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- B-1911-2015 (1)
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This work presents the first ILT observations of high redshift blazars and their study in terms of jet evolution, morphology, and interaction with the surrounding medium. Each of these represents a highly topical area of astronomywith a large number of open questions. To better understand Active Galactic Nuclei (AGN) and their fundamental inner workings, new techniques are needed to exploit the full potential of the next generation of radio interferometers. Some of these tools are presented here and applied to one of the latest generation of software radio telescopes. A major focus of the studies presented is on the unification model, where the observed blazars are discussed for their properties to be rotated counterparts of Fanaroff-Riley Class II (FR-II) radio galaxies, when classified as Flat Spectrum Radio Quasars (FSRQs). In addition, multiwavelength information has been included in the analysis. Both studies are feasibility studies that will serve as a basis for future similar studies. The characteristics discussed and their interpretation do not allow conclusions to be drawn for their respective populations. However, by applying them to a larger number of targets, population studies will be possible. The first chapters introduce the necessary topics, AGN, principles of radio observations and ILT, in the necessary depth to provide the reader with a solid knowledge base. They are particularly important for understanding the current limits and influences of uncertainties in the observation, calibration and imaging process. But they also shed light on realistic future improvements. A particular focus is on the development and evolution of the LOw-Frequency ARray (LOFAR)-Very Long Baseline Interferometry (VLBI) pipeline. With the tools at hand, the first study addresses the high redshift blazar S5 0836+710 $(z=2.218)$, which has been observed at various wavelengths and resolutions. It has a disrupted one-sided jet with an associated extended region further out. Despite the excellent wavelength coverage, only the additional ILT observations provided a complete picture of the source. With the data, the extended region could be classified as a hotspot moving at slightly relativistic speeds.. With the ILT data it was also possible to extract the flux of the core region of the AGN, and in projection to reveal the mixed counter-hotspot behind it. This also allowed constraints on jet parameters and environmental properties to be modelled, which were previously inconclusive. Technically, this study shows that the ILT can be used as an effective VLBI array for compact sources with small angular scales. However, the detection of faint components beyond redshifts of $z=2$ may require the capabilities of the Square Kilometre Array (SKA) to provide a significant number of detections to enable statistical conclusions. The second study uses a much improved calibration pipeline to analyse the high redshift blazar GB1508+5714 $(z=4.30)$. The ILT data revealed a previously unseen component in the eastern direction. A spectral index map was generated from the Karl G. Jansky Very Large Array (VLA) data, showing spectral index values of $-1.2_{-0.2}^{+0.4}$ for the western component, steeper than $-1.1$ for the eastern region, and $0.023 \pm 0.007$ for the core. Using the information provided by the ILT observation, as well as multi-wavelength information from other observations ranging from the long radio wavelengths to the $\gamma$ regime, four models were developed to interpret the observed flux with different emission origins. This also allowed to test a proposed interaction channel of the electrons provided by the jet, to cool off via inverse compton scattering with the Cosmic Microwave Background (CMB) photons, rather than by the usual synchrotron emission. This is referred to as cmb quenching in the literature, which could be shown in the study, to be necessary in any case. Finally, one of the four models was considered in which the hotspots in the detected components are unresolved and mixed by the lobe emission, with the X-ray emission coming from the lobes and partially mixed by the bright core region. The results of this preferred model are consistent with hotspots in a state of equipartition and lobes almost so. The study shows that high redshift blazars can be studied with the ILT, and expanding the sample of high redshift blazars resolved at multiple frequencies will allow a statistical study of the population. Finally, this work successfully demonstrates the powerful capabilities of the ILT to address questions that were previously inaccessible. The current state of the LOFAR-VLBI pipeline, when properly executed, allows work on the most challenging objects and will only improve in the future. In particular, this gives a glimpse of the possibilities that SKA will bring to astronomy.
Physical regimes characterized by low Mach numbers and steep stratifications pose severe challenges to standard finite volume methods. We present three new methods specifically designed to navigate these challenges by being both low Mach compliant and well-balanced. These properties are crucial for numerical methods to efficiently and accurately compute solutions in the regimes considered.
First, we concentrate on the construction of an approximate Riemann solver within Godunov-type finite volume methods. A new relaxation system gives rise to a two-speed relaxation solver for the Euler equations with gravity. Derived from fundamental mathematical principles, this solver reduces the artificial dissipation in the subsonic regime and preserves hydrostatic equilibria. The solver is particularly stable as it satisfies a discrete entropy inequality, preserves positivity of density and internal energy, and suppresses checkerboard modes.
