hybrid pacemaker electrode seamlessly integrates into engineered, functional human cardiac tissue in vitro JF - Scientific Reports N2 - Pacemaker systems are an essential tool for the treatment of cardiovascular diseases. However, the immune system’s natural response to a foreign body results in the encapsulation of a pacemaker electrode and an impaired energy efficiency by increasing the excitation threshold. The integration of the electrode into the tissue is affected by implant properties such as size, mechanical flexibility, shape, and dimensionality. Three-dimensional, tissue-like electrode scaffolds render an alternative to currently used planar metal electrodes. Based on a modified electrospinning process and a high temperature treatment, a conductive, porous fiber scaffold was fabricated. The electrical and immunological properties of this 3D electrode were compared to 2D TiN electrodes. An increased surface of the fiber electrode compared to the planar 2D electrode, showed an enhanced electrical performance. Moreover, the migration of cells into the 3D construct was observed and a lower inflammatory response was induced. After early and late in vivo host response evaluation subcutaneously, the 3D fiber scaffold showed no adverse foreign body response. By embedding the 3D fiber scaffold in human cardiomyocytes, a tissue-electrode hybrid was generated that facilitates a high regenerative capacity and a low risk of fibrosis. This hybrid was implanted onto a spontaneously beating, tissue-engineered human cardiac patch to investigate if a seamless electronic-tissue interface is generated. The fusion of this hybrid electrode with a cardiac patch resulted in a mechanical stable and electrical excitable unit. Thereby, the feasibility of a seamless tissue-electrode interface was proven. KW - biomedical materials KW - cardiac device therapy KW - hybrid pacemaker Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177368 VL - 8 IS - 14545 ER - TY - THES A1 - Weidner, Magdalena Theodora T1 - Brain serotonin throughout development - for better and for worse T1 - Der Effekt von Serotonin im sich entwickelnden Gehirn - in guten wie in schlechten Tagen N2 - The work presented in this thesis covers the effects of early-life adversity in the context of altered serotonin (5-HT; 5-hydroxytryptamine) system functioning in mice. The main body is focussing on a screening approach identifying molecular processes, potentially involved in distinct behavioural manifestations that emerge from or are concomitant with early adversity and, with regard to some behavioural manifestations, dependent on the functioning of the 5-HT system. N2 - Diese Arbeit berichtet Ergebnisse der umfassenden Erforschung des Einflusses von aversiven Bedingungen während der pränatalen und frühkindlichen Entwicklungsphase, unter dem Einfluss genetischer Variationen des serotonergen (5-HT, 5-Hydroxytryptamin) Systems, im Mausmodel. Der Hauptfokus der Thesis lag bei der hypothesenfreien Untersuchung der Konsequenzen, die durch den kombinierten Effekt aversiver Bedingungen, und genetischer Prädisposition ausgelöst werden, sowie, final, der Ermittlung potentieller Kandidatengene, die an der Manifestierung verhaltensbezogener Konsequenzen beteiligt sein können sowie durch epigenetische Mechanismen reguliert werden. KW - Gehirn KW - Serotonin KW - Entwicklung KW - Stress KW - epigenetics KW - early-life stress KW - rodent model KW - behaviour Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163345 SN - 978-94-6233-940-8 N1 - This document is also published by the University library Maastricht. Maastricht University holds the same rights as University of Würzburg PB - Magdalena T. Weidner CY - Maastricht, the Netherlands ER - TY - JOUR A1 - Wei, Chunzhu A1 - Blaschke, Thomas T1 - Pixel-wise vs. object-based impervious surface analysis from remote sensing: correlations with land surface temperature and population density JF - Urban Science N2 - Impervious surface areas (ISA) are heavily influenced by urban structure and related structural features. We examined the effects of object-based impervious surface spatial pattern analysis on land surface temperature and population density in Guangzhou, China, in comparison to classic per-pixel analyses. An object-based support vector machine (SVM) and a linear spectral mixture analysis (LSMA) were integrated to estimate ISA fraction using images from the Chinese HJ-1B satellite for 2009 to 2011. The results revealed that the integrated object-based SVM-LSMA algorithm outperformed the traditional pixel-wise LSMA algorithm in classifying ISA fraction. More specifically, the object-based ISA spatial patterns extracted were more suitable than pixel-wise patterns for urban heat island (UHI) studies, in which the UHI areas (landscape surface temperature >37 °C) generally feature high ISA fraction values (ISA fraction >50%). In addition, the object-based spatial patterns enable us to quantify the relationship of ISA with population density (correlation coefficient >0.2 in general), with global human settlement density (correlation coefficient >0.2), and with night-time light map (correlation coefficient >0.4), and, whereas pixel-wise ISA did not yield significant correlations. These results indicate that object-based spatial patterns have a high potential for UHI detection and urbanization monitoring. Planning measures that aim to reduce the urbanization impacts and UHI intensities can be better supported. KW - impervious surface areas KW - object-based image analysis KW - land surface temperature KW - population density Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197829 SN - 2413-8851 VL - 2 IS - 1 ER - TY - JOUR A1 - Wegener, Sonja A1 - Sauer, Otto A. T1 - Electrometer offset current due to scattered radiation JF - Journal of Applied Clinical Medical Physics N2 - Relative dose measurements with small ionization chambers in combination with an electrometer placed in the treatment room (“internal electrometer”) show a large dependence on the polarity used. While this was observed previously for percent depth dose curves (PDDs), the effect has not been understood or preventable. To investigate the polarity dependence of internal electrometers used in conjunction with a small‐volume ionization chamber, we placed an internal electrometer at a distance of 1 m from the isocenter and exposed it to different amounts of scattered radiation by varying the field size. We identified irradiation of the electrometer to cause a current of approximately −1 pA, regardless of the sign of the biasing voltage. For low‐sensitivity detectors, such a current noticeably distorts relative dose measurements. To demonstrate how the current systematically changes PDDs, we collected measurements with nine ionization chambers of different volumes. As the chamber volume decreased, signal ratios at 20 and 10 cm depth (M20/M10) became smaller for positive bias voltage and larger for negative bias voltage. At the size of the iba CC04 (40 mm\(^{3}\)) the difference of M20/M10 was around 1% and for the smallest studied chamber, the iba CC003 chamber (3 mm\(^{3}\)), around 7% for a 10 × 10 cm² field. When the electrometer was moved further from the source or shielded, the additional current decreased. Consequently, PDDs at both polarities were brought into alignment at depth even for the 3 mm\(^{3}\) ionization chamber. The apparent polarity effect on PDDs and lateral beam profiles was reduced considerably by shielding the electrometer. Due to normalization the effect on output values was low. When measurements with a low‐sensitivity probe are carried out in conjunction with an internal electrometer, we recommend careful monitoring of the particular setup by testing both polarities, and if deemed necessary, we suggest shielding the electrometer. KW - electrometer KW - micro-ionization chambers KW - polarity KW - relative dosimetry KW - scatter radiation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176137 VL - 19 IS - 6 ER - TY - THES A1 - Wedel, Carolin T1 - The impact of DNA sequence and chromatin on transcription in \(Trypanosoma\) \(brucei\) T1 - Der Einfluss der DNA-Sequenz und der Chromatinstruktur auf die Transkription in \(Trypanosoma\) \(brucei\) N2 - For cellular viability, transcription is a fundamental process. Hereby, the DNA plays the most elemental and highly versatile role. It has long been known that promoters contain conserved and often well-defined motifs, which dictate the site of transcription initiation by providing binding sites for regulatory proteins. However, research within the last decade revealed that it is promoters lacking conserved promoter motifs and transcribing constitutively expressed genes that constitute the majority of promoters in eukaryotes. While the process of transcription initiation is well studied, whether defined DNA sequence motifs are required for the transcription of constitutively expressed genes in eukaryotes remains unknown. In the highly divergent protozoan parasite Trypanosoma brucei, most of the proteincoding genes are organized in large polycistronic transcription units. The genes within one polycistronic transcription unit are generally unrelated and transcribed by a common transcription start site for which no RNA polymerase II promoter motifs have been identified so far. Thus, it is assumed that transcription initiation is not regulated but how transcription is initiated in T. brucei is not known. This study aimed to investigate the requirement of DNA sequence motifs and chromatin structures for transcription initiation in an organism lacking transcriptional regulation. To this end, I performed a systematic analysis to investigate the dependence of transcription initiation on the DNA sequence. I was able to identify GT-rich promoter elements required for directional transcription initiation and targeted deposition of the histone variant H2A.Z, a conserved component during transcription initiation. Furthermore, nucleosome positioning data in this work provide evidence that sites of transcription initiation are rather characterized by broad regions of open and more accessible chromatin than narrow nucleosome depleted regions as it is the case in other eukaryotes. These findings highlight the importance of chromatin during transcription initiation. Polycistronic RNA in T. brucei is separated by adding an independently transcribed miniexon during trans-splicing. The data in this work suggest that nucleosome occupancy plays an important role during RNA maturation by slowing down the progressing polymerase and thereby facilitating the choice of the proper splice site during trans-splicing. Overall, this work investigated the role of the DNA sequence during transcription initiation and nucleosome positioning in a highly divergent eukaryote. Furthermore, the findings shed light on the conservation of the requirement of DNA motifs during transcription initiation and the regulatory potential of chromatin during RNA maturation. The findings improve the understanding of gene expression regulation in T. brucei, a eukaryotic parasite lacking transcriptional Regulation. N2 - Die Transkription