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The impact of stellar feedback on the circumstellar medium and galaxy evolution
Get PDFThe formation and evolution of galaxies is an interesting field of study that has attracted considerable interest. One process that affects galaxies is the feedback from stars. It has effects not only in the stellar vicinity, but also globally in the galaxy and beyond as it can alter the star formation rate, morphology or outflows of galaxies. Due to the importance of stellar feedback, it is included in simulations of galaxies. As stars and their evolution are below the resolution achievable in these simulations, sub-grid models must be employed. However, these models are based on simplifying assumptions.
This thesis examines some of these assumptions with the aim of improving sub-grid models of stellar feedback. Special emphasis is given to early stellar feedback that occurs before the first supernovae (SNe), also known as pre-SN feedback. The early feedback was initially neglected in simulations, but is now included more frequently in some form. While also incorporating SN feedback, this thesis investigates two types of early feedback, stellar winds and, in the later projects, also photoionisation feedback.
In the first project, we derive the feedback of stellar winds from a grid of massive stellar models for a range of metallicities. To account for their effect on the feedback, the grid includes single stars with different stellar rotation velocities and, in addition, binary systems with different orbital periods. In comparison to the case of non-rotating single stars, which are commonly assumed, accounting for stellar rotation and binarity can strongly increase the feedback energy from stellar winds, especially at low metallicity. The inclusion of stellar winds in a cosmological simulation reduces the stellar mass, the outflows and the fluctuation of the star formation rate of the simulated galaxy compared to a scenario of only SN feedback. Accounting for stellar rotation and binarity in the feedback lead to similar results for the galaxy compared to the non-rotating single star case, despite the high differences in the stellar wind energy.
In the second project, we investigate how the circumstellar medium, which is below the resolution in galaxy simulations, influences the stellar feedback available at resolved scales. We perform a grid of 1D simulations of the circumstellar medium, affected by stellar winds, photoionisation and SN feedback. We calculate the cumulative energy in the ambient gas that flows through different distances from the stellar source. We find that the circumstellar medium can alter the feedback through energy dissipation and changing kinetic energy ratios. Furthermore, the arrival of energy can be delayed with respect to the stellar ejection. These effects are stronger at a large distance from the stellar source. Like in the first project, we see the importance of the early feedback, together with the low relevance of the enhance energy from populations of rotating and binary stars.
In a third project, a first attempt of a sub-grid feedback model accounting for the circumstellar medium is presented for a galaxy simulation code. Through a simple test - the evolution of an isolated feedback bubble - we reveal and discuss challenges the model faces.
In this thesis, we investigate early stellar feedback, stellar models beyond non-rotating single stars and the effect of the circumstellar medium. The findings of the thesis can improve sub-grid models of stellar feedback and advance the modelling of galaxies
Characterization of the disorganization of the inner retinal layers in diabetics using increased axial resolution optical coherence tomography
Get PDFPurpose: To compare a novel high-resolution optical coherence tomography (OCT) with improved axial resolution (High-Res OCT) with conventional spectral-domain OCT (SD-OCT) with regard to their capacity to characterize the disorganization of the retinal inner layers (DRIL) in diabetic maculopathy. Methods: Diabetic patients underwent multimodal retinal imaging (SD-OCT, High-Res OCT, and color fundus photography). Best-corrected visual acuity and diabetes characteristics were recorded. DR was graded using the international clinical diabetic retinopathy severity scale (DRSS). In each OCT B-scan, retinal layers were segmented and the loss of discernibility was annotated. DRIL areas were analyzed in en face projection using FIJI plugins. The Wilcoxon test and regression models were used for statistical analysis. Results: In 93 eyes of 93 patients (mean age, 61.8 ± 12.9 years) DRIL was identified in 48 eyes. DRIL was most frequent in the central subfield (27%). In DRIL eyes, DRSS was significantly higher (4.43 ± 1.01 vs. 2.12 ± 1.66; P P 2 ; P Conclusions: DRIL occurs in eyes with advanced diabetic retinopathy, with a characteristic spread: from the inner toward the outer retina. High-Res OCT shows significantly smaller DRIL areas compared with SD-OCT, because of a more precise delineation of the inner retinal layers
Detector development towards axion searches with BabyIAXO
No full textThe axion might be one milestone towards the solution of many long-lived problems in physics. The axion itself can couple by construction to photons via the Primakoff effect. Due to this, the Sun would be a large source of axions. To measure those axions, the inverse of the Primakoff effect can be used; within a strong magnetic field, providing virtual photons, the axions can convert into photons. Consequently, an experimental setup consisting of a large magnet pointing towards the Sun —called helioscope— can be used for the search for axions. Such an experiment is BabyIAXO, which is currently in development and proposed to be built at the DESY facility in Germany.
