The external tissues of plants and animals are colonized by microbial communities termed microbiota. When organisms are exposed to environmental pollutants, these substances will therefore... Show moreThe external tissues of plants and animals are colonized by microbial communities termed microbiota. When organisms are exposed to environmental pollutants, these substances will therefore encounter microbiota at the exposure interface. Many antimicrobial substances have been found to disturb beneficial interactions between microbiota and the host, thereby impairing host health. Nanomaterials exhibit nanoscale properties that could affect host health in two additional, understudied, microbiota-dependent ways. Firstly, owing to their large surface area, adsorption interactions between nanomaterials, microbial metabolites and microbes could alter the identity and colloidal stability of nanomaterials, and may influence the dispersal of microbes. Secondly, the immuno-modulatory effects of microbiota could affect the sensitivity of hosts to immunotoxic nanomaterials. In this dissertation, we use a combination of computational techniques and zebrafish larvae experiments to unravel and quantify these interactions. We predict the affinity of microbial metabolites to carbon and metal nanomaterials, and show that titanium dioxide nanoparticles can affect the dispersal of microbes through aquatic ecosystems, and across different life stages of oviparous animals. Additionally, we provide insight into microbiota-dependent signaling pathways that affect the sensitivity of zebrafish larvae to particle-specific, immunotoxic effects of silver nanoparticles. Altogether, these results contribute to mechanistic pathways for microbiota-inclusive nanomaterial safety assessment. Show less
Dit proefschrift beschrijft het onderzoek naar de stabiliteit van twee typen DNA volgordes (sequenties) die vaak voorkomen in DNA: microsatellieten en G-quadruplex sequenties. Microsatellieten zijn... Show moreDit proefschrift beschrijft het onderzoek naar de stabiliteit van twee typen DNA volgordes (sequenties) die vaak voorkomen in DNA: microsatellieten en G-quadruplex sequenties. Microsatellieten zijn kleine stukjes repeterend DNA en G-quadruplex sequenties hebben de unieke eigenschap om een DNA-structuur te vormen die bestaat uit vier DNA-strengen. Bij een celdeling, waarbij het DNA gekopieerd moet worden, blijken deze twee sequenties soms lastig te kopi_ren te zijn. Dit kan tot DNA-instabiliteit leiden. Deze instabiliteit wordt in verband gebracht met kanker en neurodegeneratieve ziektes zoals ALS. Het is daarom van groot belang om alles te weten te komen over microsatelliet- en G-quadruplex-instabiliteit. Allereerst worden in dit proefschrift nieuwe methodes beschreven waarmee de instabiliteit van microsatellieten en G-quadruplexes makkelijk kan worden waargenomen. Met behulp van deze methodes zijn vervolgens verschillende ontdekkingen gedaan. Zo is bijvoorbeeld ontdekt dat in menselijke cellen een klein RNA-molecuul betrokken is bij het instabiel worden van microsatellieten en het ontstaan van darmkanker. Een ander belangrijke bevinding is de ontdekking van een nieuw soort DNA-reparatie mechanisme in de rondworm. De ontdekking van dit mechanisme, waarbij het eiwit polymerase theta G-quadruplex-ge_nduceerde DNA schade repareert, heeft tot nieuwe inzichten geleid op het gebied van genetische mutaties, evolutie en het bestrijden van tumoren. Show less
Brittijn, S.A.; Duivesteijn, S.J.; Belmamoune, M.; Bertens, L.M.F.; Bitter, W.; De Bruijn, J.D.; ... ; Richardson, M.K. 2009
Basic research in pattern formation is concerned with the generation of phenotypes and tissues. It can therefore lead to new tools for medical research. These include phenotypic screening assays,... Show moreBasic research in pattern formation is concerned with the generation of phenotypes and tissues. It can therefore lead to new tools for medical research. These include phenotypic screening assays, applications in tissue engineering, as well as general advances in biomedical knowledge. Our aim here is to discuss this emerging field with special reference to tools based on zebrafish developmental biology. We describe phenotypic screening assays being developed in our own and other labs. Our assays involve: (i) systemic or local administration of a test compound or drug to zebrafish in vivo; (ii) the subsequent detection or "readout" of a defined phenotypic change. A positive readout may result from binding of the test compound to a molecular target involved in a developmental pathway. We present preliminary data on assays for compounds that modulate skeletal patterning, bone turnover, immune responses, inflammation and early-life stress. The assays use live zebrafish embryos and larvae as well as adult fish undergoing caudal fin regeneration. We describe proof-of-concept studies on the localised targeting of compounds into regeneration blastemas using microcarriers. Zebrafish are cheaper to maintain than rodents, produce large numbers of transparent eggs, and some zebrafish assays could be scaled-up into medium and high throughput screens. However, advances in automation and imaging are required. Zebrafish cannot replace mammalian models in the drug development pipeline. Nevertheless, they can provide a cost-effective bridge between cell-based assays and mammalian whole-organism models. Show less
