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Item Challenging the predictive mind(2026) Schuckart, Merle MarieIn everyday life, language comprehension rarely unfolds under ideal circumstances. Individuals may encounter reduced intelligibility of linguistic input, may be required to divide their attention between comprehension and a concurrent task, or may experience diminished sensory or executive capacities as a consequence of healthy ageing or illness. Additionally, the ways in which individuals engage with language across the lifespan are highly idiosyncratic, shaped not only by the quantity and quality of linguistic experience but possibly also by inter-individual differences in cognitive-perceptual style. Against this backdrop, it is crucial to understand the mechanisms that enable successful language comprehension, as well as the compensatory strategies that allow comprehension to remain robust when situational demands or individual predispositions are less than optimal. Language comprehension is supported by predictive processing, in which the brain continuously anticipates upcoming linguistic input based on prior context and knowledge of the speaker or situation. However, despite its central role in language comprehension, the cognitive cost of language prediction remains under debate. In particular, it is unclear whether predictive processing is an automatic consequence of exposure to linguistic input or whether it draws on domain-general executive resources, and how this potential relationship may be shaped by inter-individual differences in age as well as in the propensity to weight prior knowledge versus incoming sensory evidence. The aim of the present thesis was to address these questions within two behavioural pilot studies as well as two large-scale behavioural studies (Studies 1 and 2) and one EEG study (Study 3), employing a novel dual-task paradigm combining self-paced reading of naturalistic texts with an orthogonal, non-linguistic n-back task. This design allows cognitive load to be manipulated independently of linguistic processing, enabling a dissociation of prediction-related effects from general task difficulty. Across studies, word predictability was quantified employing word surprisal derived from a large language model (GPT-2). Predictive processing was evaluated through responses to variations in word predictability, measured both in reading times (across studies) and in neural tracking (in Study 3). In Study 1, results revealed a robust facilitation of reading by word predictability under low cognitive load. Crucially, increasing cognitive load systematically attenuated these effects, indicating that predictive language processing depends on the availability of executive resources. However, this dependency was modulated by age: older adults showed stronger predictability effects under low load but were also more susceptible to their reduction under increasing load, consistent with earlier exhaustion of cognitive capacity. In contrast, the youngest participants exhibited a qualitatively different pattern, with weak or absent predictability effects under minimal load and an increase under higher load, raising the possibility of differences in how language prediction manifests behaviourally in young and old adulthood. In Study 2, we first proposed an improved, psychometrically sound measure of cognitive- perceptual style based on responses in the Autism-Spectrum Quotient (AQ) and the Schizotypal Personality Questionnaire (SPQ), capturing the relative weighting of prior expectations versus sensory evidence. This measure revealed systematic age-related shifts toward a more sensory-driven profile, and showed that cognitive-perceptual style modulates sensitivity to word predictability, such that individuals with a more sensory-driven style exhibited greater susceptibility to variations in word predictability, particularly in older age. In Study 3, reading times reproduced the graded sensitivity to word surprisal observed in Study 1: older adults showed pronounced predictability effects overall, whereas younger adults displayed little sensitivity under low cognitive load but marked increases when executive resources were constrained. At the neural level, however, a qualitatively different pattern emerged. Results revealed age-related divergences in the cortical tracking of word predictability, with younger adults exhibiting stronger neural sensitivity to variations in word predictability than older adults, within a spatiotemporal region aligned with the canonical N400 