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Sialic acid/Siglec axis regulates antibody-mediated neutrophil cytotoxicity towards cancer cells
Get PDFThe first generation of immune checkpoint inhibitors approved are monoclonal antibodies restricted to molecules on T cells and are widely used in the clinic for the treatment of cancer patients. Neutrophils are the most abundant immune cell population in the circulation and, together with macrophages, are present in the microenvironment of many cancer types, however they are mainly suppressive immune cells and their existence is often associated with cancer progression. Targeting myeloid cells by reversing their immunosuppressive features may be beneficial. Upregulation of surface sialic acid on cancer cells activates sialic acid-binding immunoglobulin-type lectin (Siglec) inhibitory receptors on immune cells and prevents an immune response against tumor cells. This study investigates the role of sialic acid in the regulation of antibody-dependent myeloid cell activation against cancer cells. The presence of sialic acid turned out to inhibit antibody-dependent cellular phagocytosis by human macrophages (ADCP) and to diminish antibody-dependent cellular cytotoxicity mediated by human neutrophils (ADCC). Importantly, Siglec-9 could be identified as a key player in antibody-mediated cytotoxic activity of neutrophils with the application of a Siglec-9 blocking antibody. Additionally, bispecific antibody-lectin proteins that combine a cancer targeting Fab with a Siglec decoy receptor through an Fc part, were evaluated as potential and promising therapeutic tools to enhance neutrophil cytotoxicity against cancer cells. Taken together, it could be shown that the sialic acid/Siglec axis regulates antibody-dependent cytotoxic activity of myeloid cells and that it is a promising immune checkpoint to target that opens new perspectives in cancer immunotherapy
Evolution of the Australian Monsoon across the Middle Pleistocene Transition
Get PDFThe Australian Monsoon (AM) represents the Southern Hemisphere component of the large-scale Australasian monsoon system, which impacts the ecology, economy, and sustainability of some of the most densely populated regions on Earth. Located at the southern edge of the largest amplitude seasonal swing of the Intertropical Convergence Zone (ITCZ), the AM shows a different pattern of temporal variability compared to its Northern Hemisphere counterparts. However, most records of AM past variability are from the Holocene and Late Pleistocene, which limits our understanding of the AM long-term evolution. This thesis is based on sediment cores recovered at the International Ocean Discovery Program (IODP) Expedition 363 Site U1483, off northwestern Australia, which provide a unique record of the AM development over the past 2 million years (Ma). This study focuses on the evolution of the summer and winter phases of the AM across the Middle Pleistocene Transition (MPT). This highly enigmatic period was characterized by a remarkable change in climate cyclicity from 41 to 100 kyr. I performed oxygen and carbonate isotope analysis of benthic foraminifera and used X-ray fluorescence (XRF) core scanning records, spectral natural gamma-ray data, visible light reflectance spectroscopy data and benthic foraminifera assemblages to generate high-resolution proxies of AM variability over the last 1.6 Ma. Studies of radiolarian assemblages and bulk nitrogen isotopes in cooperation with researchers from institutions in Japan and the USA allowed additional insights into the variability of the Indonesian Throughflow and variations in paleoproductivity along the northwestern Australian margin over the last 2 Ma
Exploring the impact of the human FUT2 gene on gut lactobacilli and bifidobacteria to improve gut health through personalised probiotics
Get PDFThe human FUT2 gene encodes an enzyme that mediates the attachment of fucose to mucosal glycans. Individuals with one or two functional FUT2 alleles are secretors, while those with two non-functional alleles are non-secretors. Secretor status can influence gut microbiome diversity. Probiotics can improve gut health, but their relationship with host secretor status is not well understood. The aim of this project was to investigate whether secretor status influences gut microbiome taxa with probiotic potential, namely bifidobacteria and lactobacilli, to identify secretor status-based probiotic candidates. The relationship between secretor status and the abundance of lactobacilli and bifidobacteria was investigated using 16S rRNA gene sequencing data from stool samples, but there were no significant differences between secretors and non-secretors. However, different lactobacilli genera were present in the two groups, with secretors presenting mainly Limosilactobacillus and Ligilactobacillus. In parallel, bacterial colonies isolated from stool samples were identified using a novel 16S rRNA gene-based identification method and the genomes of bifidobacteria and lactobacilli strains were sequenced. Bifidobacteria were isolated significantly more often from secretors than non-secretors. However, there were no significant differences according to secretor status in terms of fucose-specific genes and functional categories in lactobacilli, bifidobacteria and B. longum subsp. longum. Finally, an opinion paper was developed to explore the evolutionary mismatch between modern weight loss goals and the survival-oriented human physiology, focusing on the influence of factors such as population genetics and the gut microbiome. Overall, the results of this study did not support the possibility of enhancing probiotic efficacy through customization based on secretor status
