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How Learning Behavior is Linked to Achievement: Bridging the Gap Between Explainable AI, Learning Analytics, and Learning Theory
No full textLearning behavior is a fundamental aspect of the learning process, playing a critical role in how students construct knowledge and develop skills. In educational practice, insights into students’ learning behaviors are key for effective lesson planning, early identification of those at risk, and the targeted allocation of support. As such, uncovering the relationship between learning behavior and academic achievement has been a longstanding focus in both educational psychology and learning analytics. While numerous studies across both fields have demonstrated associations between behavioral indicators and academic outcomes, important questions remain regarding how to best model this relationship in ways that are both theoretically meaningful and practically interpretable.
This dissertation addresses these challenges through two complementary approaches: (1) integrating explainable artificial intelligence techniques into academic performance prediction pipelines to produce interpretable machine learning models, and (2) embedding learning theory into the learning analytics workflow to guide feature engineering and the analysis of behavioral sequences. Although the ultimate aim is to integrate both approaches, this dissertation considers them separately in order to first demonstrate the individual validity and utility of each method. Following a substantive–methodological synergy approach, the present work advances both the analytical tools used to model the learning behavior–achievement link and the conceptual understanding of the mechanisms underlying it.
Across five empirical studies, this dissertation explores the relationship between learning behavior and achievement using behavioral trace and sensor data from digital learning environments collected in naturalistic settings and in the lab. The first study investigates the potential of explainable artificial intelligence to uncover interpretable patterns in behavioral data that predict academic performance. The second study applies explainable artificial intelligence techniques to examine individual differences in the behavior–achievement link, revealing heterogeneity in how students engage with learning tasks. The third study extends this work to sensor data in passive video-based learning settings, identifying multimodal behavioral markers that relate to learning outcomes. The fourth study introduces a systematic process for theory-informed feature engineering and compares behavioral indicators with self-reports to assess their relative predictive value. The fifth study conducts a theory-informed sequence analysis to explore the temporal dynamics of learning behaviors and their link to academic success. Key findings demonstrate that explainable artificial intelligence can uncover meaningful behavioral patterns associated with achievement and that theory-informed learning analytics provide additional explanatory power beyond purely data-driven models.
Taken together, this dissertation advances the methodological standards in academic performance prediction, proposes a blueprint for bridging educational theory and learning analytics, and contributes new insights into how specific learning behaviors relate to academic success. These contributions have implications for the design of adaptive learning systems, targeted interventions, and future interdisciplinary research in educational psychology and learning analytics
Food Crops and Subsistence Strategies in Post-Medieval Nubia Archaeobotanical Evidence from Old Dongola, Northern Sudan
No full textDie Dissertation ist gesperrt bis zum 26. August 2027 !This thesis presents the first comprehensive and large-scale archaeobotanical study of Old Dongola, a major urban centre in Northern Sudan, elaborating on the agricultural dynamics and subsistence strategies of post-medieval Nubia. Despite the general scarcity of archaeobotanical data from the region, systematic flotation and analysis of 53 samples have yielded a remarkable assemblage of over 60,375 seed remains, representing 66 plant taxa. These findings offer new insights into plant use, dietary practices, environmental adaptation, and the cultural transformations that shaped daily life in the Middle Nile Valley between the 14th and 18th centuries CE.
The results reveal a complex and adaptive subsistence system that integrated both cultivated and wild resources. Sorghum (Sorghum bicolor (L.) Moench) was the dominant staple across all phases, while bread wheat (Triticum aestivum L.) and hulled barley (Hordeum vulgare L.)—important in earlier periods—declined during the Kingdom of Dongola (Funj) era (16th-18th c.). These diachronic trends reflect broader transformations in crop selection driven by environmental pressures, including increasing aridity, as well as evolving cultural and economic conditions. The study also highlights shifting cultivation knowledge, with pulses, condiments, and crops like safflower and coriander appearing intermittently, suggesting a gradual narrowing of crop diversity over time.
Beyond food crops, this thesis demonstrates the multifunctionality of plants in Dongolese society. Safflower (Carthamus tinctorius L.) was likely used for dye or oil, cotton (Gossypium sp.) for textiles, colocynth (Citrullus colocynthis L.) for tar production, and tobacco (Nicotiana tabacum L.)—identified through seed remains in elite domestic contexts—as a commodity of luxurious pleasure. These findings extend the scope of archaeobotanical inquiry into the realms of sensory, medicinal, and ritual plant use, providing rare insights into social behaviour, healing practices, and the cultural negotiation of Islamic values in early modern Nubia.
