Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
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Identification and characterization of antigen-specific T cells in infectious disease and cancer using the example of SARS-CoV-2 and bladder carcinoma
Get PDFAntigen-specific T cells are an essential pillar of the adaptive immune system. They can directly kill target cells and orchestrate the immune responses by other innate and adaptive immune cells. For viral SARS-CoV-2 infections in particular, virus-specific immune responses have been shown to be directly linked to improved disease outcomes, including faster and more efficient clearing of the harmful pathogen from the organism. Therefore, in the course of the COVID-19 pandemic, this PhD project was initiated aiming for the identification of virus-specific T cell epitopes. We were able to successfully identify numerous T cell epitopes in the form of 15-mer and 9-mer peptides with restriction to different HLA allotypes. This was done using in vitro peptide stimulation assays and accompanying in silico peptide binding predictions. The mapping of immunogenic protein regions for three different cohorts also allowed us to identify differences between vaccination- and infection-induced T-cell immunity. Furthermore, the correlation to protein regions with high mutational load found in the currently circulating SARS-CoV-2 B.1.1.529 (Omicron) virus strains led to speculation about the potential protection of individuals against these virus strains. Since no evidence was found for a direct correlation between T cell immunogenic regions and mutation rates, we conclude that a major reorganization of the spike protein would be necessary to allow complete evasion of the virus from the T cell immunity built up by vaccination and natural infection with pre-omicron variants. This hypothesis is further supported by our analysis of the SARS-CoV-2 Omicron-specific T cell response in double and triple-vaccinated individuals. Here, we showed that booster vaccinations, even with first-generation vaccines, lead to increased reactivity of virus-specific CD4+ and CD8+ T cells. In addition, the proportion of T cell responses against non-mutated regions of SARS-CoV-2 Omicron increased with the third vaccination, indicating a general benefit of booster vaccinations against evolving virus strains as well.
We then wanted to investigate possible causes of severe COVID-19 infections. In collaboration with Dr. Angeliki Datsi and Prof. Dr. Johannes Fischer from the University Hospital Düsseldorf, we analyzed the immunogenic regions of SARS-CoV-2 structural proteins for individuals expressing HLA haplotypes associated with more severe COVID-19 disease progression. We found no differences in the ability to present T-cell peptides via HLA molecules between individuals with positive- or negative-associated HLA haplotypes. However, in individuals with generally more severe COVID-19 disease courses (long disease severity and duration), we found a lower frequency of virus-specific CD8+ T cells, accompanied by high bystander activation. Individuals with negative-associated HLA haplotypes, which are characterized by longer disease duration, showed significantly increased virus-specific CD4+ T cell frequencies, accompanied by increased titers of neutralizing antibodies.
Although effective, the method used is inefficient in analyzing SARS-CoV-2-specific T-cell responses. This is mainly due to the high heterogeneity of the human HLA system. Therefore, in the course of this dissertation, we propose a new technology for the identification of T-cell epitopes: the multiplex HLA binding assay. This novel method is sensitive and efficient, as it allows for multiplexing. As a proof-of-concept, this assay will be demonstrated on the identification of neoantigens from human bladder carcinomas. Although sequencing analyses are still pending, we were able to dissect the tumor samples into individual cell suspensions and analyze the immunophenotypic composition of these samples. This showed a varying and staging-independent infiltration of the tumor with immune cells. The identification of neoantigens from bladder cancer samples, which are characterized by a high mutation load, is therefore of great interest with regard to the possible application of cellular therapies directed against them
Zwischen digitaler Spielwelt und Realität: Innovative Ansätze zur Förderung von Reflexionskompetenzen im Geographieunterricht
Get PDFDie vorliegende Dissertation untersucht die Integration digitaler Spiele in den Geographieunterricht mit besonderem Fokus auf die Förderung von Reflexionskompetenzen. Durch eine Kombination aus theoretischer Analyse und empirischen Studien wird erörtert, wie digitale Spiele als didaktisches Instrument zur Vermittlung geographischer Fachinhalte sowie zur Förderung kritischer Reflexion eingesetzt werden können.
Die Arbeit beginnt mit einer umfassenden Darstellung des theoretischen Hintergrunds, in dem die Rolle von Spielen im Unterricht und insbesondere von digitalen Spielen im Geographieunterricht erläutert wird. Dabei wird auf die Potenziale digitaler Spiele eingegangen, insbesondere in Bezug auf deren interaktive und immersive Eigenschaften, die Lernprozesse unterstützen können. Gleichzeitig wird die Notwendigkeit einer didaktisch durchdachten Integration betont, da digitale Spiele oft vereinfachte oder verzerrte Darstellungen realer Prozesse enthalten.
