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- DFG Forschungsgruppe 2757 / Lokale Selbstregelungen im Kontext schwacher Staatlichkeit in Antike und Moderne (LoSAM) (2)
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The present study focuses on Rulin waishi 儒林外史 (The Unofficial History of the Scholars), a well-known Qing novel, from the perspective of gender. It attempts to contribute to the discussion about Chinese masculinity by identifying the representation of the scholars' masculinity in Rulin waishi and offer a better understanding of the novel's position regarding femininity and women.
This project shows that the novel nevertheless reflects rather than challenges gender ideologies of its time. The ideal manhood showed in the novel comprises real virtues and authentic learning. It goes against the traditional, orthodox Confucian masculinity which advocates that officialdom is the glorious path to fulfill a learned man's masculinity. It is mainly due to Wu Jingzi's own failure in the civil service examinations and official careers. Regarding the relation of masculinity and sexuality, the novel reveals that a masculine man is not tempted by female charm but can enjoy a harmonious and companionate marriage. Besides, scholars show great anxiety about their masculinity since they are in a marginal position in society. Their manliness is challenged by officials, merchants, and even commoners, as well as their colleagues.
Through a careful examination of stories of Pinniang, Miss Lu, and Mrs. Wang, it reveals that the novel holds a conventional opinion on women although it criticizes widow suicide and shows an egalitarian husband-wife relationship. It praises Confucian womanly virtues, such as following and serving the husband, managing the household, and keeping chastity. Female sexuality is blamed as an evil temptation to lead men to go astray. Women’s learning gains legitimacy when serving to fulfill domestic responsibilities. It carries the Confucian message that men should take the lead and maintain order in the household and reinforces the rightful patriarchy.
In a word, rather than go ahead of its time, Rulin waishi holds a conservative attitude towards gender issues.
Der zweizeitige Endoprothesenwechsel gilt als Goldstandard der Therapie periprothetischer Gelenkinfektionen. Ein sicherer Ausschluss einer Infektpersistenz ist für den Therapieerfolg essentiel. Es wurde der diagnostische Nutzen synovialer Marker zum Ausschluss einer Infektpersistenz bei einliegendem Kniegelenksspacer untersucht. Weder mikrobiologische noch zytologische Synovia-Analysen sind zum Ausschluss einer Infektpersistenz im Rahmen des zweizeitigen Knieendoprothesenwechsels geeignet.
Recent progress in nanotechnology has attracted interest to a biomedical application of the carbon nanoparticle C60 fullerene (C60) due to its unique structure and versatile biological activity. In the current study the dual functionality of C60 as a photosensitizer and a drug nanocarrier was exploited to improve the efficiency of chemotherapeutic drugs towards human leukemic cells.
Pristine C60 demonstrated time-dependent accumulation with predominant mitochondrial localization in leukemic cells. C60’s effects on leukemic cells irradiated with high power single chip LEDs of different wavelengths were assessed to find out the most effective photoexcitation conditions. A C60-based noncovalent nanosized system as a carrier for an optimized drug delivery to the cells was evaluated in accordance to its physicochemical properties and toxic effects. Finally, nanomolar amounts of C60-drug nanocomplexes in 1:1 and 2:1 molar ratios were explored to improve the efficiency of cell treatment, complementing it with photodynamic approach.
A proposed treatment strategy was developed for C60 nanocomplexes with the common chemotherapeutic drug Doxorubicin, whose intracellular accumulation and localization, cytotoxicity and mechanism of action were investigated. The developed strategy was revealed to be transferable to an alternative potent anticancer drug – the herbal alkaloid Berberine.
Hereafter, a strong synergy of treatments arising from the combination of C60-mediated drug delivery and C60 photoexcitation was revealed. Presented data indicate that a combination of chemo- and photodynamic treatments with C60-drug nanoformulations could provide a promising synergetic approach for cancer treatment.