Notably, wild and weedy species comprised 79% of the assemblage, indicating their importance in everyday subsistence. Plants such as Cyperus rotundus, Echinochloa sp., and Glinus lotoides were likely used as famine food, fodder, fuel, and medicine, reflecting ecological adaptations and the resilience strategies of Nubian communities living in semi-arid environments. The identification of previously undocumented taxa, such as African peach (Nauclea latifolia) and false daisy (Eclipta prostrata), further expands our understanding of local plant use and resource diversity.
The study also explores cultural continuity and transformation in plant use through a diachronic lens, tracing patterns of persistence, adaptation, and innovation in agricultural practices over centuries of political, social, and environmental changes. The presence of imported and newly introduced crops—such as tobacco, henbane (Hyoscyamus muticus), and eggplant (Solanum melongena L.)—signals participation of Old Dongola in expanding trade networks and its position as a hub of cultural exchange. These changes, set against the backdrop of Islamization and shifting political rule, highlights the dynamic interplay between environment, economy, and identity in post-medieval history of Nubia.
In synthesising archaeological, historical, and ethnobotanical data, this thesis contributes significantly to the growing body of scholarship that positions archaeobotany as a powerful lens for exploring past lifeways in Africa. It fills a critical gap in the archaeobotanical record of the Middle Nile Valley and demonstrates the potential of plant remains to reveal not only what people ate, but how they lived, adapted, and engaged with their environment. As archaeological science continues to develop in Sudan, the findings from Old Dongola provide a foundational reference point for future comparative research, regional surveys, and cross-disciplinary investigations into the historical ecology of Nubia
The potential of human induced pluripotent stem cell-derived endothelial cells for the endothelialisation of oxygenator surfaces
No full textDissertation gesperrt bis zum 30.09.2027!Im Rahmen dieser Arbeit wurden das Potential von Endothelzellen (EC), welche
von humanen induzierten pluripotenten Stammzellen (hiPSC) gewonnen wurden,
für die Endothelialisierung von Oxygenatoren untersucht. Hierfür wurden hiPSCs
kultiviert, dann mit einem 6-tägigen Protokoll zu ECs differenziert und
abschließend auf Basis der CD31 Expression mithilfe von magnetisch markierten
CD31 Antikörper separiert. HiPSC-ECs wurden dann weiter bis Tag 24 bis 26
kultiviert und daraufhin mit Ac4ManNAz inkubiert. Gleichzeitig wurden
Oxygenator-Membranen (PMP HFMs) funktionalisiert.
Es konnte gezeigt werden, dass die verschiedenen Schritte der
Funktionalisierung mit der Sauerstoff-Plasmabehandlung, der Silanisierung mit
APTMS und der Behandlung mit DBCO-PEG4-NHS Ester gleichmäßig die
gesamte Oberfläche der PMP HFMs funktionalisiert hat. Die metabolische
Modifikation der hiPSC-ECs zeigte, dass 93,9% der hiPSC-ECs Azid-Gruppen
exprimierten. Nach der Endothelialisierung der funktionalisierten Membranen mit
hiPSC-ECs mithilfe von Kupfer-freier Klick-Chemie ergaben
fluoreszenzmikroskopische Analysen, dass die gesamte Oberfläche der
Membranen mit einer konfluenten Schicht hiPSC-ECs besiedelt war. Die
Viabilität dieser Zellen ergab vergleichbare Ergebnisse mit der Positivkontrolle
(humane Nabelschnurvenen-Endothelzellen (HUVECs)).
Zusammenfassend weisen hiPSC-ECs ein großes Potential für die
Endothelialisierung von Oxygenatoren auf, da sie in großen Mengen hergestellt
werden können, eine autologe Therapieoption darstellen und erfolgreich die
Oberfläche von PMP HFMs endothelialisieren können. In zukünftigen Studien
müssen sowohl die Effekte auf die Hämokompatibilität nach der
Endothelialisierung sowie die Auswirkungen auf den Gasaustausch als auch das
Verhalten der hiPSC-ECs unter Flussbedingungen analysiert werden.In the scope of this work the potential for hiPSC-derived ECs for the
endothelialisation of oxygenator membranes was evaluated. For this, hiPSCs
were cultivated, differentiated into hiPSC-ECs with a 6-day differentiation protocol
and then separated on the basis of CD31 expression using magnetically labelled
CD31 antibodies. HiPSC-ECs were then cultivated further until day 24 to 26
before being incubated with Ac4ManNAz. At the same time, oxygenator
membranes (PMP HFMs) were functionalised.