ist ein entscheidender Prozess in der Zelle und die DNA-Sequenz nimmt hierbei eine elementare Rolle ein. Promotoren beinhalten spezifische und konservierte DNASequenzen und vermitteln den Start der Transkription durch die Rekrutierung spezifischer Proteine. Jedoch haben Forschungen im vergangenen Jahrzehnt gezeigt, dass die Mehrzahl der Promotoren in eukaryotischen Genomen keine konservierten Promotormotive aufweisen und häufig konstitutiv exprimierte Gene transkribieren. Obgleich der Prozess der Transkriptionsinitiation im Allgemeinen gut erforscht ist, konnte bisher nicht nachgewiesen werden, ob ein definiertes DNA-Motiv während der Transkription von konstitutiv exprimierten Genes erforderlich ist. In dem eukaryotischen und einzelligen Parasiten Trypanosoma brucei ist die Mehrzahl der proteinkodierenden Gene in lange polycistronische Transkriptionseinheiten arrangiert. Diese werden von einem gemeinsamen Transkriptionsstart durch die RNA Polymerase II transkribiert, allerdings konnten hier bisher keine Promotormotive identifiziert werden. Aus diesem Grund besteht die Annahme, dass Transkription keiner Regulation unterliegt. Allgemein ist der Prozess der Transkriptionsinitiation in T. brucei bisher nur wenig verstanden. Um den Zusammenhang zwischen DNA-Motiven und konstitutiver Genexpression näher zu untersuchen und Schlussfolgerungen über die DNA-Sequenz-Abhängigkeit der Transkriptionsinitiation zu ziehen, habe ich eine systematische Analyse in T. brucei durchgeführt. Ich konnte GT-reiche Promotorelemente innerhalb dieser Regionen identifizieren, die sowohl eine gerichtete Transkriptionsinitiation, als auch den gezielten Einbau der Histonvariante H2A.Z in Nukleosomen nahe der Transkriptionsstartstelle vermittelt haben. Des Weiteren zeigten Nukleosomenpositionierungsdaten, dass in Trypanosomen die Transkripitonsstartstellen nicht die charakteristische, nukleosomendepletierte Region, wie für andere Organismen beschrieben, sondern eine offene Chromatinstruktur enthalten. Zusätzlich konnte ich zeigen, dass die Chromatinstruktur eine wichtige Rolle während der mRNAProzessierung spielt. In T. brucei wird die polycistronische pre-mRNA durch das Anfügen eines Miniexons während des sogenannten trans-Splicens in individuelle mRNAs aufgetrennt. Die Daten dieser Arbeit belegen, dass die Anreicherung von Nukleosomen eine Verlangsamung der transkribierenden Polymerase bewirken und sie somit die richtige Wahl der Splicestelle gewährleisten. Zusammenfassend wurde in dieser Arbeit die Rolle der DNA Sequenz während der Transkriptionsinitiation und Nukleosomenpositionierung in einem divergenten Eukaryoten untersucht. Die Erkenntnisse bringen mehr Licht in die Konservierung der Notwendigkeit eines DNA-Motivs während der Transkriptionsinitiation und das regulatorische Potential der Chromatinstruktur während der RNA-Reifung. Zudem verbessern sie das Verständnis der Genexpressionsregulation in T. brucei, einem eukaryotischen Parasiten, der ohne transkriptionelle Regulation überlebt. KW - Transkription KW - Chromatin KW - Trypanosoma brucei KW - Genexpression KW - Epigenetik KW - RNA polymerase II KW - splicing KW - nuclesosome positioning Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173438 ER - TY - JOUR A1 - Weber-Lassalle, Nana A1 - Hauke, Jan A1 - Ramser, Juliane A1 - Richters, Lisa A1 - Groß, Eva A1 - Blümcke, Britta A1 - Gehrig, Andrea A1 - Kahlert, Anne-Karin A1 - Müller, Clemens R. A1 - Hackmann, Karl A1 - Honisch, Ellen A1 - Weber-Lassalle, Konstantin A1 - Niederacher, Dieter A1 - Borde, Julika A1 - Thiele, Holger A1 - Ernst, Corinna A1 - Altmüller, Janine A1 - Neidhardt, Guido A1 - Nürnberg, Peter A1 - Klaschik, Kristina A1 - Schroeder, Christopher A1 - Platzer, Konrad A1 - Volk, Alexander E. A1 - Wang-Gohrke, Shan A1 - Just, Walter A1 - Auber, Bernd A1 - Kubisch, Christian A1 - Schmidt, Gunnar A1 - Horvath, Judit A1 - Wappenschmidt, Barbara A1 - Engel, Christoph A1 - Arnold, Norbert A1 - Dworniczak, Bernd A1 - Rhiem, Kerstin A1 - Meindl, Alfons A1 - Schmutzler, Rita K. A1 - Hahnen, Eric T1 - BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer JF - Breast Cancer Research N2 - Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. Conclusions To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded. KW - breast cancer KW - ovarian cancer KW - BRIP1 gene KW - germline mutations Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233433 VL - 20 ER - TY - THES A1 - Wannagat, Wienke Charlotte T1 - Cognitive Processes of Discourse Comprehension in Children and Adults - Comparisons between Written, Auditory, and Audiovisual Modes of Presentation - T1 - Kognitive Prozesse beim Textverstehen bei Kindern und Erwachsenen - Vergleiche zwischen schriftlicher, auditiver und audiovisueller Darbietung - N2 - In drei Studien wurde untersucht, wie sich unterschiedliche Darbietungsformate (schriftlich, auditiv, audiovisuell (auditiv + Bilder) auf das Verständnis semantisch identischer Inhalte auswirken. Dabei interessierte insbesondere der Entwicklungsverlauf von der ersten Klasse bis zum Erwachsenenalter. Dass sich Bilder förderlich auf die Verständnisleistung auswirken können, gilt als gut untersucht (z.B. Carney & Levin, 2002). Anders als viele bisherige Studien erfassen wir Textverstehen mit impliziten Maßen, die differenziertere Rückschlüsse auf die, gängigen Theorien zufolge, zugrundeliegenden Prozesse zulassen: Textverstehen geht mit der Konstruktion von drei Ebenen mentaler Repräsentationen einher (vgl. Kintsch, 1998). Weiterhin bedeutet erfolgreiches Textverstehen, eine auf lokaler und globaler Ebene kohärente