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Ermittlung eines zirkadianen Kortikosteronprofils beim weiblichen Haushuhn (Gallus gallus domesticus)
Get PDFDie Behandlung von benignen Erkrankungen des Ösophagus im Kindes- und Jugendalter durch endoluminale Stents
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International comparison of selected European malaria recommendations for travellers
Get PDFBackground: Malaria ranks among the most frequently imported tropical diseases in Europe. It is potentially lethal. Many European countries therefore issue recommendations on malaria prevention to protect their travellers. However, the recommendations exhibit significant differences in both scope and content.
Objectives: This thesis intends to compare European malaria recommendations for travellers, analysing the differences. The aim is to lay the foundations for future efforts to harmonise a European guideline.
Methods: Internet research gathered malaria recommendations for European travellers by screening the web using the specific terms “recommendations”, “malaria”, and “travellers” in different European languages and reviewing national tropical medicine society websites. Selection criteria focused on detailed, accessible recommendations, considering historical links to malaria-endemic regions and high numbers of imported cases. Seven national recommendations from the UK, Germany, the Netherlands, Belgium, France, Spain, and Italy, published before 31 December 2020, were compared. The results were compiled in an Excel data sheet using Microsoft Office 2019 Professional Plus, version 2206.
Findings: Key findings included discrepancies in the definitions of malaria risk areas, with significant differences in the data used on the distribution of Plasmodium species in different countries and regions. In addition, there were differences in chemoprophylaxis recommendations and in advice on the procedure of emergency self-treatment. Furthermore, there were discrepancies in recommendations for pregnant and breastfeeding women and for children. Recommendations on mosquito repellents and clothing colour also differed.
Conclusions: European malaria recommendations for travellers vary due to a non-standardised and largely non-transparent methodology. In addition, the use of national data on imported malaria cases and incomplete epidemiological information from developing countries leads to varied interpretations among professional societies and regulatory bodies. Differences in the national approvals of medicines and repellents also lead to inconsistent recommendations. This underlines the need for improved communication within Europe to enable comprehensive data exchange for harmonisation. Enhanced education, particularly for the most significant risk group of travellers “visiting friends and relatives” in their country of origin (VFRs), is essential as most imported malaria cases result from traveller non-compliance rather than ineffective medication.
Two issues could contribute to knowledge transfer: differences in repellents regarding age limits for children and use during pregnancy appear to depend more on the specific product as a whole and its co-formulants, which affect absorption, than on the concentration of the active substance itself. Furthermore, wearing light-coloured clothing in tropical areas to protect against various mosquitoes, including nocturnal species, appears to be a sensible recommendation
IL1RL2 in immunity and intestinal homeostasis-Insights from patients with VEO-IBD
Get PDFVery early onset inflammatory bowel disease (VEO-IBD) is distinguished by intense, early-onset inflammation in the gastrointestinal tract and is often connected to genetic mutations. VEO-IBD patients usually exhibit intense disease indications that are unresponsive to treatments. Several signatures, including IL10R, RIPK1, MD2, and CASP8 deficiencies, have been identified in our laboratory as prominent monogenic causes of IBD. Nevertheless, the majority of VEO-IBD patients remain without a genetic diagnosis, highlighting the essential need to comprehend the pathophysiology for effective clinical management. Our laboratory has utilized whole exome sequencing to examine one of the largest international cohorts of VEO-IBD, with the objective of identifying previously unexplored genetic markers. This genetical screen revealed compound heterozygous missense mutations (c.[952A>G];[965A>C]) and splice region mutation (c.1298-4C>T) in IL1RL2 (Interleukin 1 receptor-like 2) as a novel risk factor for VEO-IBD.
This assessment purposed to enlighten the molecular mechanisms of IL1RL2 deficiency in macrophages and epithelial cells. The study utilized various advanced techniques, including CRISPR/Cas9-mediated genetic engineering, induced pluripotent stem cell (iPSC) differentiation towards macrophages and colonic organoids, and various immunological assays to investigate the impact of IL1RL2 mutations. Western blot analysis demonstrated reduced activation of the NFĸB and MAPK signaling pathways in patient-derived macrophages. Functional assays showed that the c.[952A>G];[965A>C] deficiency in IL1RL2 results in decreased expression of CD14, CD163, and CD273, indicating impaired macrophage polarization. Additionally, HCT116 cells expressing the c.952A>G or c.965A>C variants exhibited reduced NFĸB and MAPK activation, impaired wound healing, altered CCL20 expression, and increased cell death. iPSC-derived colonic organoids expressing c.[952A>G];[965A>C] or c.1298-4C>T exhibited impaired wound healing, altered IL1RL2 and CCL20 expression. This comprehensive study provides new insights into the molecular mechanisms underlying VEO-IBD and underscores the critical role of IL1RL2 in gut immunity. The findings suggest potential therapeutic targets for treating IBD through modulation of IL1RL2 signaling
Muskelaktivität in schlafnahen Bewusstseinszuständen zur Validierung von aktiven Menschmodellen
Get PDFElucidating the molecular mechanisms of developmental timing in mammals
Get PDFEmbryonic development from a single cell to a fully grown organism in mammals adheres to a strict pattern, yet the speed of these events, the developmental timescale, is unique to each species and varies significantly. In this thesis, I explore the genetic, epigenetic, and extracellular factors orchestrating this transition. By leveraging in vitro models and single-cell sequencing techniques, I uncover the relationship between the properties of pluripotent stem cells (PSCs) and their developmental speed during neural differentiation, emphasizing the role of metabolic regulation in influencing differentiation potentials.