The second scheme is designed to solve the equations of ideal MHD and combines different approaches. In order to deal with low Mach numbers, it makes use of a low-dissipation version of the HLLD solver and a partially implicit time discretization to relax the CFL time step constraint. A Deviation Well-Balancing method is employed to preserve a priori known magnetohydrostatic equilibria and thereby reduces the magnitude of spatial discretization errors in strongly stratified setups.
The third scheme relies on an IMEX approach based on a splitting of the MHD equations. The slow scale part of the system is discretized by a time-explicit Godunov-type method, whereas the fast scale part is discretized implicitly by central finite differences. Numerical dissipation terms and CFL time step restriction of the method depend solely on the slow waves of the explicit part, making the method particularly suited for subsonic regimes. Deviation Well-Balancing ensures the preservation of a priori known magnetohydrostatic equilibria.
The three schemes are applied to various numerical experiments for the compressible Euler and ideal MHD equations, demonstrating their ability to accurately simulate flows in regimes with low Mach numbers and strong stratification even on coarse grids.
Two-dimensional lattices are in the focus of research in modern solid state physics due to their novel and exotic electronic properties with tremendous potential for seminal future applications. Of particular interest within this research field are quantum spin Hall insulators which are characterized by an insulating bulk with symmetry-protected metallic edge states. For electrons within these one-dimensional conducting channels, spin-momentum locking enables dissipationless transport - a property which promises nothing short of a revolution for electronic devices. So far, however, quantum spin Hall materials require enormous efforts to be realized such as cryogenic temperatures or ultra-high vacuum. A potential candidate to overcome these shortcomings are two-dimensional lattices of the topological semi-metal antimony due to their potential to host the quantum spin Hall effect while offering improved resilience against oxidation.
In this work, two-dimensional lattices of antimony on different substrates, namely Ag(111), InSb(111) and SiC(0001), are investigated regarding their atomic structure and electronic properties with complimentary surface sensitive techniques. In addition, a systematic oxidation study compares the stability of Sb-SiC(0001) with that of the two-dimensional topological insulators bismuthene-SiC(0001) and indenene-SiC(0001).
A comprehensive experimental analysis of the \((\sqrt{3}\times\sqrt{3})R30^\circ\) Sb-Ag(111) surface, including X-ray standing wave measurements, disproves the proclaimed formation of a buckled antimonene lattice in literature. The surface lattice can instead be identified as a metallic Ag\(_2\)Sb surface alloy.
Antimony on InSb(111) shows an unstrained Volmer-Weber island growth due to its large lattice mismatch to the substrate. The concomitant moir\'{e} situation at the interface imprints mainly in a periodic height corrugation of the antimony islands which as observed with scanning tunneling microscopy. On islands with various thicknesses, quasiparticle interference patterns allow to trace the topological surface state of antimony down to the few-layer limit.
On SiC(0001), two different two-dimensional antimony surface reconstructions are identified. Firstly, a metallic triangular $1\times1$ lattice which constitutes the antimony analogue to the topological insulator indenene. Secondly, an insulating asymmetric kagome lattice which represents the very first realized atomic surface kagome lattice.
A comparative, systematic oxidation study of elemental (sub-)monolayer materials on SiC(0001) reveals a high sensitivity of indenene and bismuthene to small dosages of oxygen. An improved resilience is found for Sb-SiC(0001) which, however, oxidizes nevertheless if exposed to oxygen. These surface lattices are therefore not suitable for future applications without additional protective measures.
Vorliegende Untersuchung am Universitätsklinikum Würzburg sowie die Befragung von Anästhesisten/Anästhesistinnen im Raum der 3 DACH-Länder zeigen, dass bildgebende Verfahren bei Säuglingen mit einer niedrigen Rate an Komplikationen, zumeist in medikamentöser Sedierung mit Propofol, durchgeführt werden. Wie international üblich ist im Säuglingsalter die Magnetresonanztomographie das bildgebende Verfahren der Wahl und wird, mit überzeugender Häufigkeit, erfolgreich durchgeführt.