mentale Repräsentation zu konstruieren (z.B. Schnotz & Dutke, 2004). Mit einem Satz-Rekognitionstest (vgl. Schmalhofer & Glavanov, 1986) untersuchten wir, ob sich das Gedächtnis für die Textoberfläche, die Textbasis und das Situationsmodell bei 103 8- und 10-Jährigen zwischen schriftlicher, auditiver und audiovisueller (Studie 1) und bei 106 7-, 9- und 11-Jährigen zwischen auditiver und audiovisueller Darbietung narrativer Texte (Studie 2) unterscheidet. Weiterhin (Studie 3) untersuchten wir mit 155 9- und 11-Jährigen, inwieweit sich die Fähigkeit der Inferenzbildung zur Herstellung lokaler und globaler Kohärenz zwischen schriftlicher, auditiver und audiovisueller Darbietung unterscheidet. Als Indikator dienten die Reaktionszeiten auf Wörter, die mit einem über (global)- oder untergeordneten (lokal) Protagonistenziel assoziiert sind. Insgesamt zeigte sich, dass Schüler bis zu einem Alter von 11 Jahren nicht nur die Textoberfläche besser erinnern, sondern auch besser in der Lage sind ein Situationsmodell zu konstruieren, wenn einem Text Bilder beigefügt sind. Dies zeigte sich sowohl im Vergleich mit auditiver als auch mit schriftlicher Darbietung. Bei Erwachsenen zeigte sich kein Effekt der Darbietungsform. Sowohl 9- als auch 11-Jährigen gelingt außerdem die Herstellung globaler Kohärenz bei audiovisueller Darbietung besser als bei auditiver. Die schriftliche Darbietung zeigte sich im Vergleich zur auditiven sowohl im Hinblick auf lokale als auch auf globale Kohärenz überlegen. N2 - In three studies, we investigated, if and how different modes of presentation - written, auditory, audiovisual (auditory combined with pictures) - affect comprehension of semantically identical materials. Children, beginning from the age of 7, and adults were included into the studies. A vast amount of studies have shown that pictures can facilitate text comprehension (e.g. Carney & Levin, 2002). Other than the majority of these previous studies, we assessed text comprehension with methods that we assume to allow more differentiated insights into the cognitive processes that - according to current theories - underlie text comprehension. Text comprehension involves at least three levels of mental representations (see Kintsch, 1998). Moreover, text comprehension means constructing a locally and globally coherent mental representation of the text content. Using a sentence recognition task (see Schmalhofer & Glavanov, 1986), we examined whether the memory of the text surface, the text base, and the situation model differs between written, auditory, and audiovisual text presentation in a sample of 103 8- and 10-year-olds and adults (Study I), and between auditory and audiovisual text presentation in a sample of 106 7-, 9-, and 11-year-olds (Study II). Furthermore, we examined with 155 9- and 11-year-olds, whether the ability to draw inferences to establish local and global coherence differs between written, auditory, and audiovisual text presentation. These inferences were indicated by reaction times to words associated with a protagonist's super- (global) or subordinate (local) goal. Overall, the results of these three studies taken together, indicate that children up to age 11 do not only have better memory of not only the text surface, but also of the situation model when pictures are added to an auditory text. This effect became apparent in comparison with both auditory and written texts. For the adults, in contrast, we did not find an effect of the presentation mode. Furthermore, both 9- and 11-year-olds were better at establishing global coherence at audiovisual compared to auditory text presentation. Written presentation turned out to be superior to auditory presentation in terms of both local and global coherence. KW - Textverstehen KW - text comprehension KW - picture comprehension KW - mental representation KW - coherence KW - children Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162515 ER - TY - THES A1 - Wandtner, Bernhard T1 - Non-driving related tasks in highly automated driving - Effects of task characteristics and drivers' self-regulation on take-over performance T1 - Fahrfremde Tätigkeiten beim hochautomatisierten Fahren - Einfluss des Aufgabentyps und der Selbstregulation auf die Übernahmeleistung N2 - The rise of automated driving will fundamentally change our mobility in the near future. This thesis specifically considers the stage of so called highly automated driving (Level 3, SAE International, 2014). At this level, a system carries out vehicle guidance in specific application areas, e.g. on highway roads. The driver can temporarily suspend from monitoring the driving task and might use the time by engaging in so called non-driving related tasks (NDR-tasks). However, the driver is still in charge to resume vehicle control when prompted by the system. This new role of the driver has to be critically examined from a human factors perspective. The main aim of this thesis was to systematically investigate the impact of different NDR-tasks on driver behavior and take-over performance. Wickens’ (2008) architecture of multiple resource theory was chosen as theoretical framework, with the building blocks of multiplicity (task interference due to resource overlap), mental workload (task demands), and aspects of executive control or self-regulation. Specific adaptations and extensions of the theory were discussed to account for the context of NDR-task interactions in highly automated driving. Overall four driving simulator studies were carried out to investigate the role of these theoretical components. Study 1 