I demonstrated a robust, universal system by cultivating PSCs from mouse, human, cynomolgus, and orangutans under harmonized conditions. In addition, I employed a uniform protocol to differentiate PSCs into neural progenitor cells (NPCs), highlighting nuanced differences in developmental speed among mouse, cynomolgus, and human. This standardization provided a ground for comparative studies, free from the interfering effects of extrinsic factors.
Applying time-course single-cell multiome sequencing, I provided an in-depth view of transcriptional and chromatin changes during neural differentiation. This method revealed species-specific patterns, with mouse cells differentiating the fastest, followed by cynomolgus and human. Linear regression models showed that mouse cells differentiate approximately 2.4 times faster than human cells and 2.2 times faster than cynomolgus cells based on gene expression data. Single-cell ATAC sequencing data showed similar trends, with mouse cells differentiating 1.9 times faster than human cells and 1.7 times faster than cynomolgus cells. This analysis underscores how cells from different species resemble and differ in their differentiation trajectories.
Through single-cell RNA sequencing analysis, I identified UGP2 as a gene upregulated in slower-differentiating species and slower-differentiating cells within one species. Deleting UGP2 in human and cynomolgus PSCs using CRISPR/Cas9 technology depleted cells of glycogen and accelerated neural differentiation, indicating its role in regulating metabolic rates by controlling glucose availability.
In conclusion, my thesis enhances our understanding of the molecular mechanisms governing developmental speed across species, demonstrating the importance of UGP2 in regulating glycogen storage and influencing differentiation rates. This research lays the groundwork for future studies into species-specific developmental timing mechanisms, offering a robust framework for exploring developmental time scales across a broader array of species and developmental stages.Die Embryonalentwicklung von einer einzelnen Zelle zu einem ausgewachsenen Organismus verläuft bei Säugetieren nach einem strengen Muster, doch die Geschwindigkeit dieser Ereignisse, die Entwicklungszeitskala, ist bei jeder Art einzigartig und variiert erheblich untereinander. In dieser Arbeit untersuche ich die genetischen, epigenetischen und extrazellulären Faktoren, die diese Entwicklung steuern. Durch den Einsatz von In-vitro-Modellen und Einzelzellsequenzierungstechniken decke ich die entscheidenden Beziehungen zwischen den Eigenschaften pluripotenter Stammzellen (PSCs) und ihrer Entwicklungsgeschwindigkeit während der neuralen Differenzierung auf, wobei ich die Rolle der Stoffwechselregulation bei der Beeinflussung des Differenzierungspotenzials hervorhebe.
Ich habe ein robustes, universelles System etabliert, indem ich PSCs von Maus, Mensch, Cynomolgus und Orang-Utan unter identischen Bedingungen kultiviert habe. Darüber hinaus verwendete ich ein einheitliches Protokoll zur Differenzierung von PSCs in neurale Vorläuferzellen (NPCs), wobei ich nuancierte Unterschiede in der Entwicklungs-geschwindigkeit zwischen Maus, Cynomolgus und Mensch herausstellte. Diese Standardisierung bot eine Grundlage für vergleichende Studien, die frei von eingreifenden Einflüssen äußerer Faktoren waren.
Durch die Anwendung von Einzelzell-Multiom-Sequenzierung im Zeitverlauf konnte ich einen detaillierten Einblick in die Transkriptions- und Chromatinveränderungen während der neuralen Differenzierung gewinnen. Diese Methode hob artspezifische Muster hervor, wobei sich Zellen der Maus am schnellsten differenzieren, gefolgt von Cynomolgus und Mensch. Lineare Regressionsmodelle zeigten, dass sich Mauszellen auf der Grundlage von Genexpressionsdaten etwa 2,4-mal schneller differenzieren als menschliche Zellen und 2,2-mal schneller als Cynomolgus-Zellen. Einzelzell-ATAC-Sequenzierungsdaten zeigten ähnliche Trends, wobei sich Mauszellen 1,9-mal schneller differenzieren als menschliche Zellen und 1,7-mal schneller als Cynomolgus-Zellen. Diese Analyse unterstreicht, wie sich Zellen verschiedener Spezies in ihrem Differenzierungsverlauf gleichen und unterscheiden.
Durch die Analyse der RNA-Sequenzierung einzelner Zellen konnte ich UGP2 als ein Gen identifizieren, das sowohl in langsamer differenzierenden Arten als auch in langsamer differenzierenden Zellen innerhalb einer Art hochreguliert ist. Durch die Deletion von UGP2 in menschlichen und Cynomolgus PSCs mit Hilfe der CRISPR/Cas9-Technologie wurde Glykogen von den Zellen nicht mehr gespeichert und die neurale Differenzierung beschleunigt, was darauf hindeutet, dass UGP2 eine Rolle bei der Regulierung der Stoffwechselrate durch die Kontrolle der Glukoseverfügbarkeit spielt.
Zusammenfassend lässt sich sagen, dass diese Arbeit unser Verständnis der molekularen Mechanismen, die die Entwicklungsgeschwindigkeit bei verschiedenen Spezies steuern, verbessert und die Bedeutung von UGP2 bei der Regulierung der Glykogenspeicherung und der Beeinflussung der Differenzierungsraten zeigt. Diese Forschung legt den Grundstein für künftige Studien über artspezifische Mechanismen der Entwicklungszeitskala und bietet einen robusten Rahmen für die Erforschung der Entwicklungszeitskala bei einer breiteren Palette von Arten und Entwicklungsstadien