It was demonstrated that the various steps of the functionalisation with O2 plasma
treatment, silanisation with APTMS, and incubation with DBCO-PEG4-NHS ester
could evenly functionalise the entire surface of PMP HFMs. Metabolic
glycoengineering revealed 93.9% hiPSC-ECs expressing azide groups. After
populating the functionalised membranes with hiPSC-derived ECs using copper-
free click chemistry, analyses via fluorescence microscopy showed that the
oxygenator membranes could be confluently endothelialised using hiPSC-ECs.
The viability of these cells showed results that are comparable to the control
(HUVECs).
In conclusion, hiPSC-ECs demonstrate great potential for the endothelialisation
of oxygenator membranes as they can be generated in vast numbers, allow for
autologous treatment options and are able to successfully endothelialise the
surface of PMP HFMs. In future studies, effects on hemocompatibility after
endothelialisation and effect on gas transfer as well as behaviour of hiPSC-ECs
under flow conditions have to be analysed
Mobile Genetic Elements and Recombination in Microbial Interactions and Disease Emergence
No full textNovel traits introduced by recombination and horizontal gene transfer can alter microbial interactions
and increase the risk and severity of disease outbreaks. In this work I use the Ralstonia solanacearum
species complex (RSSC) to investigate links between mobile genetic elements (MGEs) and the
emergence of two disease outbreaks in South America and Indonesia. The first outbreak is caused
by the parallel expansion of two distantly related lineages, one of which displays the broadest host
range ever documented for Ralstonia. I defined a family of previously unrecognized integrative and
conjugative elements (ICEs) exchanged between the two lineages during the outbreak. These ICEs
encode two specialized accessory genes integration sites that carry either metabolism or defence
related genes. The ICE associated with the outbreak carries genes involved in the degradation of
reactive xenobiotics and plant-derived metabolites, thereby potentially enhancing metabolic capacity
of the two lineages. The second investigated outbreak of banana-infecting R. syzygii subsp.
celebesensis (Rsc) was first detected in Indonesia, a centre of wild host diversity. My work sampling,
sequencing, and analysing isolates from Sulawesi and Java provides new insight into the origins of
the novel lineage that threatens global banana production. Comparative analyses revealed that Rsc
exhibits significant prophage enrichment in the context of an otherwise reduced genome. Genome
assemblies of isolate pairs sampled from the same host individuals revealed extensive structural
variation and MGEs exchange, underscoring the role MGEs can play during active infection. In the
final part of my work, I show how prophage movement shapes microbial interactions by altering strain
carriage of loci mediating contact dependent inhibition (CDI) across the whole RSSC. I found RSSC
have the largest repertoires of CDI loci ever discribed for bacteria. This amplification is linked with
prophage-mediated introduction of entire loci into hotspots on the chromosome. CDI loci cluster into
four types, all of which are predicted to carry toxin and immunity genes, which are in turn subject to
rapid diversification via homologous recombination. Collectively, these findings provide insight into
how a globally significant plant pathogen has expanded its repertoire of antagonistic loci through
MGEs, thereby enhancing its competitive ability and capacity to establish successful infections. This
knowledge can in turn be used to develop novel strategies for infection prevention.Dissertation ist gesperrt bis 16. Januar 2027
Information Processing in Conflict Tasks: The role of Perceptual and Motor Processes in Conflict Resolution
No full textDie Dissertation ist gesperrt bis zum 01. Februar 2027 !Kognitive Kontrolle ermöglicht es uns, verschiedene Arten von Konflikten (z. B. perzeptuelle, entscheidungsbasierte oder motorische) zu lösen. Obwohl Konflikte omnipräsent sind und gut erforscht wurden, werden sie in Studien nicht differenziert betrachtet. In Dual-Route-Modellen beispielsweise werden Konflikteffekte oft als Ergebnis der Interferenz zwischen automatischen (aufgabenirrelevanten) und kontrollierten (aufgabenrelevanten) Aktivierungen betrachtet. Der spezifische Lokus eines Konflikts wird jedoch meist vernachlässigt. Zu verstehen, ob die Integration von automatischen und kontrollierten Aktivierungen auf einer spezifischen sensorischen und/oder motorischen Ebene oder auf einer abstrakteren Verarbeitungsebene stattfindet, kann unser Verständnis von Konfliktaufgaben vertiefen und zukünftige, differenziertere Ansätze ermöglichen. Diese Dissertation untersucht, wie automatische und kontrollierte Prozesse über die Zeit hinweg interagieren und legt dabei einen Schwerpunkt auf sensorische und motorische Konflikte sowie auf die Rolle von Belohnung in Konfliktaufgaben. Hierzu wurden verschiedene Konfliktaufgaben verwendet, die jeweils unterschiedliche Konflikte hervorheben. Unter Verwendung eines Dual-Route-Modells untersuchte ich die Loki der Konflikte der verschiedenen