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Neuropilin 2 in Osteoblasten
Get PDFNeuropilin-2 (Nrp2) wird zunehmend als potenzielles therapeutisches Ziel bei Knochenmetastasen des kastrationsresistenten Prostatakarzinoms (CRPC) diskutiert. Es spielt eine Rolle in der Regulation der Osteogenese, doch seine spezifische Funktion in Osteoblasten ist bislang unzureichend verstanden. Ziel dieser Arbeit war es, die Rolle von Nrp2 in der Osteogenese zu charakterisieren und seine potenzielle therapeutische Relevanz zu bewerten. Hierzu wurde untersucht, wie eine Depletion von Nrp2 die Differenzierung muriner Präosteoblasten beeinflusst. Analysen zur Proliferation, Viabilität, Mineralisierung, Expression osteoblastischer Marker sowie ergänzende Sekretomanalyse und RNA-Sequenzierungen zeigten, dass der Verlust von Nrp2 die Mineralisierungskapazität signifikant reduziert, während die Expression der meisten Differenzierungsmarker weitgehend unverändert bleibt. Die Ergebnisse weisen auf eine funktionelle Rolle von Nrp2 in der Osteoblastendifferenzierung hin und legen nahe, dass eine gezielte Blockierung von Nrp2 einen vielversprechenden Ansatz zur Behandlung von Knochenmetastasen des CRPC darstellen könnte
Identification of novel mediators of T cell function in chronic infection and cancer
No full textCytotoxic CD8+ T cells are critical mediators of immunity against chronic viral infection and cancer. However, when CD8+ T cells are persistently exposed to high amounts of antigen, they lose their functionality and differentiate into 'exhausted' T cells (TEX). Hallmarks of exhaustion are high expression of inhibitory receptors, also called immune checkpoints, like PD-1, increased expression of TCR-responsive transcription factors like TOX, compromised cytokine production and diminished proliferative capacity. Previous studies by our group and others have shown that the pool of exhausted T cells contains functionally important subsets with distinct epigenetically and transcriptional profiles, including precursors of exhausted T cells (TPEX). TPEX display characteristics of both, exhausted and memory T cells. Furthermore, they include a population of stem-like cells, marked by the expression of CD62L and the transcription factor Myb, that mediates long term maintenance of CD8+ T cell immunity and response to PD-1 checkpoint inhibition by a proliferative burst. It was shown that TPEX cells can differentiate into two distinct populations of TEX, including CX3CR1+ effector-like cells and CD101+ terminally exhausted cells. The molecular mechanism that regulates and drive the differentiation of TPEX and TEX and thus giving rise to new targets of cancer therapy, are still not fully understood. In this thesis we identify SATB1 as a critical factor in TPEX and TEX differentiation. SATB1 deficiency accelerates TEX formation in chronic infection and skews acute infection responses toward effector memory. It also regulates cytokine expression and PD-1 levels, making it a potential target for CAR-T therapies. Additionally, we show that migratory molecules (CD62L, CCR7, S1PR1) are crucial for TPEX maintenance and TEX generation. Their disruption primarily affects CX3CR1+ TEX cells, highlighting the role of spatial organization in exhaustion regulation. Finally, we establish KLF2 as a key regulator controlling the development of CD62L+ TPEX cells and their differentiation into CX3CR1+ TEX cells. KLF2 loss enhances effector function but increases exhaustion markers. Notably, statins upregulate KLF2, suggesting a pharmacological approach to modulating exhaustion dynamics. These findings advance our understanding of CD8+ T cell differentiation and exhaustion, providing insights for improving immunotherapies in chronic infections and cancer
Global China : New Approaches to Research on China in the World
Get PDFThe Routledge Handbook on Global China provides in-depth research that examines the multifaceted phenomenon of Global China, presenting a comprehensive view to understand China's engagement on the global stage. The introduction to this volume contextualizes the chapters that follow, exploring the complex interplay between politics, economy and society, focusing on China's emergence as a global economic power and the impact of its economic strategies and initiatives on international relations. In recent decades, China's increasing involvement in trade, investment and global supply chains has shifted global attention from economic efficiency to geopolitical concerns and normative issues, positioning China as a systemic rival to the Western collective. The Handbook, however, suggests different theoretical and analytical lenses to make sense of the emergence of Global China. It encourages a reassessment of norms, practices and knowledge production, embodying a transformative process that challenges established paradigms and promotes epistemic decolonization and postcolonial reorientations. These shifts are dynamic and subject to interactions with hegemonic discourses and political agendas, illustrating the challenges and opportunities associated with this phenomenon. Three epistemic commitments are proposed for the study of Global China: The promotion of diverse viewpoints and non-binary frameworks, the adoption of nuanced modes of analysis to analyze China's transnational relations, and the promotion of alternative methodological approaches and research designs to envision different future trajectories for China in international affairs. The chapters in this handbook aim to illuminate the multidirectional and transformative nature of Global China, fostering theoretical innovation, methodological reflection and analytical transformation, offering new ways to critically engage with China's global involvements and prompting a reassessment of existing theories about the complexity of global dynamics
