Mechanisms of growth control in the postembryonic medaka retina

Postembryonic stem cell niches are present throughout the vertebrate clade to facilitate development, homeostasis, regeneration and growth. While teleosts and amphibians display sustained stem cell activity in most organs after embryogenesis, higher vertebrates retain stem cell activity only in specific tissues. Despite these differences, similar challenges are imposed on all vertebrate organisms: new tissue has to be generated to expand or replace existent one while simultaneously ensuring integrity and functionality of the organ. Tight control of stem and progenitor cell proliferation is necessary to avoid aberrant growth such as in cancer. In the retina of the teleost medaka (Oryzias latipes), retinal stem (RSC) and progenitor (RPC) cells are located in the ciliary marginal zone (CMZ) and mediate postembryonic growth and neurogenesis. Since function and shape of the eye are intimately linked, the activity of RSCs and RPCs is tightly coordinated to establish proper cell type composition and number. In this thesis I addressed intrinsic and extrinsic regulation mechanisms of the RSC niche. I hypothesised that retinal growth underlies intrinsically active growth factor signaling, and that immune cells safeguard the RSC niche in homeostasis and injury. To analyse intrinsic regulation of RSC proliferation, I assessed the function of insulin-like growth factor (Igf) signaling in the CMZ using gain- and loss- of-function approaches. I found that Igf1 receptor over-activation increased cell cycle speed, RPC number and consequently retinal size, while simultaneously preserving the stereotypical retinal architecture. Strikingly, RSCs were not susceptible to mitogenic stimuli, indicating that RPC amplification is the determinant of retinal size and composition. To understand the extrinsic regulation of the RSC niche, I examined the interplay of immune cells and RSCs. I found that Ccl25b-positive RSCs are phagocytosed by Ccr9a-positive immune cells located in the CMZ. Ccl25b mutation abrogates reactivation of immune cells upon RSC injury, implicating Ccl25b–Ccr9a signaling in the immune–stem cell interaction during homeostatic surveillance and injury response. In summary, my results propose that accurate postembryonic growth and tissue integrity depend on both cell intrinsic and extrinsic mechanisms of growth control in the RSC niche of medaka

Migrant’s integration: Analyzing attitudes towards immigrants and national identification

In my dissertation, I investigated migrants’ integration from two perspectives. Firstly, from the perspective of individuals who already live in the country and have been members of society for some time and secondly from the perspective of individuals who recently immigrated. With regards to the former, I especially focused on the attitudes towards immigrants of two societal groups that have so far been underresearched: children and individuals with a migration background. In my first study I developed and validated a new measurement instrument for children’s attitudes towards immigrants. The new instrument is cost- and time-efficient and can easily be applied to children of various ages and across different cultural settings. Further, it is suitable for use in large-scale surveys. In my second study, I applied this new instrument and inspected the link between values and attitudes towards immigrants in children. The results indicate that the relations to some extent mirror those commonly found in adults, but they also show that we should not readily assume that relations existing in adults also exist in children. My third study on attitudes towards immigrants focused on adults, specifically on the differences in attitudes between individuals with and without migration backgrounds as well as across migrant generations. While overall migrants appeared to have more favorable attitudes towards immigration, differences between the generations became apparent. Regarding the migrants’ perspective on integration, I was particularly interested in the migrants’ national identification, so the degree to which they feel a sense of belonging towards the society. Previous research highlights migrants’ contact to natives as a key factor in explaining migrants’ national identification. In my work, I further explored this topic by analyzing and comparing the relations of national identification and contact to natives across three contact spheres: family, friends and workplace. Out of the three spheres having native friends had the strongest link with national identification. Concerning the other two spheres, the links were significantly weaker and highly depended on the control variables included

Bridgehead-methyl Analog of SC-53116 as a 5-HT4 Agonist

Pyrrolizidine benzamide (±)-2, the bridgehead-methyl analog of SC-53116, was prepared and evaluated for 5-HT4 agonism activity in the rat tunica muscularis (TMM) mucosae assay. Compound (±)-2 has an EC50 of 449 nM in the TMM assay, as compared to 23 nM for SC-53116, and 66 nM for the racemate of SC-53116

