Hier werden digitale Dissertationen und Habilitationen gespeichert, erschlossen und veröffentlicht.
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Aktuellste Veröffentlichungen
Einfluss von oxidativem Stress auf den Metabolismus humaner retinaler Endothelzellen
(2026) Ernesti, Justus-Satoshi
Maschinelle invasive Langzeitbeatmung bei Querschnittgelähmten
(2026) Rudolph, Merle Marie
In vitro analysis of factors influencing the ratio of IgE to IgG1
(2026) Freye, Sarah-Maria
Background: IgE-mediated food allergy is a common disease affecting up to one tenth of the population, especially in industrialized nations, and provoking symptoms that range from mild skin manifestations to life-threatening anaphylaxis. Curative and preventive treatment is very limited, creating a danger for the patients and an economic burden for the patients and their stakeholders. Therefore, an advanced knowledge of immunological mechanisms which could serve as a future treatment target is necessary. A promising target is the ratio of the immunoglobulins IgE and IgG4 in humans, or respectively IgE and IgG1 in mice. Several studies describe that sensitized but tolerant patients presented a higher ratio of food-specific IgG4 to IgE as opposed to food allergic patients. Hence, it is of great interest to understand which factors influence the ratio of these immunoglobulins, contributing to a more allergy-releasing or allergy-protective immune response.
Objective: This thesis aims to evaluate the impact of B cell receptor (BCR) signaling strength, differential IL-4 and glucose levels on the ratio of membrane-bound and secreted IgE and IgG1 in murine B cell cultures.
Methods: The experiments are based on an in vitro B cell culture system that mimics a T cell-dependent germinal center reaction: splenic B cells from BALB/c mice were co-cultured with cells from the feeder cell line 40 LB and stimulated with cytokines and, if applicable, F(ab’)2 fragments of anti-Ig antibodies, among others. The frequencies of IgE- and IgG1-expressing cells were evaluated by flow cytometry, the secretion of these antibodies by ELISA and the class switch recombination generating these antibodies by semiquantitative analysis of switch circles.
Results: Calcium flux experiments revealed that F(ab’)2 fragments of anti-IgM and anti-Ig kappa antibodies could serve as a model for different BCR signaling strengths. Flow cytometric analysis of IgE+ and IgG1+ B cells and plasmablasts showed that stimulation with both F(ab’)2 fragments decreased the frequencies of these isotype-switched cells. The ratio of IgE+ to IgG1+ B cells diminished with increased BCR signaling which was similar for BCR stimulation with F(ab’)2 fragments of anti-IgM and anti-Ig kappa antibodies. In contrast, increasing concentrations of IL-4 or glucose in cell cultures raised the ratio of IgE/IgG1.
Conclusion: In our germinal center model, the stimulation of the BCR with F(ab’)2 fragments of anti-Ig antibodies selectively inhibited the formation of IgE+ B cells and plasmablasts more strongly than that of IgG1+ cells. The strength of this inhibition corresponded to the BCR signaling strength. Semiquantitative analysis of switch circles showed that indirect class switching from IgM to IgG1 to IgE was the principal mechanism of IgE+ B cell generation in our cell culture system. IL-4 and glucose levels seemed to influence the IgE/IgG1 ratio, too. All in all, these findings suggest that complex B cell-extrinsic environmental stimuli differently influence the generation of IgG1- vs. IgE-switched cells, even though Th2-cytokines, especially IL-4, promote switching to both isotypes.