Development and Application of Automated Quantum Chemical Workflows for the Computation of Non-Covalent Interactions and Mass Spectra
Get PDFThe topic of this thesis is to advance the automated and efficient quantum chemical description of chemical systems, with a particular focus on non-covalent interactions (NCIs) and mass spectrometry (MS). In Chapter 1, both topics are introduced, and the associated challenges and opportunities in their computation are outlined. An overview of the relevant quantum chemical methods and theoretical concepts to accurately describe these systems is given in Chapter 2. The typically large system size of NCI complexes requires the use of efficient approximate low-cost methods, such as density functional theory (DFT), semiempirical quantum mechanical (SQM) methods, or force field (FF) methods, whose accuracy has to be benchmarked against more accurate and robust reference methods. This is addressed in the LNCI16 benchmark study, which assesses the performance of low-cost DFT, SQM, and FF methods for calculating gas-phase interaction energies of 16 very large, non-covalently bound complexes. With system sizes of up to approximately 2000 atoms, this benchmark provides a unique testing ground for evaluating the robustness of computational methods applied to large molecular systems. To describe the binding behavior of supramolecular complexes, their lowest-energy geometry must be determined, taking into account their conformational flexibility, as well as thermal and solvation effects. These factors are explored through a dedicated benchmark study named HS13L, which employs different methods in a multilevel workflow for direct comparison to experimental binding constants. Herein, excellent agreement with the experimental reference values was achieved.
In the second part of this thesis, the computation of MS is investigated. The challenges in computing mass spectra arise from the high energies involved in the experiments, which result in a large number of possible fragmentation reactions that must be computed efficiently and in an automated manner. Since a generally applicable and sufficiently accurate quantum chemical approach for this task is still lacking, a new program, QCxMS2, was developed. Whereas existing quantum chemical approaches, such as QCxMS, are based on molecular dynamics simulations, QCxMS2 follows a novel strategy based on automated reaction discovery. Herein, the development of QCxMS2 is presented, along with its superior agreement with experimental electron ionization (EI) mass spectra compared to its predecessor and main competitor, QCxMS. Furthermore, the extension of QCxMS2 to enable the calculation of collision-induced dissociation (CID) mass spectra is described. As for EI-MS, a significant improvement over QCxMS was demonstrated through comparison with experimental spectra. In conclusion, the compiled benchmark sets in this thesis yield useful information on which method to employ for the efficient modeling of supramolecular complexes. Furthermore, the newly developed open-source software QCxMS2 provides a valuable tool that can be integrated into automated structure elucidation workflows for the identification of unknown compounds
Écrire l'histoire de la littérature européenne : Actes du colloque international de St Andrews le 4 et 5 juin 2024
Get PDFL'objectif du volume est de souligner que, dans leur création, les histoires littéraires nationales en Europe ont été écrites dans le but de donner une validité historique aux traditions nationales perçues comme ayant vu le jour dans le cadre d'un canon européen et par le biais d‘échanges, d'influences et d'adaptations. À ce titre, il serait exagéré de prétendre que les histoires littéraires nationales et européennes constituent des approches exclusives. Les contributions examinent sous des angles régionaux, systématiques et méthodologiques différents la question de savoir comment écrire une histoire de la littérature européenne
Platelet-derived transcription factors as modulators of NFκB-dependent inflammatory responses in human monocytes
Get PDFPlatelets have immunomodulatory roles beyond their classical function in hemostasis, for example regulating monocyte-driven inflammation. Classical CD14+ monocytes dominate in human blood and mediate immune responses by producing pro-inflammatory cytokines such as IL-1β and TNFα. Tight regulation of these responses is crucial, as excessive activation leads to cytokine storms, whereas impaired activation causes immunoparalysis, commonly observed in sepsis or viral infections.
