Fakultätsübergreifend / Sonstige Einrichtung

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Charakterisierung der antimikrobiellen Aktivität von High-mobility group box 2
(2013) Küchler, Robert; Wehkamp, Jan
The human body is continuously exposed to an enormous amount of microbes. Especially surfaces like the skin or the gastrointestinal mucosa are in close contact with large numbers of microorganisms, including bacteria, fungi and viruses. A very effective innate immune system protects the intestinal mucosa from an overgrowth of commensal bacteria and penetration by pathogenic microbes. Besides an efficient layer of thick mucus, antimicrobial peptides and proteins (AMPs) which can inhibit the growth of microorganisms or even destroy them are an essential part of the epithelial barrier. In 2009, as a part of my diploma thesis, I could show that high-mobility group box 2 (HMGB2) exhibits antimicrobial activity against E. coli. The aim of this PhD thesis was to characterize and further clarify this new function. HMGB2 was recombinantly expressed and systematically analyzed for antimicrobial activity. Notably, several gram-negative and gram-positive bacteria of the normal gut flora were critically affected by HMGB2. In addition, bactericidal properties against the pathogenic bacterial strain Staphylococcus aureus were detected via electron microscopic analysis. Furthermore potential influences of intestinal environmental conditions on the activity of HMGB2 were investigated. Changes in the pH or the generation of a reducing environment altered the activity of the protein only to a small amount. To localize the part of HMGB2 which is essential for its antimicrobial activity, three peptides which represent three regions of the protein were recombinantly expressed. An activity screening with the three peptides showed that the two DNA-binding-domains HMG-Box A and B are crucial for the antimicrobial effects. An expression study showed that HMGB2 is present in all analyzed stomach and intestinal sections. In addition, the expression in patients with inflammatory bowel disease (IBD) was studied. No significant differences between patients with Crohn?s disease, ulcerative colitis and unaffected controls were detected. However, the examination of stool from individuals of these three groups suggests that HMGB2 might be useful as a new marker for intestinal inflammation. In summary, HMGB2 exhibits antimicrobial activity against various commensal bacteria of the normal gut flora and is expressed in all analyzed gastrointestinal tract sections. HMGB2 is part of the intestinal barrier and protects, together with other AMPs, the intestine from microorganisms.
Determination of optimal phage load and administration time for antibacterial treatment
(2024) Plunder, Steffen; Burkard, Markus; Helling, Thomas; Lauer, Ulrich M.; Hoelzle, Ludwig E.; Marongiu, Luigi
Using phages as antibacterials is becoming a customary practice in Western countries. Nonetheless, successful treatments must consider the growth rate of the bacterial host and the degradation of the virions. Therefore, successful treatments require administering the right amount of phage (viral load, Vφ) at the right moment (administration time, Tφ). The present protocols implement a machine learning approach to determine the best combination of Vφ and Tφ to obtain the elimination of the target bacterium from a system. Basic Protocol 1: One bacterium, one phage. Alternate Protocol 1: One bacterium, one phage (wrapping function). Alternate Protocol 2: One bacterium, one phage (wrapping function, alternative growing model). Basic Protocol 2: Two bacteria, one phage. Alternate Protocol 3: Two bacteria, one phage (launch from terminal).