CD4+ T cell receptor sequences during progression towards experimental pemphigoid
(2025) Bahreini, Farbod
Autoantibody-mediated diseases, such as epidermolysis bullosa acquisita (EBA), arise from a breakdown in immune tolerance, often reflected in restricted T-cell receptor repertoires (TCRRs). This thesis examines two complementary strategies for restoring tolerance, both of which converge on reshaping the TCRR. In the EBA model, pretreatment with ovalbumin in combination with Alum and TiterMax (OAT) has been shown to completely prevent disease. Building on this model, herein, we demonstrate that OAT pretreatment significantly reshaped the T follicular helper repertoire. OAT increased diversity, reduced clonal dominance, and introduced novel sequence features. Transcriptomic analysis revealed node-specific programs, with the inguinal lymph node (Ingln) shifting toward regulatory and metabolic pathways, consistent with a tolerogenic environment. A second strategy examined the effects of cell-derived nanoparticles (CDNPs), which are multi-epitopic protein aggregates of ~150 nm, reproducibly marked by Annexin A5. CDNPs modestly reduced IL-6 secretion from macrophages and broadened TCRβ repertoires within splenic T-cell zones by limiting clonal dominance. CDNPs also increased Tcrb and Gata3 expression, indicating enhanced T-cell activity with a Th2-associated bias. Together, these findings highlight two distinct but complementary approaches: OAT illustrates how antigen-specific immune deviation can reshape repertoires and support tolerance, whereas CDNPs act as multi-epitope modulators capable of reprogramming both innate and adaptive immunity. From a translational perspective, OAT suggests a model for tolerogenic vaccination in diseases with known antigens, while CDNPs provide a potential therapy where autoantigens are diverse or undefined. Both approaches underscore the TCRR as a central determinant of tolerance and a promising therapeutic target in autoantibody-driven disease.
Interdisziplinärer Einsatz der optischen Kohärenztomographie-Angiographie des Augenhintergrunds
(2026) Sochurek, Jan Alexander Maria
Screening auf konnatale CMV-Infektionen bei sehr kleinen Frühgeborenen
(2025) Leienbach, Viola
Eine Infektion mit dem humanen Cytomegalievirus ist die häufigste konnatale Infektion und kann zu akuten Erkrankungen und/oder schwerwiegenden neurologischen Langzeitfolgen führen, auch bei asymptomatischer Infektion. Aktuell gibt es keine Empfehlung eines generellen postnatalen Screenings. In dieser Arbeit geht es um die Fragen, ob innerhalb der Studienpopulation von Frühgeborenen mit einem sehr niedrigen Geburtsgewicht von unter 1500 Gramm konnatal infizierte Kinder diagnostiziert wurden, ob tiefgefrorenes Nabelschnurgewebe als mögliches Material eines Screenings auf CMV-Infektionen mittels rt-PCR verwendet werden kann und ob sich Unterschiede zwischen Frühgeborenen zeigen, welche postnatal antiviral mit Ganciclovir oder Valganciclovir therapiert wurden gegenüber nicht antiviral therapierten Frühgeborenen. Sowohl das Material (Nabelschnurgewebe) als auch die klinischen Daten wurden erhoben vom German Neonatal Network.
In vier von 3323 Nabelschnurgewebeproben wurde der Nachweis von CMV-DNA gefunden, welches als Beweis einer konnatalen CMV-Infektion angesehen wurde. Alle vier Kinder wurden postnatal mit Ganciclovir oder Valgancivlovir therapiert. Weiterhin wurden statistisch die Daten von 10217 Frühgeborenen untersucht, welche postnatal während ihres stationären Aufenthaltes Ganciclovir oder Valganciclovir als antivirale Therapie einer konnatalen oder postnatalen CMV-Infektion erhalten hatten. Antiviral therapierte Kinder ohne Nachweis von Viren in der Nabelschnur waren deutlich kleiner und unreifer und mussten häufiger mit weiteren klinischen Maßnahmen wie tracheale Beatmung, Gabe von Surfactant, Katecholaminen, Blutprodukten sowie Steroidhormonen behandelt werden. Außerdem zeigte sich häufiger ein schlechtes Outcome im Sinne eines pathologischen Hörscreenings, einer Sepsis, einer Hirnblutung oder einer anderen schweren Komplikation. Dies entspricht dem bekannten Risikoprofil der symptomatischen postnatalen CMV-Infektion, welche nur bei extrem unreifen Frühgeborenen auftritt. Die Mortalität zeigte sich nicht erhöht.
Tiefgefrorenes Nabelschnurgewebe erwies sich als geeignetes Material einer rt-PCR zum Nachweis einer konnatalen CMV-Infektion. Jedoch zeigte sich in unserer Arbeit eine niedrigere Prävalenz (0,12%) als in anderen Arbeiten. Aufgrund des retrospektiven Screenings fehlte eine weitere Untersuchung eines Kontrollmediums des Kindes wie Speichel oder Urin, welche in Kliniken als gängige Diagnostik einer CMV-Infektion durchgeführt wird. Dies ist weiterhin der Goldstandard, da laut aktueller Literatur diese Form der Diagnostik besser anwendbar sowie sehr spezifisch und sensitiv ist.
