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Item type: Item , HRS Cells and Tumor-Associated Macrophages as Dual Mediators of PD-1/PD-L1–Dependent CD8⁺ T Cell Suppression in Classical Hodgkin Lymphoma(2025) Yegoryan, HasmikClassical Hodgkin lymphoma (cHL) features rare Hodgkin/Reed–Sternberg (HRS) cells within an immune-dense microenvironment, yet refractory disease persists in a subset of patients. This thesis interrogates how PD-1/PD-L1 signaling suppresses CD8⁺ T-cell cytotoxic immunity by integrating tumor-intrinsic and microenvironmental mechanisms. We combined mechanistic co-cultures, PLA coupled to multiplex immunofluorescence (PLA/mIF) on FFPE tissues, and RNA-seq of tumor-educated macrophages to link cellular mechanism to tissue context. Using mechanistic co-cultures of antigen-specific CD8⁺ T cells with HRS cells, we show that MHC-I–intact HRS cells directly restrain CD8⁺ effector function through PD-1/PD-L1 engagement; both PD-1 blockade and HRS PD-L1 knockout enhanced CD8⁺ activation and killing. In complementary systems incorporating tumor-associated macrophages (TAMs), PD-L1⁺ macrophages suppressed CD8⁺ T-cell activity via PD-1, and this inhibition was partially reversed by PD-1 blockade. Proximity ligation assay combined with multiplex immunofluorescence on FFPE sections confirmed in situ PD-1/PD-L1 engagement at two interfaces: CD8⁺ - HRS, and CD8⁺-TAMs contacts. Notably, EBV-positive tumors exhibited higher interaction rates across both interfaces, consistent with preserved MHC-I and enriched myeloid niches. PLA/IF further demonstrated that in tumors with limited CD8–HRS contact, CD8⁺ T cells continued to form PD-1/PD-L1 interactions with macrophages, indicating that TAMs can function as alternative checkpoint partners when direct tumor engagement is reduced. Together, these data support a multilayered model in which HRS cells initiate checkpoint-mediated suppression that TAMs amplify and stabilize. Long-term co-cultures of HRS cells with PD-1–expressing cells revealed no sustained proliferative or survival advantage from PD-L1 ligation under nutrient-replete conditions, suggesting context dependence of PD-L1 reverse signaling. Finally, RNA-seq of macrophages exposed to HRS-conditioned media showed M2-like polarization with increased mediators such as VSIG4, MMP9, and PDGF ligands, reinforcing checkpoint-mediated suppression and impairing T-cell function. Together, these data support a layered model of immune evasion in cHL: HRS cells can initiate PD-1/PD-L1–dependent inhibition where MHC-I is intact, while M2-like TAMs act as compensatory/alternative partners that sustain suppression when direct CD8–HRS engagement is limited. This framework explains the variable efficacy of PD-1 blockade and supports macrophage-targeted therapies for more durable responses.Item type: Item , Ich muss nicht sein. Verteidigung einer nihilistischen Auffassung personaler Identität(2025) Junker, Leon WendelinDas Ziel dieser Arbeit ist es, einen Beitrag zur Stärkung einer nihilistischen Auffassung personaler Identität zu leisten. Eine solche Auffassung wird gemeinhin durch die Behauptung charakterisiert, dass wir nicht existieren. In dieser Arbeit wird sie genauer über die These definiert, dass wir insofern nicht existieren, als es keine objektiv in der Welt existierenden und persistierenden Einzeldinge gibt, die die jeweils einzigen Subjekte derjenigen Gedanken und Handlungen sind, die wir gemeinhin als unsere verstehen. <br>Zur Stärkung dieser These wird zunächst aufgezeigt, dass Theorien personaler Identität, welche nicht mit ihr vereinbar sind, eine Annahme klassischer natürlicher Arten voraussetzen. Eine solche Annahme klassischer natürlicher Arten besagt, dass die Welt objektiv in Einzeldinge eingeteilt ist, diese Einzeldinge wiederum objektiv in Arten eingeteilt sind und diese Artzugehörigkeit die objektiven Persistenzbedingungen des Einzeldings bestimmt. Es werden Argumente gegen eine solche Annahme klassischer natürlicher Arten zusammengestellt. Hierbei wird sich vornehmlich auf die Argumentation John Duprés sowie die Theorie natürlicher Arten als ausgezeichnet über homöostatische Eigenschaftscluster von Richard Boyd bezogen. Der Kern der dargestellten Argumentation gegen eine Annahme klassischer natürlicher Arten besteht in der These, dass diese den Anforderungen an Arten für die Zwecke naturwissenschaftlicher Untersuchungen nicht gerecht werden können und ihnen