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Deciphering the cancer ecosystem of gliomas using spatial transcriptomics.
No full textRecent efforts to incorporate a range of molecular characteristics into diagnostic guidelines underscore the necessity of comprehending the intricacies of tumour biology for better clinical decision-making. The role of environmental factors and cellular interactions is also increasingly recognised as a vital component in understanding cancer growth and progression. A complex cellular and spatial landscape is particularly evident in gliomas, which represent highly heterogeneous and plastic brain tumours. In this work, I develop a robust computational framework for the analysis of spatial single cell transcriptomics data and utilise it to conduct two studies on the spatial biology of gliomas.
In the first study, I conducted a comparative analysis of necrotic tissues in ten patients who were previously diagnosed with glioblastoma and subsequently presented with either tumour progression or radionecrosis. To this end, I generated a spatial single cell transcriptomic atlas consisting of over a million of cells and encompassing several brain-resident cell types and tumour states. The analysis of the annotated data revealed that radionecrotic samples contained abundant tumour cells with downregulated EGFR expression and were infiltrated by macrophages that contributed to gliosis. In contrast, samples with progression contained progenitor-like and cycling tumour cells that maintained high EGFR expression. The study offers invaluable insights into the spatial landscape and cellular interplay in radionecrosis and holds the potential to inform future research aimed at improving diagnostic and therapeutic strategies for glioblastoma patients.
In the second study, I designed a custom gene panel to enable a thorough investigation into the intricacies of cellular and spatial composition of over 300 samples from patients diagnosed with seven different glioma types. The examination of the annotated data set revealed both disparities and commonalities in the tumour expression patterns among adult-type diffuse gliomas and ependymal tumours. The spatial resolution permitted systematic examination of the spatial neighbourhoods that were linked to individual tumour transcription programs. The study establishes the foundation for future research projects in the group that will employ tailored panels and offers a glimpse into the spatial organisation of gliomas. I believe that the generated atlas along with standardised clinical data can facilitate further attempts to identify clinically relevant associations.
To summarise, I posit that the research conducted within the scope of this dissertation stands to provide a valuable basis for future endeavours in the spatial field. Furthermore, the biological insights derived from the generated data can be used to inform a more focused exploration of the intricate biology of necrotic tissue and the broader spatial patterns characterising multiple gliomas in the future
Spiking Matters: Exact Gradients for Deep Spiking Networks and Neuromorphic Hardware
No full textInspired by the brain's unparalleled capacity for intelligent and efficient processing, spiking neural networks offer a transformative path towards energy-efficient computation for machine intelligence, and inspire a new class of neuromorphic, or brain-inspired, hardware. However, training spiking neurons accurately and efficiently has previously posed a major obstacle in this endeavour. This thesis pioneers a solution to the exact training of deep spiking networks.
Our approach is inherently sparse: it is based on analytical equations that enable truly event-based computation, relying only on spike times. Their derivation enables, for the first time, exact error backpropagation in hierarchical networks of leaky integrate-and-fire neurons. To validate our method, we design the Yin-Yang dataset with the specific purpose of isolating true difficulty from mere scale. Using this benchmark we highlight the performance and robustness of our approach. With a time-to-first-spike coding, inspired by information processing in the brain, we demonstrate fast and energy-efficient classification on the neuromorphic system BrainScaleS-2. Because our method harmonises ideally with neuronal transmission delays, it enables the natural co-training of weights and delays in both software and hardware. This allows the exploration of the computational power of delays. Jointly analysing the structure and dynamics of deep networks, we find striking connections to computational models of neuronal sensory integration.
The present work connects studies on the computational properties of networks with experiments on analogue hardware as well as the comparison to the biological archetype. The algorithm's fundamental spiking nature pushes neuromorphic hardware to maximum efficiency. Bridging neuromorphic engineering and neuroscience, our integrated approach not only advances performance and efficiency of machine intelligence, but also drives forward the understanding of fundamental mechanisms behind spatio-temporal processing in the brain
Affective, Cognitive and Endocrinological Processes in the Daily Life of Individuals with Recurrent Major Depression and Their Course Over Time
No full textIn this dissertation, I explored the affective, cognitive, and physiological dynamics in the daily life of individuals with recurrent depressive episodes compared to healthy individuals. The dissertation is based on three studies, utilizing Ambulatory Assessment methodologies, including a measurement-burst design. These studies aimed to clarify mechanisms of micro-processes in daily life that could in-crease vulnerability to relapse and suggest potential therapeutic interventions.