showed that drivers focused NDR-task engagement on sections of highly automated compared to manual driving. In addition, drivers avoided task engagement prior to predictable take-over situations. These results indicate that self-regulatory behavior, as reported for manual driving, also takes place in the context of highly automated driving. Study 2 specifically addressed the impact of NDR-tasks’ stimulus and response modalities on take-over performance. Results showed that particularly visual-manual tasks with high motoric load (including the need to get rid of a handheld object) had detrimental effects. However, drivers seemed to be aware of task specific distraction in take-over situations and strictly canceled visual-manual tasks compared to a low impairing auditory-vocal task. Study 3 revealed that also the mental demand of NDR-tasks should be considered for drivers’ take-over performance. Finally, different human-machine-interfaces were developed and evaluated in Simulator Study 4. Concepts including an explicit pre-alert (“notification”) clearly supported drivers’ self-regulation and achieved high usability and acceptance ratings. Overall, this thesis indicates that the architecture of multiple resource theory provides a useful framework for research in this field. Practical implications arise regarding the potential legal regulation of NDR-tasks as well as the design of elaborated human-machine-interfaces. N2 - In den nächsten Jahren wird die Fahrzeugautomatisierung stufenweise immer weiter zunehmen. Im Fokus dieser Arbeit steht das Hochautomatisierte Fahren (HAF), bei dem ein System in definierten Anwendungsbereichen, z.B. auf Autobahnen, die Fahraufgabe vollständig übernehmen kann (Level 3; SAE International, 2014). Der Fahrer muss das Verkehrsgeschehen nicht mehr überwachen, jedoch bereit sein, nach Aufforderung durch das System die Fahraufgabe wieder zu übernehmen. Bisherige Forschung legt nahe, dass Fahrer die freigewordene Zeit oftmals zur Beschäftigung mit sog. fahrfremden Tätigkeiten (FFTs) nutzen werden. Die vorliegende Arbeit beschäftigt sich mit den Herausforderungen, die diese neue Rolle des Fahrers mit sich bringt. Der Fokus liegt auf dem Einfluss unterschiedlicher FFTs auf die Übernahmeleistung und der Frage, inwieweit Fahrer den Umgang mit FFTs an die situativen Bedingungen anpassen. Die Theorie der multiplen Ressourcen (Wickens, 2008) wurde dabei als Rahmenmodell gewählt und für den spezifischen Anwendungsfall von HAF-Systemen ausgelegt. In vier Fahrsimulatorstudien wurden die unterschiedlichen Komponenten der Theorie untersucht. Studie 1 beschäftigte sich mit dem Aspekt der Ressourcenallokation (Selbstregulation). Die Ergebnisse zeigten, dass Fahrer die Beschäftigung mit einer prototypischen FFT an die Verfügbarkeit des HAF-Systems anpassten. Die Tätigkeit wurde bevorzugt im HAF und nicht im manuellen Fahrbetrieb durchgeführt und vor Übernahmesituationen wurden weniger Aufgaben neu begonnen. Studie 2 betrachtete den Aspekt der Interferenz zwischen FFT und Fahraufgabe. Die Modalitäten einer FFT wurden dazu systematisch variiert. Dabei zeigte sich, dass insbesondere visuell-manuelle Tätigkeiten mit hoher motorischer Beanspruchung (z.B. ein in der Hand gehaltenes Tablet) die Übernahme erschwerten. Fahrer schienen sich der Ablenkung bewusst zu sein und brachen diese Art von Aufgaben bei der Übernahme eher ab. Studie 3 ergab Hinweise, dass neben den Aufgabenmodalitäten auch kognitive Beanspruchung die Übernahmeleistung beeinträchtigen kann. Studie 4 beschäftigte sich mit der Mensch-Maschine-Schnittstelle (HMI) für HAF-Systeme. Die Ergebnisse ergaben, dass eine explizite Vorankündigung von Übernahmesituationen die Selbstregulation des Fahrers unterstützen kann. Die Arbeit zeigt die Eignung der multiplen Ressourcentheorie als Rahmenmodell für Forschung im Bereich HAF. Praktische Implikationen ergeben sich für mögliche gesetzliche Regelungen über erlaubte Tätigkeiten beim HAF, genauso wie konkrete HMI-Gestaltungsempfehlungen. KW - Autonomes Fahrzeug KW - Fahrerverhalten KW - automated driving KW - human-automation interaction KW - driver behavior KW - driver distraction KW - Automatisiertes Fahren KW - Mensch-Maschine-Interaktion KW - Fahrerablenkung KW - Automation KW - Verkehrspsychologie KW - Mensch-Maschine-Kommunikation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173956 ER - TY - JOUR A1 - Völker, Hans-Ullrich A1 - Weigel, Michael A1 - Strehl, Annette A1 - Frey, Lea T1 - Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array JF - Diagnostic Pathology N2 - Background: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods: The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised). KW - breast cancer KW - OncotypeDX\(^{®}\) KW - uPA KW - multigene-array KW - PAI-1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176960 VL - 13 IS - 67 ER - TY - JOUR A1 - Vona, Barbara A1 - Maroofian, Reza A1 - Bellacchio, Emanuele A1 - Najafi, Maryam A1 - Thompson, Kyle A1 - Alahmad, Ahmad A1 - He, Langping A1 - Ahangari, Najmeh A1 - Rad, Abolfazl A1 - Shahrokhzadeh, Sima A1 - Bahena, Paulina A1 - Mittag, Falk A1 - Traub, Frank A1 - Movaffagh, Jebrail A1 - Amiri, Nafise A1 - Doosti, Mohammad A1 - Boostani, Reza A1 - Shirzadeh, Ebrahim A1 - Haaf, Thomas A1 - Diodato, Daria A1 - Schmidts, Miriam A1 - Taylor, Robert W. A1 - Karimiani, Ehsan Ghayoor T1 - Expanding the clinical phenotype of IARS2-related mitochondrial disease JF - BMC Medical Genetics N2 - Background: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. Methods: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. Results: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. Conclusions: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia. KW - adrenal insufficiency KW - CAGSSS KW - cataracts KW - growth hormone deficiency KW - IARS2 KW - sensory neuropathy KW - sensorineural hearing loss KW - type II esophageal achalasia KW - skeletal dysplasia Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176620 VL - 19 IS - 196 ER - TY - JOUR A1 - Vona, Barbara A1 - Hofrichter, Michaela A. H. A1 - Schröder, Jörg A1 - Shehata-Dieler, Wafaa A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Hereditary hearing loss SNP-microarray pilot study JF - BMC Research Notes N2 - Objectives: Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of copy number variation that can be mapped using SNP-microarray technology. A growing collection of literature has begun to uncover the importance of copy number variation in hereditary hearing loss. This pilot study underpins a larger effort that involves the stage-wise analysis of hearing loss patients, many of whom have advanced to high-throughput sequencing analysis. Data description: Our data originate from the Infinium HumanOmni1-Quad v1.0 SNP-microarrays (Illumina) that provide useful markers for genome-wide association studies and copy number variation analysis. This dataset comprises a cohort of 108 individuals (99 with hearing loss, 9 normal hearing family members) for the purpose of understanding the genetic contribution of copy number variations to hereditary hearing loss. These anonymized SNP-microarray data have been uploaded to the NCBI Gene Expression Omnibus and are intended to benefit other investigators interested in aggregating platform-matched array patient datasets or as part of a supporting reference tool for other laboratories to better understand recurring copy number variations in other genetic disorders. KW - copy number variation KW - genotyping arrays KW - hereditary hearing loss KW - illumina KW - infinium HumanOmni1-Quad KW - SNP-microarray Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176239 VL - 11 IS - 391 ER - TY - THES A1 - von der Mühlen, Sarah T1 - Fostering Students’ Epistemic Competences when Dealing with Scientific Literature T1 - Die Förderung epistemischer Kompetenzen von Studierenden im Umgang mit wissenschaftlicher Literatur N2 - The abilities to comprehend and critically evaluate scientific texts and the various arguments stated in these texts are an important aspect of scientific literacy, but these competences are usually not formally taught to students. Previous research indicates that, although undergraduate students evaluate the claims and evidence they find in scientific documents to some extent, these evaluations usually fail to meet normative standards. In addition, students’ use of source information for evaluation is often insufficient. The rise of the internet and the increased accessibility of information have yielded some additional challenges that highlight the importance of adequate training and instruction.The aim of the present work was to further examine introductory students’ competences to systematically and heuristically evaluate scientific information, to identify relevant strategies that are involved in a successful evaluation, and to use this knowledge to design appropriate interventions for fostering epistemic competences in university students.To this end, a number of computer-based studies, including both quantitative and qualitative data as well as experimental designs, were developed. The first two studies were designed to specify educational needs and to reveal helpful processing strategies that are required in different tasks and situations. Two expert-novice comparisons were developed, whereby the performance of German students of psychology (novices) was compared to the performance of scientists from the domain of psychology (experts) in a number of different tasks, such as systematic plausibility evaluations of informal arguments (Study 1) or heuristic evaluations of the credibility of multiple scientific documents (Study 2). A think-aloud procedure was used to identify specific strategies that were applied in both groups during task completion, and that possibly mediated performance differences between students and scientists. In addition, relationships between different strategies and between strategy use and relevant conceptual knowledge was examined. Based on the results of the expert-novice comparisons, an intervention study, consisting of two training experiments, was constructed to foster some competences that proved to be particularly deficient in the comparisons (Study 3). Study 1 examined introductory students’ abilities to accurately judge the plausibility of informal arguments according to normative standards, to recognise common argumentation fallacies, and to identify different structural components of arguments. The results from Study 1 indicate that many students, compared to scientists, lack relevant knowledge about the structure of arguments, and that normatively accurate evaluations of their plausibility seem to be challenging in this group. Often, common argumentation fallacies were not identified correctly. Importantly, these deficits were partly mediated by differences in strategy use: It was especially difficult for students to pay sufficient attention to the relationship between argument components when forming their judgements. Moreover, they frequently relied on their intuition or opinion as a criterion for evaluation, whereas scientists predominantly determined quality of arguments