First records and rediscovery of extinct species of wild bees and aculeate wasps for Schleswig-Holstein (Hymenoptera Aculeata)
Get PDFDurch intensive Sammelaktivitäten in den letzten Jahren, besonders der Mitglieder der AG Stechimmen Schleswig-Holstein im Zeitraum von 2016-2022, wurden 37 Stechimmenarten (Hymenoptera Aculeata) erstmals für Schleswig-Holstein nachgewiesen sowie 19 Arten wiedergefunden, die für das Bundesland als verschollen galten. Die Erstnachweise werden im Kontext bekannter Vorkommen aus benachbarten (Bundes-)Ländern diskutiert. Hierbei ist vor allem eine starke Nordausbreitung wärmeliebender Arten durch klimatische Veränderungen zu beobachten.Especially intensive collecting activities of the AG Stechimmen Schleswig-Holstein during the years 2016-2022 resulted in the discovery of 37 species of wild bees and aculeate wasps (Hymenoptera Aculeata) that were recorded for the first time in Schleswig-Holstein, Germany, as well as the rediscovery of 19 species that were considered extinct for this region. The newly discovered species are discussed regarding their known distribution in neighbouring regions. In particular, a strong northward dispersal of thermophilic species can be observed, presumably due to climate warming
Addressing the Challenge of Ambiguous Data in Deep Learning: A Strategy for Creating High-quality Image Annotations with Human Reliability and Judgement Enhancement
Get PDFIn machine learning, the availability of high-quality labeled data is essential for training accurate models. However, humans often disagree among themselves or over time when labeling or annotating image classification data. As a result, they create ambiguous data that poses a significant challenge to deep learning. This research focuses on addressing this issue by proposing an overview that defines the problem, provides the necessary data for research, establishes evaluation metrics and presents methods for solving the problem. The ultimate goal is to develop an effective annotation strategy for image classification based on several thousand different experiments to improve data quality while reducing cost. The main idea of this dissertation is not to rely on one annotation per image, but to consider the average of multiple annotations. However, this would not be feasible in reality without reducing the cost of acquiring such annotations. This dissertation uses proposals as a guide during the annotation process to improve the consistency of the annotations and to reduce the annotation time and thus the associated costs. The use of proposals could introduce a bias into the data. Analysis of this bias and its introduction led to possible methods to minimize or reverse it. All this research is finally unified in an annotation strategy in the form of a flowchart that allows future research to easily understand the necessary steps needed to produce high quality data for their specific use case with as little effort as possible. This strategy is successfully verified on a real biomedical task. In conclusion, this thesis presents a comprehensive investigation of the challenges posed by annotating ambiguous data in deep learning. This research provides an effective strategy to address the fundamental issue of data quality, thereby improving the quality and reliability of models and advancing the field of deep learning as a whole
Persönliche und gesellschaftsbezogene Vorteile im (pseudo-)nachhaltigen Konsum.: Ein multiperspektivischer Ansatz
No full textThis dissertation investigates consumers’ motivations, behaviors and responses to various stimuli in a specific context: sustainable business models, that provide both, self-related and society-related benefits and can potentially induce pseudo-sustainable consumption. It further exploits the diverging influences of identity-related concepts on consumer behavior in this consumption context. Hence, this doctoral dissertation also sheds light on detrimental effects. It aims to inspire academics to further explore sustainable business models that provide self-related benefits and society-related benefits with the ultimate goal of enabling a genuinely sustainable society, while avoiding the promotion of pseudo-sustainable consumption habits. Future research agendas are proposed to circumvent possible drawbacks of win-win situations in human behavior. This thesis seeks to provide practitioners, politicians, and non-governmental organizations with concrete implications on how to promote such business models without evoking negative environmental consequences across multiple consumption decisions. Ultimately, this research emphasizes the need for practitioners and researchers to shift perspective from evaluating individual consumption choices to examining aggregated consumption patterns in order to effectively cultivate a sustainable future
Minimally-invasive biomarker discovery and functional analyses in Atopic Dermatitis