Study 1 (Chapter II) examined differences in daily affect and cognitions between individuals in remis-sion from recurrent depression and healthy controls, along with their reactivity to daily negative and positive events. Key findings indicated that higher levels of positive thoughts boosted mood in both groups, while rumination predicted decreases in positive affect specifically in remitted individuals. Re-mitted individuals showed greater increases in negative affect and rumination following negative events. Notably, positive events elicited a "mood brightening" effect, marked by stronger decreases in negative affect and rumination, along with greater increases in positive affect and positive thoughts. These results highlight the protective role of positive affect and cognitions, suggesting therapeutic approaches that sustain positive mood could support long-term remission.
Study 2 (Chapter III) investigated associations between trait and state cognitions and salivary cortisol as a biological stress marker in daily life. Findings revealed that trait repetitive negative thinking, but not mindfulness, was linked to higher cortisol levels, particularly in individuals with recurrent depres-sion compared to healthy individuals. Additionally, momentary mind-wandering and mental shift prob-lems predicted increases in cortisol levels 20 minutes later. Within the recurrent depression group, higher average levels of mental shift problems were associated with elevated cortisol. Multilevel struc-tural equation models indicated that state cognitions did not mediate the effects of habitual repetitive negative thinking on cortisol release. These results underscore the independent roles of trait and state cognitions as internal stressors activating the hypothalamic-pituitary-adrenal axis, emphasizing the heightened physiological vulnerability of individuals with recurrent depression.
Study 3 (Chapter IV) applied a measurement-burst design to explore intraindividual variability and change in affective, cognitive, and endocrinological responses to daily events over 4.4 years in initially remitted individuals with recurrent depression. Over bursts, negative affect more strongly increased following negative daily events, while positive affect and self-acceptance exhibited a more pro-nounced decrease. Rumination and cortisol reactivity remained stable in response to negative events. Conversely, positive daily events were linked to a more significant increase in positive affect over bursts. Depression levels served as a moderator of intraindividual variability, with higher depression levels being linked to blunted cortisol responses toward negative events. Additionally, a “cognition brightening” effect was observed, reflected by greater increases in self-acceptance and greater de-creases in negative affect toward positive daily events in those individuals with higher depression lev-els, though this effect seemed unsustainable over bursts. These findings highlight the intricate dynam-ics of affective, cognitive and endocrinological processes in recurrent depression, emphasizing the need for targeted interventions that account for the stability of these responses and the moderating role of depression levels.
In conclusion, findings from these three studies underscore the importance of fostering positive affect and reducing maladaptive thought patterns in individuals with recurrent depression, providing valuable insights for relapse prevention. Integrating technology and advanced data methods into clinical prac-tice holds promise for tailoring interventions to individual needs and facilitating early detection of re-lapse risks, thereby promoting more effective and proactive care for those vulnerable to depressive relapses
Menstrual cycle-dependent psychological and psychoendocrinological processes, and effects of induced attention foci during daily life in women with Premenstrual Dysphoric Disorder
No full textIn this dissertation, I investigated the role of cognitive emotion regulation strategies on affective, cognitive, and cortisol trajectories across the menstrual cycle in women with and without Premenstrual Dysphoric Disorder (PMDD). PMDD has been included as a unique diagnostic entity in the ICD-11 and DSM-5 diagnostic systems and is charac-terised by at least one affective core symptom with additional cognitive or somatic symptoms that are restricted to the (late) luteal phase and resolve within a few days after the onset of menstruation in the follicular phase. Given the cyclical-dynamic course of symptoms in PMDD, longitudinal designs (e.g. using diary or ambulatory assessment data) over the menstrual cycle are of particular relevance. The overarch-ing aim of this dissertation was to use such longitudinal methods to identify cycle-phase-specific risk and protective factors for premenstrual mood deterioration and en-docrinological markers for PMDD.