The converted photons from the solar axions are in a typical energy range of 1-7 keV. To measure these specialised detectors need to be developed taking the low event rate into account. Thus, the detectors need to be very efficient, at the same time providing an extremely low background. These requirements can be fulfilled by gaseous detectors.
In this thesis, the development and commissioning of such a detector will be explained. The central part of the detector will be a GridPix sensor, consisting of a pixelised readout with a gas amplification stage mounted atop. In order to reduce the background, suitable vetoes need to be developed as well as a mechanical design using only radiopure materials. Finally, the background rate will be determined and compared to previous GridPix detectors
Soziale Strukturen lokaler Eliten im ländlichen Raum des ausgehenden Hochmittelalters bis in die Frühe Neuzeit : Die Siedlungen Bonsdorf und Pommenich sowie Haus Pesch im Süden von Inden-Pier, Kr. Düren
Get PDFArchäologische Aufnahme von zwei Siedlungen und einer Mottenanlage aus Inden-Pier. Einordnung und Analyse der lokalen Herrschaftsstrukturen des Mittelalters
Molekulargenetische Verfahren zur Untersuchung der Patienten- und Umgebungsmikrobiom-assoziierten Krankheitsentstehung und -dynamik
Get PDFDie präsentierten Ergebnisse unterstreichen die Bedeutung des Mikrobioms nicht nur als Indikator für gesundheitliche Zustände, sondern auch als aktiven Teilnehmer in der Krankheitsentwicklung. Durch die detaillierte Analyse der genetischen Merkmale von Mikroorganismen konnten spezifische Risikofaktoren identifiziert werden, die durch Wohnort, Ethnizität und spezifische Krankenhausumgebungen beeinflusst werden. Diese Erkenntnisse sind entscheidend für die Entwicklung gezielter präventiver Maßnahmen und Therapieansätze, die auf die spezifischen Bedürfnisse der Patienten und die Bedingungen ihrer unmittelbaren Umgebung zugeschnitten sind. Neue Molekulargenetische Technologien ermöglichen eine noch nie dagewesene Präzision in der Infektionsforschung und bieten die Grundlage für die Entwicklung personalisierter medizinischer Lösungen, die auf die mikrobielle Zusammensetzung und genetische Disposition des einzelnen Patienten abgestimmt sind. Durch die Nutzung der gleichen Technologieplattformen für unterschiedliche Zwecke bieten sich die molekulargenetischen Ansätze als zentrales Werkzeug in der modernen medizinischen Forschung und Praxis an und erlauben es Krankenhäuser ihre Ressourceneffizienz zu maximieren. Die generierten Daten erlauben es Risikoprofile besser zu definieren, die nicht nur auf der Präsenz einzelner resistenter Erreger basieren, sondern auch auf der Zusammensetzung der gesamten mikrobiellen Gemeinschaft. Zusammenfassend bestätigen diese Studien die kritische Bedeutung des Mikrobioms und genetischer Analysen in der modernen Medizin und legen nahe, dass eine weiterführende Erforschung und Anwendung dieser Erkenntnisse essenziell ist, um die Herausforderungen im Umgang mit Infektionskrankheiten und Antibiotikaresistenzen in Zukunft erfolgreich zu bewältigen
Erstellung einer Datenbank für Referenzsubstanzen zur Viruzidietestung anhand von vorliegenden Zertifizierungsverfahren, Gutachten und Prüfberichten
Get PDFDie Testung von Desinfektionsmitteln gegenüber Viren erfolgt abhängig ihrer Anwendungsbereiche und wird basierend auf der Wirksamkeit gegenüber behüllten und unbehüllten Viren in die Wirkungsbereiche "begrenzt viruzid", "begrenzt viruzid PLUS" und "viruzid" eingestuft. Seit 2005 existieren im wesentlichen nur zwei Richtlinien zur Viruzidietestung: auf nationaler Ebene die Leitlinien der Deutschen Vereinigung zur Bekämpfung der Viruskrankheiten und des Robert Koch-Instituts sowie auf internationaler Ebene die Normen des Technischen Kommitees CEN/TC 216 im Comité Européen de Normalisation (CEN). Chemische Desinfektionsmittel werden sowohl in quantitativen Suspensionsversuchen (Phase 2, Stufe 1) als auch in praxisnahen Tests (Phase 2, Stufe 2) auf ihre viruzide Wirksamkeit geprüft. Dabei werden die Testviren dem Desinfektionsmittel ausgesetzt und anschließend ihre Infektiosität auf Zellkulturen überprüft. Für eine Zulassung oder Zertifizierung müssen beide Tests erfolgreich bestanden sein, wobei das ungünstigere Ergebnis für die Beurteilung der Viruzidie herangezogen wird. Da die Widerstandsfähigkeit der Testviren schwanken kann und auch die Zellkulturen Einfluss auf das Ergebnis haben können, werden zur Qualitätssicherung immer interne Tests mit Referenzsubstanzen durchgeführt.