component. Moreover, when cognitive demands were high, younger adults showed attenuated updating of higher-level semantic predictive models – reflected in decreased neural tracking of word predictability within a spatiotemporal region corresponding to the Post-N400 ERP component – whereas older adults relied on sustaining and updating semantic predictions more robustly under increased task demands. Collectively, these results point to an age-dependent dissociation between overt performance and underlying neural indices of predictive processing, and indicate that executive resource availability shapes the updating of semantic predictions in qualitatively different ways across the adult lifespan. Taken together, this thesis provides converging behavioural and neural evidence that predictive language processing is not cost-free but depends on the availability of domain-general executive resources, with a central role of executive resources especially in the updating of higher-level semantic predictive models. Moreover, the findings demonstrate that when executive resources are inherently constrained, the neural mechanisms supporting predictive language processing undergo functional reorganisation. The present work thus portrays predictive processing as a sophisticated, context-sensitive mechanism – malleable to both task demands and individual differences – that dynamically guides real-time language comprehension across the adult lifespan.Item Long-read sequencing on repeat expansions(2026) Laß, JoshuaItem Einfluss von Piezo1 auf die endotheliale Nanomechanik und vaskuläre Entzündungen(2026) Borutta, Johanna-TheresItem Harmonic light from membrane resonators(2026) Wollenzin, JörnItem Hematopoietic stem cells as a niche for Mycobacterium tuberculosis(2025) Engling, PitHematopoietic stem cells (HSCs) play an indispensable role in maintaining immune competence through their differentiation into mature lymphoid and myeloid effector cells. The manipulation of the hematopoietic system by infectious agents can, therefore, significantly disrupt protective immune function, facilitating pathogen persistence and exacerbating disease. M. tuberculosis is a paradigm of pathogen persistence. The recent discovery of mycobacterial DNA within HSCs introduced a potential yet undefined strategy by which M. tuberculosis may subvert host immunity by directly targeting the source of immune cell generation. The hallmarks of this work were to characterize how otherwise non-permissive cells, namely the HSCs, internalize M. tuberculosis and to identify the underlying pathways. We identified CD36 as the potential surface receptor recognizing M. tuberculosis and showed internalization to involve macropinocytosis-independent membrane ruffling instead of canonical phagocytosis pathways and discovered a yet-to-be elucidated involvement of clathrin interactions. Further, the heterogeneity among immunophenotypically defined HSCs indiciated inflammaging-related effects to promote permissiveness to infection by M. tuberculosis. Identifying the pathways exploited by M. tuberculosis for internalization and delineating the signals that drive HSC susceptibility may help to uncover novel targets for host-directed therapies aimed at protecting these crucial cells against infection and restoring host immune competence.Item Anaphylatoxin receptors as regulators of dendritic cell differentiation and function(2026) Nowacka, Alicja AnnaItem Speckle basiertes Monitoring für Laserbehandlungen des Auges(2026) Bliedtner, KatharinaItem Hochleistungsfaserlaser und deren Wellenlängenerweiterung als flexible Lichtquelle für die biomedizinische Bildgebung(2026) Lamminger, PhilippDie Anwendung von Faserlasern im Bereich der biomedizinischen Optik gewinnt in den letzten Jahren immer stärker an Bedeutung, da sie bei kompakter Bauweise die Erzeugung kurzer Laserpulse mit hohen Spitzenleistungen ermöglichen. „Master Oscillator Power Amplifier“ (kurz MOPA)-Laser steigern in mehreren Verstärkerstufen die Spitzenleistung einer Laserdiode von einigen Milliwatt auf mehrere Kilowatt. Neben den Vorteilen konventioneller Faserlaser ermöglicht der MOPA-Laser zusätzlich eine beliebige Modulation der Pulse. Mithilfe eines elektro-optischen Modulators werden Pulse aus einer Dauerstrich-Laserdiode ausgeschnitten, wobei Zeitpunkt, Repetitionsrate, Pulsdauer und Pulsform der Pulse frei wählbar sind. Dies ermöglicht Pulse-auf-Abruf und erleichtert die Synchronisation mit anderen Systemen. Eine Limitation dieser Lasersysteme ist jedoch die Beschränkung auf Wellenlängenbereiche, die von der Dotierung