VUA

To successfully complete secondary education, persistent learning behavior is essential. Why are some adolescents more resilient to setbacks at school than others? In addition to actual ability, students’ implicit beliefs about the nature of their abilities have major impact on their motivation and achievements. Ability beliefs range from viewing abilities as “entities” that cannot be improved much by effort (entity beliefs), to believing that they are incremental with effort and time (incremental beliefs). Importantly, ability beliefs shape which goals a student pursues at school; proving themselves (performance goals) or improving themselves (learning goals). The central aims of the proposal are to unravel 1) the underlying processing mechanisms of how beliefs and goals shape resilience to setbacks at school and 2) how to influence these mechanisms to stimulate persistent learning behavior. Functional brain research, including my own, has revealed the profound top-down influence of goals on selective information processing. Goals may thus determine which learning-related information is attended. Project 1 jointly investigates the essential psychological and neurobiological processes to unravel the longitudinal effects of beliefs and goals on how the brain prioritizes information during learning, and how this relates to school outcomes. Project 2 reveals how to influence this interplay with the aim to long-lastingly stimulate persistent learning behavior. I will move beyond existing approaches by introducing a novel intervention in which students experience their own learning-related brain activity and its malleability. The results will demonstrate how ability beliefs and goals shape functional brain development and school outcomes during adolescence, and how we can optimally stimulate this interplay. The research has high scientific impact as it bridges multiple disciplines and thereby provides a strong impulse to the emerging field of educational neuroscience.

The forming of social bonds is an evolutionary imperative, and a rich target for empirical research. Social scientists have scrutinized the structure of the elaborate social networks that characterize today’s society. Neuroscientists have elucidated the brain mechanisms underlying our ability to navigate this social world. Yet, these research lines have been largely separated. This proposal aims to integrate social network research and social brain research, focusing on adolescence as the most dynamic phase shaping the interplay between social networks and the social brain. Social development in adolescents is clearly driven by maturation of specific social-cognitive functions; yet these functions are manifest in, and moulded by, interpersonal relationships within social networks. I aim to clarify how changes in the social brain relate to changes in social network position and structure during adolescent development. This can be achieved by using the quantitative tools of social network analysis in conjunction with the experimental approach of social neuroscience. I plan to investigate a cohort of approximately 1000 adolescents nested in 50 classes in a longitudinal design with 6 measurements over 3 years; fMRI investigating task-related functional activation and connectivity is conducted yearly in a subsample of 100. The neural and behavioural correlates of social cognition are investigated using experimental tasks tapping i) understanding others and ii) interacting with others; social behaviour is charted through ecological momentary assessment techniques; social networks are mapped using surveys and digital information acquired routinely via mobile phones (mobile sensing). This approach clarifies how during a crucial developmental phase the social brain shapes the social environment, and vice versa, the social environment influences maturation of the social brain.

Optical methods and fluorescent proteins to probe and manipulate cellular and subcellular processes have proven to be a major driving force behind many recent breakthroughs in biology and medicine. Recent developments in photonics have led to increased spatial and temporal resolution and now allow the study of single identified synaptic contacts between neurons as well as large-scale neuronal networks. Brain tissue strongly scatters light. Thereby, the amount of light emitted by fluorescent probes in small structures inside neuronal tissue that reaches the microscope objective is small. Fluorescence imaging in living tissue, as I use in my ERC-funded research program, is therefore limited by low signal-to-noise levels. One approach in increasing the level of such weak fluorescence is to increase the excitation power, but this has the undesirable effect of bleaching the fluorescence faster and damaging the cell. Another approach is to optimize the fluorescence collection by using high-end microscope objectives in the 20,000 eur range with improved light transmission, high numerical aperture and low magnification that can collect fluorescence more efficiently. Although these objectives brought a significant improvement to imaging applications, physical limitations in their design cannot offer anymore a similar qualitative improvement as previously. Since there is a great need to further improve biological imaging, the present proof of concept application aims to achieve this by developing advanced, but low-cost, electronics for the optical detection of weak fluorescence signals through Photon Counting, and bring this technology to the market.

The objective of this proposal is the elucidation of general principles for the design of bioavailable peptide-derived macrocyclic compounds and their use for the development of inhibitors of protein‒protein (PPI) and protein‒RNA interactions (PRI). Over the last decade, drug discovery faced the problem of decreasing success rates which is mainly caused by the fact that numerous novel biological targets are reluctant to classic small molecule modulation. In particular, that holds true for PPIs and PRIs. Approaches that allow the modulation of these interactions provide access to therapeutic agents targeting crucial biological processes that have been considered undruggable so far. Herein, I propose the use of irregularly structured peptide binding epitopes as starting point for the design of bioactive macrocycles. In a two-step process high target affinity and bioavailability are installed: 1) Peptide macrocyclization for the stabilization of the irregular bioactive secondary structure 2) Evolution of the cyclic peptide into a bioavailable macrocyclic compound Using a well-characterized model system developed in my lab, initial design principles will be elucidated. These principles are subsequently used and refined for the development of macrocyclic PPI and PRI inhibitors. The protein‒protein and protein‒RNA complexes selected as targets are of therapeutic interest and corresponding inhibitors hold the potential to be pursued in subsequent drug discovery campaigns.

A key component of the Standard Model is Quantum Electrodynamics (QED). QED explains e.g. the anomalous magnetic moment of the electron and small energy shifts in the energy structure of atoms and molecules due to vacuum fluctuations. After decades of precision measurements, especially laser spectroscopy in atomic hydrogen, QED is considered the most successful and best-tested theory in physics. However, in 2010 precision spectroscopy in muonic-hydrogen (where the electron is replaced with a muon) has lead to discrepancies in energy level structure that cannot be accounted for. If QED is considered correct, then one way of interpreting the results is that the size of the proton is different in normal (electronic) hydrogen by as much as 4% (a 7 sigma effect) compared to muonic hydrogen. Despite great theoretical and experimental efforts, this 'proton size puzzle' is still unsolved. I propose to perform precision spectroscopy in the extreme ultraviolet near 30 nm in the helium+ ion, to establish an exciting new platform for QED tests and thereby shed light on the proton-size puzzle. The advantages of helium ions over hydrogen atoms are that they can be trapped (observed longer), QED effects are more than an order of magnitude larger, and the nuclear size of the alpha particle is better known than the proton. Moreover, the CREMA collaboration has recently measured the 2S-2P transition in muonic He+ (both 3He and 4He isotopes) at the Paul Scherrer Institute. Evaluation of the measurements is ongoing, but could lead to an 8 fold (or more) improved alpha-particle radius, so that it is no longer limiting QED theory in normal He+. I will use several ground-breaking methods such as Ramsey-comb spectroscopy in the extreme ultraviolet to measure the 1S-2S transition in trapped normal electronic He+, with (sub) kHz spectroscopic accuracy. This will provide a unique and timely opportunity for a direct comparison of QED in electronic and muonic systems at an unprecedented level.