Serotonin 5-HT4 Agonist Activity of a Series of Meso-Azanoradamantane Benzamides

A series of meso-amino(methyl)azanoradamantane benzamides has been prepared and evaluated for 5-HT4agonism activity in the rat tunica muscularis mucosae (TMM) assay. Compound 8i is the most potent 5-HT4agonist in the series, with an EC50 of 217 nM

Enantioselective Synthesis of Dual Serotonergic Azanoradamantane SC-52491

A racemic synthesis of azanoradamantane (±)-3 was accomplished via Yamamoto\u27s MAD-catalyzed Diels-Alder protocol. Subsequently, a scalable asymmetric synthesis of azanoradamantane benzamide SC-52491 was carried out employing Helmchen\u27s asymmetric Diels-Alder methodology to construct all four contiguous asymmetric centers with the correct relative stereochemistry and in 99.3% e.e

Candida albicans adhesion to central venous catheters: Impact of blood plasma-driven germ tube formation and pathogen-derived adhesins

Candida albicans-related bloodstream infections are often associated with infected central venous catheters (CVC) triggered by microbial adhesion and biofilm formation. We utilized single-cell force spectroscopy (SCFS) and flow chamber models to investigate the adhesion behavior of C. albicans yeast cells and germinated cells to naïve and human blood plasma (HBP)-coated CVC tubing. Germinated cells demonstrated up to 56.8-fold increased adhesion forces to CVC surfaces when compared to yeast cells. Coating of CVCs with HBP significantly increased the adhesion of 60-min germinated cells but not of yeast cells and 30-min germinated cells. Under flow conditions comparable to those in major human veins, germinated cells displayed a flow directional-orientated adhesion pattern to HBP-coated CVC material, suggesting the germ tip to serve as the major adhesive region. None of the above-reported phenotypes were observed with germinated cells of an als3Δ deletion mutant, which displayed similar adhesion forces to CVC surfaces as the isogenic yeast cells. Germinated cells of the als3Δ mutant also lacked a clear flow directional-orientated adhesion pattern on HBP-coated CVC material, indicating a central role for Als3 in the adhesion of germinated C. albicans cells to blood exposed CVC surfaces. In the common model of C. albicans, biofilm formation is thought to be mediated primarily by yeast cells, followed by surface-triggered the formation of hyphae. We suggest an extension of this model in which C. albicans germ tubes promote the initial adhesion to blood-exposed implanted medical devices via the germ tube-associated adhesion protein Als3

Novel minimally invasive tape suture osteosynthesis for instabilities of the pubic symphysis: a biomechanical study

INTRODUCTION Open book fractures are challenging injuries oftentimes requiring surgical treatment. The current treatment of choice is symphyseal plating, which requires extensive surgery and entirely limits physiological movement of the symphyseal joint, frequently resulting in implant failure. Therefore, we investigated the biomechanical properties of a semi-rigid implant (modified SpeedBridge™) as a minimally invasive tape suture construct for the treatment of open book fractures and evaluated the superiority of two techniques of implementation: criss-cross vs. triangle technique. MATERIALS AND METHODS Nine synthetic symphyseal joints were dissected creating an open book fracture. The different osteosynthesis methods (plating, modified SpeedBridge™ in criss-cross/triangle technique) were then applied. All constructs underwent horizontal and vertical loading, simulating biomechanical forces while sitting, standing and walking. For statistical analysis, dislocation (mm) and stiffness (N/mm) were calculated. RESULTS Symphyseal plating for the treatment of open book fractures proved to be a rigid osteosynthesis significantly limiting the physiological mobility of the symphyseal joint (dislocation: 0.08 ± 0.01~mm) compared to the tape sutures (dislocation: triangle technique 0.27 ± 0.07~mm, criss-cross technique 0.23 ± 0.05~mm) regarding horizontal tension (p 0.05 in all directions). Considering vertical loading, no statistical difference was found between all osteosynthesis methods (caudal: p = 0.41; cranial: p = 0.61). CONCLUSIONS Symphyseal plating proved to be the osteosynthesis method with the highest rigidity. The modified SpeedBridge™ as a semi-rigid suture construct provided statistically sufficient biomechanical stability while maintaining a minimum of symphyseal movement, consequently allowing ligamental healing of the injured joint without iatrogenic arthrodesis. Furthermore, both the criss-cross and the triangle technique displayed significant biomechanical stability without one method being superior