Die Untersuchung am Universitätsklinikum Würzburg legt nahe, dass männliche Säuglinge häufiger eine Bildgebung benötigen und häufiger höheren ASA-Kategorie zugeschrieben werden. Dabei scheinen sie auch häufiger Komplikationen zu erleben und bedürfen daher besonderer Aufmerksamkeit. Eine eventuelle Alternative zur Sedierung kann dabei die „feed-and-sleep“ Methode darstellen. In unserer Umfrage konnten wir erheben, dass diese Methode bisher wenig verbreitet ist, obwohl in diesem Zusammenhang eventuell Abläufe und Prozesszeiten strukturiert und optimiert werden können, da beispielsweise die Nachüberwachung entfällt. Vorstellbar wäre beispielsweise, mehrere Säuglinge zum gleichen Zeitpunkt ins MRT zu bestellen, um gegebenenfalls den am frühesten eingeschlafenen Säugling vorzuziehen. Diese Methode sollte zukünftig Einzug in die wissenschaftliche Untersuchung von bildgebenden Verfahren bei Säuglingen finden.
Die Umfrage im deutschsprachigen Raum zeigt eine Leitlinien-gerechte Betreuung von Säuglingen für bildgebende Verfahren, die mit einer hohen Qualität, und zumeist erfolgreich von erfahrenen Anästhesisten/Anästhesistinnen durchgeführt wird. Eventuelle Verbesserungen können im Bereich der Ausbildung nachfolgender Ärztinnen/Ärzte und in der häufigeren Verwendung der „feed-and-sleep“ Methode liegen, die vielen Kollegen/Kolleginnen bekannt ist, aber nur selten durchgeführt wird.
Ziel ist eine qualitativ hochwertige, schnellstmöglich durchgeführte Bildgebung, die ohne oder mit der niedrigst möglichen Dosierung eines sedierenden Medikamentes zu erreichen ist.
Colon carcinomas (CRC) are statistically among the most fatal cancer types and hence one of the top reasons for premature mortality in the developed world. CRC cells are characterized by high proliferation rates caused by deregulation of gene transcription of proto-oncogenes and general chromosomal instability. On macroscopic level, CRC cells show a strongly altered nutrient and energy metabolism.
This work presents research to understand general links between the metabolism and transcription alteration. Mainly focussing on glutamine dependency, shown in colon carcinoma cells and expression pathways of the pro-proliferation protein c-MYC.
Previous studies showed that a depletion of glutamine in the cultivation medium of colon carcinoma cell lines caused a proliferation arrest and a strong decrease of overall c-MYC levels. Re-addition of glutamine quickly replenished c-MYC levels through an unknown mechanism. Several proteins altering this regulation mechanism were identified and proposed as possible starting point for further in detail studies to unveil the precise biochemical pathway controlling c-MYC translation repression and reactivation in a rapid manner.
On a transcriptional level the formation of RNA:DNA hybrids, so called R-loops, was observed under glutamine depleted conditions. The introduction and overexpression of RNaseH1, a R-loop degrading enzyme, in combination with an ectopically expressed c-MYC variant, independent of cellular regulation mechanisms by deleting the regulatory 3’-UTR of the c-MYC gene, lead to a high rate of apoptotic cells in culture. Expression of a functionally inactive variant of RNaseH1 abolished this effect. This indicates a regulatory function of R-loops formed during glutamine starvation in the presence of c-MYC protein in a cell. Degradation of R-loops and high c-MYC levels in this stress condition had no imminent effect on the cell cycle progression is CRC cells but disturbed the nucleotide metabolism. Nucleotide triphosphates were strongly reduced in comparison to starving cells without R-loop degradation and proliferating cells.
This study proposes a model of a terminal cycle of transcription termination, unregulated initiation and elongation of transcription leading to a depletion of energy resources of cells. This could finally lead to high apoptosis of the cells. Sequencing experiments to determine a coinciding of termination sites and R-loop formation sides failed so far but show a starting point for further studies in this essential survival mechanism involving R-loop formation and c-MYC downregulation.
Evaluierung prognostischer und prädiktiver Biomarker beim neoadjuvant vorbehandelten Rektumkarzinom
(2024)
Fragestellung. Osteopontin (OPN) kann im Blut nachgewiesen werden und wird bei vielen Tumorentitäten exprimiert, wie auch der Tyrosinkinaserezeptor c-Met und sein Ligand, das Zytokin Hepatocyte Growth Factor (HGF). In der vorliegenden Arbeit untersuchten wir die prognostische und prädiktive Wertigkeit der Plasmakonzentrationen von OPN, c-Met und HGF bei Patienten mit lokal fortgeschrittenem Rektumkarzinom (LARC).