Ziel der Arbeit war es die Suspensionsversuche Phase 2, Stufe 1 hinsichtlich möglicher Einflussnahme durch die Wahl unterschiedlicher Parameter auf die Virustiterreduktion zu untersuchen und zeitgleich bestehende Referenzbereiche für Referenzsubstanzen sowohl für die nationale Richtlinien als auch für die europäischen Normen enger zu definieren.
Als Grundlage für die Untersuchung dienten die aus den Jahren 2000-2022 insgesamt 532 vorliegenden Prüfberichte und Gutachten, die beim Verbund für angewandte Hygiene zur Zertifizierung eingereicht wurden.
Aufgrund der Datenlage konzentrierte sich die Auswertung auf die Referenzsubstanz Formaldehyd 0,7%, sowie die Parameter Prüflabor, Testvirus und Zellkultur. Mittels gemischter linearer Regressionsmodelle wurden diese Parameter auf Einflussnahme geprüft und anschließend die 95% Konfidenzintervalle ermittelt.
Es konnte gezeigt werden, dass die Wahl der Prüflabore und Zellkulturen vereinzelt Einfluss auf die Virustiterreduktion der jeweiligen Testviren nahmen. Es gelang für die Suspensionsversuche Phase 2, Stufe 1 mit der Referenzsubstanz 0,7% Formaldehyd neue 95% Konfidenzintervalle für das Vacciniavirus, das Bovine Viral Diahrreah Virus, das murine Parvovirus, das Adenovirus, das murines Norovirus, das Poliovirus und das Polyomavirus unter Berücksichtigung der unterschiedlichen Einwirkzeiten sowohl auf nationaler als auch internationaler Ebene neu zu berechnen und bestehende Referenzbereiche enger zu definieren (s. A14, A15).
Die Ergebnisse dieser Arbeit stellen somit einen wichtigen Beitrag zur Standardisierung und Qualitätssicherung dar und bieten eine verbesserte Grundlage für die Vergleichbarkeit der Wirkungsbereiche
Enteric glial reactivity in intestinal inflammation and colorectal cancer
No full textEnteric glial cells (EGCs) are important regulators of gastrointestinal functions in health and disease. Over the last few years, their role in intestinal inflammation and their interplay with the local tissue microenvironment has raised increasing attention. As EGCs can react to various environmental stimuli, such as cytokines and chemokines, and contribute to the inflammatory milieu, it is critical to understand the signaling pathways inducing their reactive phenotype and the resulting actions on their tissue microenvironment. Using primary EGC cultures and glial-specific genetic modifications, we revealed specialized extracellular matrix compositions, the sympathetic nervous system, and interleukin (IL)-1 as important regulators of EGCs' immune functions. Applying brightfield and immunofluorescent imaging and RNA-sequencing, we demonstrated distinct effects of extracellular matrix substrates on EGC primary cultures, pinpointing Matrigel and laminin as superior coating substrates in EGC purity, network formation, and reactivity. Postoperative RNA sequencing results expanded our knowledge about EGC reactivity by identifying the sympathetic nervous system as an early EGC activator during acute intestinal inflammation. Using EGC cultures, we discovered norepinephrine signaling via β-1/2-adrenergic receptors as a responsible inducer of immediate postoperative glial reactivity. Moreover, we used a targeted approach to analyze the effect of the well-known and strong immune activator IL-1 on glial-specific reactivity in acute postoperative intestinal inflammation. Strikingly, glial activation via IL-1 led to increased expression of genes related to ‘enteric gliosis' both in vitro and in intestinal inflammatory models in vivo. Furthermore, glial reactivity correlated with macrophage activation and migration, highlighting EGCs' contribution to the inflammatory microenvironment. Finally, we transferred the insights gained from the acute postoperative intestinal inflammation studies into the field of tumor immunology, representing a chronic inflammatory condition as it occurs in colorectal cancer (CRC). Applying three murine CRC models, including EGC-specific molecular reporters and gene deficiencies, we identified a bidirectional signaling cascade between EGCs and tumor-promoting macrophages in CRC, leading to cancer progression. Unraveling the molecular pathways involved, monocyte-derived IL-1 was identified as an EGC activator via glial IL-1 receptor 1 signaling, triggering the secretion of IL-6 into the tumor microenvironment, which promotes the differentiation of infiltrating monocytes into tumor-promoting SPP1+ macrophages. Together, we highlighted the significance of EGCs in intestinal inflammatory diseases. Identifying the extracellular matrix, the sympathetic nervous system, and IL-1 as crucial regulators of glial biology and immune reactivity, we substantiated our understanding of the molecular pathways involved in EGCs' reactive phenotype. Importantly, IL-1-mediated glial activation was proven essential for glia-macrophage interactions in intestinal inflammation and CRC, underlining EGCs' vital role as immune regulators actively modifying disease outcomes in inflammation-driven intestinal diseases and disorders
Expressionsmodulation der Hitzeschockproteine HSP27 und HSP70 in malignen Zellen nach Exposition gegenüber nicht-invasivem physikalischem Plasma
Get PDFAufgrund seines vor allem wachstumshemmenden Effekts auf maligne Zellen gilt Nicht-invasives physikalisches Plasma (NIPP) als vielversprechende Therapieoption in der Onkologie.
