Invasion and metastases remain to date the major causes of cancer mortality around the world. Rab27A is a small GTPase that regulates vesicles trafficking and is involved in many physiological processes, e.g. melanosome transport. Being a small GTPase, Rab27A acts as a molecular switch that cycles between an inactive state (GDP bound) and an active state (GTP bound), in which this protein is able to bind to specific effectors to trigger signalling cascades in cells. Current studies suggest a role for Rab27A in exosome-mediated pre-metastatic niche promotion. Hence, interfering with Rab27A PPIs could be effective in reducing and preventing the occurrence of metastasis in cancer. Small GTPases are renowned as challenging targets and have been long considered undruggable, but the unique presence of two non-conserved cysteines in Rab27A offers a perfect starting point for the development of selective covalent inhibitors. These residues are located in the proximity of a major interaction site with a known effector of Rab27A, Slp2, therefore encouraging for targeting PPIs. A screen of covalent fragments based on the recently developed quantitative Irreversible Tethering (qIT) assay has led to the discovery of novel hits with enhanced reactivity for Rab27A against glutathione. The current project aims to (i) obtain potent Rab27A covalent inhibitors by growing hit fragments, and (ii) demonstrate selective Rab27A target engagement in cells, and efficient disruption of the PPIs of Rab27A with its main effectors. Collaboration with the CRUK Beatson Institute will provide direct access to in vivo models to validate the contribution of Rab27A to metastatic development in cancer by use of such chemical probes, whilst state-of-the-art covalent fragment know-how will be accessed for compound optimisation at the Francis Crick Institute/GSK LinkLab, enabling prompt evaluation of the therapeutic potential of optimised lead compounds that will derive from my work.

The increasing demand for environmentally friendly, healthier, and better performing formulated products means that the process industry needs more than ever predictive models of formulation performance for rapid, effective, and sustainable screening of new products. Processing flows and end use produce deformations that are extreme compared to what is accessible with existing experimental methods. As a consequence, the effects of extreme deformation are often overlooked without justification. Extreme deformation of structured fluids and soft materials is an unexplored dynamic regime where unexpected phenomena may emerge. New flow-induced microstructures can arise due to periodic forcing that is much faster than the relaxation timescale of the system, leading to collective behaviors and large transient stresses. The goal of this research is to introduce a radically innovative approach to explore and characterize the regime of extreme deformation of structured fluids and interfaces. By combining cutting-edge techniques including acoustofluidics, microfluidics, and high-speed imaging, I will perform pioneering high-precision measurements of macroscopic stresses and evolution of the microstructure. I will also explore strategies to exploit the phenomena emerging upon extreme deformation (collapse under ultrafast compression, yielding) for new processes and for adding new functionality to formulated products. These experimental results, complemented by discrete particle simulations and continuum-scale modeling, will provide new insights that will lay the foundations of the new field of ultrafast soft matter. Ultimately the results of this research program will guide the development of predictive tools that can tackle the time scales of realistic flow conditions for applications to virtual screening of new formulations.

Optical laser-based technologies are a key technology of the 21st century. Extension of the range of scientific and commercial laser applications requires a constant expansion of the accessible regimes of laser operation. Concepts from nonlinear optics, driven with ultra-fast lasers provide all means to achieve this goal. However, nonlinear optics typically suffer from low efficiencies, e.g. if high-order processes are involved or if the driving laser pulse intensities must be limited below damage thresholds (e.g. in nonlinear microscopy of living cells, or nonlinear spectroscopy of com-bustion processes). Hence, we require methods to enhance nonlinear optical processes. The field of “coherent control” provides techniques to manipulate laser-matter interactions. The idea is to use appropriately designed light-matter interactions to steer quantum systems towards a desired out-come, e.g. to support nonlinear optical processes. The goal of HICONO is to combine the concepts of coherent control with high-intensity nonlinear-optical interactions. The particular aim is to enhance the efficiency of nonlinear optical processes and extend the range of high-intensity laser applications. HICONO will develop new coherent con-trol strategies matched to high-intensity nonlinear optics. This will push high-order frequency con-version towards larger output yield, enable novel applications in high-resolution spectroscopy and microscopy, and drive novel technologies for ultra-short pulse generation and characterization. The close cooperation of HICONO with industry partners will lead to commercially relevant devices. In terms of training, HICONO aims at the development of young researchers with appropriate skills to exploit the concepts of high-intensity laser technologies, laser-based control, and applied nonlinear optics. HICONO provides a unique, very broad and technology-oriented early-stage training program with strong exposure of the fellows to industry environment.

A definitive conclusion about the dangers associated with human or animal exposure to a particular nanomaterial can currently be made upon complex and costly procedures including complete NM characterisation with consequent careful and well-controlled in vivo experiments. A significant progress in the ability of the robust nanotoxicity prediction can be achieved using modern approaches based on one hand on systems biology, on another hand on statistical and other computational methods of analysis. In this project, using a comprehensive self-consistent study, which includes in-vivo, in-vitro and in-silico research, we address main respiratory toxicity pathways for representative set of nanomaterials, identify the mechanistic key events of the pathways, and relate them to interactions at bionano interface via careful post-uptake nanoparticle characterisation and molecular modelling. This approach will allow us to formulate novel set of toxicological mechanism-aware end-points that can be assessed in by means of economic and straightforward tests. Using the exhaustive list of end-points and pathways for the selected nanomaterials and exposure routs, we will enable clear discrimination between different pathways and relate the toxicity pathway to the properties of the material via intelligent QSARs. If successful, this approach will allow grouping of materials based on their ability to produce the pathway-relevant key events, identification of properties of concern for new materials, and will help to reduce the need for blanket toxicity testing and animal testing in the future.