Ein zentraler Bestandteil der Dissertation ist die Untersuchung von Reflexionsprozessen im schulischen Kontext. Dabei dient das theoretische Modell von Lux und Budke (2023) als Grundlage für die Konzipierung von Reflexionsmethoden (Reflexionstagebuch, Reflexionscoaching). Das Modell umfasst vier Reflexionsebenen bei digitalen Spielen: die Reflexion der Spiellogik, den Vergleich zwischen Spielwelt und realer Welt, die Selbstreflexion und die Reflexion des Mediums Spiel.
Der empirisch erhobene Inhalt basiert auf drei aufeinander aufbauenden Studien, die im Rahmen des Design-Based Research-Ansatzes entwickelt wurden:
1. Die erste Studieuntersucht, inwiefern Schülerinnen und Schüler ohne gezielte Anleitung digitale Spiele reflektieren. Die Ergebnisse zeigen, dass Reflexionen oft auf der internen Ebene des Spiels verbleiben und eine vertiefte Auseinandersetzung mit realen geographischen Prozessen fehlt.
2. Die zweite Studie erweitert das Konzept durch den Einsatz von Reflexionstagebüchern, die den Schülerinnen und Schülern helfen sollen, ihre Erfahrungen systematisch zu dokumentieren und zu reflektieren. Die Ergebnisse deuten darauf hin, dass Reflexionstagebücher die Reflexionstiefe signifikant steigern.
3. Die dritte Studiekombiniert das Reflexionstagebuch mit dem Peer- Reflexionscoaching, um zu untersuchen, wie sich interaktive Reflexionsprozesse auf das Lernen auswirken. Die Ergebnisse zeigen, dass die Kombination aus schriftlicher und mündlicher Reflexion besonders effektiv ist, um ein tiefergehendes Verständnis für die geographischen Inhalte zu fördern.
Die Dissertation schließt mit einer umfassenden Diskussion der Ergebnisse und deren Implikationen für die geographiedidaktische Praxis, die Hochschullehre und zukünftige Forschungsperspektiven ab. Es wird betont, dass digitale Spiele ein wertvolles Lerninstrument sein können, jedoch nur dann ihr volles Potenzial entfalten, wenn sie durch gezielte Reflexionsmethoden begleitet werden. Lehrkräfte sollten daher in der Nutzung und didaktischen Einbettung digitaler Spiele geschult werden, um deren pädagogische Möglichkeiten optimal zu nutzen.
Insgesamt trägt die Arbeit dazu bei, die Bedeutung digitaler Spiele für den Geographieunterricht zu unterstreichen und zeigt auf, wie Reflexionsprozesse gezielt gefördert werden können, um nachhaltiges Lernen zu unterstützen
Implementation of the CAHF/CASCI Method and Application on Actinide-DOTA Complexes
Get PDFThis thesis presents the implementation of the Configuration-Averaged Hartree-Fock (CAHF) method combined with Complete Active Space Configuration Interaction (CASCI) within the Quantum Object Library (QOL), and their application to Ac-DOTA complexes (DOTA^4- = 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetate).
The CAHF/CASCI approach offers a computationally efficient route for accurately describing near-degenerate f-orbitals and the resulting states in lanthanide and actinide complexes.
The QOL framework was extended to enable medium- and large-scale computations through a more memory-efficient integral transformation procedure.
Its capabilities were further improved by introducing a unified input system, enhancing existing methods, and adding new features such as a general overlap calculation between any wave functions, a robust CASCI implementation, and the incorporation of pseudopotential (PP) spin-orbit integrals.
The second part applies the CAHF/CASCI method to investigate An-DOTA complexes (for An = Pa, U, Np), focusing on ground state character, conformer stability, and ligand field splitting.
Using small-core pseudopotentials (SPPs) and high-quality basis sets, a systematic trend favoring the square antiprismatic (SAP) conformer was observed, consistent with experimental findings.
This study highlights the utility of the CAHF/CASCI method for exploring the electronic structure of f-element complexes and provides insights into the chemistry of actinide-DOTA systems
Entwicklung eines ICF Kodierungssets für Patienten mit Tiefer Hirnstimulation bei Morbus Parkinson
Get PDFMorbus Parkinson führt durch chronisch fortschreitende Degeneration der Neurone der Substantia Nigra und einem damit einhergehenden Dopaminmangel zu multiplen neurologischen Symptomen mit unterschiedlichen Schwerpunkten und verändert damit das Leben der betroffenen Patienten/Patientinnen, sowie das Leben ihrer Angehörigen auf mehreren Ebenen.