Study 1 of my dissertation (Chapter II) examines the role of habitual (trait) tendencies of cognitive emotion regulation strategies for momentary mood across the menstrual cycle in women with PMDD. Compared to healthy controls, women with PMDD showed stronger tendencies towards unfavourable emotion regulation strategies (higher rumi-nation and lower reappraisal and mindfulness tendencies). Multilevel analyses re-vealed that favourable manifestations of these habitual cognitive emotion regulation strategies in women with PMDD were associated with improved mood during the men-strual, follicular and ovulatory phases, but did not protect affected women against mood deterioration during the late luteal phase. This suggests possible cycle-phase-specific difficulties in the implementation of adaptive emotion regulation strategies and possible limitations of conventional psychotherapy methods that address emotion reg-ulation across phases in the treatment of PMDD. The results of this study were repli-cated in Study 2 (Chapter III) in an independent sample. In contrast, favourable mo-mentary cognitive states during the luteal phase predicted better premenstrual mood. Thus, this study points to the potential of cycle-phase-specific microinterventions in which luteal-phase-specific cognitive processes could act as therapeutic mechanisms. Furthermore, in Study 2, women with PMDD did not show cyclical fluctuations in corti-sol activity, whereas healthy women had lower cortisol levels during the late luteal phase compared to the follicular phase, with additional cortisol reductions following moments of favourable cognitive states. Lack of cortisol cyclicity and reactivity to pre-menstrual cognitive processes may therefore represent a possible endocrinological marker for PMDD.
In Study 3 (Chapter IV), I investigated affective and cognitive responses to induced ruminative and mindful self-focus across the menstrual cycle using experimental am-bulatory inductions in the daily lives of women with and without PMDD. Women with PMDD responded to induced mindfulness with greater increases in positive affect than healthy controls, especially during the late luteal phase. Regardless of cycle phase and clinical status, induced rumination predicted greater momentary negative affect and momentary rumination and decreased momentary mindfulness, whereas induced mindfulness predicted greater momentary self-acceptance.
In Study 4 (Chapter V), I examined a sample with subthreshold PMDD. Here, adaptive habitual emotion regulation (mindfulness and acceptance) was associated with weaker increases in premenstrual symptoms and functional impairment. Stronger increases in premenstrual symptoms and functional impairment in turn predicted increases in rumi-nation and perceived daily stress during the luteal phase. These findings point to the potential of dimensional approaches to investigate possible risk and protective factors for the transition from subclinical to clinical manifestations of premenstrual symptoms, as well as the potential of habitual mindfulness and acceptance as preventive measures for PMDD.
In Study 5 (Chapter VI), I showed that in women with PMDD, adverse childhood expe-riences were associated with stronger premenstrual mood deterioration and an addi-tional cortisol decrease during the luteal phase. This suggests the clinical importance of childhood adversity for the cyclical course of symptoms and cortisol in PMDD.
Taken together, these studies point to the relevance of a multilevel approach that ex-amines macro-processes (e.g. habitual emotion regulation, adverse childhood experi-ences) as well as meso- and micro-processes (cycle-phase-specific cognitive and en-docrinological risk factors) of psychobiological factors in PMDD in order to identify their potential inter- and intra-individual variations. Evidence from this research approach may inform the development and advancement of personalised treatment approaches for PMDD
Carmel, Capharnaum, and the Sacred Topography of the Holy Land in John Baconthorpe’s Laus religionis Carmelitanae
No full textEinflussfaktoren auf die Lebensqualität bei primär kutanen B-Zell-Lymphomen
No full textPrimär kutane B-Zell-Lymphome, die etwa 22 % aller primär kutanen Lymphome ausmachen, sind eine heterogene Gruppe von malignen lymphoproliferativen Hauterkrankungen. Die Subtypen der primär kutanen B-Zell-Lymphome können nach ihrem Verlauf in zwei unterschiedliche Gruppen eingeteilt werden: indolente und aggressive Formen. Zu den indolenten Verlaufsformen gehören das primär kutane Marginalzonenlymphom und das primär kutane Follikelzentrumslymphom. Zu den aggressiven Verlaufsformen zählt das primär kutane diffus-großzellige B-Zell-Lymphom. Bei Patient*innen mit primär kutanen T-Zell-Lymphomen haben Studien bereits eine Beeinträchtigung der gesundheitsbezogenen Lebensqualität gezeigt. Bis heute gibt es jedoch nur Studien mit geringer Anzahl an Patient*innen mit primär kutanen B-Zell-Lymphomen, die die gesundheitsbezogene Lebensqualität untersuchen, ohne eine erweiterte Analyse in Abhängigkeit von den Subtypen durchzuführen.