Previous research from my group demonstrated that platelets are required for optimal monocyte cytokine responses independently of classical co-stimulation. Platelet depletion reduces pro-inflammatory cytokine secretion and gene expression in activated monocytes, mirroring conditions like ITP. Supplementation with platelets restores inflammatory functions of monocytes, highlighting platelet-derived factors as critical regulators.
This thesis identifies a previously unrecognized mechanism in which platelets enhance monocyte cytokine production through extracellular vesicle (EV)-mediated transfer of NFκB pathway components. Particularly, SILAC-based proteomic analyses demonstrated that platelets transfer essential NFκB pathway components, such as the transcription factor NFκB2. This vesicle-mediated delivery occurs constitutively and independent of platelet activation or external stimulation. Using CRISPR-Cas9-generated NFκB-deficient THP-1 monocytes and pharmacological inhibitors, I confirmed that platelet-derived factors are essential for robust monocyte cytokine responses. Furthermore, I was able to show that platelet-derived EVs contain active NFκB components both ex vivo and in human serum and plasma, highlighting their physiological relevance. Comparative interspecies analyses indicate evolutionary conservation of platelet-monocyte interactions and EV-mediated transcription factor transfer between humans and mice.
Overall, this work defines a novel axis of immune regulation driven by platelet-derived EVs delivering bioactive transcriptional regulators. These insights enhance our understanding of platelets as key inflammatory regulators and suggest new therapeutic strategies for inflammatory and immunodeficiency disorders.Thrombozyten-abgeleitete Transkriptionsfaktoren als Modulatoren NFκB-abhängiger inflammatorischer Antworten in humanen Monozyten
Thrombozyten besitzen immunmodulatorische Funktionen, die über ihre klassische Rolle in der Hämostase hinausgehen, beispielsweise indem sie die von Monozyten getriebene Entzündung regulieren. Klassische CD14+-Monozyten dominieren im menschlichen Blut und vermitteln Immunantworten durch die Produktion proinflammatorischer Zytokine wie IL-1β und TNFα. Die präzise Regulierung dieser Antworten ist essenziell, da eine überschießende Aktivierung zu Zytokinstürmen führt, während eine unzureichende Aktivierung eine Immunparalyse hervorrufen kann, wie sie häufig bei Sepsis oder Virusinfektionen beobachtet wird.
Frühere Arbeiten aus meiner Arbeitsgruppe zeigten, dass Thrombozyten für optimale Monozyten-Zytokinantworten erforderlich sind – unabhängig von klassischen Kostimulationssignalen. Eine Depletion von Thrombozyten reduziert die Sekretion proinflammatorischer Zytokine und die Genexpression in aktivierten Monozyten und spiegelt damit Zustände wie ITP wider. Die Zugabe von Thrombozyten stellt die inflammatorische Funktion der Monozyten wieder her, was Thrombozyten-abgeleitete Faktoren als entscheidende Regulatoren hervorhebt.