Ein frühes Erkennen von ersten Krankheitsanzeichen genauso wie eine multidisziplinäre therapeutische Begleitung sind für die Lebensqualität und Prognose der Betroffenen entscheidend und eine Erfassung der Funktionsfähigkeit und ihre Auswirkungen auf das tägliche Leben für die Evaluation, Koordination und Planung erleichternd.
Die Internationale Klassifikation der Funktionsfähigkeit, Behinderung und Gesundheit (ICF) ermöglicht über eine sprachliche Vereinheitlichung ein System, mit dem relevante Informationen über Fachdisziplinen und Sprachgrenzen hinweg ausgetauscht und verglichen werden können.
Im Übersetzungsprozess konnten die meisten vorweg gebildeten Kategorien bestimmten Kodierungen der ICF zugeordnet werden. Es bleiben aber mehrere hundert Kategorien, die nicht oder nicht spezifisch genug zugeordnet werden konnten. Entweder ist ein Rückschluss von der ICF zurück auf die Kategorie aufgrund von Komplexität oder zeitlicher Dimension der Kategorien nicht sicher möglich. Oder aber es fehlen der ICF Kodierungen, die sich in der zugrundeliegenden Studie allerdings als krankheitsrelevant herauskristallisierten.
Die von den Patienten/Patientinnen und Angehörigen genannten Personbezogenen Faktoren sollten in einer Zusammenfassung von ICF Kodierungen für Morbus Parkinson ebenfalls nicht fehlen, weil sie 38% der in dieser Studie kodierbaren Kategorien ausmachen.
Weitere Forschungsfragen betreffen damit die Kompatibilität/Integration Personbezogener Faktoren in die ICF oder die Abbildung komplexer Kategorien.
Es wurde zudem ein Fallbeispiel erstellt, um die praktische Anwendbarkeit von ICF Kodierungen darzustellen.
Zusammengefasst unterstützt die Nutzung der ICF sowohl in der Forschung, als auch im klinischen Alltag eine interdisziplinäre und integrative Zusammenarbeit. Sie ist in ihren Begriffen nicht in der Sprache und der Struktur einer besonderen Fachrichtung formuliert oder angeordnet, sondern erhebt den Anspruch allgemein übergreifender Formulierungen. Zudem erleichtert sie die Koordination von Gesundheitsdaten durch die Kodierung von Informationen. Im Rahmen der Behandlung von Patienten/Patientinnen mit Morbus Parkinson ist regelmäßig ein Team bestehend aus Ärzten/Ärztinnen, Psychologen/Psychologinnen, Krankenpflegern/Krankenpflegerinnen, Logopäden/Logopädinnen und Sozialarbeitern/ Sozialarbeiterinnen für die möglichst optimale medizinische, psychische und soziale Versorgung und die Aufrechterhaltung der Funktionsfähigkeit der Patienten/Patientinnen erforderlich. Die ICF kann hier als Schnittstelle wirken.
Wünschenswert wäre dabei, dass die relevanten Entscheidungen nicht weiterhin defizitorientiert und maßgeblich durch die Diagnosen der ICD-10 getroffen werden. Durch die Kodierungen der ICF, die im Wesentlichen Lebens- und Alltagsumstände beschreiben, werden die ICD-10 Diagnosen im besten Falle dynamisiert, verringern ihre festlegende Qualität und Elemente des biopsychosozialen Modells kommen hinzu.
Thematisch wird in der ICF ein Schwerpunkt auf Aspekte der Teilhabe gelegt und ist damit für jegliche Bemühungen der Inklusion und für die Eingliederung von Menschen mit Morbus Parkinson hilfreich.
Die internationale Vereinheitlichung und Standardisierung der Daten wirkt förderlich auf Vergleichbarkeit und Dokumentation, was die ICF als ein wichtiges Instrument für die Forschung und als politische Evaluierungsgrundlage qualifiziert.
Um mit einer handhabbaren Menge an Klassifikationen krankheitsspezifisch arbeiten zu können, werden weltweit sogenannte Core Sets entwickelt. Für Morbus Parkinson besteht bisher kein Core Set und daher ist diese Arbeit ein Schritt in diese Richtung, indem Daten aus einem internationalen Forschungsprojekt zu Tiefer Hirnstimulation bei Morbus Parkinson in ICF Kodierungen übersetzt werden. Im Anschluss sind für die Erstellung eines ICF Core Sets weitere umfangreiche Studien erforderlich
Speech processing in cochlear implant patients across different modalities
Get PDFHearing loss is one of the leading causes of chronic disability (Vos et al., 2016) and it
causes major problems in interpersonal communication. Cochlear implants (CIs) are
the world’s most successful neural prosthesis and they allow patients with severe to
profound hearing loss to regain their hearing ability. However, hearing with a CI is
very different from normal hearing (NH), as only limited auditory input is provided
by the device. The capacity of the human cortex to adapt to this new auditory input,
however, enables the patients to extract meaningful information within months
after switch-on of the processor. During the period of deprived hearing, patients
typically rely more strongly on visual cues like lip movement for communication.