des Fasermaterials mit seltenen Erden abhängen aber für die Verstärkung der Pulse notwendig sind. Ziel dieser Arbeit war es, die Spitzenleistung von MOPA-Systemen zu erhöhen und die Wellenlänge mittels nichtlinearer Effekte zu verschieben. Die Verstärkung auf eine hohe Spitzenleistung ist dabei eine große Herausforderung, da hierfür eine hohe Pumpleistung benötigt wird, die wiederum zu unerwünschten Nebeneffekten, wie z.B. einem Untergrundsignal führen kann. Hierfür wurde ein MOPA-System mit mehreren Verstärkerstufen aufgebaut, mit denen das störende Untergrundsignal minimiert und so höhere Spitzenleistungen ermöglicht wurden. In der letzten Verstärkerstufe wurde eine Faser mit 25 µm Kerndurchmesser eingesetzt, die nichtlineare Effekte im Laser reduziert und damit eine schmale Linienbreite für eine anschließende gezielte nichtlineare Wellenlängenkonversion erlaubt. Eine Spitzenleistung von 91 kW wurde auf diese Weise erreicht. Ausgehend von dem optimierten 1063 nm MOPA-Laser und einem 1300 nm „Fourier Domain Mode Locked“ (kurz FDML)-Laser konnte mittels degeneriertem Vier-Wellen-Mischen (engl. „four wave mixing“, kurz FWM) in einer photonischen Kristallfaser (engl. „photonic crystal fiber“, kurz PCF) eine schmalbandige Verstärkung bei 1300 nm und eine Konversion zu 900 nm erzielt werden. Dieser Wellenlängenbereich eignet sich beispielsweise zur Anregung von grün fluoreszierendem Protein in der Zwei-Photonen-Mikroskopie. Durch die parametrische Verstärkung im FWM-Prozess konnten die 1300 nm auf 1,4 kW verstärkt und gleichzeitig Pulse mit 2,7 kW um 900 nm erzeugt werden. Dabei kann die Wellenlänge mit der Durchstimmgeschwindigkeit des FDML-Lasers geändert werden und erreicht eine Bandbreite von 105 nm um 1300 nm und 54 nm um 900 nm. Dieses Ergebnis ist besonders relevant für schnelle Versionen der Zwei-Photonen- und Raman-Mikroskopie, da es sowohl die Zahl der erreichbaren Fluorophore erhöht als auch die Abdeckung der Raman-Banden erweitert. In der Raman-Mikroskopie könnte die hohe Spitzenleistung des abstimmbaren Abtastlasers eine epi-direktionale Detektion und damit den Einsatz in Endoskopen ermöglichen. Es konnte zudem gezeigt werden, dass die hohe Spitzenleistung in einer längeren PCF für die Erzeugung eines breitbandigen Superkontinuums von 490 nm bis über 1750 nm verwendet werden kann. Nach zeitlicher Streckung mittels Dispersion in einer langen Glasfaser wurde es für hyperspektrale Bildgebung eingesetzt. Erste Bilder im roten Wellenlängenbereich konnten generiert werden, während die Leistung im grünen und blauen Wellenlängenbereich noch optimiert werden muss, um korrekte Farbbilder darzustellen. Künftig muss die Leistung in diesen Wellenlängenbereichen erhöht und Verluste reduziert werden, um das Superkontinuum für eine zeitlich gestreckte hyperspektrale Bildgebung im Sichtbaren vollständig nutzen zu können. Im Rahmen dieser Forschungsarbeit wurden aktiv modulierte MOPA-Systeme durch eine gezielte Leistungssteigerung und Wellenlängenerweiterung erfolgreich für die biomedizinische Bildgebung optimiert. Dadurch wurde ein extrem flexibles System geschaffen, welches die Grundlage für verschiedene zukünftige Anwendungen bildet.Item Characterization of cryptic antinuclear autoantibody targets antigens(2021) Zeng, ZitaoItem Identification and characterization of type VII collagen-targeting autoantibodies in experimental epidermolysis bullosa acquisita(2025) Schmidt-Jiménez, Leon FelipeAutoantibodies (Aab) are a major cause of autoimmune diseases. Understanding the generation and molecular properties of Aab is pivotal to understanding Aab-mediated autoimmunity. Epidermolysis bullosa acquisita (EBA) is a severe Aab-mediated autoimmune blistering disease (AIBD) characterized by Aab targeting type VII collagen (COLVII) at the dermal-epidermal junction (DEJ) in the skin. In EBA, Aab deposition at the DEJ leads to subsequent inflammation through effector functions mediated by the Aab constant region. Despite significant advances in understanding downstream pathomechanisms after Aab binding, the etiology of Aab — their clonal origins, genetic constraints, and subclass contributions determining pathogenicity remain poorly characterized. Monoclonal Aabs capable of inducing disease in murine models have not been identified, limiting mechanistic insights into Aab-mediated tissue damage. This study employed phage display coupled with next-generation sequencing (NGS) to isolate and characterize monoclonal antibodies (mAbs) targeting murine COLVII (mCOLVII). This represents the first comprehensive genetic-level analysis of the