Aufgaben und nutzte verschiedenste Untersuchungsmethoden (z. B. distributionsbasierte Analysen) sowie verschiedene experimentelle Manipulationen. Die erste Studie analysierte die Integration und den Transfer von Informationen über Modalitäten hinweg (visuell und auditiv). Nach der Bestimmung von modalitätsspezifischen Basiseffekten, untersuchte ich den Transfer durch modalitätsspezifische Manipulationen der Kongruenzverhältnisse. Während kein globaler Transfer zwischen den Modalitäten beobachtet wurde, deuteten sequenzielle Analysen auf eine lokale, modalitätsübergreifende Modulation hin. Die zweite Studie konzentrierte sich darauf, wie unterschiedliche motorische Anforderungen die Konfliktlösung in einer Simon-Aufgabe, mit komplexeren Antwortbewegungen, beeinflussen. In drei Experimenten wurden reduzierte Konflikteffekte unter höheren motorischen Anforderungen (d.h. Kraft und Präzision) beobachtet. Eine Differenzierung der Antwortzeit zeigte, dass diese Reduktion nur während der Bewegungsdurchführung auftrat. Abschließend untersuchte ich, ob Belohnungen die Konfliktlösefähigkeit in verschiedenen Konflikttypen gleichermaßen fördern. Die Ergebnisse von drei Experimenten lieferten keine Hinweise auf konfliktspezifische Effekte von Belohnungen. Detaillierte Reaktionszeitanalysen auf Verteilungsebene (Deltaplots) auf Basis aller drei Studien zeigten deutliche aufgaben- und anforderungsabhängige Muster
Tamoxifen metabolites by BKCa oncochannel modulation control the K+ and Ca2+ homeostasis in breast cancer cells
No full textBreast cancer (BC) is the primary cause of cancer-related deaths in women. Ion channels and in particular K+ channels drive tumorigenesis in various types of cancer including BC, considering these channels as potential targets for new anti-cancer strategies. Among these, K+ channels are important regulators of cell migration and proliferation, involved in cellular processes such as membrane potential, cell volume and Ca2+ signaling. As such, voltage- and Ca2+-activated K+ channels with large conductance (BKCa) are aberrantly expressed in BC, promoting tumor growth and progression, and are associated with high tumor grade and poor outcome. Expression of BKCa channels were found to be linked with worse outcome of patients receiving tamoxifen (TAM) as endocrine therapy, and in vitro low concentrations of the active metabolites of TAM (TAM+M) promoted proliferation of human and murine BKCa-proficient BC cells. This thesis aims to better understand the molecular mechanism of TAM+M-induced BKCa-dependent proliferation in BC cells by applying gene expression analysis, whole cell patch clamp recordings and FRET-based K+ imaging as well as molecular docking studies. TAM+M induced K+ currents and dynamics in a BKCa-dependent manner and irrespective of the ER expression level. Genetic and pharmacological ablation of BKCa activity confirmed the channel-stimulating effects of TAM+M in murine and human BC cells. Mechanistically, the data suggest that the gain of BKCa activity upon TAM+M stimulation increased the driving force of Ca2+ from multiple stores. Elevation of the intracellular Ca2+ concentration leads to a depolarized membrane potential that activates the BKCa channels in a voltage-dependent manner. Additionally, the increased cytosolic Ca2+ levels may represent a feed forward mechanism for BKCa channel activation.
Regarding the role of auxiliary BKCa subunits, increased KCNMB1 expression in BC patients was linked with better event-free survival and lower risk of recurrence. In vitro the TAM+M-induced intracellular K+ dynamics were inhibited by β1-subunit expression in human BKCa-proficient BC cells. Altogether, the data suggest that TAM+M modulates BKCa activity causing alterations in K+ and Ca2+ homeostasis. These alterations likely influence malignant BC cell behaviors and contribute to the outcome of BC patients receiving endocrine therapy.Die Dissertation ist gesperrt bis zum 13. Juli 2027
Cognitive Control in Number Processing
No full textIn letzter Zeit häufen sich die Hinweise darauf, dass die Zahlenverarbeitung unter kognitiver Kontrolle steht. Kognitive Kontrolle bezeichnet die Fähigkeit, sich flexibel an veränderte Aufgabenanforderungen anzupassen, indem die Aufmerksamkeit auf relevante Aufgabenmerkmale gerichtet wird. Die meisten Belege dafür, dass die Verarbeitung von Zahlen durch kognitive Kontrolle beeinflusst wird, stammen jedoch aus experimentellen Paradigmen, bei denen sich die Studienteilnehmer*innen an veränderte Stimulusmerkmale anpassen mussten (z. B. die Häufigkeit kongruenter und inkongruenter Versuche) anpassen mussten. In Erweiterung der bisherigen Forschung konzentriert sich diese Dissertation auf die Frage, wie die kognitive Kontrolle die Zahlenverarbeitung in Fällen beeinflusst, in denen die Teilnehmer aktiv kognitive Kontrolle ausüben müssen, um sich an veränderte Aufgabenanforderungen anzupassen. Aufbauend auf früheren Erkenntnissen habe ich eine Kombination aus computergestützter Modellierung und drei empirischen Studien eingesetzt, um die Mechanismen zu verallgemeinern und zu spezifizieren, die der Interaktion zwischen Zahlenverarbeitung und kognitiver Kontrolle zugrunde liegen.
