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Integration of TGF-β and EGF signaling pathways control liver progenitor cell proliferation in acute liver failure
No full textBackground and Aims: In acute liver failure (ALF), massive hepatic necrosis (MHN) results in severe clinical manifestations and high mortality. Remarkably, liver progenitor cells (LPCs) can rescue ALF in patients through performing vital liver function. To date, key signals that induce LPC proliferation and mediate cellular fate changes allowing gene expression patterns compensating for loss of essential liver functions remains largely unknown. This study aims to investigate how LPCs maintain proliferative quiescence under physiological conditions and how they are activated in ALF towards rapid proliferation.
Methods: SMAD7 transgenic mice were fed with DDC diet to examine the role of TGF-β signaling in LPC proliferation. Spatial transcriptomics was performed on 4 ALF patient liver samples to analyze cell-cell communication between LPCs, hepatocytes and macrophages. Mechanistically, integration of TGF-β and EGF signaling pathways was investigated in the LPC line HepaRG through multiple cellular and molecular approaches, including colony formation, cell cycle analysis, qPCR, Western blot, immunofluorescence staining, and ChIP-qPCR.
Results: Cytostatic TGF-β signaling maintains LPC quiescence under physiological conditions through impeding G1-S phase transition. Overexpression of SMAD7 increases LPC proliferation in DDC-fed mice by inhibiting TGF-β-induced SMAD3 phosphorylation. In ALF, significant levels of TGF-β are still present, provided from activated macrophages, rather than hepatic stellate cells. Interestingly, despite of the presence of TGF-β signaling, in this setting LPCs are proliferating. Mechanistically, EGF signaling effectively inhibits the anti-proliferative TGF-β effect through multiple mechanisms. EGF induces FOXO1 phosphorylation and nuclear exclusion, thereby preventing canonical SMAD-mediated transcription of the cell cycle inhibitors. Additionally, EGF promotes expression of c-MYC, which directly binds to CCND1 gene regulatory regions to drive cyclin D1 expression.
Conclusion: Our study provides novel insights into how LPCs remain non-proliferative in healthy liver and how they may rapidly achieve proliferative activity and take over liver-specific functions following MHN. Cytostatic TGF-β-SMAD signalling physiologically keeps LPC quiescent. In ALF, EGF overrides TGF-β's growth-inhibitory in LPCs
Die auf die Krisenbewältigung nach dem StaRUG bezogenen Organkompetenzen und Pflichten in der GmbH und in der AG
No full textLow-energy electronic recoils in XENONnT: new physics searches, first sub-keV calibration, and improved krypton assay
No full textWithin the context of the XENONnT experiment, this thesis presents contributions to low-energy electronic recoil (ER) searches and characterizations, advancing the quest for physics beyond the Standard Model (BSM).
Analysis of 1.16 tonne-years of XENONnT data from the first science run achieves a record-low ER background rate of (15.8 ± 1.3) events/(tonne·year·keV) in the 1 to 30 keV range, a 5-fold reduction over XENON1T. Calibration with the 2.82 keV 37Ar K-shell line establishes an accurate detector response in the critical few-keV region. The findings establish world-leading laboratory upper limits on solar axions, bosonic dark matter, and new neutrino physics. Specifically, the limits on new neutrino physics include those on non-standard interactions with vector and scalar mediators, as well as on an enhanced magnetic moment and millicharge. These results effectively rule out a BSM explanation for the previously observed XENON1T low-energy excess.
This work also reports the first calibration and observation of sub-keV ERs in liquid xenon (LXe), detecting the 0.27 keV 37Ar L-shell decay with 11.9σ significance. This is realized by combining a lowered energy threshold, resulting in a signal acceptance increase by a factor of about 66, with robust data-driven accidental coincidence background modeling and an improved suppression strategy. Validated full-chain simulations are used to understand sub-keV detector response and to determine the photon yield. From 37Ar L-shell events, a scintillation photon yield of PY = 2.96 ± 0.08 (stat.) +0.57/-0.33 (syst.) γ/keV is measured, providing essential data for sub-keV ER emission modeling.