Ein generelles Screening auf eine konnatale CMV-Infektion für sehr kleine Frühgeborene nach Geburt ist daher laut dieser Arbeit empfehlenswert, um bei einem hohen Risiko für Langzeitfolgen entsprechend engmaschige Follow-up Untersuchungen durchführen zu können. So können frühzeitig Gegenmaßnahmen getroffen werden, um die Folgen gering zu halten.
Reporter-based reverse genetics of murine norovirus reveals insertion-tolerant sites and a position in the capsid linked to antibody escape
(2026) Lane, Miranda Sophie
Noroviruses are members of the Caliciviridae family: positive-sense, single-stranded RNA encased within a 90 dimer protein capsid. Human norovirus (HNoV) is a major cause of gastrointestinal disease. Murine norovirus (MNV) is used as a surrogate in the study of HNoV due to it being the only norovirus currently reliably cultivatable in cell culture and possessing a reverse genetics system. Previous studies have used MNV to develop our understanding of norovirus capsid protein structure with regards to infection. Various ligands have been observed to bind the norovirus capsid including divalent cations, neutralising antibodies, bile acids, and a cellular receptor mCD300lf (MNV only). The effect of bile acids on MNV infection was previously investigated in this lab but recent research suggests dynamic conformational changes observed in the MNV capsid are due to environmental factors such as bile acid binding, pH change and divalent cation binding. This study set out to determine the effects of divalent cation binding with regards to infection.
Multiple reverse genetics techniques have been developed for MNV with an RNA-based technique in a recombinant cell line developed within the last few years. This technique allows for the indirect observation of protease production via a GFP reporter system. This work compared wild‑type MNV‑1.CW1 RNA transfections with transfected MNV‑1.CW1 RNA with mutations introduced to a cDNA plasmid construct via site-directed mutagenesis. This system was used in the testing of the non‑structural (NS) polyprotein, protease cleavage sites with the aim of identifying potential sites for the insertion of a short protein-coding sequence, and to generate recombinant mutant MNVs used in the study of divalent cations.
Transfection experiments of MNV‑1.CW1 RNA with an HNoV protease cleavage site identified a potential site of NS1‑2/NS3 as being suitable for a potential inserted protein, with the site receptive to a short peptide coding sequence insertion. Five recombinant MNV‑1.CW1s with mutations in the major capsid protein were generated. The generation of two divalent cation non-binding mutants (D410A and D440A) and the extensive testing of these in cell culture assays identified D440 as a crucial site of cation binding, preventing the neutralisation of the virus with a monoclonal antibody. Previous work identifying bile acid in preventing neutralisation from monoclonal antibodies was revaluated, this time controlling for divalent cations. Divalent cations were found to be essential in small concentrations – that alone could not prevent neutralisation – but assisted bile acid in neutralisation escape.
Understanding (dys)functional self-belief formation
(2026) Czekalla, Nora
Self-beliefs are essential to our identity and emotional well-being. They are formed through self-related feedback from the environment. The processing of feedback is influenced by self-related motivations and emotional experiences. This can lead to biased weighting of incoming information when updating beliefs depending on whether it is better or worse than expected. In depression, these biases can perpetuate maladaptive beliefs. This dissertation explores how novel self-beliefs are formed, using neuroscientific and computational methods to model belief formation in response to feedback. Across four studies, biases in self-belief formation were examined in individuals with and without depression, considering individual and contextual factors such as affective experiences, symptom burden, and stress. Participants engaged in a learning task with trial-by-trial performance feedback in relatively unfamiliar domains, designed to elicit the formation of novel self-beliefs.