Peptide receptor radionuclide therapy (PRRT) is a molecular targeted radiation therapy involving the systemic administration of radiolabeled somatostatin receptor binding peptides designed to target with high affinity and specificity receptors overexpressed on tumors. Peptides are applied which either target as agonist (with internalization) or antagonist (little to no internalization). Recently, two novel antagonistic agents have been developed for clinical use: OPS202 and OPS201. 68Ga-labelled OPS202 is used for diagnostic purposes with positron emission tomography and 177Lu-labelled OPS201 is used for the therapy in patients with neuroendocrine tumors (NETs). Both agents are presently under clinical evaluation. Despite the very low internalization rate, the use of somatostatin receptor antagonists which target more binding sites on receptors are expected to result in higher specificity, more favorable pharmacokinetics and higher tumor retention and better visualization than the agonists. The main goal of this thesis was analyzing the biodistribution, biokinetics and internal dosimetry of the recently developed somatostatin receptor antagonists (OPS201 and OPS202) for therapeutic and diagnostic purposes in different species (mice, pigs and patients). In addition, an analysis of the influence of image quantification and the integration of time activity curves on kidney dosimetry in a pig model was carried out. Furthermore, extrapolation methods, which are used for predicting organ absorbed doses for humans based on preclinical animal models, were systematically compared for blood, liver, and kidneys of OPS201 injected species. Based on the OPS202 injected patients’ investigations, 68Ga-OPS202 shows promising biodistribution and imaging properties with tumor contrast which is optimal one hour after injection of the radiotracer. OPS202 is well tolerated and delivers absorbed doses to organs that are lower than those by 18F-FDG and similar to other 68Ga-labeled somatostatin receptor ligands. As a result of 68Ga OPS202 injection, the highest absorbed doses were observed in the urinary bladder (0.10 mGy/MBq) and kidneys (0.84 mGy/MBq). The calculated mean effective dose coefficient of 68Ga-OPS202 injected patients was 0.024 mSv/MBq (3.6 mSv for 150 MBq 68Ga-OPS202 injection) which is similar to other 68Ga-labeled compounds. Based on the OPS201 biokinetics and dosimetry investigations, after the injection of 177Lu-OPS201, a fast blood clearance of the compound is observed in the first phase (half-life: 1.83 h) for each species. 10 min after injection, less than 5% of the injected activity per milliliter of blood circulates in pigs and humans. The analysis of the mice, pig and preliminary patient data provides evidence that, patients enrolled in a phase 1 177Lu-OPS201 trial would not be at risk of overexposure. Based on our results, for 177Lu labelled studies, late time points after 72 h have a great impact on absorbed dose calculations. That is why follow-up times especially at late time points (more than 72 h) are required for the time-integrated activity coefficient (TIAC) calculations in order to represent the area under the curve appropriately and to analyze both biokinetics and dosimetry accurately. In addition, to find the most adequate extrapolation methods that minimize the interspecies differences of dosimetry data, several extrapolation methods from animal to human have been tested. For OPS201 time scaling or combination of relative mass and time scaling results in most similar TIAC values, if the organ mass ratios between the species are high. In time scaling, the scan/sampling time is scaled by using the ratio of the whole body masses of the respective species. In relative mass scaling, the TIACs are scaled based on the ratio of the whole body and organ mass of respective species. Other methods tested showed higher deviations. For the study on the influence of image quantification and the choice of the optimal scanning time points, a study in a pig model, which was performed in collaboration with Aalborg University and Octreopharm Sciences GmbH, was reanalyzed. As kidneys are organs-at-risk in PRRT with 177Lu labelled peptides, several quantification methods, based on 2D and 3D quantitative imaging were chosen. For this purpose, a 3D printed pig kidney phantom was prepared and measured with/without background activities representing the activities in the pig SPECT/CT scans. The phantom dosimetry data based on multiple SPECT/CT images and based on multiple planar images in combination with one SPECT/CT scan (MP1S Imaging) were compared to the pig dosimetry. The calculated TIACs of the phantom with background based on multiple SPECT/CT and MP1S imaging were quite similar to the multiple SPECT/CT based pig TIAC. In addition, in order to investigate the effect of late time points on dosimetry and absorbed dose values in 177Lu therapies, the difference, associated with eliminating the late two scan time points, on the TIACs was analyzed. When the TIACs (including all time points) of the pig based on multiple SPECT/CT and MP1S imaging were investigated, the use of MP1S imaging results in considerably lower TIAC values to the kidney (by a factor of 1.4). With eliminating late time points from the created time activity curve, the factor increases up to 2.4 times with a corresponding increase in TIAC uncertainties. As a consequence, further evaluation of 68Ga-OPS202 for PET/CT imaging and 177Lu-OPS201 for the treatments of NET patients is necessary. In particular, a head-to-head comparison of agonists and OPS peptides with respect to biokinetics, biodistribution and dosimetry would be helpful. In addition, the influence of the late scan time points on dosimetry needs further attention in particular for kidney dosimetry
In dieser Dissertation wird der MEK5/ERK5- Signalweg als möglicher Angriffspunkt in der zielgerichteten Melanomtherapie identifiziert. Die Adressierung von ERK5 bietet eine Alternative, um einer Resistenzentwicklung gegenüber Inhibitoren des MAPK- Signalwegs entgegenzuwirken. Das maligne Melanom ist ein hochaggressiver Tumor mit steigender Inzidenz. Zunehmende Sonnenstunden im Rahmen des Klimawandels mit erhöhter Belastung der Haut durch UV-Strahlung werden die Problematik des malignen Melanoms für den Menschen in den nächsten Jahren weiter zunehmen lassen.