Looking towards the next generation of LXe observatories like XLZD, this thesis includes developments for the automated rare gas mass spectrometer (Auto-RGMS), an instrument combining a cryogenic gas chromatography stage and a mass spectrometer for ultra-sensitive parts-per-quadrillion (ppq) quantification of krypton traces in xenon gas. Controlling and characterizing the beta-decaying 85Kr isotope is critical, as it represents a significant ER background in low-energy analyses. By using the new adsorbent, HayeSep Q, a 12-fold improvement in chromatographic resolution is achieved. This enhancement enables processing of much larger samples and helps achieve the designed few-ppq detection limit needed for XLZD's future high-precision measurements of solar pp neutrinos and the weak mixing angle.
Furthermore, sensitivity projections demonstrate that the newly validated sub-keV ER analysis framework can enhance XLZD's searches for BSM physics, improving sensitivity to neutrino electromagnetic properties by up to 19% and to boosted dark matter by up to a factor of two, thereby maximizing the scientific output of future multi-ten-tonne scale LXe experiments
Das säkulare Selbst zwischen Hypergut und Hyperselbst. Versuch einer Interpretation von Charles Taylors 'Philosophie der Säkularität'
No full textCharles Taylors Philosophie der Säkularität verknüpft Religionsphilosophie mit Gesellschaftskritik und Erkenntniskritik mit Moralphilosophie. Für ihn wird die Entwicklung eines Säkularen Zeitalters und damit von Religion als einer Option unter anderen, erst durch die Transformation der religiösen Optionen innerhalb einer pluralen Moderne verständlich. Dabei wird Säkularität als ein vielseitiger Prozess der Mobilisierung und Veränderung von Religion sowie des Aufkommens alternativer, säkular-humanistischer Weltanschauungen beschrieben. Diese Arbeit versucht aufzuzeigen, dass eine solche Auffassung mit seiner früheren Philosophie von Hypergütern des Selbst in Verbindung steht. Ein säkulares Selbst verweist auf den Menschen als sich selbst interpretierendes Wesen, welches mit höchsten Gütern für ein Selbst, den Hypergütern, die den Wert anderer Güter und des Selbst bestimmen, das Hyper seines Selbst begründet. Dieses kann verschiedenste Formen annehmen, wenn religiöse Optionen wie beispielsweise bei Rudolf Otto, William James und Emile Durkheim um die säkular-humanistischen David Humes und Friedrich Nietzsches ergänzt werden. Eine solche mehrdeutige Säkularität von Optionen unter anderen entspricht einer Philosophie des säkularen Selbst - als lebendige Interpretation des Selbst zwischen Hypergut und Hyperselbst
Bayesian Deep Learning Framework for Radiogenomics Analysis of Cancer
No full textGlioblastoma Multiforme (GBM) is a highly aggressive and heterogeneous brain tumor, requiring innovative approaches for prognosis and treatment planning. This thesis investigates multiview modeling of imaging-genetics data and the development of a Bayesian deep learning framework to address challenges in integrating multimodal data, quantifying uncertainty, and improving interpretability.
Multiview modeling integrates imaging, genomics, and clinical data to uncover complementary insights. Deep learning methods leverage non-linear relationships across multimodal data and often outperform traditional ap- proaches. The Bayesian deep learning framework combines Bayesian Neural Networks (BNNs) to quantify uncertainty and Bayesian Belief Networks (BBNs) to enhance interpretability by revealing feature dependencies. Al- though the framework performed worse at prediction compared to con- ventional methods, it provided cautious predictions and valuable insights, making its outputs more actionable for clinical decision-making.
