Cognitive deficits in children with neurofibromatosis Type I: from recognition to treatment

__Abstract__ Over the past few years, mouse models have significantly contributed to our understanding of the molecular mechanisms underlying cognitive dysfunction in genetic disorders. Moreover, several preclinical studies in mouse models of for instance Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex, Down syndrome, Rett syndrome, and Fragile X syndrome have provided evidence that some of these cognitive deficits may be reversible by targeting the underlying molecular disturbances.l-5 These new findings have sparked a great interest in the search for drugs that may be used in patients to ameliorate their cognitive problems.6 A recent study described the beneficial effects of a statin, one of the most widely prescribed classes of medications, on cognitive deficits of a mouse model for NF1.7 This finding offered an exciting and unique opportunity to assess the effect of a drug that has been validated in preclinical studies and for which substantial clinical safety data is available, on cognitive problems in NF1 patients. This thesis focuses on the recognition and treatment of cognitive problems in children with NF1. It aims to provide an overview of the specific aspects of cognitive performance that affect daily life functioning in NF1 children, and tries to identify possible outcome measures that can be used to assess potential therapeutic interventions. This knowledge was used to perform the first randomized, double blind, placebo-controlled trial to assess the effect of statins on cognitive problems in children with NF1

Dispersal of bacteria and stimulation of permafrost decomposition by Collembola

Contrary to most soils, permafrost soils have the atypical feature of being almost entirely deprived of soil fauna. Abiotic constraints on the fate of permafrost carbon after thawing are increasingly understood, but biotic constraints remain scarcely investigated. Incubation studies, essential to estimate effects of permafrost thaw on carbon cycling, typically measure the consequences of permafrost thaw in isolation from the topsoil and thus do not account for the effects of altered biotic interactions because of e.g. colonization by soil fauna. Microarthropods facilitate the dispersal of microorganisms in soil, both on their cuticle (ectozoochory) and through their digestive tract (endozoochory), which may be particularly important in permafrost soils, considering that microbial community composition can strongly constrain permafrost biogeochemical processes.Here we tested how a model species of microarthropod (the Collembola Folsomia candida) affected aerobic CO2 production of permafrost soil over a 25 d incubation. By using Collembola stock cultures grown on permafrost soil or on an arctic topsoil, we aimed to assess the potential for endo- and ectozoochory of soil bacteria, while cultures grown on gypsum and sprayed with soil suspensions would allow the observation of only ectozoochory.The presence of Collembola introduced bacterial amplicon sequence variants (ASVs) absent in the no-Collembola control, regardless of their microbiome manipulation, when considering presence–absence metrics (unweighted UniFrac metrics), which resulted in increased species richness. However, these introduced ASVs did not induce changes in bacterial community composition as a whole (accounting for relative abundances, weighted UniFrac), which might only become detectable in the longer term.CO2 production was increased by 25.85 % in the presence of Collembola, about half of which could be attributed to Collembola respiration based on respiration rates measured in the absence of soil. We argue that the rest of the CO2 being respired can be considered a priming effect of the presence of Collembola, i.e. a stimulation of permafrost CO2 production in the presence of active microarthropod decomposers. Overall, our findings underline the importance of biotic interactions in permafrost biogeochemical processes and the need to explore the additive or interactive effects of other soil food web groups of which permafrost soils are deprived

Developing teamwork skills beyond cross-cultural barriers: a case study for engineering students in higher education

In 2013, our university has implemented a new educational model that puts team projects at the core of all BSc programmes, requiring that students develop teamwork skills. On top of this, in 2018, our Chemical Science & Engineering BSc has become an English-taught, international programme. In consideration of this challenging transition, we have developed additional training to facilitate students' acquisition of knowledge, skills, tools, and attitudes to aid conscientious intercultural teamwork. For this, it is paramount that students become aware of, and learn to appreciate, differences in the educational and cultural backgrounds of themselves and their peers. Concurrently, students should practice what they have learned and adjust their behaviour when appropriate. In this paper, we share our experiences, best practices, and lessons learned. More specifically, our study: i) explores which factors are key to a successful intercultural team, ii) investigates how diversity in teams can be cherished and used for the benefit of the team, its members, and its goals, and iii) how these teamwork skills can effectively be taught in engineering programmes. Building on this, the paper describes how the new curricular education has been designed, what is taught, and how an inclusive, regardful, and pleasant atmosphere has been created for the intercultural project teams

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation

Biotic interactions with mycorrhizal systems as extended nutrient acquisition strategies shaping forest soil communities and functions

Plant nutrient acquisition strategies involving ectomycorrhizal (EcM) and arbuscular mycorrhizal (AM) associations, are key plant functional traits leading to distinct carbon (C) and nutrient dynamics in forests. Yet, little is known about how these strategies influence the structure and functioning of soil communities, and if such mycorrhizal effects may be more or less pronounced depending on the type of forest and various abiotic factors. Here we explore the potential interactions occurring between plant-EcM and plant-AM systems with the diverse soil organisms occurring in forest soils, and in the process draw attention to major issues that are worthy for future research directions. Based on these potential interactions, we suggest that EcM systems, especially those involving gymnosperms in colder climates, may select for a soil community with a narrow set of functions. These EcM systems may exhibit low functional redundancy, dominated by symbiotic interactions, where EcM fungi maintain low pH and high C/N conditions in order to tightly control nutrient cycling and maintain the dominance of EcM trees. By contrast, AM systems, particularly those involving deciduous angiosperm trees in mild and warmer climates, may facilitate a functionally more diverse and redundant soil community tending towards the dominance of competitive and antagonistic interactions, but also with a range of symbiotic interactions that together maintain diverse plant communities. We propose that the contrasting belowground interactions in AM and EcM systems act as extended nutrient acquisition traits that contribute greatly to the prevailing nutrient and C dynamics occurring in these systems

What's up down there?: Climate change effects on subarctic springtail communities and their role in carbon turnover

Cornelissen, J.H.C. [Promotor]Berg, M.P. [Copromotor