murine B cell receptor repertoire in EBA research, revealing germinal center-driven affinity maturation of autoreactive clones. Using two immune-libraries from lymphoid tissues of an mCOLVII-immunized mouse, four dominant variable heavy chain (VH) clonotypes with restricted genetic diversity were identified, suggesting constraints in the autoreactive B cell response. B cell receptor repertoire sequencing (BCR-seq) revealed tissue-specific isotype distribution and expansion patterns, while tracking clonotypes to originating tissues. BCR-seq uncovered an unexpected predominance of IgG1 in highly mutated clones in the draining lymph nodes (dLN), potentially challenging the current understanding of subclass roles in EBA pathogenesis. Selected clones were expressed in the complement-activating IgG2b format, demonstrating antigen specificity and constant region functionality in vitro. Additional mCOLVII-targeting clones were acquired from fellow researchers and likewise expressed and characterized. In vivo validation of six phage display-derived clones and two acquired clones revealed DEJ binding of all and complement C3 deposition for the latter; however, these molecular events proved insufficient for clinical disease manifestation, indicating additional requirements for pathogenic Aab beyond target recognition and complement activation. These findings suggest that synergistic epitope targeting, enhanced Fc-mediated effector functions or multiple subclasses may be required for clinical disease induction. This study provides critical insights into anti-mCOLVII Aab genetics and functionality, establishing foundations for understanding Aab pathogenicity determinants in EBA while providing valuable tools for understanding tissue-specific Aab mechanisms.Item Einfluss von oxidativem Stress auf den Metabolismus humaner retinaler Endothelzellen(2026) Ernesti, Justus-SatoshiItem CD4+ T cell receptor sequences during progression towards experimental pemphigoid(2025) Bahreini, FarbodAutoantibody-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.Item Reporter-based reverse genetics of murine norovirus reveals insertion-tolerant sites and a position in the capsid linked to antibody escape(2026) Lane, Miranda SophieNoroviruses 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.Item Understanding (dys)functional self-belief formation(2026) Czekalla, NoraSelf-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.Item Host and environmental modulators of norovirus infection(2026) Chaika, MarynaHuman noroviruses (HNoV) are the leading cause of non-bacterial gastroenteritis worldwide. Despite the significant disease and economic burden, currently no licensed vaccines or antivirals are available against norovirus infection. Progress in understanding norovirus biology has long been hindered by the inability to efficiently cultivate HNoV. This limitation was overcome with the development of the human intestinal enteroid (HIE) platform, which enables infection with clinical HNoV isolates in a physiologically relevant system that recapitulates the cellular diversity and the architecture of the human gut. This dissertation investigates how host and environmental factors influence HNoV infection in the 3DHIE. A robust and reproducible HNoV infection model in 3D-HIEs enabled detailed investigation of viral entry, replication, passaging, and virus-host interactions. From a laboratory owned biobank of diagnostic stool samples, four infectious HNoV isolates were identified, sequenced and genotyped. Through virological and biochemical approaches, glycans, divalent cations, bile acids, and polyamines were characterized as key host determinants that modulate HNoV infectivity, replication, and escape from antibody neutralization. The 3D-HIE platform was extended to also study infection of a clinical human rotavirus (HRoV) isolate and an established human influenza A virus (IAV) laboratory strain. Active fucosylation in 3D-HIEs was identified as a critical determinant for infection by both HNoV GII.4 and HRoV G3.P[8]eq.