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Design and synthesis of potential STING-degrading PROTACs via a modular click chemistry approach
Get PDFConstantinople/Istanbul as an artistic hub of the Émigrés from the former Russian Empire in 1919–1927
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The role of the CRH/CRHR1 system in glial cells following acute brain injury
Get PDFThis cumulative-style doctoral thesis consists of two studies revolving around the corticotropin-releasing hormone (CRH), its role in oligodendrogenic processes following injury as well as the in-depth characterization of mouse models for its analysis. We identified a subpopulation of oligodendrocyte progenitor cells (OPCs) in which CRH expression is triggered upon acute injury by using different CRH reporter models, direct anti-CRH staining and Crh mRNA visualization. This CRH-expressing subpopulation of OPCs showed an OPC-like injury response with inward migration, strong proliferation and later differentiation. Although the general injury reaction of CRH+ OPCs was comparable to the whole population of OPCs, their dynamics differed, supposedly caused by their high maturation rate of 80%. CRH expression was further found to happen at very early stages, starting within the first 12h following injury, therefore, preceding proliferation. Subsequently, expression of CRH persisted only within the first 3 days post injury (dpi). Furthermore, CRHR1, the high affinity receptor of CRH, was identified on OPCs and astrocytes surrounding the injury site, serving as potential targets of injury-triggered CRH expression and release. Using different gain- and loss-of-function approaches we demonstrated that CRH modulates astrocytic activation stages in a CRHR1-dependent manner, as elevated GFAP levels were only observed following CRH injection when CRHR1 was present. Furthermore, CRH system downregulation by global CRHR1 or OPC-specific CRH inactivation led to a reduced number of OPCs at 7 dpi and an increased number of OLs, that was later explained by an increased generation of new OLs using a label retaining experiment. Therefore, CRH released from OPCs apparently triggers a stalling mechanism of OPC differentiation which is mediated by CRHR1-expressing OPCs and astrocytes. In sum this study presents a novel neuropeptide system modulating OPC differentiation processes, which could serve as therapeutic target to enhance OL regeneration following acute injury.
This study was complemented by a much-needed characterization of a newly available CRH-FlpO reporter line. In this study, the CRH-FlpO line was compared to the widely used CRH-Cre line, which is considered as the gold standard for transgenic CRH reporting. By using 9 different reporter lines we were able to show that FlpO-dependent reporting in CRH-FlpO::Ai65F mice, although replicating endogenous CRH expression patterns, is inferior in its capacity to report the whole population of CRH-expressing cells. By using Cre and FlpO in combination with different reporters, we demonstrated that overall recombination efficacy of FlpO is lower than that of Cre. Additionally, we determined that an elevation in CRH expression by applying an acute stress model increases the number of reported cells. Therefore, FlpO dependent recombination and reporting is highly dependent on the overall strength but also context-dependent activity of the driving promoter. This has consequences for all studies using mouse lines harboring FlpO for genetic recombination: i) When comparing Cre- and FlpO-driven reporting the strength of the driving promoter has to be taken into account, ii) when using intersectional approaches to label specific subpopulations the efficacy of reporting is determined by the recombination efficiency of FlpO and iii) when using FlpO for overexpression or knock-out of a certain marker an in-depth validation of their efficacy in the specific population is necessary. In sum, our results show that a careful and comprehensive analysis of FlpO-driven mouse lines is mandatory and should pay particular attention to the expression strength of the driving promoter.
Results connected to the characterization of FlpO were essential when interpreting the data related to the identification of CRH expression in OPCs. Because of the limited accessibility of CRH and its receptor CRHR1 by antibody-mediated approaches, the study relied heavily on transgenic mouse models, using both Cre and FlpO. Especially, differences in the number of reported cells between different mouse lines could be explained by these results which made a reasonable evaluation of gathered data possible.
In sum, this thesis presents a thorough evaluation study of FlpO driven recombination efficacy whose results laid the ground for the identification and characterization of a novel OPC-derived neuropeptide system contributing to OLC differentiation processes
Characterization of microbial resistome in bacteria isolated from human, environmental and animal sources using DNA microarray technology and genome sequencing
Get PDFBackground: Antimicrobial resistance (AMR) is a growing threat to public health globally. The impact is even worse in resource constrained countries. The occurrence of antimicrobial resistant bacteria in animals, the environment, and apparently healthy humans exacerbates the problem and serves as a reservoir for further dissemination. In the study area, Jimma, Ethiopia, there is no comprehensive data about the prevalence, diversity, and distribution of AMR in various sectors. Therefore, the current study aimed to address the existing scarce data related to AMR and to provide comprehensive information on the matter.