Aktuelle Studien konnten eine Beteiligung der Hitzeschockproteine (HSP) HSP27 und HSP70 an Tumorgenese und Metastasierung sowie eine Korrelation zwischen Tumorstadien und Prognose maliger Erkrankungen mit erhöhten HSP-Spiegeln nachweisen. Auch Korrelationen zwischen erhöhten HSP-Spiegeln und Therapieresistenz auf bereits etablierte Therapien konnten durch verschiedene Autoren gezeigt werden.
Ziel dieser Arbeit war eine Betrachtung der Expression von HSP27 und HSP70 in den Zelllinien OVCAR-3, MCF-7 und LNCaP nach NIPP-Exposition. Überprüft werden sollte, ob (1) eine Verminderung der HSP-Expression Teil des Wirkmechanismus des NIPP sein könnte, oder (2) eine Erhöhung der Spiegel nach der Behandlung nachweisbar sein würde, was auf einen Resistenzmechanismus hinweisen könnte.
Hierzu wurde zunächst ein antiproliferativer Effekt nachgewiesen und anschließend mittels Western Blot die Expression der Hitzeschockproteine nach NIPP-Exposition im Vergleich mit der Kontrolle bestimmt.
Eine signifikante Hemmung des Wachstums durch NIPP-Applikation konnte in OVCAR-3 und MCF-7 nach 30 s Exposition und in LNCaP nach 15 s Exposition gezeigt werden.
Eine Hemmung der Expression von HSP27 und HSP70 konnte in keiner der betrachteten Zelllinien nachgewiesen werden.
Jedoch zeigte sich in LNCaP eine signifikante Steigerung der HSP70-Expression nach 30 s NIPP-Exposition zu den betrachteten Zeitpunkten (24 h, 48 h, 72 h). Diese könnte ein Hinweis auf eine mögliche induzierte Resistenz gegen die Behandlung sein
Development of Histone Deacetylase Inhibitors and Degraders with Antiplasmodial and Anticancer Activity
No full textHistone deacetylases (HDACs) are key targets in epigenetic drug discovery, as they catalyze the removal of acetyl and acyl groups from lysine side chains of histones and other proteins, thereby influencing gene expression and protein function. In humans, 18 HDAC isoforms have been identified: eleven are Zn2+-dependent, while seven use NAD+ as a cofactor, the latter are also known as sirtuins. Efforts in drug discovery have led to the FDA approval of five HDAC inhibitors: vorinostat, romidepsin, belinostat, panobinostat, and givinostat. HDAC inhibitors have also shown activity against Plasmodium falciparum, the deadliest malaria parasite. Malaria remains a major global health problem, with the WHO estimating 263 million cases and 597,000 deaths in 2023, coupled with rising resistance to current antimalarial drugs.
The first project in this thesis focused on developing novel antiplasmodial HDAC inhibitors through structure-activity relationship studies of heteroaryl-decorated peptoid-based inhibitors. These inhibitors were synthesized using a straightforward approach involving the Ugi four-component reaction (U-4CR). A set of 16 compounds was synthesized and screened for activity against asexual blood-stage P. falciparum parasites, followed by testing against liver-stage parasites and assessment of the metabolic stability. Compound 6i was identified as the most potent inhibitor, showing promise as a starting point for antimalarial drug development.