Self-belief updates were best described by prediction error valence, with consistent findings of a negativity bias specific to self-beliefs but absent for beliefs about others. Study 1 investigated audience effects on self-belief formation and links to global prior self-beliefs indicated by self-esteem. It showed that more negative global self-beliefs were associated with more negative self-belief formation. In a public context, belief formation was more negative in those with higher subclinical social anxiety. Study 2 combined functional magnetic resonance imaging (fMRI), pupillometry, and emotion ratings to demonstrate that more negative self-belief formation was associated with the experience of more embarrassment and less pride, as well as more arousal, as indicated by pupil dilation. Neurally, it was linked to a heightened activity to more negative prediction errors in the anterior insula, amygdala, midbrain regions, and medial prefrontal cortex. Study 3 examined individuals with depression and healthy controls using fMRI. Individuals with depression showed stronger reactivity in the insula to negative compared to positive prediction errors. Despite no group differences in behavior, individuals with a higher symptom burden exhibited more biased belief formation, displaying more negativity towards themselves and more positivity towards others. In individuals with depression, in particular, symptom burden was linked to reduced updates following positive prediction errors. Study 4 showed that self-belief formation was less negatively biased following social-evaluative threat, which was associated with better recovery from stress-induced negative affect.
In summary, the studies show a negativity bias when forming beliefs about one’s ability. This may be related to motivations present in performance contexts like improvement motivation or motivation to avoid failure with a threat driven focus on negative feedback. The findings also highlight the critical role of individual factors like current affective experience, global prior self-beliefs, and symptom burden, alongside contextual factors like social evaluative stress in self-belief formation. Neurally, the studies identify the insula as central to processing affective, self-related feedback linked to biased updating. Notably, in individuals with depression, reduced self-belief updating following positive prediction errors with increased symptom burden suggests a diminished receptivity to corrective positive feedback, which may perpetuate maladaptive self-beliefs.
Investigation of the influence of cyclin-dependent kinase inhibitors on neutrophils activation
(2025) Mehlberg, Daniel Felipe Teixeira Dionis
Neutrophils, the most abundant leukocytes, play a crucial role in the initial defense against invading microbes by detecting them through various receptor systems. Nevertheless, pathological activation of neutrophils is involved in many chronic and autoimmune diseases, such as epidermolysis bullosa acquisita (EBA) where activation of neutrophils ultimately elicits skin blisters. Current treatment primarily relies on immunosuppression, contributing to increased morbidity and mortality. Hence effective and safe therapeutic strategies are urgently needed. Cyclin-dependent kinase inhibitors (CDKIs) block endogenously cell cycle progression under unfavorable conditions, leading to apoptosis, prompting interest in their potential for treating autoinflammatory and autoimmune diseases, including EBA. This study explores the impact of eleven specific CDKIs on neutrophil activation induced by immune complexes (ICs) in vitro, utilizing assays for reactive oxygen species (ROS) release and fluorescence-activated cell sorting (FACS). Among the CDKIs tested, four CDKIs Palbociclib (PD-0332991) HCl (CDK4/6I), THZ2 (CDK7I), BAY 1251152 (CDK9I, PTEFbI), and OTS964 (TOPKI, CDK11I) significantly reduce ROS production in stimulated human polymorphonuclear leukocytes (PMNs). Two CDKIs Palbociclib (PD-0332991) HCl (CDK4/6I) and THZ2 (CDK7I) showed significance regarding reducing CD18pos cells, although no CDKI demonstrated significant effects on the reduction of CD62Lneg cells. All eleven inhibitors maintained a proportion of viable cells close to 100% compared to the IC- stimulated positive control.
To summarize, CDKIs have emerged as promising candidates for anti-inflammatory therapeutics, owing to their capacity to modulate the resolution of inflammatory processes, and this work confirms this impression in vitro for EBA. Furthermore, of the 11 CDKIs analyzed, THZ2 (CDK7I) and OTS964 (TOPKI, CDK11I) stand out as the most promising for further testing of the efficacy of systemic application in the murine model of EBA induced by antibody transfer.
Von der Leitlinie zur Anwendung
(2026) Mersmann, Stefan
Der zunehmende gesellschaftliche und politische Druck auf unser Gesundheitssystem, stetig mehr Behandlungsqualität bei gleichzeitig sinkenden Behandlungskosten zu liefern, ist in den letzten Jahrzehnten rasant gestiegen. Dies betrifft auch und im Besonderen die geräte- und pflegeintensiven, medizinischen Disziplinen der Anästhesiologie. Die den täglichen Alltag bestimmenden klinischen Prozesse bieten ein enormes Optimierungspotenzial, wenn sie denn geeignet durch entsprechende Software-Anwendungen unterstützt werden.
