Feedback dynamics in mechanochemical matter

Non-equilibrium microscopic processes can drive macroscopic shape changes in soft materials. Feedback arises when such shape changes alter the geometry constraining the microscopic dynamics. Although such feedback is common in living materials, which can actively change their chemical composition in response to environmental signals, the underlying theoretical principles, and the resulting dynamical phenomena are not well understood. Motivated by biological cells exchanging shape-dependent signals at physical contacts, I investigated incompressible droplets adjusting their interfacial tensions in response to contact-dependent signals. I derived a minimal set of equations governing the macroscopic droplet states controlled by two dimensionless feedback parameters. I discovered that the droplet’s adaptive wetting properties give rise to rich dynamical phenomena, including regimes of multistability, symmetry-breaking, excitability, and self-sustained shape oscillations. For some configurations, the topology of the arising phase-space structures is analogous to Hodgkin-Huxley type neuronal models, allowing me to identify parallels between adaptive wetting dynamics and signal processing in neurons. Applying these theoretical results to experimental shape measurements from imaging data of zebrafish embryos, I found that the critical point arising from a shape multistability promotes the formation of boundaries between different developing tissues. Moreover, using fully data-derived contact-networks, I predicted cellular differentiation patterns driven by contact-dependent signaling in mechanosensory epithelia of zebrafish larvae. Together, this thesis provides new paradigms for physical signal processing through shape adaptation in soft active materials, and uncovers novel modes of self-organisation in the collective dynamics of biological tissues

Active repression of alternative cell fates safeguards hepatocyte identity

Cell identity plasticity is a normal and essential feature of cells during development, but is also a hallmark of diseases such as cancer. The mechanisms involved in suppressing inappropriate cell fates are poorly understood. Gene repression in terminally-differentiated cells is typically thought to be mediated by passive epigenetic silencing, such as through DNA methylation and repressive histone modifications. However, recent studies suggest that active repression by cell type-specific transcription factors may play an essential role in maintaining cell identity. MYT1L, a neuron-specific transcriptional repressor, has been shown to maintain neuronal identity by the inhibition of non-neuronal lineages. The observation that deficiencies in MYT1L may lead to diseases such as neurodevelopmental disorders and cancer demonstrates its important role in cell identity maintenance by inhibition of cellular plasticity. In this thesis, I investigate whether active, lifelong transcriptional repression of alternate lineages – or safeguard repression – is a general mechanism for cell identity stabilisation. Using computational prediction and direct cell reprogramming, I demonstrate that PROX1 safeguards hepatocyte identity by directly suppressing alternate lineage programs, hence demonstrating safeguard repression in a second cell type and germ layer. With single-cell transcriptomics analysis, I find that PROX1 robustly silences donor and alternative cell identities. I also show that PROX1 directly binds to promoters of key mesodermal transcription factors, including Prrx1 and Pparg, hence decreasing their chromatin accessibility and expression. In addition, repression of PROX1 target genes during hepatocyte reprogramming mimicked effects of Prox1 overexpression. On the other hand, Prox1 deletion or target gene activation permitted inappropriate gene expression. Finally, in a hepatocellular carcinoma mouse model, Prox1 overexpression prevented tumour initiation, reducing overall tumour load and extending survival substantially. Prox1 depletion in the same model induced cholangiocarcinoma-like morphology and gene expression, demonstrating the role of PROX1 in cell identity maintenance. These results show that PROX1 is a repressive safeguard of hepatocyte identity. They also support a model whereby continuous silencing of alternate lineage gene expression programs by safeguard repressors prevents cell fate plasticity, thereby maintaining cell identity

A cryogenic microscope for state detection of Be+ ions confined in an ultra-low noise environment

Optical frequency standards are some of the best characterized systems in physics these days. While optical transitions highly charged ions are excellent candidates for pushing the limits of laser spectroscopy at highest precision further, they require sophisticated quantum logic schemes to be cooled and interrogated. A novel superconducting quadrupole resonator is characterized to confine both, HCI and logic beryllium ion in an environment free of external electromagnetic noise. By utilizing atomic transitions sensitive to magnetic field fluctuations, the Meissner state of the resonator was investigated

Open Science in the Humanities: Galaxy as a Flexible and yet Reproducible Platform