Die Aktivierung des MEK5/ERK5- Signalwegs scheint eine Reaktion von Tumorzellen auf Therapiestress zu sein. Diese Aktivierung liefert den Melanomzellen einen Überlebensvorteil und verhindert ein langfristiges Therapieansprechen. ERK5 beeinflusst den Zellzyklus von Melanomzellen und ist somit möglicherweise von wichtiger Bedeutung in der Tumorgenese des malignen Melanoms.
Patienten mit NRAS- Mutation profitieren auffallend weniger von einer gezielten MEKi-Therapie als solche mit BRAF Mutation. Für ersteres Patientenkollektiv steht aktuell lediglich die Immuntherapie zur Verfügung, wodurch oft nur ein kurzes, progressionsfreies Intervall erreicht werden kann und die Patienten häufig unter schweren Nebenwirkungen leiden. Grund für die problematische Behandlung könnte das häufige Auftreten einer basalen ERK5- Aktivierung in NRAS- mutierten Melanomen sein. Diese Arbeit liefert eine positive Prognose über den Nutzen einer ERK5- Inhibition als Erweiterung des Therapieschemas. Diese These gilt auch für Melanompatienten mit einer BRAF- Mutation. Patienten, die an einem malignen Melanom erkrankt sind, weisen zu 80% eine Mutation in einem dieser beschriebenen Onkogene auf. Die Arbeit lässt darauf schließen, dass eine ERK5- Inhibition in der Therapie von beiden Gruppen erfolgreich sein könnte und somit das Leben nahezu aller Melanompatienten betrifft.
This work revealed spin states that are involved in the light generation of organic light-emitting diodes (OLEDs) that are based on thermally activated delayed fluorescence (TADF). First, several donor:acceptor-based TADF systems forming exciplex states were investigated. Afterwards, a TADF emitter that shows intramolecular charge transfer states but also forms exciplex states with a proper donor molecule was studied. The primary experimental technique was electron paramagnetic resonance (EPR), in particular the advanced methods electroluminescence detected magnetic resonance (ELDMR), photoluminescence detected magnetic resonance (PLDMR) and electrically detected magnetic resonance (EDMR). Additional information was gathered from time-resolved and continuous wave photoluminescence measurements.
The first Borono-Strecker reaction has been developed to synthesize α-aminoboronates via a multicomponent reaction of readily available carbonyl compounds (aldehydes and ketones), amines and B2pin2. The preparation of α-amino cyclic boronates can be achieved via multicomponent coupling of salicylaldehydes, amines, and B2(OH)4. In addition, the diazaborole-based PBP pincer palladium chloride and the diazaborole-based PBP pincer palladium trifluoromethanesulfonate complexes were synthesized and fully characterized for the first time, and used as catalysts for Suzuki-Miyaura cross-coupling reactions.
The quantum Hall (QH) effect, which can be induced in a two-dimensional (2D) electron gas by an external magnetic field, paved the way for topological concepts in condensed matter physics. While the QH effect can for that reason not exist without Landau levels, there is a plethora of topological phases of matter that can exist even in the absence of a magnetic field. For instance, the quantum spin Hall (QSH), the quantum anomalous Hall (QAH), and the three-dimensional (3D) topological insulator (TI) phase are insulating phases of matter that owe their nontrivial topology to an inverted band structure. The latter results from a strong spin-orbit interaction or, generally, from strong relativistic corrections. The main objective of this thesis is to explore the fate of these preexisting topological states of matter, when they are subjected to an external magnetic field, and analyze their connection to quantum anomalies. In particular, the realization of the parity anomaly in solid state systems is discussed. Furthermore, band structure engineering, i.e., changing the quantum well thickness, the strain, and the material composition, is employed to manipulate and investigate various topological properties of the prototype TI HgTe.