Modelling and simulation for preclinical cardiac safety assessment of drugs with human iPSC-derived cardiomyocytes
(2020) Kügler, Philipp
As a potentially life threatening side effect, pharmaceutical compounds may trigger cardiac arrhythmias by impeding the heart’s electrical and mechanical function. For this reason, any new compound needs to be tested since 2005 for its proarrhythmic risk both during the preclinical and the clinical phase of the drug development process. While intensive monitoring of cardiac activity during clinical tests with human volunteers constitutes a major cost factor, preclinical in vitro tests with non cardiac cells and in vivo tests with animals are currently under serious debate because of their poor extrapolation to drug cardiotoxicity in humans. For about five years now, regulatory agencies, industry and academia are working on an overhaul of the cardiac drug safety paradigm that is built a) on human heart muscle cells, that can be abundantly bioengineered from donor stem cells without ethical concerns (human induced pluripotent stem cell derived cardiomyocytes, hiPSC-CMs), and b) on computational models of human cardiac electrophysiology both at the cellular and the organ level. The combined use of such human in vitro and human in silico models during the preclinical phase is expected to improve proarrhythmia test specificity (i.e. to lower the false-positive rate), to better inform about the need of thorough heart monitoring in the clinic, and to reduce or even replace animal experiments. This review article starts by concisely informing about the electrical activity of the human heart, about its possible impairment due to drug side effects, and about hiPSC-CM assays for cardiac drug safety testing. It then summarizes the mathematical description of human cardiac electrophysiology in terms of mechanistic ODE and PDE models, and illustrates how their numerical analysis may provide insight into the genesis of drug induced arrhythmias. Finally, this paper surveys proarrhythmic risk estimation methods, that involve the simulation of human heart muscle cells, and addresses opportunities and challenges for future interdisciplinary research.
The therapeutic potential of vitamins A, C, and D in pancreatic cancer
(2025) Piotrowsky, Alban; Burkard, Markus; Schmieder, Hendrik; Venturelli, Sascha; Renner, Olga; Marongiu, Luigi
The pancreatic ductal adenocarcinoma (PDAC) is among the deadliest tumor diseases worldwide. While treatment options have generally become more diverse, little progress has been made in the treatment of PDAC and the median survival time for patients with locally advanced PDAC is between 8.7 and 13.7 months despite treatment. The aim of this review was to explore the therapeutic potential of complementing standard therapy with natural or synthetic forms of vitamins A, C, and D. The therapeutic use of vitamins A, C, and D could be a promising addition to the treatment of PDAC. For all three vitamins and their derivatives, tumor cell-specific cytotoxicity and growth inhibition against PDAC cells has been demonstrated in vitro and in preclinical animal models. While the antitumor effect of vitamin C is probably mainly due to its pro-oxidative effect in supraphysiological concentrations, vitamin A and vitamin D exert their effect by activating nuclear receptors and influencing gene transcription. In addition, there is increasing evidence that vitamin A and vitamin D influence the tumor stroma, making the tumor tissue more accessible to other therapeutic agents. Based on these promising findings, there is a high urgency to investigate vitamins A, C, and D in a clinical context as a supplement to standard therapy in PDAC. Further studies are needed to better understand the exact mechanism of action of the individual compounds and to develop the best possible treatment regimen. This could contribute to the long-awaited progress in the treatment of this highly lethal tumor entity.
Visual tracking of a moving target in 360-degree virtual reality: analysis of the effects on attention and mood
(2025) Sellner, T.; Ehmann, P.; Spielmann, J.; Gogolla, F.; Rösgen, A.; Mayer, J.; Schoenfeld, M. A.; Flor, H.
The training of attentional capacities is an important part of many rehabilitative efforts, for example, in the treatment of stroke. The Helix-Arena is an innovative virtual reality (VR) training device, which enables multimodal training in a 360-degree virtual environment. A pursuit training was developed for the Helix-Arena. In this study, we evaluate the effectiveness of the pursuit training in the Helix-Arena compared to a control group [CG, training on a personal computer (PC)] in 34 healthy participants. The experimental group (EG, N = 19) participated in four training sessions in the Helix-Arena over a period of 2 weeks. The control group (N = 15) completed similar training sessions in a non-VR environment on a PC. During each training session, changes in attention (Test of Attentional Performance battery, TAP) and general mood (Positive and Negative Affect Schedule, PANAS) were assessed pre- and post-training. A significantly higher pre-to-post improvement was observed in the EG for the TAP subtest attention shift in the subcategory invalid instructor ( p = 0.04) than that in the CG. In addition, we found a higher positive affect after the training in the EG but not in the CG (p < 0.01). These results suggest advantages of the VR environment for attentional and affective processes. The VR training can thus improve not only cognitive abilities but also training motivation. In a next step, the training can be used with patients in a rehabilitation context, but it is also suitable for educational and gaming contexts.

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