Get PDFAtopic dermatitis (AD) is the most common chronic inflammatory skin disease and characterized by a great heterogeneity including eczematous lesions, intense pruritus and a chronic or relapsing disease course. Despite increasingly complex and high-quality studies have advanced our understanding of disease pathology and led to the development of accurate targeted therapies, various questions regarding the pathogenesis and the triggering factors contributing to disease manifestation remain unclear. This thesis demonstrates that keratinocytes present one major source of reactive oxygen species (ROS) underlining their substantial contribution to skin inflammation. Pan and specific NADPH oxidase (NOX) inhibition was performed and revealed that inhibition of NOX seems to be effective in lowering oxidative stress and improving survival in AD-model keratinocytes. Moreover, tape strips, a tool to perform minimally invasive biosampling, obtained from children at high risk for developing AD were used in order to characterize the pro-inflammatory environment in the epidermis. Several pro-inflammatory proteins are highly abundant in the stratum corneum of children at AD onset or even precede disease manifestation. This thesis thereby underlines the feasibility of tape strips for characterization of the inflammatory environment in the skin which would notably improve biosamples quantity required for biomarker identification. In a third and fourth study, 3-dimensional (3D) models of human skin were applied and refined. T cells and Staphylococcus aureus were incorporated into the 3D skin model to better mimic an in vivo scenario. This resulted in improved model complexity that is essential to conduct functional experiments related to AD pathology
Sophie von Dänemark (1557–1631): Von der jugendlichen Braut zur einflussreichen Königinwitwe
Get PDFKönigin Sophie von Dänemark war eine bemerkenswerte Persönlichkeit und eine Schlüsselfigur innerhalb der protestantischen Dynastien. Als einzige Tochter des Herzogs Ulrich von Mecklenburg und der dänischen Prinzessin Elisabeth war sie ebenso ehrgeizig wie hartnäckig. Im Alter von 14 Jahren mit dem 23 Jahre älteren König Friedrich II. von Dänemark verheiratet und nach 14 Jahren verwitwet, wurde sie zu einer der einflussreichsten Frauen ihrer Zeit. Mit einem breiten Spektrum an Interessen und der Fähigkeit, als Witwe neue Tätigkeitsfelder zu erschließen, war Sophie wirtschaftlich äußerst erfolgreich und spielte eine wichtige Rolle bei der Finanzierung der Kriege ihres Sohnes Christian IV. von Dänemark und der protestantischen Fürsten des Heiligen Römischen Reiches.Queen Sophie of Denmark was a remarkable personality and a key figure within the Protestant dynasties. As the only daughter of Duke Ulrich of Mecklenburg and the Danish Princess Elisabeth, she was as ambitious as she was tenacious. Married at the age of 14 to King Frederick II of Denmark, who was 23 years her senior, and widowed after 14 years, she became one of the most influential women of her time. With a wide range of interests and the ability to open up new fields of activity as a widow, Sophie was extremely successful economically and played an important role in financing the wars of her son, Christian IV of Denmark, and the Protestant princes of the Holy Roman Empire
Schwesterliches Handeln in dynastischer Krise: Kurfürstin Elisabeth von Brandenburg (1485–1555) in Beziehung zu ihrem Bruder König Christian II. von Dänemark (1481–1559)
Get PDFDer Aufsatz konzentriert sich auf Kurfürstin Elisabeth von Brandenburg (1485-1555) in ihrer Rolle als jüngere Schwester des dänischen Königs Christian II. (1481-1559) und untersucht an diesem lehrreichen Beispiel eines Geschwisterpaares in nahezu permanenter Krise die Bedeutung von Geschwisterbeziehungen innerhalb des Hochadels. Zunächst werden der familiäre Hintergrund und der Lebensweg von Elisabeth und Christian skizziert. Anschließend wird das Handeln der Kurfürstin in ihrer Rolle als Schwester anhand ihrer umfangreichen erhaltenen Korrespondenz analysiert. Es wird gezeigt, dass die Beziehung zum Bruder als Repräsentant der Herkunftsfamilie für die Identität einer hochadligen Frau von größerer Bedeutung sein konnte als etwa die Beziehung zum Ehemann oder zu den leiblichen Kindern, und dass diese Bedeutung entsprechende Entscheidungen und Handlungen nach sich zog.This essay focuses on Electress Elisabeth of Brandenburg (1485–1555) in her role as the younger sister of the Danish King Christian II (1481–1559), using this instructive example of a sibling pair in almost permanent crisis mode to examine the significance of sibling relationships within the high nobility. Initially, the family background and life paths of Elisabeth and Christian are outlined. Subsequently, the Electress’s actions in her role as a sister are analyzed through her extensive preserved correspondences. This essay demonstrates that the relationship with a brother, as a representative of the family of origin, could hold greater significance for the identity of a woman of high nobility than, for instance, her relationship with her husband or biological children, and that this significance entailed corresponding decisions and actions
Dorothea von Brandenburg: Die zentrale Fürstin der dänischen und schleswig-holsteinischen Geschichte
Get PDFDieser Beitrag untersucht die zentrale Rolle, die Königin Dorothea von Brandenburg (ca. 1431-1495) in der skandinavischen Geschichte spielte. Sie war mit dem letzten König der Jelling-Dynastie verheiratet und wurde nach dem Tod des letzten Königs zum Bindeglied und Türöffner für die neue Oldenburger Dynastie. Gleichzeitig nutzte sie ihre Rolle als Königin, um aktiv Macht in der Politik auszuüben und sich mit Schleswig und Holstein eine persönliche Machtbasis zu schaffen, die sie an ihren jüngsten Sohn Friedrich weitergeben wollte.This article examines the central role that Queen Dorothea of Brandenburg, circa 1431–1495, played in Scandinavian history. Married to the last king of the Jelling dynasty, she became the link to and door-opener for the new Oldenburg dynasty after the last king’s death. At the same time, she used her position as queen to actively exercise political power and to establish a personal power base for herself with Schleswig and Holstein, which she intended to pass on to her youngest son, Frederick