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Establishment of novel axial stem cell states recapitulating neuromesodermal and dorsal neural tube progenitor identities
Get PDFGebärmutterhalskrebs in Tansania
Get PDFGebärmutterhalskrebs ist eine der wenigen Tumorerkrankungen, die als nahezu vollständig vermeidbar gilt. Dies liegt an präventiven Impf- und Screening-Programmen, gezielten Untersuchungen, die durch die Identifikation von Tumorvorstufen und frühen Tumorstadien eine frühzeitige Behandlung möglich machen. Der Großteil der Frauen erkrankt global betrachtet in einkommensschwachen Ländern, dabei ist das subsaharische Afrika durch die Überlappung einer hohen Last an HIV und Gebärmutterhalskrebs besonders betroffen. Die meisten Daten zur Versorgung von Gebärmutterhalskrebs liegen aus einkommensstarken Ländern vor. Die vorliegende Arbeit hat zum Ziel, die Versorgung in einem einkommensschwachen Land, Tansania, unter Berücksichtigung des Einflusses einer HIV-Koinfektion darzustellen. Es handelt sich um eine observierende, prospektive, longitudinale Kohortenstudie, die zwischen 2013 und 2019 Frauen aus dem nationalen Vorsorgeprogramm mit der Diagnose Gebärmutterhalskrebs einbezog. Alle Frauen erhielten eine Überweisung zum Staging und zur Therapieberatung durch einen Gynäkologen. Jährliche Nachuntersuchungen hatten zum Ziel, die erfolgreiche Verlinkung der Frauen mit dem Gesundheitssystem, erhaltene Interventionen und das Überleben zu erfassen. Es wurden Faktoren, welche die Adhärenz beeinflussen, Kaplan-Meier-Überlebensgraphen und Poisson-Regressionsanalysen zur Bestimmung der Mortalitätsraten 2 Jahre nach Diagnosestellung berechnet. 270 Frauen wurden eingeschlossen, für 98,9 % lag eine histologische Sicherung und für 68,5 % ein Staging der Diagnose vor. Eine HIV-Infektion bestand bei 123 Frauen (45,6 %). Die meisten Frauen wurden vor dem 50. Lebensjahr diagnostiziert, der Großteil (84,9 %) im fortgeschrittenen Stadium. HIV-infizierte Frauen waren bei Diagnosestellung 11 Jahre jünger (medianes Erkrankungsalter 44,8 vs. 55,9 Jahre). Die mediane Nachuntersuchungszeit lag bei 11,9 Monaten (Spannweite 0,2 - 67,2 Monate) und war durch hohe Mortalitätsraten gekennzeichnet. Die longitudinalen Überlebensdaten – verfügbar für 231 Frauen – zeigten ein medianes Überleben im frühen Tumorstadium von 38,3 Monaten, im fortgeschrittenen Tumorstadium von 16 Monaten und im Endstadium von 6,5 Monaten. Ein Jahr nach Diagnosestellung waren 42 % der Frauen verstorben. Die Therapieadhärenz war mit einem höherem Bildungsniveau und einer HIV-Koinfektion assoziiert. Ein relevanter Anteil der Frauen (30 %) erhielt keine Tumortherapien. Die am häufigsten durchgeführte Therapie war eine kombinierte Radiochemotherapie (27,8 %), chirurgisch wurden 8,1 % der Frauen versorgt. Erhaltene Therapien waren mit niedrigeren Mortalitätsraten assoziiert. Eine HIVKoinfektion hatte keinen statistisch signifikanten Einfluss auf die Überlebenszeit nach Diagnose. Die Therapieadhärenz war mit einem höherem Bildungsniveau und einer HIV-Koinfektion assoziiert. Die Datenauswertung dieser Arbeit ermöglicht einen Einblick in den (inter-)nationalen Ausbau der Gesundheitssysteme und das Herausarbeiten spezifischer Herausforderungen in der Patienten- und Patientinnen- orientierten Versorgung – in diesem Fall mithilfe von Daten aus dem südlichen Hochland von Tansania
Einfluss von Sarkopenie und Adipositas bei Patienten mit extrakorporaler Membranoxigenierung bei Lungen- und/oder Kreislaufversagen auf das klinische Therapieergebnis
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The impact of clinical indicators and type of physician on health-related quality of life (HRQoL) in COPD patients: a real-world study
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Role of peripheral CB1 cannabinoid receptors in atherosclerosis and metabolism
Get PDFAtherosclerosis is a chronic immune disease fueled by a complex interplay of lipid, inflammatory, and biomechanical factors. Previous studies demonstrated that the cannabinoid CB1 receptor plays a detrimental role in metabolic and cardiovascular diseases. While the development of peripherally restricted CB1 antagonists, which are devoid of central side effects, hold promise in treating metabolic disorders such as diabetes and obesity, their potential benefit in atherosclerosis is unknown. The aim of this thesis was to clarify the endothelial cell-specific effects of CB1 and underlying mechanisms in the pathophysiology of atherosclerosis. It was found that endothelial Cnr1 expression was upregulated upon oscillatory shear stress (OSS) in human aortic endothelial cells (HAoECs) and preferentially expressed in atheroprone areas of mouse aortic endothelium. Endothelial Cnr1 deficiency (Cnr1EC-KO) in female mice on atherogenic apolipoprotein E (Apoe) deficiency background reduced plaque formation, particularly in atheroprone sites. Only moderate effects were observed in male mice, which may hint to a sex-specific difference in endothelial CB1 signalling. Moreover, aortic endothelial cells of female Cnr1EC-KO mice exhibited a less pro-inflammatory phenotype with decreased adhesion molecule ICAM1 and VCAM1 expression. Interestingly, ex vivo imaging of carotid arteries via two-photon microscopy revealed less endothelial DIL-LDL uptake in female Cnr1EC-KO mice endothelial cells along with a significantly reduced aortic endothelial expression of caveolin-1 (CAV1), a key structural protein involved in lipid transcytosis. RNA sequencing of aortic endothelial cells further supported the role of CB1 in regulating caveolar signalling. In vitro, pharmacological blocking with CB1 antagonist AM281 in HAoECs under OSS resulted in a decreased LDL uptake, which was mediated through a cAMP-PKA-dependent regulation of CAV1 expression. Vice versa, the stimulation of HAoECs with the CB1 agonist ACEA increased DIL-LDL uptake and enhanced CAV1 expression. Notably, endothelial CB1 deficiency protected against metabolic dysfunction in adipose tissue and liver, while improving insulin sensitivity. Finally, treating mice with the peripherally active CB1 antagonist JD5037 reduced plaque progression, CAV1 expression, and endothelial adhesion molecule expression, which was only observed in females. Collectively, impaired CB1 signalling in endothelial cells inhibits endothelial LDL uptake, attenuates vascular inflammation, and improves metabolic function, leading to protection against atherosclerosis