Diese Arbeit identifiziert einen bisher unentdeckten Mechanismus, durch den Thrombozyten die Zytokinproduktion von Monozyten durch einen extrazellulären Vesikel (EV)-vermittelten Transfer von NFκB-Signalwegkomponenten verstärken. Insbesondere zeigten SILAC-basierte Proteomik-Analysen, dass Thrombozyten essenzielle Bestandteile des NFκB-Signalwegs, wie den Transkriptionsfaktor NFκB2, in Monozyten übertragen. Diese vesikelvermittelte Übertragung erfolgt konstitutiv und unabhängig von Thrombozytenaktivierung oder externer Stimulation. Mithilfe von CRISPR-Cas9-generierten NFκB-defizienten THP-1-Monozyten sowie pharmakologischen Inhibitoren konnte ich bestätigen, dass Thrombozyten-abgeleitete Faktoren für eine robuste monozytäre Zytokinantwort unerlässlich sind. Zudem konnte ich zeigen, dass thrombozytäre EVs aktive NFκB-Komponenten sowohl ex vivo als auch in humanem Serum und Plasma enthalten, was ihre physiologische Relevanz unterstreicht. Vergleichende Interspezies-Analysen weisen zudem auf eine evolutionäre Konservierung der Thrombozyten-Monozyten-Interaktion und des EV-vermittelten Transfers von Transkriptionsfaktoren zwischen Mensch und Maus hin.
Zusammenfassend beschreibt diese Arbeit eine neuartige Achse der Immunregulation, die durch thrombozytäre EVs vermittelt wird, welche bioaktive transkriptionelle Regulatoren übertragen. Diese Erkenntnisse erweitern unser Verständnis von Thrombozyten als zentrale Regulatoren inflammatorischer Prozesse und eröffnen neue therapeutische Perspektiven für entzündliche Erkrankungen und immunologische Funktionsstörungen
Drivers of commercial poultry development in Sub-Saharan Africa : Lessons from case studies of commercial poultry operations in Nigeria and Senegal
Get PDFTransforming agrifood systems is a global priority, particularly in Africa where food security, nutrition and environmental issues remain critical. The poultry sector has the potential to contribute to this by providing affordable animal protein and improving rural livelihoods, while having a smaller environmental footprint than other types of livestock. However, despite growing demand, poultry production in Sub-Saharan Africa (SSA) remains low, averaging around 7 million tonnes per year between 2015 and 2022, far behind production in America (50.4 million tonnes), Asia (49.4 million tonnes) and Europe (21.5 million tonnes) (FAOSTAT, 2025). This results in a persistent reliance on imports. The sector is dominated by smallholder family systems with low productivity, which challenges its ability to meet the growing demand. Literature suggests that the more productive commercial sector has a key role to play in meeting demand. Understanding the mechanisms of success in this sector is important. However, there is a notable lack of research into the drivers of success in commercial poultry enterprises. This study addresses this gap by focusing on poultry businesses in Nigeria and Senegal, which were selected because West Africa has dominated poultry production in recent decades, with Nigeria being the largest producer and Senegal maintaining a long-standing ban on poultry imports. Their contrasting commercial poultry development and policy environments provide valuable nuances in the analysis. Using qualitative data and a framework emphasising entrepreneurial traits, business characteristics and the business environment as dimensions of success, the study finds that, while the business environment (including policy and industry conditions) plays an enabling or limiting role, business characteristics and strategic responses are crucial for leveraging opportunities or overcoming challenges. Although entrepreneurial traits are less directly linked to success, they influence entry capacity and enhance strategic approaches, thereby indirectly supporting long-term sustained performance. These insights enrich the literature on the poultry sector in SSA and offer guidance on how to strengthen its role in advancing broader food system goals
Robust COVID-19 Vaccine Responses Despite Filarial Co-Infection : Insights from a Lymphatic Filariasis Cohort in Ghana
Get PDFBackground/Objectives: Although the COVID-19 pandemic has largely concluded, the varied trajectories it has followed in different regions of the world remain incompletely understood. Intensive research is needed to fully grasp its course and the implications for future global health challenges. Notably, the milder trajectory of the COVID-19 pandemic in Sub-Saharan Africa has defied initial predictions. An emerging body of evidence suggests that, in addition to the continent’s younger average age and the lower prevalence of relevant comorbidities, co-infections with helminths may have also impressively shaped the pandemic’s milder trajectory in the region. Indeed, helminths are renowned for their ability to modulate human immune responses, which, while potentially