-like strain but not IAV. However, use of fucosylated surface glycans differed between HNoV and HRoV as identified by lectin competition. Exogenous fucose supplementation enhanced HNoV replication rather than competing with infection. Environmental ligands, specifically divalent cations and bile acids, were shown to shape norovirus infectivity and immune recognition. In both murine and human norovirus systems, magnesium ions and the bile glycochenodeoxycholic acid (GCDCA) were enhancing MNV and HNoV infections. Magnesium ions facilitated escape from neutralizing antibodies for two MNV strains and one GII.4 HNoV stool-isolate. For HNoV, magnesium was able to revert a loss in viral titers observed after storage of diluted stool isolates. Host-derived polyamines were identified as broad host dependency factors for norovirus infection. Depletion of polyamines strongly suppressed MNV replication, inhibited capsid protein synthesis, and prevented virus-induced cytopathic effect (CPE), in a reversible manner. Mechanistic studies linked polyamine metabolism, norovirus replication, and virus-induced CPE with PI3K/Akt signaling and cholesterol metabolism as downstream targets. The dependency on polyamines for both MNV and HNoV infections suggests a broad relevance and a novel target for antiviral therapy suited to pharmacologically target chronic norovirus disease. Collectively, this work advances understanding of the host and environmental determinants that promote norovirus infection by shaping viral entry, replication, infectivity, and neutralization escape. The identified host dependency factors, including fucosylated glycans and polyamines, emerge as critical regulators of infection and promising therapeutic targets, while the influence of environmental modulators on HNoV GII.4 infection and antibody escape provides important insights into norovirus biology and caveats for rational vaccine development.Item T helper cytokines in systemic sclerosis(2026) Mehrpouyan, AfsanehBackground and Objectives: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, vasculopathy, and progressive fibrosis affecting the skin and internal organs. Immune dysregulation and endothelial dysfunction are essential players in the development of SSc. A bias toward T helper 2 (Th2) cytokines has been demonstrated to be associated with SSc, implicating SSc as a Th2-associated disease. This study aimed to investigate the role of T helper cytokines in patients with SSc and in an experimental model of SSc-associated pulmonary arterial hypertension (PAH). Methods: A total of 128 patients with SSc were recruited from the Department of Rheumatology and Clinical Immunology, University of Lübeck. 69 healthy individuals served as controls and were enrolled at the Research Center Borstel. The experimental model of SSc-PAH was induced in IL-13 transgenic (IL-13tg) mice via immunization with membrane extracts of CHO cells overexpressing human angiotensin II type 1 receptor (AT1R). To assess therapeutic potential of targeting IL-6 signaling, IL-13tg mice, either naïve or AT1R-immunized, were treated with neutralizing monoclonal antibodies (mAbs) against murine IL-6 or IL-6 receptor (IL-6R), or with corresponding isotype control antibodies. Lung pathology was evaluated by histological analysis using hematoxylin and eosin (H&E) staining. The levels of human and murine T helper cytokines were measured in serum and/or bronchoalveolar lavage (BAL) fluid using LEGENDplex™ Multi-Analyte Flow Assay Kit. Lung transcriptomes were analyzed using Agilent Mouse GE 4x44K v2 microarrays. Results: Patients with SSc exhibited significantly elevated serum levels of multiple T helper cytokines compared to healthy controls, including IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α. Among these cytokines, serum IL-6 levels were positively correlated with as the presence of both interstitial lung disease (ILD) and PAH. In the experimental model, treatment with anti-IL6 or anti-IL-6R did not prevent the development of experimental occlusive vasculopathy in AT1R-immunized IL-13tg mice. By contrast, a trend toward a more severe vascular pathology was observed in AT1R-immunized IL-13tg mice treated with IL-6 or IL-6R-neutralizing mAbs compared to isotype-treated controls, although the differences were not statistically significant. Furthermore, treatment with anti-IL-6 mAb alone was sufficient to induce pulmonary occlusive vasculopathy in non-immunized IL-13tg mice. Transcriptomic analysis revealed that anti-IL-6 mAb treatment dysregulated the expression of immune-related genes in the lungs of unimmunized IL-13tg mice. Conclusion: Although IL-6 has been shown to exert a proinflammatory role in many diseases, this function could not be confirmed in the present study. Moreover, my findings suggest that, in an experimental model of pulmonary vasculopathy in the context of systemic sclerosis, IL-6 may act as a protective regulator. These results provide new insights into both the pro- and anti-inflammatory roles of IL-6 in the pathogenesis of systemic sclerosis and highlight the importance of carefully