somit ihre zentrale Motivation entzogen wird. <br>Im Anschluss wird dem größten Vorbehalt gegenüber einer nihilistischen Auffassung personaler Identität begegnet – diese und/oder deren Konsequenzen seien zutiefst kontraintuitiv und deprimierend. Dies wird zunächst getan, indem die Haltbarkeit eines solchen Vorbehalts als schlagendes Argument gegen eine nihilistische Position in Frage gestellt wird. Hierbei ist die These zentral, dass diejenigen Intuitionen, auf die sich hier gestützt werden soll, nicht weit verbreitet, stark und stabil genug sind, um die Ablehnung einer nihilistischen Position personaler Identität alleine auf dieser Grundlage zu rechtfertigen. Zuletzt werden Möglichkeiten aufgezeigt, unsere Intuitionen bezüglich personaler Identität auf eine Weise einzufangen, die mit einer nihilistischen Auffassung personaler Identität vereinbar ist. Dabei wird sich auf die Theorien personaler Identität von Derek Parfit sowie Marya Schechtman bezogen.Item type: Item , From Motion to Emotion: A Multilevel Investigation of Affective Intention Decoding(2025) Keck, JohannesUnderstanding others’ affective states is fundamental to successful social interaction. However, inferring such states poses a challenge — emotions and intentions are inherently inaccessible and must be expressed or communicated through observable cues. While facial expressions have been extensively studied, the human body also serves as a key channel for communicating affective intentions, offering high adaptive value. Prior research has identified several factors influencing how we perceive others’ affect, including movement features and the bodily states of the observer. The action observation network (AON) reliably activates during the observation of other people’s actions. Within this network, regions such as the inferior frontal gyrus, inferior parietal lobule, and premotor cortex are thought to support understanding by mapping observed movements onto motor representations, thereby providing a neural foundation for inferring others’ actions and intentions. However, the precise role of the AON in affective intention decoding remains under debate. Emerging evidence also suggests that the observer’s own motor repertoire and physiological states, such as acute inflammation, may modulate how affect is perceived in others’ body movement — yet, how these internal factors interact with specific movement cues is still poorly understood. This dissertation investigates which features of body movement contribute to affect perception in complex social interactions, and whether similarity between observed and internal motor representations modulates this process. Four experiments were conducted. Project 1 employed a computational feature-based approach to analyze whole-body movements in affective interactions. Project 2 targeted brain regions involved in action observation and valence processing. Project 3 examined how exercise-induced inflammation affects perception of emotional interactions. Project 4 combined methods from Project 1 and 2 to test how movement similarity influences both perception and neural activation. The findings show that kinematic features support emotion recognition, while postural cues relate more closely to subjective valence ratings. Interactive movement enhances recognition of socially salient emotions such as affection. Neural data revealed that a fronto-parietal network — especially the inferior parietal lobule — encodes valence from movement and responds more strongly to dissimilar movements, suggesting a central role in affective intention decoding. Inflammation was found to alter gaze behavior and reduce both sensitivity and emotion recognition, linking internal altered physiological states to perceptual processes. These results point to a close interaction between movement features, physiological states, movement similarity, and the fronto-parietal system in decoding affective intentions.Item type: Item , Charakterisierung eines Mausmodells der humanen idiopathischen pulmonalen Fibrose: Rolle des alveolären endoplasmatischen Retikulum Stresses (ER-Stress)(2025) Smeda, Mohamed SmaidaDie idiopathische pulmonale Fibrose (IPF) ist eine chronisch progrediente und letale interstitielle Lungenerkrankung, deren Pathogenese noch nicht vollständig verstanden ist. Insbesondere der endoplasmatische Retikulum (ER)-Stress in alveolären Epithelzellen wird als ein zentraler pathogenetischer Faktor