This work highlights the potential of multiview modeling and Bayesian deep learning to improve data integration and interpretability for survival analysis in GBM, laying a foundation for future research on advanced mod- eling strategies and clinical applications
What’s in a name? The Carmelites' presence on Mount Carmel in the Speculum de Institutione Ordinis pro Veneratione Beatae Mariae
No full textFrom River to Reef: Developing Coral δ234U as a Proxy for Freshwater Influence in the Caribbean and Beyond
No full textFreshwater input plays a critical role in shaping marine environments and regional hydroclimate, yet reliable marine archives for reconstructing past freshwater variability remain limited. Traditional proxies often conflate temperature, salinity, upwelling, and/or biological effects, making it difficult to isolate freshwater contributions. This thesis explores the potential of uranium isotopes in corals, specifically δ234U, as a proxy for freshwater flux, with a focus on applications in the Caribbean region.
The research assesses the precision and reliability of coral δ234U measurements, identifying methodological constraints and best practices for sampling tropical corals. A baseline value for the Caribbean basin is then established, confirming that the region shares the open-ocean δ234U signature. Building on this foundation, site-specific studies reveal the sensitivity of coral δ234U to local hydrological influences. A Cuban coral record demonstrates a stable baseline with variability linked to local precipitation, while enhanced variability at the end of the Little Ice Age points to increased Mississippi River influence or change in Cuban land use. Along the Yucatán Peninsula, δ234U variability is dominated by submarine groundwater discharge, which in turn is modulated by relative sea-level changes. A comparative study in Tahiti further illustrates the proxy’s potential, showing distinct δ234U signatures in seawater, river water, and groundwater, as well as a sea-level dependence of groundwater discharge that may allow for the reconstruction of ENSO variability.
A synthesis of all available Caribbean coral records indicates that no coherent basin-wide freshwater signal emerges. Instead, local hydrological processes dominate coral δ234U, and the strong Atlantic throughflow effectively dilutes freshwater inputs, rendering the Caribbean basin similar to the open ocean on average. In contrast, marginal basins with restricted circulation, such as the Mediterranean or the East China Sea, exhibit clearer freshwater signals.
Overall, this thesis demonstrates the potential of coral δ234U as a freshwater proxy. While it also captures valuable information about local hydrology and land-ocean interactions, its application in regions with high oceanic exchange requires careful interpretation. These findings expand the methodological toolkit of paleoclimate research and provide new insights into the hydroclimatic dynamics of the Caribbean and beyond
Mapping Ionized Gas Outflows in and Beyond AGN: A Multi-Wavelength Approach Using SDSS-IV MaNGA
No full textThe role of active galactic nuclei (AGN) in regulating galaxy evolution is widely accepted as a feedback process suppressing star formation. However, observational evidence for it remains controversial. This thesis examines ionized gas outflows across and beyond AGN populations, utilizing SDSS-IV MaNGA’s spatially resolved spectroscopy together with multi-wavelength AGN selection. We demonstrate that radio and optical diagnostics identify distinct AGN populations. Radio-selected AGN exhibit broader emission lines reaching larger radii, suggesting evolved or longer-lasting feedback. Furthermore, when radio and optical AGN signatures are simultaneously present, feedback appears maximized, hinting at combined radiative and kinetic modes. Since radio signatures appear to hint at long-lasting AGN signatures, we investigate galaxies lacking ongoing AGN. Strikingly, radio-detected galaxies without current AGN exhibit broader emission linewidths than those without radio. These show outflow-like kinematics and share global properties (e.g., radio compactness and redder colors) with radio-detected AGN. This alignment suggests shared physical origins, likely connecting past AGN activity. Pointing to feedback that persists beyond the AGN’s observable phase, these systems are strong fossil-outflow candidates. This thesis presents a time-dependent view of AGN feedback, laying the foundation for future studies that connect AGN duty cycles, multiwavelength selection, and spatially resolved diagnostics
Data-driven synthesis of photoacoustic images
No full textMethodological progress in the age of Artificial Intelligence (AI) is increasingly driven
by large-scale, high-quality datasets. Medical imaging is no exception. As the amount
of imaging data grows exponentially, the development and validation of data-driven al-
gorithms critically depend on realistic, well-annotated datasets. Photoacoustic imaging
(PAI), a hybrid modality combining optical contrast with ultrasound resolution, holds great
promise for non-invasive, functional biomedical imaging with the potential for quantitative
measurement of blood oxygen saturation. Prospective clinical applications range from
cardiovascular imaging to early diagnosis and treatment monitoring in oncology. However,
as a comparatively young modality, PAI faces a fundamental challenge: the absence of
sufficiently large, annotated datasets for the development and validation of quantitative
methods.