The energy metabolic footprint of predictive processing in the human brain
Get PDFTo maximize our chances of survival and procreation, we need to process our environment in a highly sophisticated and accurate manner. In their limit, these two demands are mutually exclusive: While better sound localization, quicker reflexes or more accurate vision could improve survivability, the necessary energy consumption might not be sustainable. Luckily, our sensory systems strike an impressive balance between performance and energetic cost. In a both active and passive process, we learn about the rules that determine our experience and use them to form expectations. Efficient brain activity is then achieved by limiting the forward transmission of signals to deviations from what we predicted.
In the visual domain, this means that our perception is dominated by our expectations when we are in a familiar environment. Research in cognitive neuroscience has shown that expected input elicits weaker brain activity than surprising input, without any behavioral disadvantages. However, knowledge about associated energetic efficiency is limited by three gaps in the current literature. First, conventional imaging techniques do not provide direct measurements of energy metabolism. Second, previous research has focused on localizing areas of maximal effect, potentially missing weaker, but more widespread patterns. Third, our knowledge about the world is imperfect, leading to uncertain expectations. This has rarely been accounted for.
Neuronal activity is fueled by ATP, most of which is produced with chemical reactions that need oxygen. In the present work, I assessed energy metabolism with a novel imaging method that measures the rate of oxygen consumption across all parts of the brain. I used an experimental design during which participants saw visual object sequences that were either predictable, random, or surprising. Behavioral tests indicated that predictable sequences were learned without any feedback which resulted in anticipation of upcoming objects. I further found that participants varied in the confidence of their expectations. This had a major impact on oxygen consumption when viewing predictable sequences: The lowest energy usage was found for high levels of confidence. This effect was not limited to sensory regions but extended across large parts of the brain. Interestingly, my results suggest that confidence led to energy savings even when the visual input was objectively random. In conclusion, this work provides the first evidence that our expectations are a major promoter of efficient processing, which is crucial for any organism with limited energy availability
Nucleic acid phase separation and replication drive selection in prebiotic pools
Get PDFNucleic acids are considered to be early molecules owing to their dual ability to store information and catalyze reactions. The evolution of complex functional nucleic acids from a diverse pool of building blocks or short fragments necessitates the selective preference of certain sequences over others. The sequence space of nucleic acid pools with dozens or hundreds of bases is too vast to be fully explored. For this reason, it is believed that selection occurs as the pools become more complex, not only after attaining a sufficient length to support a ribozyme. Throughout the stages of nucleic acid elongation and copying, strands are subjected to various selection pressures, intrinsic to the replication or elongation mechanisms, or extrinsic, where certain sequences are better suited to survive in specific environments.
In Chapter 1, selection for nucleic acids capable of phase separation was studied as the result of extrinsic selective pressures such as flux changes and dilution. Sequences capable of phase separation were enriched over cycles of supernatant removal by sedimenting at the bottom of the pore while other sequences were washed-out. These enriched sequences were the ones prone to forming network-like secondary structures. The wash-out and refeeding conditions mimic geological settings with varying fluxes such as bodies of water subjected to
day-night cycles or tidal waves. Sequence pools with low compositional diversity (i.e. those that contained a binary alphabet - A / T or G / C ) did not exhibit phase separation. However, the introduction of a single mutation of the opposite alphabet restored this capacity, indicating a high sequence specificity of phase separation as a driving force for selection.
In Chapter 2, the influence of replication on pools of short, biased oligomers was examined as an intrinsic factor. Random pools of short DNA strands, on average biased toward a specific nucleotide, underwent templated polymerization with Bst. While the overall pool compositional diversity increased at the nucleotide level due to the templated nature of the mechanism, remnants of the initial bias persisted at specific positions of the replicated strands. Initially unstructured pools developed patterns such as periodicity, enhancing replicability through increased intra- and inter-strand binding sites. In this case the overall pool composition also shifted to specific secondary structures, and therefore sequence motifs, due to the selective pressure exerted by the replication mechanism.
In Chapter 3, a non-enzymatic RNA replication system employing 2′,3′-cyclic phosphates is described. This activation group, formed during RNA hydrolysis, nucleotide polymerization, and prebiotic phosphorylation, is readily available prebiotically. For the first time, templated RNA replication through ligation was achieved without the addition of organic catalysts. This system exhibited high sequence specificity, with a ligation fidelity exceeding 82%. Long sequences up to 100-mer were synthesized through consecutive ligation, paving the way for the
creation of pools capable of hosting molecular evolution. Describing such a system represents the initial step in investigating the intrinsic influence of replication on a prebiotically plausible pool