Der erste Schritt zur Untersuchung der Einflüsse einer aktiven Ausübung der kognitiven Kontrolle auf die Zahlenverarbeitung bestand darin, frühere Erkenntnisse über die Einflüsse der kognitiven Kontrolle auf die Verarbeitung von Zahlengrößen auf die Paritätsverarbeitung zu verallgemeinern. Aufbauend auf dieser Verallgemeinerung untersuchte ich den Aufgabenwechsel zwischen Größenvergleichen und Paritätsurteilen als eine Instanz der aktiven Ausübung kognitiver Kontrolle. Studie 1 lieferte Evidenz dafür, dass kognitive Kontrollprozesse Paritätsurteile in einer Weise beeinflussen, die strukturell mit der Verarbeitung von Größen identisch ist. Dies wurde durch die erfolgreiche Verallgemeinerung eines zuvor für die Verarbeitung von Größen verwendeten Modells gezeigt. Insbesondere sagte das Modell der Paritäts-verarbeitung Auswirkungen von kognitiver Kontrolle auf die Paritäts-verarbeitung voraus (wie zuvor bei der Größenverarbeitung beobachtet).
Um die Auswirkungen der aktiven Ausübung der kognitiven Kontrolle auf die Verarbeitung von Zahlengrößen und Paritäten zu untersuchen, habe ich eine Reihe empirischer Studien durchgeführt. In allen Studien habe ich den Aufgabenwechsel als Operationalisierung verwendet, wobei die Teilnehmer aktiv kognitive Kontrolle ausüben mussten, um sich beim Wechsel zwischen den Aufgaben auf bestimmte Stimuli zu konzentrieren. Aufbauend auf Studie 1 untersuchte Studie 2 den Wechsel zwischen zweistelligen Größenvergleichen und Paritätsbeurteilungen. Die Ergebnisse von Studie 2 deuten darauf hin, dass aufgabenirrelevante Informationen in Situationen, die aktive Anpassungen durch kognitive Kontrolle erfordern, gehemmt werden, was sich in reduzierten numerischen Kongruenzeffekten bei Aufgabenwechseln widerspiegelte.
Zusätzlich zu Studie 2 wurde in den Studien 3 und 4 näher untersucht, wie spezifische Aufgabenanforderungen den Einfluss der aktiven Ausübung kognitiver Kontrolle auf die Zahlenverarbeitung beeinflussen. Insbesondere untersuchte ich den numerischen Distanz- und den SNARC-Effekt. Studie 3 deutete auf eine effizientere Verarbeitung von Zahlengrößen hin (was sich in einem kleineren numerischen Distanzeffekt widerspiegelte), wenn zwischen einstelligen Größenvergleichen und Paritäts-beurteilungen gewechselt wurde. In Studie 4 verwendete ich ein Paradigma zum Wechsel der Modalitätskompatibilität, bei dem die Teilnehmer zwischen Eingabe- und Ausgabemodalitäten wechselten, während sie einstellige Zahlenvergleiche
durchführten. Im Gegensatz zu Studie 3 wies Studie 4 auf eine weniger effiziente Verarbeitung von Zahlenwerten hin (was sich in einem größeren numerischen Distanzeffekt widerspiegelte). Die Integration der unterschiedlichen Ergebnisse der Studien 3 und 4 bezüglich der Verarbeitung von Zahlenwerten legt nahe, dass explizit verarbeitete Informationen in Situationen, die eine aktive kognitive Kontrolle erfordern, bevorzugt werden.
