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Macrophage colony-stimulating factor receptor (M-CSFR/CSF1R) signaling is crucial for the differentiation, proliferation, and survival of myeloid cells. The CSF1R pathway is a promising therapeutic target in many human diseases, including neurological disorders and cancer. Zebrafish are commonly used for human disease modeling and preclinical therapeutic screening. Therefore, it is necessary to understand the proper function of cytokine signaling in zebrafish to reliably model human-related diseases. Here, we investigate the roles of zebrafish Csf1rs and their ligands (Csf1a, Csf1b, and Il34) in embryonic and adult myelopoiesis. The proliferative effect of exogenous Csf1a on embryonic macrophages is connected to both receptors, Csf1ra and Csf1rb, however there is no evident effect of Csf1b in zebrafish embryonic myelopoiesis. Furthermore, we uncover an unknown role of Csf1rb in zebrafish granulopoiesis. Deregulation of Csf1rb signaling leads to failure in myeloid differentiation, resulting in neutropenia throughout the whole lifespan. Surprisingly, Il34 signaling through Csf1rb seems to be of high importance as both csf1rb D4bp-deficient and il34 D5bp-deficient zebrafish larvae lack granulocytes. Our single-cell RNA sequencing analysis of adult whole kidney marrow (WKM) hematopoietic cells suggests that csf1rb is expressed mainly by blood and myeloid progenitors, and the expression of csf1ra and csf1rb is nonoverlapping. We point out differentially expressed genes important in hematopoietic cell differentiation and immune response in selected WKM populations. Our findings could improve the understanding of myeloid cell function and lead to the further study of CSF1R pathway deregulation in disease, mostly in cancerogenesis.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function., King Salman Center for Disability Research; NSTIP/King Abdulaziz City for Science and Technology; King Abdullah University of Science and Technology, Office of Sponsored Research; NSTIP/KACST; Netherlands Organisation for Scientific Research (ZonMW Veni); European Union (EU); Horizon 2020; LEaDing Fellowship; Marie Sklodowska-Curie Grant Agreement; Deutsche Forschungsgemeinschaft; European Union (EU); Horizon 2020; European Research Council (ERC); ERC StG TREATCilia; NTSIP/King Abdulaziz City for Science and Technology; King Faisal Specialist Hospital and Research Centre; KFSHRC Research Grant; Brain & Behavior Research Foundation NARSAD Young Investigator Grant; Erasmus MC Fellowship 2017; Erasmus MC Human Disease Model Award 2018; Erasmus University Rotterdam (EUR) Fellowship; Suna and İnan Kıraç Foundation; Koç University Research Center for Translational Medicine (KUTTAM)

Recreational use of laughing gas is gaining popularity among young people in the Netherlands. This drug is unjustly seen as harmless, since recreational use can have serious consequences. Little research has been conducted into laughing gas and the behavioural intention of the youth. The educational project LOS wants to improve their education for UU students with regards to laughing gas. The aim of this study was twofold. Firstly, identifying the behavioural determinants which play a role in forming the behavioural intention of students with regards to laughing gas. Secondly, formulating implications for further development of the education of LOS. For this analysis, the stages of the Transtheoretical model of change (TTM) were integrated within the Attitude–Social influence–self-Efficacy (ASE) Model. Data was collected through questionnaires and seventeen semi-structured interviews, among six users, four ex-users and seven non-users. The data were analyzed using a systematic and inductive method. Results of this exploratory study showed that respondents did not regard laughing gas as something worth mentioning (attitude). Respondents also experienced a similarly indifferent stance among their friends (social influence). This stance of students and their friends seemed to be related to the idea that sporadic use of laughing gas is not harmful (self-efficacy). Another insightful result showed that students from Utrecht that use laughing gas only do this occasionally. Using the results of this study, implications were formulated for further development of the education on laughing gas of LOS, both for specific motivational stages and universal education. It seems important to focus on increasing the risk perception, especially for the group that uses laughing gas. While increasing skills that make people more resilient to peer pressure seemed important for all the participants.

Wet- en regelgeving - Om op te kunnen treden tegen bepaalde vormen van dierenverwaarlozing en –mishandeling kan de rechter een houdverbod van dieren opleggen. In dit onderzoek wordt nagegaan hoe het houdverbod in de uitvoeringspraktijk verloopt.

Catches of sharks and bycatch in large-mesh nets and baited drumlines used by the Queensland Shark Control Program were examined to determine the efficacy of both gear types and assess fishing strategies that minimise their impacts. There were few significant differences in the size of both sharks and bycatch in the two gear types, apart from significantly smaller (p < 0.05) tiger sharks Galeocerdo cuvier being taken on drumlines and smaller green turtles Chelonia mydas in nets. Catch per unit effort showed orders of magnitude differences among species, even within the same family. Hammerhead sharks and rays were particularly vulnerable to net capture, whereas higher catch rates of tiger sharks were observed for drumlines. Nets caught more marine mammals, teleost fish and rays, whereas drumlines exhibited higher catch rates of the threatened loggerhead turtle Caretta caretta. Survival of most taxa (particularly obligate ram ventilators) was lower in nets than drumlines. Bycatch species (turtles and marine mammals) were able to swim to the surface to breathe when they were hooked on drumlines, enhancing their survival potential. Fishing strategies that recognise the different selectivity patterns of the gear can be developed to suit local biotic and abiotic conditions, although it is recognised that quantification of both ecological risk and risk to bathers is not a simple task.

Catches of sharks and bycatch in large-mesh nets and baited drumlines used by the Queensland Shark Control Program were examined to determine the efficacy of both gear types and assess fishing strategies that minimise their impacts. There were few significant differences in the size of both sharks and bycatch in the two gear types, apart from significantly smaller (p < 0.05) tiger sharks Galeocerdo cuvier being taken on drumlines and smaller green turtles Chelonia mydas in nets. Catch per unit effort showed orders of magnitude differences among species, even within the same family. Hammerhead sharks and rays were particularly vulnerable to net capture, whereas higher catch rates of tiger sharks were observed for drumlines. Nets caught more marine mammals, teleost fish and rays, whereas drumlines exhibited higher catch rates of the threatened loggerhead turtle Caretta caretta. Survival of most taxa (particularly obligate ram ventilators) was lower in nets than drumlines. Bycatch species (turtles and marine mammals) were able to swim to the surface to breathe when they were hooked on drumlines, enhancing their survival potential. Fishing strategies that recognise the different selectivity patterns of the gear can be developed to suit local biotic and abiotic conditions, although it is recognised that quantification of both ecological risk and risk to bathers is not a simple task.

Nationale Landschappen zijn in 2004 in het leven geroepen door het rijk. Deze thesis kijkt naar Nationaal Landschap Graafschap. Door middel van interviews met bewoners en recreanten in dit gebied, een diepte-interview met een expert en literatuuronderzoek worden de landschappelijke kwaliteiten en de bekendheid van NL Graafschap onderzocht.