Open Science ist ein Prinzip, dem vom Grundsatz breit zugestimmt wird. In den Humanities sehen viele Forschende für sich jedoch keinen schnellen oder praktikablen Weg, dem zu folgen. Open Science wird mit Digitalisierung assoziiert, die in den Humanities vielerorts Abwehr auslöst. Mit dem Poster wird gezeigt, wie die Open Source Plattform Galaxy als Self-Service-Tool den Einstieg erleichtert. Für viele Fachbereiche gibt es zahlreiche Trainingsmodule und Best-Practice-Workflows, die ohne Barrieren zugänglich sind. Das Poster zeigt Beispiele von Workflows, die das auf Analyseverfahren der Humanities übertragbar machen. Zu Galaxy gibt es eine grafisch orientierte Oberfläche, die zum Experimentieren einlädt. Auf Wunsch kann das Herumspielen aufgezeichnet, im Nachgang bereinigt und als Prozedur gespeichert werden. Solche Workflows werden so zum Ausgangspunkt weiterer Verfeinerung, sind teilbar, transparent und im besten Fall reproduzierbar. Die FAIR-Prinzipien bleiben kein schwer erfüllbarer Anspruch, sondern werden beiläufig gelebtes Prinzip. Wir stellen ein Beispiel zum Textvergleich chinesischer historischer Zeitungen vor, wo zensierte und unzensierte Zeitungsartikel mit chinesischen Zeichen gegenübergestellt werden. Der Vergleich ist visuell aufschlussreich und kann mit Standardtools wie diff ausgewertet werden. Dadurch können auch große Datenmengen schnell analysiert werden. Technisch überraschend einfach, aber mit hoher Aussagekraft hinsichtlich der Forschungsfrage, welche Inhalte in den Zeitungen zensiert wurden. Bei der Auswertung ist weiterhin spezifische Erfahrung aus den Humanities gefragt, besonders bei der kritischen Einordnung von Zwischenergebnissen und daraus folgend der experimentierenden weiteren Bearbeitung des Materials. Die Nutzung von Galaxy zeigt, wie Teile der Analyse auch in den Geisteswissenschaften teilautomatisiert werden können, so dass größere Textmengen verarbeitet werden können. So werden Ergebnisse aussagekräftiger. Gleichzeitig bleibt für die eigentliche Auswertung mehr Zeit. Der Workflow, die einzelnen Analyseschritte und die Daten jedes Teilschritts können dabei gemäß der guten wissenschaftlichen Praxis geteilt und wiederholt werden. Obwohl die Ausgangsdaten wegen ihres proprietären Ursprungs nicht zugänglich sind, kann so der Prozess geteilt werden. Das zeigt gleichzeitig, dass Open Science selbst dort möglich ist, wo Daten aus guten Gründen nicht offen sind. Analysen werden parametrisierbar und schaffen eine neue Vergleichbarkeit von Ergebnissen. Daten und Inhalte von Plattformen, wie beispielsweise Zenodo, können in Galaxy importiert und in einem Workflow algorithmisch analysiert werden. Die Ergebnisse sind wiederum in einem frei wählbaren Repositorium (Zenodo, FreiData, etc.) als Faires Digitales Objekt (FDO), beispielsweise RO-Crate, speicherbar. FDO sind auf Export und maschinenlesbare Weiterverarbeitung ausgelegt. Galaxy bietet Open Educational Resources (OER) — ebenso Arbeitsfeld von Open Science — im Galaxy Training Network (GTN), das bereits über 400 Tutorials enthält, die in offenen Lizenzen bereitgestellt sind. Neben den praktischen Tutorials bietet es Beispieldatensätze, E-Learning-Material, Videos, Aufzeichnungen und komplette Schulungsworkshops, die Forscher*innen weltweit lizenzfrei zum Selbststudium zur Verfügung stehen. Das Schulungsnetzwerk wird von einer globalen Community unterstützt, die neuen Nutzer*innen den Einstieg erleichtert und in kollaborative Arbeitsformen einführt. Durch diesen Ansatz haben verschiedene Wissenschaftsfelder Galaxy für sich entdeckt. Erste Analyseprojekte aus den Humanities finden sich bereits auf der Plattform

From Activity Inference to Multi-Omics Network Contextualization: Deciphering Cellular Signaling and Disease Mechanisms