Methods: A cross-sectional study design was employed to understand the prevalence, diversity, and distribution of AMR in bacteria isolated from clinical, animal, environmental, and apparently healthy human samples. All the bacterial isolates were re-identified with matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI TOF MS). Antibiotic susceptibility testing (AST) was determined using the Kirby-Bauer disk diffusion method and Etest strips. The phenotype ESBL screening was done by double disc synergetic test (DDST) and Mast isks. Molecular characterization of Gram-negative bacteria (GNB) was performed by multiplex polymerase chain reaction (PCR) and deoxyribonucleic acid (DNA) microarray techniques.
Result: A wide range of bacterial species were identified in samples obtained from patients, animals, the environment, and apparently healthy humans. E. coli (22.9%) was the most predominant isolate followed by Klebsiella species (21.1%), Enterobacter species (10.7%), and Acinetobacter species (12.5%). In GNB, a high rate of resistance against ampicillin (90%), cefuroxime (82%), amoxicillin-clavulanic acid (76%), piperacillin (75%), and cefotaxime (74%) was observed. Extended spectrum beta-lactamase (ESBL) producers were isolated in all sample categories. However, the prevalence and diversity were variable. The highest proportion was exhibited in clinical samples (76.6%) followed by environmental (49.2%) and animal samples (28.2%). The molecular analysis of GNB showed that blaCTX-M and blaNDM were the predominant acquired ESBLs and carbapenemase encoding genes, respectively. The co-existence of multiple resistance genes was observed in a lot of isolates.
Conclusions: The findings revealed a high rate of resistant bacterial species in clinical, environmental, animal, and human samples from apparently healthy subjects. Various genes encoding for beta-lactam resistance were identified in all sample categories, predominantly was blaCTX-M and blaNDM
γ-substituted N-acylated-N-aminoethyl peptide mimetics of mucin MUC1 B-cell epitopes and photoswitchable peptide hormones for photopharmacology
Get PDFEnhanced photovoltaic performance and stability of mixed-dimensional lead-based perovskite solar cells through utilization of organic cations
Get PDFRetrospektive Auswertung von Schlachtdaten immunologisch kastrierter Eber im Vergleich zu chirurgisch kastrierten und intakten Ebern sowie weiblichen Mastschweinen
Get PDFInvestigating ultrafast nanoscale surface dynamics using reaction nanoscopy
Get PDFPhotochemistry, the study of light-induced chemical reactions, plays a crucial role in numerous natural and synthetic processes, including photosynthesis and solar energy conversion. While advancements in nanotechnology and laser technology have fueled remarkable progress in photochemistry, understanding the dynamic behavior of materials at the nanoscale remains challenging due to the involved length and time scales. This thesis employs reaction nanoscopy to address this challenge that goes beyond the abilities of existing techniques in observing reactions occurring at the nanoscale. Reaction nanoscopy utilizes three-dimensional ion momentum spectroscopy and enables a comprehensive investigation of the energy and momentum distribution of ions emitted from the nanoparticle surface during laser-induced reactions.
The ability of nanoparticles to localize and enhance electric fields is crucial for manipulating surface reactions at the nanoscale. While previous research has observed laser-induced bond-breaking and formation on nanoparticle surfaces, achieving nanoscale optical control of near-field-mediated surface reactions has remained elusive. This thesis bridges this gap by presenting the first experimental demonstration of all-optical, nanoscopic spatial control of molecular reaction yields on isolated silica nanoparticles. By tailoring near-fields with waveform-controlled linear and bicircular two-color laser pulses, and employing reaction nanoscopy, we probe the birth location of molecular fragments on the nanoparticle surface with an angular resolution around 8°. This corresponds to a spatial resolution of about 20 nm for 300 nm silica nanoparticles. Notably, a site-selective proton emission from the dissociative ionization of adsorbate molecules is observed, dependent on the polarization and relative phase of the two-color pulses. The findings are corroborated by classical trajectory Monte Carlo simulations based on strong field ionization in near-fields and quasi-static charge interactions.
The second part of the thesis advances on the previous work toward the spatiotemporal tracing of the reaction products with unprecedented spatial and temporal resolution at the nanometer-femtosecond scale. It demonstrates the first realization of pump-probe reaction nanoscopy to probe surface charge dynamics in individual silica nanoparticles. The study investigates the process of surface charge relaxation and its impact on the bond-weakening of the adsorbed molecular groups on single, isolated silica nanoparticles. The study offers a four-dimensional visualization of the surface charge density. It allows the distinction of the contributions of the underlying physical process comprising of diffusion and charge loss on different timescales, supported by semi-classical simulations. The simulations shed light on the role of laser-induced surface charges in the weakening of the terminal O-H bonds at the interface, whose dynamics are caused by the redistribution of initially localized charge carriers.