diskutiert. Ziel dieser Arbeit war die Charakterisierung eines Mausmodells der humanen IPF mit besonderem Fokus auf die Rolle des ER-Stresses und des Transkriptionsfaktors Chop. Hierzu wurde ein experimentelles Mausmodell unter Verwendung des murinen Gammaherpesvirus 68 (MHV-68) etabliert und im Sinne eines „Two-hit“-Modells untersucht. Die Analysen umfassten molekularbiologische Methoden wie qPCR und Proteinanalysen zur Untersuchung von ER-Stress-assoziierten Signalwegen. Die Ergebnisse zeigen, dass die Aktivierung des ER-Stresses und die Überexpression von Chop allein nicht ausreichen, um eine ausgeprägte fibrotische Reaktion im Mausmodell zu induzieren. Erst in Kombination mit einer zusätzlichen Belastung, wie einer viralen Infektion, kommt es zu einer verstärkten fibrotischen Antwort im Sinne eines „Two-hit“-Mechanismus. Zusammenfassend deuten die Daten darauf hin, dass ER-Stress und Chop eine wichtige Rolle in der Pathogenese der pulmonalen Fibrose spielen, jedoch zusätzliche Faktoren erforderlich sind, um die Erkrankung vollständig auszulösen. Dies unterstreicht die Bedeutung komplexer pathogenetischer Mechanismen bei der IPF.Item type: Item , Size Constancy in Motion: Neural Signatures of Perception in Dynamic Visual Environments(2025) Schellen, ElefIntroduction Perceptual constancy refers to our ability to correctly perceive stable properties of the outside world, despite the fact that their corresponding sensory signals are in flux. Size constancy in particular refers to our visual system’s ability to correctly perceive an object’s size despite the fact that the retinal image may shrink or grow as our distance to it changes. This constancy affords us a stable impression of the physical world around us, and allows us to perform essential actions that we may take for granted like catching a ball, estimating the width of a doorway and being able to determine whether an approaching animal is a cat or a tiger. Much of the literature on size constancy and its neural underpinnings makes use of static displays, which leaves a gap in our understanding of what happens during ordinary, everyday episodes where the distance between an object and the observer changes. The overarching question of this thesis therefore relates to the neurophysiology of size perception when things are moving. Motivation and research Question The literature on moving stimuli is mixed. Under impoverished cues, motion can hinder size and distance perception and encourage reliance on retinal size. In richer scenes there is evidence that movement can help maintain size constancy, but studies often use ambiguous stimuli or illusory depth. The ambiguity in prior work motivates testing in depth cue rich environments that mimic real life viewing conditions, while measuring how neural representations in early visual areas behave when stimuli move in depth with either physical size held constant or retinal size held constant. The experiments described in this thesis address the neurophysiology of size perception right before and after movement, when the stimulus has recently been in motion in a depth cue rich environment. To probe the activity in the early visual cortex, and more specifically the size of object representations in these areas, we will make use of steady state visual evoked potentials (SSVEP) measured via electroencephalography (EEG), a method with proven effectiveness. These experiments will take place both in Virtual Reality, (VR), and in a physical setup that preserves the same geometry and depth cues. Experiments in this thesis will examine whether the primary visual cortex continues to encode physical size (as it does under static conditions), or whether it reverts to a purely retinotopic representation when motion is involved. Conceptual Advances Across matched experiments in VR and using a physical setup, we find the same neuroscientific result, namely that for objects that have just moved in depth, early visual cortex does not show size constant encoding. The SSVEP responses reflect retinal size after motion in both implementations of the task. By contrast, a control experiment using static but otherwise comparable stimuli shows partial size constancy of object representations in early visual cortex, replicating previously published findings. The conceptual advance is a clear dissociation between dynamic and static conditions. Following motion, early visual cortex represents the fixated