The integration of diverse omics layers with advanced computational methods can help to decipher cellular signaling and disease mechanisms. Thereby it is crucial to ensure that computational predictions truly reflect biological mechanisms and that different omics layers are cohesively integrated. This thesis focuses on evaluating approaches to infer the activity of transcription factors and kinases as well as advancing methods to uncover context-dependent signaling networks. First, to identify the most reliable strategies for activity inference, benchmarking frameworks were established to assess various inference methods. This revealed that a novel collection of signed transcription factor-gene interactions outperforms existing resources in predicting transcription factor activities. Similarly, manually curated kinase-substrate libraries combined with less complex computational models were shown to provide higher accuracy for kinase activity inference. Next, to reveal the role of these regulators in signaling pathways across diverse biological contexts, methods for network contextualization were developed, incorporating phosphoproteomics data alone and in combination with transcriptomics data. For phosphoproteomics-based network modeling, signed protein-protein interactions were incorporated to account for regulatory directionality, improving the representation of biological networks. Additionally, a multi-omics network contextualization approach was established which is able to link upstream stimuli to kinase and transcription factor activities in a cohesive manner, bridging phosphoproteomics and transcriptomics data. The network models were then applied to study the effects of metformin on colorectal cancer and the mechanisms driving hepatic stellate cell activation, uncovering condition-specific regulatory mechanisms and potential interactions between key signaling pathways. This highlights that integrating experimental data with reliable prior knowledge and advanced computational approaches can aid in understanding context-dependent signaling processes in complex biological systems

Künstliche Intelligenz und FDM: Synergien, Herausforderungen und Grenzen der Risikominderung

Das Poster zeigt die wechselseitigen Beziehungen zwischen Künstlicher Intelligenz (KI) und dem Forschungsdatemanagement (FDM). Es illustriert die Unterstützung von FDM-Prozessen durch KI und weist gleichzeitig auf neue Herausforderungen wie algorithmische Verzerrung und Intransparenz hin. Um Risiken zu minimieren, müssen gut dokumentierte Daten und transparente Verfahren verwendet sowie fortgeschrittene ethisch fundierte FDM-Strategien entwickelt werden

Wissenschaft aktivieren. Wegweiser zu gesellschaftlichen Wirkungen. Ein Handbuch mit Fallbeispielen. Aufbauend auf dem Social Impact Readiness Index (SIRI)

Dieses Handbuch wurde als Teil des Social Impact Readiness Index (SIRI) am Centrum für Soziale Investitionen und Innovationen an der Universität Heidelberg entwickelt (Krippl, Hussain & Mildenberger, 2024). Ziel von SIRI ist es, Wissenschaftler*innen für die sozialen Wirkungspotentiale ihrer Forschung auch über ökonomisch quantifizierbare Ertragslogiken hinaus zu sensibilisieren und die interdisziplinäre Transferkultur am Wissenschaftsstandort Heidelberg zu stärken. Das Handbuch ist entlang zentraler Wirkungspfade strukturiert, die verschiedene Umsetzungsformate wissenschaftlicher Arbeit umfassen und i. S. strukturierter Theories of Change unterschiedliche Formen des gesellschaftlichen Einflusses und Transfers systematisieren. Zu den Wirkungsformaten gehören beispielsweise der gesellschaftliche Forschungsdialog mit partizipativen Forschungsmethoden, Wissenschaftskommunikation durch Pressearbeit, Social Media und kulturelle Veranstaltungsformate, sowie  Verwertungs- und Dienstleistungswege wissenschaftlicher Erkenntnisse. Weitere Schwerpunkte bilden die Beratung von Entscheidungsträger*innen, Netzwerk- und Partnerschaftsbildung sowie Social Entrepreneurship und Non-Profit-Ansätze. Zudem widmet sich das Handbuch der Rolle universitärer Lehre und Weiterbildung im Kontext gesellschaftlicher Wirkung. Durch konzeptuelle Einordnungen, Fallbeispiele und methodische Handlungsvorschläge bietet es Wissenschaftler*innen ein Instrumentarium zur gezielten Reflexion und strategischen Förderung der gesellschaftlichen Relevanz ihrer Forschung