The final part of the thesis presents a study focusing on the formation of trihydrogen cation on the surface of strong-field irradiated citrate-capped gold nanoparticles. The study elucidates how variations in shape can alter the reaction landscape of the nanoparticle surface by comparing the reaction products emitted from strong-field ionized spherical and faceted gold nanoparticles. The study underscores the significant role of charge localization in driving reaction dynamics, with steric effects contributing to the overall reactivity enhancement. It is shown that by leveraging the proton-rich environment created by laser-induced nanoparticle surface ionization, faceted gold nanoparticles demonstrate increased catalytic activity, highlighting their potential for various chemical transformations.
Overall, this thesis explores ultrafast nanoscale surface dynamics comprising an all-optical spatial control over nanoscopic reaction yields, revealing four-dimensional surface charge dynamics on nanoparticles, the impact of surface charges in bond-weakening and uncovering morphology-dependent effects on catalytic behavior modulation in gold nanoparticles. The ability to control and analyze surface reactions on nanoparticles paves the way for advancements in photocatalysis, atmospheric chemistry, and other fields reliant on these fundamental processes.Die Photochemie, die Erforschung lichtinduzierter chemischer Reaktionen, spielt eine entscheidende Rolle bei zahlreichen natürlichen und synthetischen Prozessen, einschließlich der Photosynthese und der Umwandlung von Sonnenenergie. Während Entwicklungen in der Nanotechnologie und der Lasertechnik zu bemerkenswerten Fortschritten in der Photochemie geführt haben, bleiben Untersuchungen des dynamischen Verhaltens von Materialien auf der Nanoskala aufgrund der beteiligten Längen- und Zeitskalen eine Herausforderung. In dieser Arbeit wird die Reaktions-Nanoskopie eingesetzt, um diese Herausforderung zu meistern, und neue Möglichkeiten zur Beobachtung von Reaktionen im Nanomaßstab aufgezeigt. Die Reaktionsnanoskopie nutzt die dreidimensionale Ionenimpulsspektroskopie und ermöglicht dadurch eine umfassende Untersuchung der Energie- und Impulsverteilung von Ionen, die während laserinduzierter Reaktionen von der Oberfläche von Nanopartikeln abgegeben werden.
Die Fähigkeit von Nanopartikeln, elektromagnetische Felder zu lokalisieren und zu verstärken, ist von entscheidender Bedeutung für die Beeinflussung von Oberflächenreaktionen auf der Nanoskala. Während frühere Forschungen das laserinduzierte Brechen und Bilden von Bindungen auf Nanopartikeloberflächen beobachtet haben, ist die optische Kontrolle von Nahfeld-vermittelten Oberflächenreaktionen im Nanobereich schwer zu erreichen. Die vorliegende Arbeit schließt diese Lücke, indem sie die erste experimentelle Demonstration der rein optischen, nanoskopischen räumlichen Kontrolle molekularer Reaktionsausbeuten auf isolierten Siliziumdioxid-Nanopartikeln vorstellt. Durch die Anpassung von Nahfeldern mit wellenformgesteuerten linearen und bizirkularen Zweifarben-Laserpulsen und den Einsatz von Reaktions-Nanoskopie wird gezeigt, dass der Entstehungsort von Molekülfragmenten auf der Oberfläche von Nanopartikeln mit einer Winkelauflösung von etwa 8° bestimmt werden kann. Dies entspricht einer räumlichen Auflösung von etwa 20 nm für 300 nm Siliziumdioxid-Nanopartikel. Insbesondere wird eine ortsselektive Protonenemission aus der dissoziativen Ionisierung von adsorbierten Molekülen beobachtet, die von der Polarisation und der relativen Phase der Zweifarbenpulse abhängt. Die Ergebnisse werden durch klassische Trajektorien-Monte-Carlo-Simulationen bestätigt, die auf starker Feldionisation in Nahfeldern und quasi-statischen Ladungswechselwirkungen basieren.
Der zweite Teil der Arbeit ist eine Weiterentwicklung der vorangegangenen Arbeiten zur räumlichen und zeitlichen Verfolgung der Reaktionsprodukte mit einer bisher unerreichten räumlichen und zeitlichen Auflösung im Nanometer- und Femtosekundenbereich. Sie demonstriert die erste Realisierung der Pump-Probe-Reaktions-Nanoskopie zur Untersuchung der Oberflächenladungsdynamik in einzelnen Siliziumdioxid-Nanopartikeln. Die Studie untersucht den Prozess der Oberflächenladungsrelaxation und seine Auswirkungen auf die Bindungsschwächung der adsorbierten Molekülgruppen auf einzelnen Siliziumdioxid-Nanopartikeln. Die Studie bietet eine vierdimensionale Visualisierung der Oberflächenladungsdichte. Sie ermöglicht die Unterscheidung der Beiträge des zugrundeliegenden physikalischen Prozesses, der aus Diffusion und Ladungsverlust auf verschiedenen Zeitskalen besteht, unterstützt durch semiklassische Simulationen. Die Simulationen geben Aufschluss über die Rolle der laserinduzierten Oberflächenladungen bei der Schwächung der terminalen O-H-Bindungen an der Grenzfläche, deren Dynamik durch die Umverteilung von anfangs lokalisierten Ladungsträgern verursacht wird.