beneficial in limiting excessive inflammation, could also diminish vaccine efficacy and impede viral clearance. This study investigated different aspects of the intricate interactions between COVID-19 and Lymphatic Filariasis (LF), a helminth infection caused by parasitic worms such as Wuchereria bancrofti, Brugia malayi, and Brugia timori and endemic to various regions in Sub-Saharan Africa and the tropics. Methods: For this purpose, samples of a larger and ongoing clinical trial (ethical approval codes: CHRPE/AP/525/17 and 325/21; trial registration number ISRCTN14042737) were collected from 222 individuals from endemic areas of Ghana, along with comprehensive clinical and demographic data. The samples include LF patients (n = 222) grouped according to their Lymphoedema (LE) stages, as well as COVID-19 vaccinated (n = 81) and non-vaccinated individuals (n = 141). All vaccinated participants received the COVID-19 vaccine ChAdOx1-S (also known as Vaxzevria) developed by the University of Oxford and AstraZenca. The expressions of SARS-CoV-2 and filarial-specific antibodies (IgG, IgA) were accessed using ELISA, while Luminex-based immunoassays were employed to measure the expression of SARS-CoV-2 variant-specific neutralizing antibodies. The interplay between vaccine responses and demographic factors was analyzed using group comparisons with the Kruskal-Wallis or Mann-Whitney U tests. Results: The results indicate that a remarkable portion of unvaccinated individuals (56% IgA seropositive, 39% IgG seropositive) developed antibodies against SARS-CoV-2 despite no confirmed infection. Notably, the study identified a robust antibody response to COVID-19 vaccination, which was independent of the degree of LF pathology or parasitic status. An important observation was the reduced SARS-CoV-2 antibody response in individuals seropositive for Ascaris lumbricoides (p = 0.0264), highlighting an interaction between roundworm infection and COVID-19. Conclusions: The study concludes that the ChAdOx1-S COVID-19 vaccine (AstraZeneca) triggers a strong immune response in LF patients; however, filarial and/or soil-transmitted helminth seropositivity might influence the COVID-19 infection-induced response. These findings emphasize the complexity of infectious disease dynamics in co-infected populations and the need to decipher parasite-induced immunomodulatory mechanisms on COVID-19 vaccination
cOmicsArt : a customizable Omics Analysis and reporting tool
Get PDFMotivation: The availability of bulk-omic data is steadily increasing, necessitating collaborative efforts between experimental and computational researchers. While software tools with graphical user interfaces (GUIs) enable rapid and interactive data assessment, they are limited to pre-implemented methods, often requiring transitions to custom code for further adjustments. However, the most available tools lack GUI-independent reproducibility such as direct integration with R, resulting in very limited support for transition. Results: We introduce the customizable Omics Analysis and reporting tool—cOmicsArt. cOmicsArt aims to enhance collaboration through integration of GUI-based analysis with R. The GUI allows researchers to perform user-friendly exploratory and statistical analyses with interactive visualizations and automatic documentation. Downloadable R scripts and results ensure reproducibility and seamless integration with R, supporting both novice and experienced programmers by enabling easy customizations and serving as a foundation for more advanced analyses. This versatility also allows for usage in educational settings guiding students from GUI-based analysis to R Code
Untargeted lipidomics reveals unique lipid signatures of extracellular vesicles from porcine colostrum and milk
Get PDFExtracellular vesicles (EV) are membranous vesicles considered as significant players in cell-to-cell communication. Milk provides adequate nutrition, transfers immunity, and promotes neonatal development, and milk EV are suggested to play a crucial role in these processes. Milk samples were obtained on days 0, 7, and 14 after parturition from sows receiving either a standard diet (ω-6:ω-3 = 13:1) or a test diet enriched in ω-3 (ω-6:ω-3 = 4:1). EV were isolated using ultracentrifugation coupled with size exclusion chromatography, and characterized by nanoparticle tracking analysis, transmission electron microscopy, and assessment of EV markers via Western blotting. The lipidome was determined following a liquid chromatography–quadrupole time-of-flight mass spectrometry approach. Here, we show that different stages of lactation (colostrum vs mature milk) have a distinct extracellular vesicle lipidomic profile. The distinct lipid content can be further explored to understand and regulate milk EV functionalities and primordial for enabling their diagnostic and therapeutic potential