object in a retinotopic way, whereas in a completely static condition, partial size constancy emerges in these same brain regions. This dissociation marks a key conceptual advance. It suggests that motion alters the balance between feedforward and feedback processing in early visual cortex, perhaps tipping it in favor of bottom-up input at the expense of perceptual (top-down) tuning. The result is that the same region of cortex (V1) that supports size constancy under static conditions fails to do so immediately after motion—even when behavioural responses indicate correct, size constant perception. This means that size-constant representations in V1 are not a fixed property, but dynamically modulated by viewing conditions. The static control experiment’s results also show that our SSVEP approach is sensitive to size constant signals when they are present, and demonstrates the replicability of earlier findings of this effect. This is to say that our findings are most likely related to motion rather than due to the specific visual environment being used or a failure to replicate earlier findings. A potential explanation for these findings is that during more dynamic viewing conditions, bottom up processing in early visual cortex dominates over feedback processing, at least in the cortical layers that contribute most to the SSVEP. Our findings highlight a need to understand the temporal dynamics and laminar specificity of feedforward and feedback influences in early vision—especially under ecologically valid, dynamic conditions. Methodological contributions A second major contribution is methodological. This work pairs a carefully controlled VR environment with a custom apparatus that moves a physical monitor along the sagittal axis, and equates stimulus geometry, timing and depth cues across the two. This design makes it possible to test the ecological validity of the VR environment and data quality in VR without substantially changing the paradigm. Two insights follow: 1. Behavioral validity: despite differences between VR and real life in size and distance judgements reported in the literature, we find VR to be an appropriate medium for experimentation, provided that the virtual scene is cue rich and closely mirrors the physical setup. In the behavioural tasks, errors are essentially identical between VR and the physical setup, with an average difference under one millimetre. 2. EEG signal quality: SSVEP data quality is much reduced in VR. Headset interference with electrodes results in remarkably worse signal-to-noise ratios. Although VR offers unmatched control over complex dynamic scenes, this comes at the cost of EEG data quality and necessitates careful attention to signal integrity. The thesis also catalogues VR specific pitfalls that matter for experimental design. Distance is often overestimated in sparsely cued scenes. To keep SSVEP contrast stable, some cues (like shading) cannot be used, so scenes must be constructed with careful anchoring to preserve depth information. Comparing VR to a physical counterpart helps validate that these design choices do not distort the effects of interest. All things considered, this work finds support for the use of VR in neuroscientific experiments in vision sciences. Broader implications The broader implication of these findings is that we should not assume neuroscientific findings related to perceptual constancy which are collected from experiments using static conditions generalize to more ecologically valid, dynamic contexts. While we demonstrate this distinction for size perception in particular, it should be noted that other forms of perceptual constancy (such as shape, colour or brightness constancy) tend to be studied in static conditions, while in real world viewing, these mechanisms emerge in dynamic visual environments. Although the precise temporal characteristics of this transition remain to be mapped, and our data do not by themselves prove that this transition is caused by a shift in feedforward versus feedback balance. They do, however, motivate future experiments that are sensitive to more specific cortical layers and temporal dynamics, which could give us a clearer picture of the neural underpinnings of size perception specifically and visual perception more broadly. Ultimately, the thesis invites a rethinking of perceptual neuroscience: one that more fully embraces the complexity and dynamism of real-world vision.