Precise frequency measurements enable accurate determinations of physical constants, stringent tests of fundamental theories and searches for possible drifts of the fundamental constants. Simple atoms, hydrogen in particular, have long been the dedicated systems for confronting experimental data and accurate quantum electrodynamics theoretical calculations. With continued progress to ab initio calculations, precision measurements in small molecules, such as molecular hydrogen H2, are gaining much relevance and may be envisioned as an independent way to determine fundamental constants and to test quantum-chemistry theory. In this project, we will develop an instrument of precision molecular spectroscopy, based on frequency combs, broad spectra composed of equidistant narrow lines whose absolute frequency can be known within the accuracy of an atomic clock. Building on our unique know-how, this revolutionary ultraviolet spectrometer will simultaneously combine broad spectral coverage, Doppler-free resolution and extreme accuracy for precise studies of small molecules. Using two-photon excitation and dual-comb spectroscopy with comb lasers of low repetition frequency, we will devise an optical analogue of the Ramsey-fringe method where many molecular transitions will be simultaneously and unambiguously observed and assigned. While such a spectrometer will enable significant progress in our understanding of the structure of many small molecules, it will first be applied to absolute-frequency measurements of rovibronic transitions in the EF – X system of H2 around 3000 THz. The measured frequencies can be used to benchmark molecular theory in the involved ground and excited states. They may contribute to an improved determination of the dissociation energy of H2, set new basis for an independent determination of the proton-charge radius and for searches of variations of the proton-electron mass ratio via comparison to astrophysical measurements.

The chromophores of photo-responsive proteins (PRPs) are increasingly exploited in science and technology from time and spatially resolved studies of neural signaling to the engineering of fully synthetic molecular devices. This justifies the increasing need for interdisciplinary studies aiming at controlling the chromophore function and achieving novel applications. In this doctoral network we will combine design, preparation and theory of PRP chromophores operating as rotary molecular-level devices with the novel tool of time-resolved photoemission spectroscopy (TRPES) to unravel basic principles of their rotary function. The most prominent PRPs, e.g. retinal proteins, the green fluorescent protein or xanthopsin all convert the photon energy into rotary motion by leveraging efficient ultrafast double-bond isomerizations. There is a consensus that such energy conversion is mediated by conical intersections (CIs) between ground and excited state potential energy surfaces. TRPES is a novel method, emerging at the interface of ultrafast physics and chemistry, capable of imaging the dynamics through CIs, thus providing a unique view on the photon-to-nuclear-rotation transduction process. More specifically, novel TRPES tools developed within the network will be employed to study devices based on oxindoles and oxipyrroles, mimicking the green-fluorescent protein chromophores, and on cinnamic ester derivatives, mimicking the chromophores of xanthopsins. We will investigate and learn to control these systems studying selected sets of chemical substitutions and environmental effects. The development of an effective research protocol focused on the combination of novel syntheses, TRPES and interpretative state-ofthe-art quantum chemical methods, will provide a cutting-edge interdisciplinary training arena for talented doctoral students and will be complemented by a modern soft-skill learning program and intense knowledge exchange between science and industry.

The Phosphoinositide 3-kinase (PI3K) pathway is at the core of multiple fundamental biological processes controlling metabolism, protein synthesis, cell growth, survival, and migration. This inevitably leads to the involvement of the PI3K signalling pathway in a number of different diseases, ranging from inflammation and diabetes to cancer, with PI3K pathway alterations present in almost 80% of human cancers. Therefore, PI3Ks have emerged as important targets for drug discovery and, during 2014, the first PI3K inhibitor was approved by FDA in the US for the treatment of a lymphocytic leukaemia. Nonetheless, our understanding of PI3K-mediated signalling is still poor and only a fraction of the potential therapeutic applications have been addressed so far, leaving a large amount of translational work unexplored. Europe features a set of top quality research institutions and pharmaceutical companies focused on PI3K studies but their activities have been so far scattered. This proposal fills this gap by providing a multidisciplinary network (biochemistry, mouse studies, disease models, drug development, software development) and an unprecedented training opportunity from the bench to the bedside (from pre-clinical discoveries to clinical trials), through cutting edge molecular biology, drug discovery and clinical trial organization. The proposal is aimed at training young investigators in deep understanding of the different PI3K isoforms in distinct tissues and to translate this knowledge into a new generation of PI3K inhibitors, treatment modalities and into identify new uses for existing PI3K inhibitors.