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Morphological and molecular characterization of columnar cholinergic neurotransmission onto T5 cells of Drosophila
Get PDFSensory feedback initiates bottom-up brain processing, which in line activates top-down processing. Vision is a major sensory input in this processing loop, that eventually leads to perception and decision making. Navigating the environment while choosing attractive visual cues over aversive ones, evaluating ego-motion to stabilize a course, chromatically and achromatically detect objects, are some of the tasks that visual systems perform. To elucidate the cellular and molecular mechanisms of such neural computations and the resulting behaviors, more simplistic, yet powerful, visual systems have been explored. Being a genetically tractable model organism that exhibits high neuronal and behavioral diversity, Drosophila melanogaster serves this purpose well. Neuronal connectivity is now accessible thanks to connectomic approaches, but the morphological and molecular identities of each chemical connection are still quite elusive. This cumulative-style doctoral thesis consists of two manuscripts that explore chemical synapses in the OFF-motion vision circuitry of Drosophila. The first manuscript investigates the polyadic morphology of chemical synapses between the primary motion detectors in the OFF pathway, T5 cells, and their columnar cholinergic inputs Tm1, Tm2, Tm4 and Tm9. In this work, I used the open-data connectomics database FlyWire and identified the Tm-to-T5 wiring via various polyadic synapse types. Then, I focused on the T5 dendritic distribution of the different polyadic types and found differences in their spatial patterns. Lastly, I showed that the polyadic morphology is setting a directional wiring architecture at the T5 network level. This work demonstrated the subsynaptic level of complexity in Tm-to-T5 connectivity. In the second manuscript of my doctoral thesis, we investigated the molecular identity of each Tm-to-T5 chemical connection. Fast ionotropic nicotinic (nAChRs) and slow metabotropic muscarinic (mAChRs) acetylcholine receptors are expressed in the brain of Drosophila, but the contribution of different AChRs to visual information processing remained poorly understood. We used a suit of genetic tools and gained accessibility to AChRs, thus finding the nAChRα1, nAChRα3, nAChRα4, nAChRα5, nAChRα7 and nAChβ1 subunits and the mAChR-B receptor localizing on T5 dendrites. Mapping the most highly expressed nAChR subunits across Tm-to-T5 synapses showed the nAChRα5 prevalence in Tm1-, Tm2- and Tm4-to-T5 synapses and of nAChRα7 in Tm9-to-T5 synapses. In vivo functional characterization of nAChRα4, nAChRα5, nAChRα7 and mAChR-B revealed alterations in the fly optomotor response and T5 directional tuning after AChR knock-down. Collectively, this work exhibited the complexity of cholinergic neurotransmission and consequently of preferred direction enhancement in T5 cells, which is introduced by the different receptor categories, subunit stoichiometries, isoforms and their synaptic localization
Development of an oxidation stress testing workflow for high-throughput liquid formulation screening of therapeutic antibodies
Get PDFMeasuring Theory of Mind in mental disorders: validation and exploration of Theory of Mind deficits using the Faux-Pas Recognition Test
Get PDFInterplay between gut homeostasis-regulating enzyme intestinal alkaline phosphatase and bacterial lipopolysaccharides in patients undergoing abdominal surgery for cancer
Get PDFBackground: Intestinal alkaline phosphatase (IAP) is a key player in preserving gut health, regulating bacterial populations, promoting gut barrier integrity, and dephosphorylating proinflammatory molecules like lipopolysaccharides (LPS). LPS, a virulence factor in gram-negative bacteria, triggers inflammatory responses. It is associated with various cancers (such as pancreatic, colorectal, and liver cancer) and negatively contributes to surgical outcomes (sepsis, postoperative cognitive function). IAP's potential in pancreatic, colorectal, and liver health is a reassuring aspect of our research, with current studies highlighting its critical interplay and potential therapeutic implications across diverse health conditions.
Study Design: The study encompassed 118 patients from the Department of General, Visceral and Transplant Surgery at Ludwig-Maximilians-University between June 22nd, 2022, and September 15th, 2023. Among them, 91 had cancer (25 pancreatic, 21 colorectal, 14 liver, 31 other adenocarcinomas), and 27 had non-cancer cases. Additionally, 8 blood samples from healthy individuals served as controls. We conducted the Para-Nitrophenyl Phosphate (PNPP) method to assess the stool IAP activity of 23 preoperative samples. Additionally, we utilized the Limulus Amebocyte Lysate (LAL) assay to measure serum LPS levels of 113 preoperative and 35 postoperative samples and the Human IAP ELISA assay to quantify serum IAP concentrations of 83 preoperative samples.