Um die erzielten Ergebnisse umfassend zu integrieren und zu diskutieren, wird in der allgemeinen Diskussion ein zusätzliches Rechenmodell vorgeschlagen, das den Aufgabenwechsel zwischen zweistelligen Zahlengrößenvergleichen und Paritäts-urteilen simuliert. Das Modell simulierte erfolgreich die Auswirkungen der aktiven Ausübung kognitiver Kontrolle auf die Verarbeitung mehrstelliger Zahlen und bestätigte damit, dass die aktive Ausübung kognitiver Kontrolle die Zahlenverarbeitung beeinflusst.
Insgesamt deuten die Ergebnisse dieser Dissertation, zusätzlich zu vorherigen Perspektiven von Einflüssen kognitiver Kontrolle auf die Zahlenverarbeitung, darauf hin, dass i) die aktive Ausübung kognitiver Kontrolle die Zahlenverarbeitung moduliert und insbesondere ii) dass spezifische Aufgabenanforderungen (d.h. nur numerische Aufgaben vs. Modalitäts- & Zahlenaufgaben) beeinflussen, welche numerischen Informationen priorisiert werden. Dementsprechend spezifizieren bisherige verallgemeinernde Aussagen wie "Zahlenverarbeitung steht unter kognitiver Kontrolle" die Nuancen der Einflüsse der kognitiven Kontrolle auf die Zahlenverarbeitung nicht ausreichend. Angesichts dieser neuen Erkenntnisse schlage ich stattdessen vor, dass kognitive Kontrolle als Mechanismus zur Priorisierung von Informationen fungiert, der den am explizitesten verarbeiteten Aufgaben und Aufgabenmerkmale zusätzliche kognitive Ressourcen zuweist.Recently, evidence accumulated suggesting that number processing is under cognitive control. Cognitive control denotes the ability to flexibly adjust to changing task demands by focusing attention on relevant task characteristics. However, most of the evidence of number processing being influenced by cognitive control comes from experimental paradigms requiring participants to adapt to changing stimulus set characteristics (e.g., the frequency of congruent and incongruent trials). Extending previous research, this dissertation focuses on how cognitive control influences number processing in instances, which require to actively exert cognitive control to adjust to changing task requirements. Building on previous evidence, I employed a combination of computational modelling and three empirical studies to generalize and specify the mechanisms underlying the interaction between number processing and cognitive control.
The first step for investigating influences of an active exertion of cognitive control on number processing was to generalize previous evidence on influences of cognitive control on number magnitude processing to parity processing. Building on the generalization I investigated task switches between magnitude comparison and parity judgements as an instance of active exertion of cognitive control. Study 1 provided computational modelling evidence for cognitive control processes to affect parity judgements in a way structurally identical to magnitude processing, as indicated by the successful generalisation of a model previously used for magnitude processing. Notably, the computational model predicted effects of cognitive control on parity processing similar to those previously observed for magnitude processing.
To evaluate effects of active exertion of cognitive control on number magnitude- and parity processing, I conducted a series of empirical studies. In all studies, I used task switching as an operationalization, requiring participants to actively exert cognitive control to focus on specific stimuli attributes when switching between tasks. Building on Study 1, Study 2 investigated switches between two-digit magnitude comparisons and parity judgements. The results of study 2 suggested that task-irrelevant information is inhibited in situations requiring active adaptations via cognitive control, which was reflected by reduced numerical congruence effects in switch trials.
In addition to Study 2, Studies 3 and 4 further zoomed into how specific task requirements affect the influence of active exertion of cognitive control on number processing. In particular, I investigated the numerical distance- and the SNARC effect. Study 3 indicated more efficient number magnitude processing (as reflected by a smaller numerical distance effect) when switching between single-digit magnitude comparisons and parity judgements. In Study 4, I employed a modality compatibility task switch paradigm, in which participants switched between input-output modalities while executing single-digit number magnitude comparisons. Contrary to Study 3, Study 4 indicated less efficient number magnitude processing (reflected by a larger numerical distance effect). Integrating the differential results regarding number magnitude processing of Studies 3 and 4, I suggest that explicitly processed information is prioritised in instances requiring the active exertion of cognitive control.
In addition, to comprehensively integrate and discuss the obtained results, the general discussion proposes an additional computational model, simulating task switching between two-digit number magnitude comparisons and parity judgements. The computational model successfully simulated effects of active exertion of cognitive control on multi-digit number processing and, thereby, corroborated that active exertion of cognitive affects number processing.