Mit dieser Arbeit wird ein generatives, flexibles Software-Framework vorgestellt und bewertet, das die Entwicklung, den Betrieb, die Wartung sowie die Wieder-
und Weiterverwendung von Software-Anwendungen für eben solche klinischen Prozesse unterstützt. Im Fokus stehen diagnostische wie auch therapeutische
Prozesse als medizinische Leitlinien im Anwendungsbereich der Anästhesiologie.
Das Software-Framework selbst ist in Java implementiert und basiert auf einer hybriden, mehrschichtigen Systemarchitektur, die den Einsatz einer virtuellen Maschine unterstützt und damit hohe Flexibilität hinsichtlich Portierbarkeit, Erweiterbarkeit und Wiederverwendung gewährleistet.
Es wird gezeigt, wie klinische Software-Anwendungen zur Entscheidungsunterstützung, halb- und vollautomatisierten Therapie spezifiziert, entworfen, konstruiert,
realisiert, verifiziert und validiert und schließlich im hochregulatorischen Umfeld in Verkehr - also in den Markt und damit an den Patienten - gebracht werden
können.
Entlang eines hybriden Vorgehensmodells werden die zentralen Themen Methodik, Software-Entwicklung und Knowledge Engineering, Technologie, Produktqualifizierung, klinische Evaluierung sowie Zulassung, Inverkehrbringung, Betrieb und Ökonomie eingehend betrachtet und untersucht.
Darüber hinaus ermöglicht die Reflektion auf neuere Ansätze und Technologien aus diesem Bereich aktuelle Ideen und praktische Empfehlungen zu Transfer
und Verwertung in gegenwärtigen aber vor allem auch zukünftigen, industriellen Anwendungsszenarien wie auch wissenschaftlichen Forschungsinteressen.
Die Untersuchung klassischer Themen, Methoden und Ansätze aus dem modernen Geschäftsprozessmanagement klärt, inwieweit Technologien aus diesem Bereich
das Software-Framework zukunftssicherer gestalten können.
Optimizing synthetic and real training data distributions for deep learning in image recognition
(2026) Niemeijer, Joshua
The recent advances in deep learning have enabled a large variety of applications. Among these are, for example, the environment perception of robots, including self-driving cars, and medical image analysis, which helps identify medical conditions or planning treatment. To build deep learning systems that generalize well, large quantities of relevant human-labeled data must be available for training.
This requirement introduces several challenges. Annotations are costly due to the large amounts of data that need to be labeled and the complex nature of the annotation process. This is made more complex by the fact that relevant data needs to be recorded before data can be labeled. Depending on the field of application, this can be challenging. The challenge arises because relevant data is seldom available, which introduces the need to capture large quantities of data to find rare but critical cases.
The work investigates a more efficient use of manual annotation through intelligent data selection for labeling, utilizing active learning (AL). In this context, semi-supervised learning (SSL), which aims to replace manual annotation, is utilized. The thesis investigates the use of synthetic data to replace the acquisition of data itself. The work presents strategies to guide the generation process towards creating rare but critical data. Finally, it is shown how to utilize these insights to create models that generalize well toward unseen distributions with minimal human intervention.
For each of these methodologies, the thesis contributes novel approaches and analyses. It is shown that the choice of active learning approaches is highly dependent on the type of distribution the selection is performed on and the annotation budget. Next, the work shows how AL and semi-supervised learning are effectively integrated. This insight shows how to develop best practices for the application of AL and SSL. For the use of SSL in adapting networks to novel data domains, this work provides an extensive review of this dynamic field and derives novel low-complexity methods from it. These methods prove useful in their application to the environment perception of autonomous vehicles and the medical domain, as well as for adapting from synthetic to real data. The work provides novel methods for the targeted creation of synthetic data. Building on the creation of synthetic data and the research on SSL, the thesis presents an approach for generalizing to unseen domains.
Overall, this thesis provides solutions for minimizing the cost and human effort involved in annotating and acquiring relevant data. The solutions provide efficient adaptation and generalization to new domains and distributions.
Der Einfluss der Covid-19- Pandemie auf Wasser- und Seenotrettung
(2026) Bensch, Frederike Alina
Genexpressionsanalysen des ossär und pulmonal metastasierten Prostatakarzinoms
(2026) Wulf, Katharina Johanna