Methodik. Das Plasma von 63 Patienten mit LARC wurde untersucht. Die Blutentnahmen (EDTA-Plasma) erfolgten vor Therapiebeginn sowie im Verlauf. Die Plasmaspiegel von OPN, c-Met und HGF wurden mittels Enzyme-Linked Immunosorbent Assay analysiert. Die Konzentrationen wurden auf eine Korrelation mit den klinischen Parametern untersucht.
Ergebnisse. 68 Patienten wurden neoadjuvant mit einer Radiochemotherapie behandelt, 63 Blutproben wurden untersucht. Initial befanden sich nach UICC 14 Patienten in Stadium II, 47 in Stadium III und 7 in Stadium IV. Das mediane Follow-Up betrug 29,87 Monate. 20 der 68 Patienten (29,4 %) verstarben, 19 entwickelten Fernmetastasen. OPN korrelierte signifikant mit dem Überleben (p=0,001). OPN-Werte korrelierten mit dem pT-Stadium (R:0,445 p=0,018) und dem pUICC-Stadium (R:0,412 p=0,018), sowie mit dem Auftreten von Fernmetastasen (R:0,271 p=0,031). Eine Korrelation zwischen OPN und dem Therapieansprechen konnte gezeigt werden: pathologisch komplette Remission (pCR) (R:0,379 p=0,001), NAR-Score (R:0,373 p=0,015), TRG (R:0,380 p=0,020). Die logistische Regressionsanalyse ergab eine Prädiktivität OPNs für pCR (OR:0,990 p=0,009), NAR-Score (OR:1,008 p=0,007), TRG (OR:0,459 p=0,008). C-Met und HGF korrelierten nicht mit dem Überleben. Für c-Met und HGF ergab sich keine Korrelation zu initialen klinischen Daten und Therapieansprechen. Die logistische Regression ergab keinen prädiktiven Wert.
Schlussfolgerung. Die Plasmakonzentration von OPN besitzt prognostische und prädiktive Wertigkeit beim LARC. Die Konzentrationen von c-Met und HGF sind nicht prognostisch für das Überleben oder prädiktiv für das Therapieansprechen.
Interactions between host and pathogen determine the development, progression and outcomes
of disease. Medicine benefits from better descriptions of these interactions through increased
precision of prevention, diagnosis and treatment of diseases. Single-cell genomics is a
disruptive technology revolutionizing science by increasing the resolution with which we study
diseases. Cell type specific changes in abundance or gene expression are now routinely investigated
in diseases. Meanwhile, detecting cellular phenotypes across diseases can connect
scientific fields and fuel discovery. Insights acquired through systematic analysis of high resolution
data will soon be translated into clinical practice and improve decision making. Therefore,
the continued use of single-cell technologies and their application towards clinical samples will
improve molecular interpretation, patient stratification, and the prediction of outcomes.
In the past years, I was fortunate to participate in interdisciplinary research groups bridging
biology, clinical research and data science. I was able to contribute to diverse projects through
computational analysis and biological interpretation of sequencing data. Together, we were
able to discover cellular phenotypes that influence disease progression and outcomes as well
as the response to treatment. Here, I will present four studies that I have conducted in my PhD.
First, we performed a case study of relapse from cell-based immunotherapy in Multiple Myeloma.
We identified genomic deletion of the epitope as mechanism of immune escape and implicate
heterozygosity or monosomy of the genomic locus at baseline as a potential risk factor. Second,
we investigated the pathomechanisms of severe COVID-19 at the earliest stage of the COVID-
19 pandemic in Germany in March 2020. We discovered that profibrotic macrophages and
lung fibrosis can be caused by SARS-CoV-2 infection. Third, we used a mouse model of chronic
infection with Staphylococcus aureus that causes Osteomyelitis similar to the human disease.
We were able to identify dysregulated immunometabolism associated with the generation of
myeloid-derived suppressor cells (MDSC). Fourth, we investigated Salmonella infection of the
human small intestine in an in vitro model and describe features of pathogen invasion and host
response.
Overall, I have been able to successfully employ single-cell sequencing to discover important
aspects of diseases ranging from development to treatment and outcome. I analyzed samples
from the clinics, human donors, mouse models and organoid models to investigate different
aspects of diseases and managed to integrate data across sample types, technologies and
diseases. Based on successful studies, we increased our efforts to combine data from multiple
sources to build comprehensive references for the integration of large collections of clinical
samples. Our findings exemplify how single-cell sequencing can improve clinical research and
highlights the potential of mechanistic discoveries to drive precision medicine.