Overall, extending previous perspectives on influences of cognitive control on number processing, the results of this dissertation suggest that i) the active exertion of cognitive control modulates number processing and more specifically ii) that specific task requirements (i.e., the combination of tasks between one has to switch) affect which numerical information is prioritized. Accordingly, previous generalizing statements such as “number processing is under cognitive control” do not sufficiently specify the nuances of influences of cognitive control on number processing. Instead, in light of these new findings, I suggest that cognitive control acts as an information prioritization mechanism which allocates cognitive resources to the most explicitly processed task and task characteristic
Synthese und Reaktivität heterobimetallischer Verbindungen des Germaniums, Zinns und Bleis
No full textDie Dissertation ist gesperrt bis zum 23. Juni 2027 !Die Synthese und Reaktivität heterobimetallischer Verbindungen des Germaniums, Zinns und Bleis wird beschrieben. Zunächst gelingt die Darstellung einer trinuklearen Rhodiumverbindung durch eine nukleophile Substitution des Dihydridogermaniumanions an [Rh(COD)Cl]2 und einer für das Germanium ungewöhnlichen Transferhydrierung. Eine anschließende Chloridabstraktion mit den Alkalisalzen schwach koordinierender Anionen sowie einem Ligandenaustausch mit CO führt zu den unterschiedlich substituierten Dirhodagermaallylkationen. Diese zeichnen sich durch das neuartige Strukturmotiv einer Bis(hexahapto)-Koordination der Phenylreste des Terphenylliganden an die Rhodiumatome sowie einer über das GeRh2-Fragment delokalisierten Doppelbindung aus. In der Reaktion mit verschiedenen Übergangsmetallchloridverbindungen der Gruppen 9, 10 und 11 bleibt die Bis(hexahapto)-Koordination des Kations erhalten. Hierbei wird die Metall-Chlorid-Bindung jeweils gespalten und die GeRh2-Einheit agiert als chelatisierende Metall-Lewis-Base für das Übergangsmetallfragment. Desweiteren wird eine in situ Reduktionsroute zur Darstellung von Übergangsmetalltetrylidinen untersucht. Auf diesem Weg wird das bislang unbekannte Rhodiumgermylidin sowie die entsprechenden schwereren Homologe des Zinns und Bleis erhalten und deren Reaktivität untersucht. In einer neuartigen Metathesereaktion mit den leichteren Chlorotetrylenen reagieren die schwereren Homologe zu den jeweils leichteren Homologen. Desweiteren wird die Reaktivität der Rhodiumtetrylidine gegenüber unterschiedlichen Verbindungen wie Wasserstoff, Wasser, Phenol, Benzoesäure, Dimethylbutadien, Kohlenstoffdioxid, Aceton, Acetophenon, Trimethylsilylazid, Kohlenstoffdioxid und Goldchlorid als Triphenylphosphanaddukt untersucht. Zusätzlich wird die Synthese weiterer heterobimetallischer Verbindungen des Rhodiums und des Platins vorgestellt
Design of novel Surfactin Derivatives via Genetic Engineering
No full textCyclic lipopeptides like surfactin, iturin, fengycine etc. are a group of natural products with a wide range of promising properties, including antibiotic and surface activity. They usually consist of a peptide ring and a lipid moiety. In times of emerging antibiotic-resistant bacteria lipopeptides could offer new structures for the solution of this problem. Furthermore, due to their surface activity they could also be used as environment friendly oil dispersant.
Cyclic lipopeptides are produced by nonribosomal-peptide synthetases (NRPS) or occasionally in combination with polyketide synthases (PKS). NRPS and PKS show a modular structure which is reflected in their genetic organization. This modular structure genetic organization could be utilized to create new derivatives of cyclic lipopeptides. Modules could be deleted, added or replaced by others to create new cyclic lipopeptides derivatives.