based on their internal consistency. In addition to students’ evaluation of the plausibility of informal arguments, Study 2 examined introductory students’ competences to evaluate the credibility of multiple scientific texts, and to use source characteristics for evaluation. The results show that students struggled not only to judge the plausibility of arguments correctly, but also to heuristically judge the credibility of science texts, and these deficits were fully mediated by their insufficient use of source information. In contrast, scientists were able to apply different strategies in a flexible manner. When the conditions for evaluation did not allow systematic processing (i.e. time limit), they primarily used source characteristics for their evaluations. However, when systematic evaluations were possible (i.e. no time limit), they used more sophisticated normative criteria for their evaluations, such as paying attention to the internal consistency of arguments (cf. Study 1). Results also showed that students, in contrast to experts, lacked relevant knowledge about different publication types, and this was related to their ability to correctly determine document credibility. The results from the expert-novice comparisons also suggest that the competences assessed in both tasks might develop as a result of a more fundamental form of scientific literacy and discipline expertise. Performances in all tasks were positively related. On the basis of these results, two training experiments were developed that aimed at fostering university students’ competences to understand and evaluate informal arguments (Study 3). Experiment 1 describes an intervention approach in which students were familiarised with the formal structure of arguments based on Toulmin’s (1958) argumentation model. The performance of the experimental group to identify the structural components of this model was compared to the performance of a control group in which speed reading skills were practiced, using a pre-post-follow-up design. Results show that the training was successful for improving the comprehension of more complex arguments and relational aspects between key components in the posttest, compared to the control group. Moreover, an interaction effect was found with study performance. High achieving students with above average grades profited the most from the training intervention. Experiment 2 showed that training in plausibility, normative criteria of argument evaluation, and argumentation fallacies improved students’ abilities to evaluate the plausibility of arguments and, in addition, their competences to recognise structural components of arguments, compared to a speed-reading control group. These results have important implications for education and practice, which will be discussed in detail in this dissertation. N2 - Die Fähigkeit, wissenschaftliche Texte und die darin enthaltenen Argumente zu verstehen und kritisch zu beurteilen, ist ein zentraler Aspekt wissenschaftlicher Grundbildung, wird jedoch in der Schule kaum vermittelt. Obwohl Studierende die Behauptungen und Befunde, denen sie in der wissenschaftlichen Literatur begegnen, zu einem gewissen Grad kritisch bewerten, zeigen verschiedene Forschungsergebnisse, dass sie dies nicht in ausreichendem Maße tun und diese Evaluationen oft nicht den normativen Standards entsprechen. Darüber hinaus nutzen Studierende Quellenmerkmale nur unzureichend zur Beurteilung. Die Entstehung des Internets und die damit verbundene zunehmende Verfügbarkeit von Informationen stellen uns zudem vor einige wichtige Herausforderungen im Umgang mit diversen Informationsquellen und unterstreichen die Relevanz entsprechender Trainings und Förderungsprogramme. Ziel der vorliegenden Arbeit war es, die Kompetenzen beginnender Studierender, wissenschaftliche Informationen heuristisch und systematisch zu bewerten sowie wesentliche Strategien, die für eine erfolgreiche Beurteilung wissenschaftlicher Informationen benötigt werden, weiter zu erforschen und auf dieser Grundlage Interventionen zu entwickeln, um diese Kompetenzen bei Universitätsstudierenden gezielt zu fördern. Dazu wurden mehrere computergestützte Studien entwickelt, die sowohl qualitative, als auch quantitative Daten, sowie experimentelle Untersuchungsdesigns beinhalten. Die ersten beiden Studien wurden konzipiert, um Förderbedarf gezielt zu ermitteln und Verarbeitungsstrategien zu identifizieren, die in verschiedenen Aufgaben und unter verschiedenen Bedingungen hilfreich sind. Dazu wurden zunächst zwei Experten-Novizen-Vergleiche entwickelt, in denen die Leistungen von deutschen Psychologiestudierenden (Noviz(inn)en) in einer Reihe unterschiedlicher Aufgaben, z.B. bei der systematischen Bewertung der Plausibilität informeller Argumente (Studie 1) oder der heuristischen Bewertung der Glaubwürdigkeit multipler wissenschaftlicher Texte (Studie 2), mit den Leistungen von Wissenschaftler(inn)en aus dem Bereich der Psychologie (Expert(inn)en) verglichen wurden. Die Verwendung von Protokollen lauten Denkens diente dazu, die während der Aufgabenbearbeitung verwendeten Strategien, die die Leistungsunterschiede zwischen Studierenden und Wissenschaftler(inn)en möglicherweise mediieren, in beiden Gruppen genau zu erfassen. Darüber hinaus wurde untersucht, inwiefern unterschiedliche Strategien und die Nutzung bestimmter Strategien sowie relevantes konzeptuelles Wissen zusammenhängen. Basierend auf den Ergebnissen der Experten-Novizen-Vergleiche wurde anschließend eine Interventionsstudie, bestehend aus zwei Trainingsexperimenten, entwickelt, um