Hence it has been suggested that these individuals show a pronounced binding
of the auditory and the visual system, allowing them to integrate auditory and
visual speech information after cochlear implantation more efficiently. The included
projects therefore investigate auditory, visual and audiovisual speech processing in
hearing deprived individuals and different groups of CI users. They comprise three
event-related potential (ERP) studies, split over four publications, each focusing on
an individual perspective.
The main result of the first study shows a side-of-implantation effect in the auditory
cortex of SSD CI users for auditory stimulation of both the CI ear and the NH ear.
This is shown by an enhanced functional asymmetry for the left-ear implanted
SSD CI users when compared to right-ear implanted SSD CI users. The second
study reveals multisensory integration for NH listeners, SSD CI users and CI users
with bilateral hearing loss, as depicted in shorter response times for audiovisual as
compared to unimodal stimuli. Nevertheless, both CI user groups show delayed
auditory-cortex responses and enhanced visual-cortex responses in comparison to
the NH listeners. Different processing patterns are also evident in our prospective
longitudinal study. Regarding the audiovisual speech stimuli, the CI group displays
a more occipitally pronounced topography, especially in a visually attended
condition, as well as a reduced auditory cortex response when compared to the
NH listeners. Additionally, a condition difference between visually and auditory
attended stimuli is present in the beta frequency range for the NH listeners only,
which indicates an enhanced allocation of attention when processing the visually
attended stimuli. Regarding the visual only speech stimuli, the CI group displays a
reduced visual cortex activation, but a stronger functional connectivity between the
visual and auditory cortex when compared to the NH listeners. All the results of
the longitudinal study seem to be deprivation induced and remain unchanged after
six months of CI use. Furthermore the altered visual processing relates to the CI
outcome.
Taken together, the included projects contribute to a better understanding of speech
processing in hearing deprived individuals and CI users in different modalities
(auditory, visual and audiovisual). They reveal distinct processing strategies used
to overcome the deprivation and the limited regained auditory input via a CI. The results could be used to improve the clinical rehabilitation process by including visual
speech information into the currently purely auditory training and assessment.
Moreover, first evidence for a relation between electrophysiological measures and
the CI outcome pave the way for more precise prediction models
Pioneering genome editing in parthenogenetic stick insects: CRISPR/Cas9-mediated gene knockout in Medauroidea extradentata
No full textExploring Strong Correlations and Strong Disorder in Fermionic Systems: Independent Investigations
Get PDFDespite significant advancements in condensed matter physics, analyzing strongly
interacting and disordered systems presents notable challenges that this thesis aims to
address. Divided into two distinct projects, this work investigates strongly interacting
fermion systems and strongly disordered fermion systems independently. However, both
projects share a commonality in the analytical tool employed: the superbosonization
formula introduced in [1, 2].
The first project addresses the lack of methods available for analyzing strongly interacting
systems. We develop a general analytical framework based on the bosonization formula [1,
2] within the functional integral approach. As a specific application, we examine the
one-dimensional strongly interacting Hubbard model at half-filling. However, we encounter
challenges in properly defining the continuum limit in time. Consequently, we incorporate
the concept of renormalization, exploring how it can be integrated into the bosonization
scheme. We acknowledge that the complete execution of these ideas remains a work in
progress, reserved for future research.
The second project centers on investigating strongly disordered fermion systems within
symmetry class D, as outlined by the Altland-Zirnbauer classification of non-interacting
fermions [3]. This research is motivated by the proposal of a novel spontaneous symmetry
breaking (SSB) phenomenon in class A [4, 5, 6], and aims to uncover similar phenomena in
class D systems. We begin with a general formulation of supersymmetric field theory
applied to disordered class D systems, focusing on the strong disorder limit and its
implications. To explore the potential for novel spontaneous symmetry breaking in class D,
we analyze a specific system: monitored free fermions that exhibit measurement-induced
phase transitions. We propose a reformulation of the theory that provides a new perspective
on investigating this system. Nevertheless, a complete investigation of the possibility of
novel SSB phenomena in class D remains an open question for future exploration
An Experience-Sampling Study on the Frequency and Diversity of Positive and Negative Affective States
No full textKCNT1-Associated Epileptic Encephalopathies in Mouse Models: Phenotypic Characterization and Targeted Therapeutic Interventions
Get PDFDevelopmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by refractory seizures, cognitive deficits, and behavioral abnormalities. Among these, KCNT1-associated DEE are caused by gain-of-function (GoF) mutations in the KCNT1 gene, encoding the sodium-gated potassium channel KNa1.1 (Slack). These mutations disrupt neuronal excitability, leading to profound impairments in brain development and function. Despite the severity of these disorders, treatment options remain extremely limited, and there are no approved therapies specifically targeting KCNT1 mutations. This thesis investigates the pathophysiological mechanisms underlying KCNT1-associated epilepsy and evaluates potential therapeutic interventions using two novel knock-in mouse models harboring patient-derived KCNT1 mutations, p.I335N (KCNIN) and p.R950Q (KCNRQ), which exhibit distinct GoF properties.