We are using the surfactin NRPS in Bacillus subtilis 168 to create novel surfactin derivatives. The peptide ring of surfactin consists of seven amino acids and its lipid chain ranges in size from C12 to C16. Our focus was put on the modification of the peptidic portion. The amino acid composition and order of surfactin is glutamic acid, leucine, D-leucine, valine, aspartic acid, D-leucine and followed by leucine. In our work we aimed at the modification of the stereochemistry of surfactin, the charged amino acid at position five, the leucine at position seven, the lactam ring formation and the creation of novel lipopeptides utilizing COM-domains. The charged amino acids should be deleted or replaced to increase the surfactin stability in sea water. The stereochemistry of surfactin was modified by introducing an E-domain in module 5 and by deleting the E-domain in module 6. The charged amino acid at position 5 was removed by using three different approaches and resulted in the production of [ΔAsp5]surfactin and [ΔAsp5ΔLeu7]surfactin derivatives. Leucin at position seven was removed in three different ways and unveiled different mechanisms of how [ΔLeu7]surfactin derivatives could be formed. The production of lactamo-surfactin was not achieved, but we were able to determine factors that could contribute to the success of this project in future. A further way to generate novel lipopeptides could be the utilization of COM-domains in order to create new cross communications between different NRPS subunits. We were not able to introduce cross communication between the surfactin and the fengycin gene cluster. However, based on the results of this study we developed an optimized concept to achieve this in future.Die Dissertation ist gesperrt bis zum 30. März 2027
Towards PET Imaging of α-Synuclein Aggregates: Preclinical Evaluation of Potential α-Synuclein PET Tracers
No full textThe accumulation of misfolded α-synuclein (αSYN) is a hallmark of synucleinopathies, including Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies. Positron emission tomography (PET) imaging of αSYN aggregates would be a game changer in facilitating the diagnosis and monitoring of synucleinopathies and the development of novel disease-modifying therapies. Despite the considerable endeavors leading to the identification of several potential αSYN PET tracers, none have been successfully translated to clinical applications thus far. This thesis work aimed to advance PET tracer development efforts towards αSYN PET imaging in synucleinopathies by focusing on the preclinical evaluation of potential radiotracers targeting αSYN aggregates.
The primary part of this work comprises a comprehensive in vitro and in vivo assessment of MODAG-005. Its binding characteristics were studied in vitro using fibril binding assays and brain tissue autoradiography, and subsequently in vivo in three animal models of αSYN. Exceptional binding of [3H]MODAG-005 to aggregated αSYN was demonstrated by its high binding affinities to four distinct αSYN fibril strains (Kd = 0.2–1.9 nM). Autoradiography experiments on brain tissues corroborated the findings, presenting a clear macroscopic and microscopic evidence of [3H]MODAG-005 binding to glial cytoplasmic inclusions in MSA brain tissues with an unprecedented high binding affinity (Kd = 0.25 nM), exceeding those of other reported αSYN tracer candidates. We confirmed the feasibility of using [11C]MODAG-005 for in vivo imaging by demonstrating its specific target binding and improved imaging contrast in the acute αSYN fibril injection rat model, as well as its increased retention in the pathology-rich brain regions in the A30P αSYN mouse model of PD. Additionally, we generated a rat model with accelerated αSYN pathology progression by performing fibril seeding in the BAC αSYN transgenic rats. However, the target binding of [11C]MODAG-005 in these fibril-seeded BAC αSYN rats could not be conclusively determined due to relatively low levels of αSYN pathology. Furthermore, the potential applicability of MODAG-005 in facilitating the clinical development of a therapeutic candidate was demonstrated, which confirmed the drug target engagement of anle138b, both in vitro and in vivo. Limitations of this work include the inconclusive binding specificity of the tracer to Lewy bodies and Lewy neurites in PD tissues due to concomitant pathology, as well as the presence of off-target binding in brain tissues of Alzheimer’s disease and progressive supranuclear palsy, highlighting the pervasive challenge and the need for improvement in future development. Overall, the preclinical evidence strongly supports [11C]MODAG-005 as a promising tracer for αSYN, thus warranting its progression to clinical studies for in vivo validation in human subjects with synucleinopathies.
In the second part of this work, we aimed to identify and evaluate additional ligands targeting αSYN. Three novel classes of αSYN ligands, designed based on different approaches, were screened using fibril binding assays. The first library, developed via the molecular hybridization of diphenylpyrazole and phenothiazine, showed decreased binding affinity to αSYN fibrils compared to their parent molecules. Screening of the second library, consisting of 2-styrylbenzothiazole derivatives designed by modification of a fluorescent probe, led to the discovery and selection of two promising ligands exhibiting selectivity towards αSYN fibrils for 18F-radiolabeling. Nevertheless, both [18F]PFSB and [18F]MFSB displayed high non-specific binding in human brain tissues through autoradiography, which was corroborated by a very slow brain clearance of [18F]MFSB in PET pharmacokinetic study. For the third library, screening of the isoxazole derivatives, which were generated based on a pharmacophore modelling approach, led to the selection of five ligands for radiolabeling and further evaluation. Notably, we encountered several challenges commonly discussed in the literature for αSYN PET tracer development, such as low affinity, insufficient selectivity, and unfavorable pharmacokinetics. Our findings emphasized the use of diversified development strategies to drive a range of possible outcomes and highlighted the increasing significance of computational approaches to enhance efficiency. To overcome the persistent challenges and accomplish the aspiration of αSYN PET imaging, the adoption of upcoming innovative techniques will be pivotal.Die Dissertation ist gesperrt bis zum 05. Juni 2026