Die von Friedhelm Brusniak und Ulrich Konrad betreute und angenommene Dissertation nimmt den Briefwechsel zwischen August Heinrich Hoffmann von Fallersleben und dem jüngeren Augsburger Kapellmeister und Komponisten Hans Michael Schletterer in den Jahren 1862 bis 1873 in den Blick und dokumentiert dabei Hoffmanns Einfluss auf den Entstehungsprozess der Vertonungen seiner Lieder, besonders seiner Kinderlieder. Die Arbeit beleuchtet zudem den Erfahrungsschatz, den sich der ‚Dichter-Sänger‘ Hoffmann von Fallersleben auch durch die Zusammenarbeit mit anderen Musikern seiner Zeit, vorrangig Ludwig Christian Erk (1807–1883) und Ernst Heinrich Leopold Richter (1805–1876), erworben hatte. Darüber hinaus werden in der Korrespondenz Themen des gesellschaftlichen und politischen Lebens, der privaten und beruflichen Situation beider wie auch Hoffmanns Rolle als väterlicher Berater Schletterers berührt. Die Arbeit darf als neuer substantieller Beitrag der Hoffmann-Forschung und der interdisziplinären Liedforschung angesehen werden, der insbesondere der Kinderliedforschung neue Impulse verleiht.
This thesis investigates the charged moments and the symmetry-resolved
entanglement entropy in the context of the AdS3/CFT2 duality. In the
first part, I focus on the holographic U(1) Chern-Simons-Einstein gravity,
a toy model of AdS3/CFT2 with U(1) Kac-Moody symmetry. I
start with the vacuum background with a single entangling interval. I
show that, apart from a partition function in the grand canonical ensemble,
the charged moments can also be interpreted as the two-point
function of vertex operators on the replica surface. For the holographic
description, I propose a duality between the bulk U(1) Wilson line and
the boundary vertex operators. I verify this duality by deriving the
effective action for the Chern-Simons fields and comparing the result
with the vertex correlator. In the twist field approach, I show that the
charged moments are given by the correlation function of the charged
twist operators and the additional background operators. To solve the
correlation functions involved, I prove the factorization of the U(1) extended
conformal block into a U(1) block and a Virasoro block. The
general expression for the U(1) block is derived by directly summing
over the current descendant states, and the result shows that it takes
an identical form as the vertex correlators. This leads to the conclusion
that the disjoint Wilson lines compute the neutral U(1) block. The final
result for the symmetry-resolved entanglement entropy shows that
it is always charge-independent in this model. In the second part, I
study charged moments in higher spin holography, where the boundary
theory is a CFT with W3 symmetry. I define the notion of the
higher spin charged moments by introducing a spin-3 modular charge
operator. Restricting to the vacuum background with a single entangling
interval, I employ the grand canonical ensemble interpretation
and calculate the charged moments via the known higher spin black
hole solution. On the CFT side, I perform a perturbative expansion for
the higher spin charged moments in terms of the connected correlation
functions of the spin-3 modular charge operators. Using the recursion
relation for the correlation functions of the W3 currents, I evaluate the
charged moments up to the quartic order of the chemical potential. The
final expression matches with the holographic result. My results both
for U(1) Chern-Simons Einstein gravity and W3 higher spin gravity
constitute novel checks of the AdS3/CFT2 correspondence.
The focus of this thesis is on analysing a linear stochastic partial differential equation (SPDE) with a bounded domain. The first part of the thesis commences with an examination of a one-dimensional SPDE. In this context, we construct estimators for the parameters of a parabolic SPDE based on discrete observations of a solution in time and space on a bounded domain. We establish central limit theorems for a high-frequency asymptotic regime, showing substantially smaller asymptotic variances compared to existing estimation methods. Moreover, asymptotic confidence intervals are directly feasible. Our approach builds upon realized volatilities and their asymptotic illustration as the response of a log-linear model with a spatial explanatory variable. This yields efficient estimators based on realized volatilities with optimal rates of convergence and minimal variances. We demonstrate our results by Monte Carlo simulations.
Extending this framework, we analyse a second-order SPDE model in multiple space dimensions in the second part of this thesis and develop estimators for the parameters of this model based on discrete observations in time and space on a bounded domain. While parameter estimation for one and two spatial dimensions was established in recent literature, this is the first work that generalizes the theory to a general, multi-dimensional framework. Our methodology enables the construction of an oracle estimator for volatility within the underlying model. For proving central limit theorems, we use a high-frequency observation scheme. To showcase our results, we conduct a Monte Carlo simulation, highlighting the advantages of our novel approach in a multi-dimensional context.