We propose to create an attractive future-oriented postdoctoral programme – Physics for Future (P4F) – with a carefully designed combination of advanced scientific, transferable and soft skill training. In two calls and in an open transparent, merit-based, equitable selection process we will recruit 60 postdoctoral fellows to join the Institute of Physics (FZU) of the Czech Academy of Sciences. The scientific scope of the programme is defined by the fundamental areas of research pursued at FZU: Particle and Theoretical Physics, Condensed matter, Solid State Physics, Optics, Laser and Plasma Physics. With sustainable research and development in mind we have identified three broadly defined domains – Materials for Society, Matter under Extreme Conditions and Emerging tools leading to a strong synergy among these research fields. With its interdisciplinary and intersectoral aspects and embedded outlook towards new tools & technologies – such as 3D printing, artificial intelligence (AI), machine learning and advanced computing – P4F aims to further strengthen the European knowledge capital, and thus contribute to the generation of frontier science; facilitate the R&D-industry discourse and interaction; accelerate innovation; and, importantly, contribute to the career development of the future leaders in the field of physics, who will be able to address and solve the needs of society in the perspective of global sustainable development. We will educate a new generation of physicists fluent in interaction with industry and ready to face future societal challenges. In this effort, FZU joins forces with 16 national and 36 international academic and 20 non-academic partners, 72 in total. This wide network has been crafted to specifically foster deep interdisciplinary thinking and promote knowledge exchange between academia and industry, with the aim of creating a stronger impact on both society and economy.

The crucial step for selective cleavage and formation of C-H bonds is a concerted transfer of proton (PT) and electron(s) (ET): hydrogen atom abstraction (HAA) or hydride transfer (HT). The HAA and HT processes can be employed to various chemical transformations: from activation of inert bonds to reduction of CO2. This approach, however, requires a strict control of the regioselectivity of the reaction. Notably, enzymes - catalysts developed by Nature, are characterised by high activity and selectivity. In this project, we would like to provide insight into the interplay of reaction thermodynamics and sterics given by the microenvironment of prototypical enzymatic active sites (employing HAA or HT as a key step in catalysis) and to decipher which of these effects is more important in enzymatic selectivity. The focal point of the project is the novel three component thermodynamic-based model for reactivity, developed for concerted H+/e− abstraction. The model captures the coupled nature of PT and ET by the relative magnitutes of redox potentials and acidity constants of the reactants - their values determine not only the the reaction driving force but also the two novel contributions: asynchronicity and frustration with opposing effects on the barrier for the reaction. An asynchronous process, featuring a large disparity in ET and PT components of the reaction driving force, is more efficient. In contrast, a common large size of these ET and PT components makes HAA more frustrated and hence less effective. Based on this model we would like to look into systems capable of CO2 reduction and C-H bond activation to assess to what extent their reactivity is tweaked by the local conditions given by the enzymatic microenvironment versus the “canonical” factors affecting enzymatic activity, such as sterics and specific interactions. The studies may serve as a guide for design for systems capable of effective reduction of CO2 and rational redesign of C-H activating enzymes.

It sounds simple: A cell cannot divide without nucleotides. Indeed, the disruption of pyrimidine de novo synthesis (PDNS) efficiently blocks proliferation of cancer cells. Yet still today, PDNS-directed anticancer treatment has not entered clinics due to the lack of efficacy. Why? Cancer cells gain pyrimidines via PDNS or from salvage pathways, and PDNS inhibition in cancer cells can likely be bypassed by pyrimidines produced in the tumor environment or gained from the systemic circulation. Can we target this microenvironmental interaction to improve treatment efficacy? A crucial component of tumor environment are blood vessels. Tumors stimulate their growth, angiogenesis, to gain oxygen and nutrients. Metabolism of endothelial cells (ECs), the inner vessel lining, is rewired in tumors, and tumor ECs upregulate PDNS. However, whether and how elevated PDNS in ECs supports tumorigenesis is unknown. I hypothesize that PDNS in ECs affects tumor environment either directly by providing pyrimidines to cancer cells or indirectly by stimulating angiogenesis, making systemic resources more accessible to cancer cells. The central goals of this project are (i) to identify the metabolic communication of ECs with other cell types in tumors, (ii) asses if endothelial PDNS promotes angiogenesis, and (iii) to seek novel metabolic targets in ECs, whose inhibition improves efficacy of PDNS inhibitors in vivo. To reach these goals, I will use an inducible mouse model to selectively disable PDNS in the endothelium. With this unique tool available at my host institute, I will integrate a state-of-the-art multi-omics and my expertise in metabolism to disentangle the network of metabolic communication using a powerful combination of spatially resolved single cell transcriptomics, metabolomics and functional genomics. My innovative approach will open a way for understanding the EC contribution to metabolic balance in tumors with a potential to identify new metabolic anti-cancer strategies.