This thesis addresses the data scarcity problem in quantitative PAI through a comprehensive
pipeline for the generation and validation of synthetic spectral imaging data. First, the
thesis reviews the current role of deep learning in PAI, identifying the generation of
realistic simulated data and domain adaptation as key techniques to address data scarcity.
Consequently, SIMPA is introduced, the open-source simulation and image processing
for photonics and acoustics framework enabling large-scale and reproducible PA image
simulation. To overcome the remaining domain gap between simulated and experimental
data, a conditional invertible neural network-based method is proposed for unsupervised
domain transfer. For empirical validation of data-driven PA methods, anatomically realistic
tissue-mimicking phantoms are fabricated and characterized, enabling the creation of a
comprehensive dataset, including experimental and simulated multispectral images. This
resource allows, for the first time, rigorous benchmarking of quantitative methods such as
oximetry.
This thesis contributes not only technically through novel methods and validation strate-
gies, but also promotes reproducibility and open science by making all software tools and
datasets publicly available. In doing so, it lays the foundation for systematic and transpar-
ent development and validation of data-driven methods in PAI and supports the broader
translation of PAI into preclinical and clinical applications
Multimodal neuroimaging in adverse childhood experiences and related PTSD
No full textBackground: Adverse Childhood Experiences (ACE) are strongly associated with various mental health disorders, including Post-Traumatic Stress Disorder (PTSD). Although neuroimaging studies have investigated the neurobiological correlates of ACE and PTSD, there is no consensus on the specific neurobiological mechanisms underlying ACE and related PTSD. Many studies use single-modality imaging techniques, often examining structural and functional data separately, potentially overlooking crucial interactions and shared information across modalities. This study addresses this gap by using multimodal neuroimaging (MN) approaches to explore the neurobiological impact of ACE and related PTSD.
Methods: Two studies were conducted using complementary and joint multimodal neuroimaging analyses (CoMNA and JoMNA). The CoMNA study performed complementary analyses of T1-weighted MRI and diffusion MRI (dMRI) in a total of 78 adults to assess cortical morphometry and white matter integrity related to ACE. JoMNA study used a total of 119 participants with ACE (70 with ACE-related PTSD and 49 ACE-exposed controls). T1-weighted MRI, dMRI, and resting-state functional MRI (rs-fMRI) data were acquired, and joint connectivity matrix independent component analysis was employed to examine shared information across modalities and identify structural and functional connectivity differences between groups.
Results: The CoMNA study identified reduced cortical volume in the right superior parietal lobe (rSPL) associated with childhood abuse. Reduced rSPL volume also mediated the relationship between childhood abuse and PTSD avoidance symptoms, with corresponding changes in connected white matter integrity. The JoMNA study revealed functional hyperconnectivity in the medial prefrontal cortex and inferior temporal regions, hypoconnectivity in the lateral prefrontal cortex, and structural hypoconnectivity in white
matter pathways, including the right orbitofrontal region, in the ACE-related PTSD group.
Conclusion: Both studies identified significant neurobiological alterations associated with ACE and PTSD, including structural and functional alterations in brain regions involved in cognitive control, self-referential processing, and social behavior. These findings underscore the potential of MN to elucidate the complex neurobiological basis of ACE-related psychopathology. Future, larger MN studies could contribute to developing predictive models to identify individuals at risk for psychopathology and enable personalized treatment approaches