einige Kompetenzen, die sich in den Vergleichen als besonders defizitär erwiesen hatten, gezielt zu fördern (Studie 3). In Studie 1 wurde untersucht, inwiefern beginnende Studierende in der Lage sind, die Plausibilität informeller Argumente normativ angemessen zu beurteilen und gängige Argumentationsfehler zu erkennen, sowie verschiedene strukturelle Bestandteile von Argumenten zu identifizieren. Die Ergebnisse der Studie 1 legen nahe, dass es vielen Studierenden im Vergleich zu Wissenschaftler(inne)n an relevantem Wissen über die Struktur von Argumenten fehlt und die angemessene Bewertung ihrer Plausibilität für viele von ihnen eine große Herausforderung darstellt. Gängige Argumentationsfehler wurden häufig nicht richtig erkannt. Diese Leistungsunterschiede wurden teilweise durch eine unterschiedliche Strategienutzung mediiert: Studierende zeigten große Schwierigkeit darin, Beziehungen zwischen Argumentbestandteilen ausreichend Beachtung zu schenken. Darüber hinaus verließen sie sich bei der Beurteilung häufig auf ihre Intuition oder Meinung zum Textinhalt, während Wissenschaftler(innen) die Qualität der Argumente in erster Linie auf der Grundlage ihrer internen Konsistenz beurteilten. Neben Plausibilitätsbeurteilungen informeller Argumente untersuchte Studie 2 die Kompetenz beginnender Studierender, die Glaubwürdigkeit multipler wissenschaftlicher Texte angemessen zu beurteilen und dabei auch Quellenmerkmale zur Beurteilung heranzuziehen. Die Ergebnisse zeigen, dass es Studierenden nicht nur schwerfiel, die Plausibilität von Argumenten angemessen zu beurteilen, sondern auch die Glaubwürdigkeit wissenschaftlicher Texte heuristisch zu bewerten. Die Defizite auf Studierendenseite wurden dabei vollständig durch eine unzureichende Nutzung von Quellenmerkmalen mediiert. Wissenschaftler(innen) waren dagegen in der Lage, Strategien zur Beurteilung flexibel zu nutzen. Wenn eine systematische Verarbeitung nicht möglich war (Zeitlimit), griffen sie vor allem auf Quellenmerkmale zurück. Wenn eine systematische Verarbeitung jedoch möglich war (kein Zeitlimit), nutzten sie komplexere normative Kriterien zur Beurteilung, wie etwa die Bewertung der internen Konsistenz der Argumente (Vgl. Studie 1). Die Ergebnisse zeigen außerdem, dass es Studierenden an relevantem Wissen über verschiedene Publikationsarten fehlte und diese Schwierigkeiten waren korreliert mit der Fähigkeit, die Glaubwürdigkeit von Texten angemessen zu beurteilen. Die Befunde der Experten-Novizen-Vergleiche liefern zudem Hinweise darauf, dass sich die in den unterschiedlichen Aufgaben erfassten Kompetenzen auf der Basis einer allgemeineren Form der wissenschaftlichen Grundbildung und disziplinären Expertise entwickeln könnten. Die Leistungen in unterschiedlichen Aufgaben waren positiv korreliert. Auf der Grundlage dieser Ergebnisse wurden zwei Trainingsexperimente entwickelt, um die Kompetenzen Studierender in Bezug auf das Verständnis und die kompetente Bewertung informeller Argumente, gezielt zu fördern (Studie 3). Experiment 1 beschreibt einen möglichen Interventionsansatz, um Studierende, basierend auf Toulmins (1958) Argumentationsmodell, besser mit der Struktur von Argumenten vertraut zu machen. Die Leistungen der Versuchsgruppe, verschiedene Argumentbestandteile dieses Modells korrekt zu identifizieren, wurden dabei in einem Prä-Post-Follow-up Design mit den Leistungen einer Kontrollgruppe verglichen, in der die Fähigkeit des schnellen Lesens trainiert wurde. Die Ergebnisse zeigen, dass das Training vor allem für das Verständnis komplexer und weniger typischer Argumente hilfreich war und Elemente, die die Beziehung zwischen verschiedenen Bestandteilen deutlich machten, im Posttest besser verstanden wurden als in einer Kontrollgruppe. Darüber hinaus konnte ein Interaktionseffekt mit der Studienleistung gezeigt werden. Besonders „gute“ Studierende mit hohen Durchschnittsnoten konnten am meisten von diesem Training profitieren. Die Ergebnisse von Experiment 2 zeigten, dass ein Training, in dem das Konzept der Plausibilität, normative Kriterien der Argumentbewertung, sowie Argumentationsfehler vermittelt wurden, die Kompetenzen Studierender, die Plausibilität informeller Argumente normativ angemessen zu beurteilen, im Vergleich mit einer Kontrollgruppe, deutlich verbessern konnte. Die Ergebnisse der genannten Studien liefern wichtige Implikationen für die wissenschaftliche Praxis an den Hochschulen, welche in dieser Arbeit ausführlich diskutiert werden. KW - Textverstehen KW - Wissenschaftliche Literatur KW - Epistemic Competences KW - Higher Education KW - Student KW - Förderung KW - Epistemische Kompetenzen KW - Kompetenzen im Hochschulsektor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167343 N1 - Prof. Dr. Tobias Richter supervised this dissertation. Two of the studies reported have been published in international journals, the third study was submitted (see references below). References: von der Mühlen, S., Richter, T., Schmid, S. & Berthold, K. (2017). How to Improve Argumentation Comprehension in University Students: Experimental Tests of Two Training Approaches. Manuskript zur Publikation eingereicht. von der Mühlen, S., Richter, T., Schmid, S., Berthold, K. & Schmidt, E. M. (2016). The use of source-related strategies in evaluating multiple psychology texts: A student-scientist comparison. Reading and Writing, 8, 1677–1698. von der Mühlen, S., Richter, T., Schmid, S., Schmidt, E. M. & Berthold, K. (2016). Judging the plausibility of arguments in scientific texts: A student-scientist comparison. Thinking & Reasoning, 22, 221–246. ER -