The second project aimed at modifying the clinical-stage anticancer HDAC inhibitor quisinostat, which had previously shown potent antiplasmodial activity but exhibited significant toxicity to human cells. To improve its selectivity profile, multicomponent syntheses were used to generate small sets of compounds based on three different chemotypes. These compounds were evaluated for antiplasmodial activity and for antiproliferative activity against solid cancer cell lines. 18b emerged as the most potent antiplasmodial HDAC inhibitor, while 9b, 9d, and 13f showed promising antiproliferative effects against different cancer cell lines.
The third project focused on modifying an existing HDAC inhibitor cap group by combining it with different linkers and zinc-binding groups (ZBGs) to create new HDAC inhibitors with alternative ZBGs.
Sixteen compounds were synthesized and screened for their inhibition of HDAC1-3 and HDAC6, as well as for antiplasmodial activity against P. falciparum and antiproliferative activity against selected cancer cells. Although most of the compounds showed low HDAC inhibitory properties or weak activity in the phenotypic assays, compound 20 (named DS-103) emerged as a potent ethyl hydrazide-based HDAC inhibitor. Further studies showed that DS-103 was effective in reversing cisplatin resistance in cancer cells and exhibited strong synergism with cisplatin.
Building on these results, the fourth project aimed at the development of HDAC proteolysis-targeting chimeras (PROTACs) using the ethyl hydrazide moiety as the ZBG. The subsequent screening of the synthesized PROTACs featuring VHL- and CRBN-targeting ligands identified several compounds that selectively degraded HDAC6, with 17c being the most potent degrader (Dmax = 91%; DC50 = 14 nM). Mechanistic studies showed that 17c-induced HDAC6 degradation is dependent on neddylation and binding to both HDAC6 and CRBN. Chemoproteomics further confirmed the selectivity of 17c for HDAC6
Molecular insights into abiotic stress responses in barley and Arabidopsis
Get PDFThis cumulative thesis, titled "Molecular insights into abiotic stress responses in barley and Arabidopsis", investigates two critical aspects of plant responses to abiotic stress. The first part explores hydrogen peroxide (H2O2) and its interaction with calcium (Ca2+) signalling in barley (Hordeum vulgare L.), while the second part examines drought stress regulation in Arabidopsis thaliana, revealing a novel mechanism involving the genes GASA3 and AFP1.
H2O2 plays a pivotal role in signalling pathways that enable plants to adapt to environmental challenges. Despite its importance, its transcriptomic impact remains underexplored. To address this, RNA-Seq analysis was used to examine changes in gene expression in barley roots and leaves after H2O2 treatment. This revealed 1883 differentially expressed genes (DEGs) in roots and 1001 in leaves, with most responses being tissue-specific. Only 209 DEGs were commonly regulated, and 37 showed opposing regulation across tissues. Gene ontology (GO) analysis highlighted the organ-specific nature of the response: leaf DEGs were enriched in hormone signalling, H2O2 response, and abiotic stress adaptation, while root DEGs were associated with H2O2 detoxification, glutathione metabolism, and cell wall modifications. A follow-up study examined the cross-talk between H2O2 and Ca2+ signalling using RNA-Seq under conditions that blocked Ca2+-transients. By comparing expression profiles from H2O2-only and LaCl3+H2O2 treatments, 331 Ca2+-dependent H2O2-responsive genes in leaves and 1320 in roots were identified and grouped into five and four clusters, respectively. A SKM network analysis further revealed transcription factors potentially governing this H2O2–Ca2+ cross-talk.
Drought is one of the most severe abiotic stresses impacting plant growth, development, and reproduction. Like H2O2, drought triggers extensive transcriptomic reprogramming. In this study, two strongly drought-induced genes, GASA3 and AFP1, were identified. Loss-of-function mutants showed enhanced drought resistance, while constitutive overexpression of either gene led to reduced tolerance. The gasa3afpl double mutant exhibited even greater resistance than single mutants. Both genes are also ABA-inducible, though GASA3 expression remained low in the absence of AFP1. The improved drought tolerance in mutants was linked to higher leaf water content due to smaller stomatal apertures and reduced transpiration. Additionally, ABA levels were elevated in mutants under drought stress- not due to increased biosynthesis, but via the release of conjugated vacuolar ABA-GE through β-glucosidase BG2. Consistent with this, ABA-responsive genes such as RD29A/B and ABF2/3 were more strongly upregulated in mutants than in wild type (WT). Conversely, PP2CA, which encodes a phosphatase involved in ABA negative feedback, was repressed in the absence of GASA3 and AFP1. These results suggest that both genes act as negative regulators of drought tolerance, with AFP1 influencing GASA3 expression.
Altogether, this thesis offers new insights into plant abiotic stress responses and provides a foundation for future functional studies in barley and other crops, potentially guiding breeding strategies for improved stress resilience under changing climates