The Role of IKZF3 Expression in T Cells of Patients with Multiple Myeloma

In my dissertation, I investigated the role of IKZF protein family in T cells by establishing a CRISPR Cas9 model in CD8+ T cells. I analysed the down-stream signaling pathway of IKZF3 by high-throughput RNA bulk sequencing method and proteomics analysis, including co-immunoprecipitation and protein binding analysis, to identify function and regulatory mechanisms of this protein family in T cells. I demonstrated that IKZF3 regulates the IFN-inducible gene expression, and thus, IKZF3 KO CD8+ T cells showed increased expression of cell surface markers for T cell activation and exhaustion. In addition, I showed that IKZF3 binds to IKZF1 at the C’ terminal for heterodimerization in exhausted CD8+ T cells. Whereas in the absence of IKZF1, IKZF3 forms heterodimer complexes with MX1 and DTX3L. Single KO of IKZF1 in CD8+ T cells showed that the transcription factor regulates gene expression involved in T cell activation on transcriptomic level and on functional level, I found increased cell surface marker expression of T cell activation. In MM patients, I found that newly diagnosed MM patients with high IKZF3 expression levels have significantly higher amount of effector T cells. In conclusion, I found evidence of IKZFs playing a superior role in T cell activation and drive T cells to exhaustion, and gave preliminary conclusions of the IKZF protein family functionality in CD8+ T cells. Previously, studies were mainly focusing on IKZF within the B cell compartment as a critical regulator of B cell development and functionality. My findings indicate novel IKZF regulatory mechanisms within the CD8+ T cell compartement, providing new insights in T cell modulation, and therefore, making the transcription factor protein family a promising target for cancer immunotherapy

Signal analysis in ion treatment monitoring with charged nuclear fragments - A simulation study

Carbon-ion radiotherapy (CIRT) offers highly localized dose delivery and enhanced biological effectiveness. However, its precision also makes it highly sensitive to anatomical changes between treatment fractions. In-vivo monitoring of the dose delivery via detection of secondary radiation has emerged as a non-invasive method for assessing such changes. The ongoing InViMo clinical trial conducted at the Heidelberg Ion-Beam Therapy Center (HIT) and the German Cancer Research Center is evaluating the feasibility of identifying and localizing anatomical changes in patients with skull base tumors by measuring the localization of the primary carbon ions’ breakup (fragments) in the patient. The results are very promising to date. For this purpose, a monitoring system composed of seven mini-trackers was designed and developed in order to measure fragment tracks outside the patient. Interpreting the signals proved highly complex, highlighting the need for access to physical quantities that cannot be measured experimentally, such as the true origin of the fragments. The primary objective of this thesis was to develop, validate, and implement a Monte Carlo (MC) simulation framework for in-vivo monitoring of CIRT. The developed simulation framework, based on the FLUKA MC code, was first validated against experimental data using a single mini-tracker. Thereafter, the framework was extended to simulate the full monitoring system, comprising the seven mini-trackers, and integrated into FICTION, a CT-based dose calculation Monte Carlo environment developed at HIT. It was used to simulate a cohort of eight patients treated at HIT, including retrospective cases, patients from the InViMo study, and a prostate cancer case, all under realistic clinical conditions. Signal analysis demonstrated that shallow anatomical changes, such as nasal swelling or cavity filling, were successfully detected and localized using reconstructed fragment origin. Deep-seated changes, those distant from the detector or near the end of the beam range proved more challenging to resolve. For the prostate case, the signal from the clinical InViMo detection system was found not to be sufficient to capture the changes in the rectal filling. Therefore, an alternative in-table detection system was designed using the simulation framework. A significant improvement in the detectability of such changes was demonstrated. These results highlight the framework’s versatility. In conclusion, an MC–based simulation environment for studying in-vivo treatment monitoring in carbon-ion therapy was established and validated in this thesis. By enabling detailed modeling of the fragment creation and tracking in patient-specific geometries, the framework can be used for a deeper understanding of the complex clinical signal and for the optimization of monitoring strategies. Its flexibility across anatomical sites makes it a highly valuable tool for future investigations of the clinical potential of fragment-based treatment verification

Characterising the suppression of non-radial modes in red giants

Magnetic fields are thought to play a significant role in various phenomena in the Universe, in particular in the evolution and the structure of stars. With asteroseismology, it is possible to probe the inner structure of stars. In this thesis, we investigate the properties of the oscillations of red giants that show signs of energy loss. We observationally constrained the mechanism causing this energy loss and found that it is consistent with the predicted effect of magnetic field in the core of the red giant. Using recent developments, we were also able to observe frequency shifts due to a magnetic field in the core of stars. We analysed stars with both magnetic frequency shifts and energy loss in the oscillations and showed that both phenomena can be explained by a magnetic field with the same field strength located in the core of the stars