Comprehensive phenotypic characterization of these models revealed spontaneous generalized seizures, significant hippocampal pathology, and pronounced behavioral abnormalities. Histological analyses demonstrated reactive astrogliosis, enhanced perineuronal net density in the dentate gyrus, and elevated neuropeptide Y expression in the hippocampal mossy fibers, indicative of extensive hippocampal network remodeling. Behavioral experiments revealed increased locomotion, reduced anxiety-related behavior, and impaired memory performance. Electrocorticography (ECoG) recordings uncovered significant disruptions in sleep architecture and interictal network activity, including reductions in cortical theta power during both sleep and wakefulness. Together, these findings establish the face and construct validity of these mouse models for KCNT1-associated epileptic encephalopathies.
To address the limited efficacy of existing treatment options, brain-permeable KCNT1 channel blockers were identified through high-throughput screening of FDA-approved compounds and validated on KCNT1 channels in vitro. Chronic treatment with these blockers in adult mice failed to ameliorate seizure phenotypes, highlighting the importance of targeting earlier developmental periods. Notably, treatment administered during the neonatal period increased the proportion of seizure-free animals but did not prevent the alterations in interictal network activity, emphasizing the need for therapeutic interventions that address the early stages of epileptogenesis. This study provides a detailed characterization of KCNT1-associated epilepsy models, elucidates their underlying pathophysiology, and highlights important challenges of developing therapies for these disorders. These findings underscore the urgent need for precision medicine approaches targeting developmental windows to address the unmet clinical need for effective treatments
Using exceptional points and non Hermitian topology to study fractional charges and apparent event horizons in superconducting circuits.
Get PDFConventional superconductors are one of the most well known example of macroscopic quantum phenomena, therefore superconducting circuits have emerged as a promising platform for qubits, quantum information processing and simulating light-matter interactions. The endeavor of simulating exotic physics on superconducting circuits is also accompanied with search of new circuit elements, apart from already existing elements such as capacitors, inductors and Josephson junctions, that can help in reproducing these novel phenomena experimentally. In this thesis we discuss three different projects that are unified by presence of exceptional points and non-Hermitian topology, that touch on one or both of these aspects of superconducting circuits. In the first project we study a system with both supercurrents and lossy currents in order to unify the two distinct ways of detecting fractional charges. We find that charge quantization is here a conserved property of the detector basis of the Lindbladian, while charge fractionalization is a topological property of its
complex-valued eigenspectrum. We show that already conventional superconductor-normal metal hybrid circuits exhibit a variety of topological phases, including an open quantum system version of a fractional Josephson effect, due to the presence of exceptional points in its spectrum. In the second project we study topology of a dissipative system, that can mimic some essential features of an Andreev bound state spectrum of a multi-terminal Josephson junction. We find that this system indeed has topological properties that are encoded in an open system version of Chern number. We also find the full counting statistics for this toy model and conclude that this Chern number is not measurable via any regular transport experiment. Finally in the third project we show how superconducting circuit hardware can implement a variety of classical and quantum spacetime geometries on lattices, by both using established circuit elements and introducing new ones. We demonstrate the possibility of a metric sharply changing within a single lattice point, thus entering a regime where the modulation of system parameters is (in a sense) trans-Planckian, and the Hawking temperature ill-defined. In fact, our approach suggests that stable, thermal event horizons are incompatible with strictly discrete lattice models. Contrary to regular Hawking radiation (nonzero boson occupation number), the instability manifests as an accumulation of charge and phase quantum fluctuations over short time scales- a robust signature even in the presence of an environment. Moreover, we present a loop-hole for the typical black/white hole ambiguity in lattice simulations: exceptional points in the dispersion relation allows for the creation of pure black (or white) hole horizons, at the expense of radically changing the interior wormhole dynamics