Im letzten Teil der Arbeit wird eine Studie vorgestellt, die sich auf die Bildung von Trihydrogenkationen auf der Oberfläche von stark feldbestrahlten Goldnanopartikeln mit Citrat-Oberfläche konzentriert. Die Studie verdeutlicht, wie Formvariationen die Reaktionslandschaft der Nanopartikeloberfläche verändern können, indem sie die Reaktionsprodukte vergleicht, die von stark feldionisierten kugelförmigen und facettierten Goldnanopartikeln abgegeben werden. Die Untersuchungen unterstreichen die bedeutende Rolle der Ladungslokalisierung bei der Steuerung der Reaktionsdynamik, wobei sterische Effekte zur allgemeinen Steigerung der Reaktivität beitragen. Es wird gezeigt, dass facettierte Goldnanopartikel durch die Ausnutzung der protonenreichen Umgebung, die durch die laserinduzierte Ionisierung der Nanopartikeloberfläche entsteht, eine erhöhte katalytische Aktivität aufweisen, was ihr Potenzial für verschiedene chemische Umwandlungen hervorhebt.
Insgesamt erforscht diese Arbeit die ultraschnelle Oberflächendynamik im Nanomaßstab, die eine rein optische räumliche Kontrolle über nanoskopische Reaktionsausbeuten umfasst, und enthüllt die vierdimensionale Oberflächenladungsdynamik auf Nanopartikeln, die Auswirkung von Oberflächenladungen auf die Bindungsschwächung und die Aufdeckung morphologieabhängiger Effekte auf die Modulation des katalytischen Verhaltens von Goldnanopartikeln. Die Fähigkeit, Oberflächenreaktionen auf Nanopartikeln zu kontrollieren und zu analysieren, ebnet den Weg für Fortschritte in der Photokatalyse, der Atmosphärenchemie und anderen Bereichen, in denen diese grundlegenden Prozesse eine Rolle spielen
Probing the Hubble constant: time delay cosmography of SDSS J1433 with the Hubble Space Telescope and the 2.1-meter Wendelstein telescope
Get PDFWhile LCDM cosmology is the most successful cosmological model at our disposal today, being able to explain most of the observed phenomena, it has been challenged by more and more tensions. One of the greatest, both in terms of numerical tension and of the importance of the parameter measured, is the infamous Hubble tension. This refers to the disagreement between measurements of the Hubble constant, which describes the rate of expansion of the Universe, a cornerstone of our cosmological understanding. In recent years the methods for measuring H0 have grown in number and sophistication, and yet, as the uncertainties of the measurements have decreased, the tension has not been solved; in fact, it has increased.
Such methods can be roughly divided between "early" and "late" probes of H0, approximately referring to the time of origin of the phenomenon observed. While "early" probes, based for example on the cosmic microwave background, are strongly dependent on the assumed cosmology, "late" probes are generally model-independent but are more susceptible to systematic errors in the measurements. In this context, the time delay cosmographic method is a "late" time probe which can measure H0 directly, without requiring any calibration. This analysis is based on the well-tested general relativity phenomenon of strong gravitational lensing. Given a background variable source and a foreground strong gravitational lens, the time delay between the multiple lensed images can be measured by monitoring and analysing their luminosity over time. A separate modelling analysis of the system can then constrain the mass profile of the lens. The two combined information can then be used to constrain the Hubble constant. In this work, I implemented this analysis based on Hubble Space Telescope archival data and a dedicated observational campaign from the 2.1-meter telescope at Wendelstein. I employed the space-based data by taking advantage of the multiple filters available and their higher resolution to model the lens mass, obtaining a result with 3% precision on the Fermat potential.
I instead used the data from the Wendelstein observational campaign to produce the lightcurves of the image and analyse them in order to constrain the time delay, which was obtained with a precision ranging from 8% to 15% depending on the image pair.
I then combined the results following a Bayesian approach, reaching a constraint on H0 of 71.3+5.0 -4.5 km/(s*Mpc) with a precision ~6.7% considering random uncertainty.
Notably, this work has been mostly independent of major collaborations, such as TDCOSMO, thus providing an unbiased validation of the methodology. Furthermore, the result is proof of the capabilities of the Wendelstein observatory, which should be considered a reliable asset for time delay cosmography or similar projects that require high-sampling, high-quality data