reconsidering this cytokine as a potential therapeutic target for SSc-associated PAH.Item Item Elucidating genetic causes of dystonia by large-scale next-generation sequencing(2025) Thomsen, MirjaItem Flowful work design(2025) Kloep, LeonieModern work contexts present new kinds of changes and flexibilization, digitalization, and new dynamics confront people with novel challenges. These changes also alter opportunities to experience positive states at work, such as flow and team flow. Flow is defined as the state of being completely absorbed in an activity that is perceived as optimally demanding, and it is associated with positive effects on well-being and performance. Similar assumptions apply to team flow, which is defined as a shared experience of flow within a team during optimal team dynamics. Different work design models propose systematically considering the characteristics of a work task to further develop and redesign it towards specific goals. However, the overarching context is often overlooked. This dissertation aims to examine flow and team flow promoting forms of work design from a context-specific perspective. The goal is to identify factors that promote or hinder flow and team flow at work, and to investigate the effect of external contextual factors in challenging work environments. To this end, three examples of modern work contexts are examined: work in a start-up, industrial manufacturing work, and virtual teamwork. Study I employs qualitative interviews to investigate how flow and team flow are experienced during the early start-up stage, which is often characterized by high levels of autonomy and meaningfulness, yet also by uncertainty and lack of support. Some of the influencing factors and consequences discussed are known from previous research, while others appear specifically relevant to the challenges start-ups face. Overall, the importance of promoting flow and team flow in the context of start-ups becomes apparent, and the results provide some recommendations for work design. Study II focuses on manufacturing work, which can be considered a flow-aversive context due to monotony and boredom. The study examines how gamification, a strategy for designing work to promote flow, affects both flow and performance. The study suggests that gamification could be particularly effective at the beginning of work processes; however, flow can also arise in non-gamified manufacturing work via other mechanisms. Study III examines the context of international virtual teams and investigates team flow experiences, exploring the possibility of identifying them through communication parameters. Depending on the task type, the examined communication parameters are insufficient for identifying team flow. Nevertheless, the study makes an important contribution to the ongoing methodological debates in flow research concerning the development of interruption-free measurement approaches. While each of the studies conducted in this cumulative dissertation addresses different research questions, they all contribute to a better understanding of flow and team flow in the workplace. Furthermore, they enable the development of recommendations for work designs that promote flow and team flow. The central results of the three studies are integrated into a work design model. This model is developed as an extension of an Input-Process-Output model and is based on the Job Characteristics Model. The model systematizes the various factors influencing flow and team flow at work, as well as the consequences of these states, with an emphasis on the influence of the context. The relevance of the key contextual factors examined in the dissertation, such as playful approaches and intercultural perspectives in work design, is also addressed. Furthermore, methodological reflections on the dynamics and the measurement of flow and team flow are presented. Based on the three contexts studied, concrete work design practices and recommendations are formulated. Future research should consider additional work contexts relevant to the evolving challenges faced in today's working world and evaluate the effectiveness of specific interventions. The methodological questions raised regarding the operationalization and measurement of flow and team flow should be examined more closely in light of the results. Overall, this dissertation demonstrates that promoting flow and team flow may be possible in challenging and dynamic modern work contexts. However, this is context-dependent and should be planned in a reflective, evidence-based manner.