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Bipyridine modified DNA G-quadruplexes
(2025) Durmisevic, Armin; Clever, Guido; Mutschler, Hannes
DNA G-quadruplexes are four-stranded secondary DNA structures formed through Hoogsten hydrogen bonds of four individual guanines, creating a G-tetrad whereby several of such tetrads can stack on top of each other to create the final construct. They are closely involved in the regulation of several biological processes such as transcription and translation, core mechanisms of life on earth. This makes them prime targets for several therapeutic approaches. Amongst them is the development of small molecule ligands capable of targeting and stabilising or destabilising G-quadruplex structures. Yet their polymorphic character and their complex interaction with other biomolecules, primarily proteins, remains a challenging aspect of understanding G-quadruplex chemical and biological features. Concomitantly this renders them an interesting playground to introduce modifications into these systems that potentially offer a novel understanding of their characteristics. In this thesis, a novel artificial bipyridine ligandoside was incorporated covalently into short DNA oligonucleotides capable of forming G-quadruplex structures. It was shown that these modifications had little to no impact on the parental structure, retaining the original topology and thermal stability. Although almost all sequences showed thermal stabilisation to some degree through complex formation of the bipyridine moieties and divalent metal cations such as Cu2+, Ni2+, Zn2+, Co2+, Cd2+ and Fe2+, only few G-quadruplexes experienced a structural reorganisation resulting in a novel distinct topology. Of these particular examples, kinetic experiments revealed how the refolding was mostly driven by hydrogen bond and π-stacking interactions of the DNA structure and merely kinetically enables through the initial fast formation of the metal complex. Furthermore, it was showcased that these artificial G-quadruplexes retained interaction capabilities with proteins and in particular helicases Pif1 and DHX36. As the topology of some modified G-quadruplexes was metal dependent, the resulting binding constants (Kd) where impacted as preferential interaction with either hybrid, antiparallel or parallel topologies was observed. For the best systems low nM Kd values could be obtained while taking advantage of the thermal stabilisation by the metal complex and thus greatly impeding the unwinding the G-quadruplex structure proven by luciferase assays. Lastly, these modified systems were transfected into human cancer cell lines HeLa and U2OS where their spontaneous localisation into the cell nucleus as well as the retention of their structure stabilised ideally by Ni2+ cations be proven by fluorescence based microscopy. Overall, these novel modified G-quadruplex systems bearing bipyridine modifications granted a more detailed insight into structural properties of these DNA secondary structures and also made for promising novel therapeutic approaches and an application as potential molecular decoy.
Prognosemodelle für den Straßenverkehrslärm mit einem Zeithorizont 2050 als Grundlage für die Entwicklung von Maßnahmen zur städtebaulichen Lärmminderung
(2025) Evli-Fründt, Rumeysa; Willems, Wolfgang M.; Peter, Schmidt
Der Straßenverkehr ist nicht nur ein wesentlicher Faktor für Treibhausgasemissionen, sondern auch eine der Hauptquellen von Umgebungslärm. Während die Reduzierung des CO2 Ausstoßes im Verkehrssektor durch das Klimaschutzgesetz zunehmend politisch, wirtschaftlich und gesellschaftlich diskutiert wird, bleibt die langfristige Entwicklung des Straßenverkehrslärms - der jedoch auch physiologische und psychische Gesundheitsprobleme verursachen kann - weit weniger beachtet. Zwar wird häufig darauf hingewiesen, dass die Maßnahmen zur Emissionsminderung auch positive Auswirkungen auf die Lärmbelastung haben könnten, doch eine systematische und langfristige Betrachtung der tatsächlichen Auswirkungen fehlt bislang.
Die vorliegende Dissertation untersucht die Entwicklung des Straßenverkehrslärms in Deutschland für den Zeithorizont 2050 unter Berücksichtigung der aktuell diskutierten Planungs- und Entscheidungsprozesse. Sie stellt zugleich ein Instrument für die zukünftige Stadtplanung unter dem Gesichtspunkt der Lärmbekämpfung dar.
Mithilfe der Szenariotechnik werden die für den Straßenverkehrslärm relevanten Schlüsselfaktoren untersucht und die vorhandenen nationalen Szenarien einbezogen, um zwei unterschiedliche Zukunftsszenarien für den Zeithorizont 2050 zu entwickeln. Das Referenzszenario beschreibt die zukünftige Entwicklung, wenn keine weitergehenden Entscheidungen getroffen und Maßnahmen ergriffen werden. Was zur Folge hat, dass die Klimaschutzziele verfehlt werden. Im Stabilitätsszenario werden ambitionierte Maßnahmen umgesetzt, um die Ziele im Bereich Gebäude und insbesondere Verkehr zu erreichen.
Die Daten dieser Szenarien werden durch statistische Analysen und Berechnungen in quantitative Prognosedaten überführt, die als Berechnungsgrundlage für den zukünftigen Straßenverkehrslärm relevant sind. Dazu werden städtebauliche Übersichtspläne als Grundlage für die Prognosemodelle simuliert. Diese befassen sich mit den aktuellen Planungssituationen in der Bestandsentwicklung allgemeiner Wohngebiete unterschiedlicher siedlungsstruktureller Kreisstypen. Aufbauend darauf werden die Prognosemodelle für das Referenz- und das Stabilitätsszenario unter Anwendung der quantifizierten Prognosedaten simuliert. Sowohl für die aktuelle als auch für die zukünftige Planungssituation werden Schallimmissionspläne berechnet und miteinander verglichen.