Diese Studie zielt darauf ab, die gesundheitsbezogene Lebensqualität bei Patient*innen mit primär kutanen B-Zell-Lymphomen zu untersuchen und Einflussfaktoren auf die gesundheitsbezogene Lebensqualität zu identifizieren, um die Zusammenarbeit zwischen medizinischem Personal und Patient*innen und damit die gesundheitsbezogene Lebensqualität bei primär kutanen B-Zell-Lymphomen zu verbessern.
Diese multizentrische Querschnittsstudie liefert Informationen über die gesundheitsbezogene Lebensqualität und deren Einflussfaktoren von 111 Patient*innen mit primär kutanen B-Zell-Lymphomen, die zwischen März 2021 und Juni 2022 aus zehn deutschen Zentren rekrutiert wurden. Die Patient*innen füllten den dermatologischen Standard-Fragebogen Skindex-29 und einen eigens entwickelten Fragebogen mit einem krankheitsspezifischen Fokus aus.
Die gesundheitsbezogene Lebensqualität von Patient*innen mit primär kutanen B-Zell-Lymphomen war nach den Ergebnissen des Skindex-29-Fragebogens mild bis moderat beeinträchtigt. In der multiplen Regressionsanalyse wurden angenommene Vorbehalte anderer Menschen gegenüber den primär kutanen B-Zell-Lymphomen-Patient*innen, Bedenken hinsichtlich der Letalität der Erkrankung und die Beeinträchtigung der täglichen Aktivitäten als unabhängige Einflussfaktoren ermittelt, die mit einer höheren Beeinträchtigung der gesundheitsbezogenen Lebensqualität verbunden waren.
Bei der Analyse der verschiedenen Subtypen der primär kutanen B-Zell-Lymphome war die Strahlentherapie bei Patient*innen mit einem primär kutanen diffus-großzelligen B-Zell-Lymphom, die Verabreichung von Rituximab intravenös bei Patient*innen mit einem primär kutanen Follikelzentrumslymphom und das „Watch and Wait“-Vorgehen bei Patient*innen mit einem primär kutanen Marginalzonenlymphom mit einer signifikant schlechteren gesundheitsbezogenen Lebensqualität verbunden.
Die gesundheitsbezogene Lebensqualität ist bei Patient*innen mit primär kutanen B-Zell-Lymphomen beeinträchtigt, selbst bei indolenten Formen. Daher sind eine klare und individualisierte Kommunikation und eine gemeinsame Entscheidungsfindung mit den Patient*innen wichtig, um die gesundheitsbezogene Lebensqualität zu verbessern. Ein spezifischer und standardisierter Fragebogen zur Erhebung der Lebensqualität bei Patient*innen mit primär kutanen Lymphomen ist dringend erforderlich. Eine schriftliche Patient*inneninformation über die Prognose und den Verlauf der Erkrankung und auch ein Austausch in Selbsthilfegruppen wären weitere Ansatzpunkte zur Verbesserung der Kommunikation und der gesundheitsbezogenen Lebensqualität
Numerical Methods For Optimal Control Of Switched Systems
No full textThe challenges in real-life applications, like e.g., managing systems with load fluctuations, start-up, and shut-down, represent complex mathematical problems. This complexity stems from strong nonlinearities (especially in transients), mixed-integer decision variables and controls (e.g., for coupling components), state-dependent discontinuities (from phase transitions or controllers), and the large system dimension. While industry often relies on decoupling and recipe-based controls, these prove insufficient for such intricate, coupled systems, highlighting a need for innovative nonlinear optimization methods. For processes under uncertainty, static open-loop controls are inadequate; optimal feedback control laws, dependent on estimated states, are preferred. The presently most popular approach for general nonlinear optimal control problems with state and control constraints is Nonlinear Model Predictive Control (NMPC). The main idea is to estimate the present state from measured data on a finite "moving" time horizon of the past and to optimize the control on a "moving" time horizon in an open-loop. The first instant of the control is then applied during a sampling time interval, during which the next re-optimization is computed.
