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.
Mathematics is a human activity, and as for all human activities ethical considerations arise. However, so far the ethics of mathematics has remained an under-explored topic both among philosophers and mathematicians. Because mathematics is a collective epistemic endeavour injustices in its social structure, such as biased refereeing practices, impact its epistemic output. These injustices have not yet received sustained critical reflection, even though they are both socially relevant, since they impact the careers and hence lives of mathematicians, and epistemologically relevant, because they shape publicly available mathematical knowledge. VaViM will study the virtues and vices that manifest in such injustices and develop an interventionist philosophy which supports concrete recommendations, such as policy advice. VaViM expands the theoretical frameworks provided by the virtue-theoretic literature to a study of cases of injustices in mathematical practices. This empirically informed philosophy will provide detailed investigations of how virtues (e.g. charity) and vices (e.g. egotism) manifest in mathematical knowledge-making. This will reveal points of connection between the ethics and epistemology of mathematical practices and open up a discursive field for philosophers and mathematicians to engage with the ethics of mathematics. As a European centre of excellence in socially relevant philosophy the VU Amsterdam is the perfect host for VaViM. The shared philosophical interest in the sciences ensures the two-way transfer of knowledge between VaViM and its host and provides ample opportunity for collaboration. The VU’s expertise with public philosophy and its research networks provide excellent means for dissemination for VaViM’s findings on the societal challenges mathematicians are facing in Europe in a changing world. Through VaViM I will enrich the European Research Area as a pioneer of a socially and epistemologically relevant philosophy of mathematics.
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.