Im Vergleich zur aktuellen Planungssituation zeigen die Prognosemodelle insgesamt nur geringfügige – teilweise gerade noch wahrnehmbare – Pegeldifferenzen. Dies zeigt, dass sich der Straßenverkehrslärm bis zum Jahr 2050 weder durch die zukünftigen Entwicklungen wahrnehmbar verschlechtern noch durch zusätzliche Klimaschutzmaßnahmen wahrnehmbar verbessern wird. Die Lärmbelastung bleibt somit ein städtebauliches und vor allem gesundheitliches Problem in Deutschland.
Identification and characterization of serial killing natural killer cells
(2025) Niemann, Jens Alexander; Watzl, Carsten; Zimmer, Philipp
Human natural killer (NK) cells have been shown to be heterogeneous and differ in their ability to kill target cells. NK cells with the ability to sequentially kill multiple targets are called serial killers. The serial killing activity of NK cells is essential for their cytotoxic function since the majority of kills can be performed by a minority of cells. Consequently, serial killing NK cells are of particular interest for therapeutic applications. However, while it is known that only a fraction of NK cells perform serial killing, it is currently not possible to predict which NK cells will engage in serial killing. Additionally, current methods to identify serial killing NK cells rely mostly on low throughput, time consuming microscopy or micro-fluidic setups which makes it hard to integrate them into a normal workflow.
To investigate serial killing NK cells, we established a staining protocol that can differentiate between the timing and the count of multiple NK cell degranulation events occurring during target cell co-culture. NK cells are analyzed via flow cytometry which enables us to combine degranulation data with other phenotypic readouts. Our method can reproducibly identify donors with high proportions of serial degranulating NK cells. Multiple degranulation events were paralleled by a stepwise loss of granzyme B and perforin. Loss of CD16 was associated with the number of degranulation events, whereas the upregulation of CD69 correlated with the timing of degranulation. Isolating multiple, single and not degranulated NK cells and rechallenging them resulted in the same pattern emerging. Education influenced the performance of NK cells in the serial degranulation assay with educated NK cells outperforming uneducated ones. RNAseq analysis of sorted NK cells that degranulated multiple times compared to ones that did not degranulate identified several differentially expressed genes. However, most of these genes were activation induced and therefore they cannot be used to identify serial killers beforehand. Investigation of a selection of NK cell receptors did also not result in a clear marker for serial killing NK cells. Still, enrichment could be seen for the receptor NKG2A which is involved in education. When sorting NK cells for expression of that receptor the sorted cells reflected the prediction. Overall, our data support a stochastic model of serial killing compared to a predetermined one and offers a method that can be easily picked up and adapted by other research groups.
Dynamic modeling and robust optimal operation of the hydrothermal synthesis of zeolites in a continuous oscillatory baffled reactor
(2024-03-01) Semrau, Robin; Ramirez Mendoza, Heidy; Lutz, Cécile; Engell, Sebastian
Continuous flow synthesis offers major advantages in the production of specialty products, e.g. zeolites, such as tight temperature control and lower variation in product quality. Here we consider the hydrothermal synthesis of NaX zeolites in a continuous oscillatory baffled reactor (COBR). A process model is derived from physico-chemical relationships to analyze and optimize the operation of a pilot scale continuous oscillatory baffled reactor for zeolite synthesis. The process model is validated using plant data. Furthermore, the uncertainty of the model predictions is quantified. Based on this analysis, robust optimization is used to compute robust optimal operation points of the COBR. These optimal operation points are validated by the application to a real pilot plant.
Direct numerical simulation of dispersion and mixing in gas–liquid Dean-Taylor flow with influence of a 90° bend
(2024-09-01) Mierka, Otto; Münster, Raphael; Surkamp, Julia; Turek, Stefan; Kockmann, Norbert
Gas-liquid capillary flow finds widespread applications in reaction engineering, owing to its ability to facilitate precise control and efficient mixing. Incorporating compact and regular design with Coiled Flow Inverter (CFI) enhances process efficiency due to improved mixing as well as heat and mass transfer leading to a narrow residence time distribution. The impact of Dean and Taylor flow phenomena on mixing and dispersion within these systems underscores their significance, but is still not yet fully understood. Direct numerical simulation based on finite element method enables full 3D resolution of the flow field and detailed examination of laminar flow profiles, providing valuable insights into flow dynamics. Notably, the deflection of flow velocity from the center axis contributes is followed by tracking of particle with defined starting positions, aiding in flow visualization and dispersion characterization. In this CFD study, the helical flow with the influence of the centrifugal force and pitch (Dean flow) as well as the capillary two-phase flow (Taylor bubble) is described and characterized by particle dispersion and related histograms. Future prospects in this field include advancements in imaging techniques to capture intricate flow patterns, as well as refined particle tracking methods to better understand complex flow behavior.