Like the QH phase, the QAH phase exhibits unidirectionally propagating metallic edge channels. But in contrast to the QH phase, it can exist without Landau levels. As such, the QAH phase is a condensed matter analog of the parity anomaly. We demonstrate that this connection facilitates a distinction between QH and QAH states in the presence of a magnetic field. We debunk therefore the widespread belief that these two topological phases of matter cannot be distinguished, since they are both described by a $\mathbb{Z}$ topological invariant. To be more precise, we demonstrate that the QAH topology remains encoded in a peculiar topological quantity, the spectral asymmetry, which quantifies the differences in the number of states between the conduction and valence band. Deriving the effective action of QAH insulators in magnetic fields, we show that the spectral asymmetry is thereby linked to a unique Chern-Simons term which contains the information about the QAH edge states. As a consequence, we reveal that counterpropagating QH and QAH edge states can emerge when a QAH insulator is subjected to an external magnetic field. These helical-like states exhibit exotic properties which make it possible to disentangle QH and QAH phases. Our findings are of particular importance for paramagnetic TIs in which an external magnetic field is required to induce the QAH phase.
A byproduct of the band inversion is the formation of additional extrema in the valence band dispersion at large momenta (the `camelback'). We develop a numerical implementation of the $8 \times 8$ Kane model to investigate signatures of the camelback in (Hg,Mn)Te quantum wells. Varying the quantum well thickness, as well as the Mn-concentration, we show that the class of topologically nontrivial quantum wells can be subdivided into direct gap and indirect gap TIs. In direct gap TIs, we show that, in the bulk $p$-regime, pinning of the chemical potential to the camelback can cause an onset to QH plateaus at exceptionally low magnetic fields (tens of mT). In contrast, in indirect gap TIs, the camelback prevents the observation of QH plateaus in the bulk $p$-regime up to large magnetic fields (a few tesla). These findings allowed us to attribute recent experimental observations in (Hg,Mn)Te quantum wells to the camelback. Although our discussion focuses on (Hg,Mn)Te, our model should likewise apply to other topological materials which exhibit a camelback feature in their valence band dispersion.
Furthermore, we employ the numerical implementation of the $8\times 8$ Kane model to explore the crossover from a 2D QSH to a 3D TI phase in strained HgTe quantum wells. The latter exhibit 2D topological surface states at their interfaces which, as we demonstrate, are very sensitive to the local symmetry of the crystal lattice and electrostatic gating. We determine the classical cyclotron frequency of surface electrons and compare our findings with experiments on strained HgTe.
DD is a cardiac disturbance, which has gained increasing importance in recent years due to its important role in different cardiac disease and cardiomyopathies including ischemic cardiomyopathy, arterial hypertension and diabetic cardiomyopathy.
ECG-gated 18F-FDG PET is an imaging technique, that can distinguish between districts of myocardial viability and myocardial scars and further provides information of great interest on the efficacy of experimental approaches designed to improve the cardiac function and/or myocardial metabolism in experimental small animal models. However, ECG-gated 18F-FDG PET is a technique whose feasibility in the assessment of the LV diastolic function in small animals has not been a subject of study.
In this thesis, the ability of the ECG-gated 18F-FDG PET for the assessment of both the systolic and diastolic function in eight control rats and in seven ZDF rats, which are an experimental animal model mimicking T2DM conditions and diabetic related complications in humans including DCM, has been investigated The ECG-gated 18F-FDG PET imaging was performed under hyperinsulinemic-euglycemic clamping and the data were stored in list mode files and retrospectively reconstructed. The systolic and diastolic parameters were achieved from the time/volume and the time/filling curve calculated from the software HFV. Additionally, the influence of the number of gates per cardiac cycle on the LV volumes and function parameters has been studied.
Hyperinsulinemic-euglycemic clamp procedure and blood glucose measurement did confirm the development of a manifest diabetes in the ZDF rats at the timepoint of the experiments.
Regarding the systolic parameters, no significant difference could be detected between the ZDF and ZL rats. The values for the CO were similar in both groups, which demonstrates a similar LV systolic function in the ZDF and the ZL rats at the age of 13 weeks. Values for the systolic parameters are in good line with previous PET, MRI and cardiac catheterization-based studies in diabetic rats.
The main finding of this study was that by using in vivo ECG-gated 18F-FDG PET and the software HFV, reliable diastolic parameters could be calculated. Moreover, it was possible to detect the presence of a mild impaired diastolic filling in the ZDF rats in absence of any systolic alteration. This impaired diastolic function in an early stage of diabetes could also be detected by other investigators, who used echocardiography or cardiac catheterization. Therefore, this is the first study showing, that the assessment of the diastolic function in rats can be carried out by ECG-gated 18F-FDG PET imaging.
In conclusion, additionally to calculating LV volumes and LV EF, ECG-gated 18F-FDG PET can evaluate the diastolic function of healthy and diabetic rats and is able to detect a DD in ZDF rats.
Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.