Results: Our study revealed a significant negative correlation between preoperative stool IAP and preoperative serum LPS (r=-0.514, p=0.029), reinforcing previous findings in pancreatic cancer patients and the entire study population. Moreover, a positive correlation between preoperative stool and serum IAP emerged (r=0.524, p=0.040), while preoperative serum IAP displayed a negative correlation with serum LPS (r=-0.397, p<0.001). The analysis of preoperative serum IAP and LPS alongside various clinical parameters showed that preoperative serum IAP values displayed a negative association with preoperative IL-6 levels (r=-0.334, p=0.020) and CRP (r=-0.348, p=0.001), as well as a positive relationship with albumin (r=0.425, p<0.001). Preoperative serum IAP levels were notably lower in the cancer group compared to healthy controls (p=0.0012). Preoperative serum IAP levels were lower in patients diagnosed with pancreatic (p=0.0144) and colorectal cancer (CRC) (p = 0.0349). However, no significant differences in preoperative serum IAP were detected when comparing liver cancer and healthy controls (p=0.0984). In all abdominal surgery patients (p=0.0071) and all cancer resected patients (p=0.0128), respectively, a significant reduction in postoperative serum LPS levels compared to preoperative levels was observed, indicating a potential impact of surgeries on LPS levels.
We showed that higher preoperative serum IAP levels were associated with a favorable outcome (Clavien-Dindo ≤ II) following abdominal surgery (p = 0.0016). A ROC analysis identified a cutoff value for preoperative serum IAP that could predict surgical outcomes effectively (AUC = 0.749; Youden-Index = 0.4620). Higher preoperative serum IAP levels correlated with better abdominal surgical outcomes, also indicated by shorter intensive care unit (ICU) stays (r = -0.375, p = 0.012). Among patients undergoing surgery for all cancer resection, preoperative serum IAP values were lower in the Clavien-Dindo > II, in which III or higher is relevant to complications where intervention is required, compared to the Clavien-Dindo II or lower group (p = 0.0096). Notably, a negative correlation existed between preoperatively IAP and hospital stay (r = -0.437, p < 0.001) in cancer resection patients. There was a negative correlation between preoperative serum IAP and the length of ICU stay among cancer patients (r = -0.413, p = 0.008). Among liver cancer patients undergoing surgery, our study identified a significant negative correlation between preoperative serum IAP levels and hospital stay (r = -0.603, p = 0.038). Additionally, when comparing patients based on ICU admission following liver cancer surgeries, those admitted (p = 0.0485).
Conclusion: Our study emphasizes the potential of preoperative serum IAP as a valuable biomarker for predicting surgical outcomes, particularly in abdominal and cancer resection surgeries. Higher preoperative serum IAP levels were associated with more favorable outcomes, lower Clavien-Dindo grade, and shorter ICU and hospital stays, while lower IAP levels were linked to higher serum LPS and elevated inflammatory markers, such as IL-6 and CRP. This suggests that serum IAP could serve as a critical prognostic marker, particularly in predicting recovery and complications after abdominal and cancer surgeries. Additionally, while LPS levels did not predict surgical outcomes as strongly as IAP, their significant postoperative reduction highlights their relevance in post-surgical inflammation and gut integrity. Further studies are needed to refine the clinical application of both biomarkers in managing postoperative complications
Ischemic Stroke induces a persisting perturbation of key bacterial populations and metabolites
Get PDFDie rechnergestützte Rekonstruktion des Harnblasenreliefs anhand von Bilddateien eine Projektstudie mittels der Structure from Motion (SfM) Fotogrammmetrie
Get PDFZiel dieser Arbeit war die Entwicklung einer computergestützten Methode zur vollständigen räumlichen Darstellung des Innenraums der Harnblase anhand von Bilddateien mittels Structure-from-Motion-(SfM)-Fotogrammmetrie. Es wurde gezeigt, dass diese Technik, ursprünglich für die Architektur und Geodäsie entwickelt, erfolgreich auf kleine Hohlräume angewendet werden kann. Die Forschung umfasste die Analyse und Optimierung der Bildaufnahme sowie die Fehleranalyse der SfM-Prozesse, um eine fotorealistische, plastische und vollständig orientierbare 3D-Rekonstruktion zu erstellen.
Im Rahmen der Untersuchung wurden Bewegungsfehler und Unschärfen bei der freihändigen Endoskopie als zentrale Herausforderung identifiziert. Zur Lösung wurde ein Verfahren zur Einzelbildaufnahme entwickelt, das eine sehr gute und vollständige Umsetzbarkeit in Modellversuchen zeigte. Mithilfe von 54 Versuchszyklen konnten detaillierte Fehleranalysen durchgeführt und ein standardisiertes Protokoll für die Bildaufnahme und -verarbeitung erstellt werden.
Das Ergebnis der Arbeit ist die erstmalige Darstellung einer vollständigen und frei drehbaren 3D-Abbildung des Harnblaseninnenraums, die kleinste Läsionen mit hoher Präzision sichtbar macht. Diese Methode ermöglicht eine patientenunabhängige, automatisierte Erfassung und Beurteilung der Harnblase und schafft die Grundlage für klinische Anwendungen wie Tumor-Flächenkalkulationen und Diagnose-Assistenzsysteme. Die erzielten Ergebnisse bieten eine Basis für weiterführende Forschung in den Bereichen Medizintechnik und Endoskopie