This dissertation develops numerical methods for computing open-loop and feedback controls in certain classes of mixed-integer optimal control problems with switched ODEs (SwOCP), which exhibit important applications to characterize the complex properties of dry friction problems. We follow Filippov's rule, according to which the SwOCP is reformulated to an optimal control problem with mixed integer controls and special mixed control-state constraints. We investigate the relaxed formulation of this optimal control problem and derive necessary optimality conditions from the Pontryagin maximum principle (PMP), where the regularity property of the mixed constraints is carefully considered. Numerical methods for the relaxed problem based on the multiple shooting approach and an appropriate "rounding scheme" to handle implicit switching are investigated. In order to compute optimal feedback control laws, we generalize the "NMPC" approach to the general SwOCP class above. We develop a direct approach to derive feedback control laws. It is based on the PMP approach to computing "neighbouring feedback" controls to find out the explicit switching of integer controls. The numerical methods are illustrated with benchmark problems via the MUSCOD-II tool software with PGPLOT or MATLAB
The Greater Antilles Arc of Cuba, a natural laboratory to understand the evolution of intra-oceanic convergent margin magmatism
No full textIntra-oceanic convergent margins represent one of the primary sites for the generation of juvenile continental crust through subduction-related processes. Magmas in these systems are derived from mantle sources with minimal continental input and preserve direct evidence of source components, magma differentiation, and crustal maturation. Most modern intra-oceanic arcs remain submerged, limiting direct observation of their crustal architecture and petrogenetic evolution. Fossil arcs that have been accreted and uplifted above sea level therefore provide invaluable archives for reconstructing the complete life cycle of intra-oceanic arc systems. Among these, the Greater Antilles Arc, a major segment of the Great Arc of the Caribbean, preserves one of the most extensive and accessible records of long-lived intra-oceanic subduction system spanning the Early Cretaceous to the Eocene. The central Cuban segment, where forearc ophiolites and mélanges, volcanic-plutonic sequences, and arc-related metamorphic complexes are well exposed, offers an exceptional window into the temporal and structural evolution of an intra-oceanic arc from its initiation to collisional termination.
This study examines the temporal, geochemical, and structural evolution of the Greater Antilles Arc system through three complementary investigations. First, a regional synthesis integrating over 650 radiometric ages and more than 1500 geochemical analyses from subduction-related rocks across Cuba, Hispaniola, Puerto Rico, and the Virgin Islands identified three major stages of arc evolution: subduction initiation, magmatic and metamorphic climax, and the waning of subduction magmatism and collisional termination. The temporal overlap between peak magmatism and emplacement of the Caribbean Large Igneous Province suggests a transient plume-arc interaction, most pronounced in the retro-arc region.
Building on the regional framework, the second part of the study focuses on the Mabujina Amphibolite Complex in central Cuba, a tectonically important arc-related metamorphic assemblage formed during active arc development, and long debated in regional tectonic reconstuctions. Petrochemical and isotopic data provide new constraints indicating that the protolith represents a proximal segment of the Caribbean arc, rather than a far-traveled exotic terrane derived from the Pacific realm. The accretionary event occurred during the mid-Cretaceous, when oblique convergence cross Caribbean arc system promoted a transspressional regime.
At a finer scale, the third component of this study investigates the Central Cuban Arc segment, which preserves an exceptional ~60 Myr record of magmatism from subduction initiation to collisional termination. Field, geochemical, and geochronological data reveal a transition from early submarine tholeiitic to Late Cretaceous calc-alkaline magmatism. Pressure-senstive geochemical proxies and thermobarometric estimates indicate increasingly complex magma storage, progressive crustal thickening, and enhanced magmatic differentiation through time. Amphibole-bearing magmas tapped lower crustal levels approaching present-day Moho depths during major plutonism shortly after athe accretionary event. The mantle source remained largly homogeneous, with limited slab input, demonstrating that intra-oceanic arc systems can generate juvenile continental crust prior to collision.
Collectively, these results provide a comprehensive reconstruction of the Greater Antilles Arc as a natural laboratory for studying intra-oceanic arc construction, accretion, and crustal differentiation. Integration of regional and local datasets defines the Greater Antilles Arc as a long-lived oceanic arc that evolved from tholeiitic to calc-alkaline magmatism and progressively developed a hydrous, transcrustal plumbing system capable of generating proto-continental crust. This study offers new insights into the mechanisms of crustal growth and differentiation at intra-oceanic convergent margins