Despite the abundance of organic compounds in Nature, only 12 contain fluorine. In contrast, fluorinated organic materials account for over 40% of all pharmaceuticals and agrochemicals. Closer inspection of the fluorination patterns in these functional molecules reveals striking extremes towards perfluorination (in both 2D and 3D scaffolds) or single site fluorination predominantly in aryl substituents. Consequently, most fluorinated moieties in functional materials lack stereochemical information and are thus achiral. This disparity between the paucity of naturally occurring organofluorine compounds and their venerable history in functional molecule design confirms the enormous potential of fluorinated materials in the discovery of novel properties. That progress has largely been confined to 3 dimensional achiral and 2 dimensional achiral architectures reflects the synthetic challenges associated with preparing stereochemical defined multiply fluorinated systems. A major limitation in the construction of C(sp3)-F units remains the need for substrate pre-functionalisation via oxidation and the competing substitution/elimination scenario that compromises efficiency in the deoxyfluorination. This problem is magnified in the synthesis of optically active fluorides where the deoxyfluorination can compromise the enantiopurity of the starting materials. The principle aim of RECON is to facilitate exploration of 3D, chiral space by providing access to multiply fluorinated, stereochemically complex organofluorine materials from simple feedstock using inexpensive, commercially available fluoride sources. In providing a modular platform to rationally place function on a structural basis, exploration of uncharted chemical space will accelerate the discovery of next generation materials for medicinal and agrochemistry, material sciences and bio-medicine.

Water activation, which allows the transfer of universally abundant hydrogen into value added compounds, is an important research field in modern science. This task has been realized mainly by using transition-metal-based systems. Herein we will use a conceptually novel mild water activation strategy which proceeds through a photocatalytic phosphine-mediated radical process. The active species in these processes is a metal-free R3P-OH2 radical cation intermediate where both hydrogen atoms are used in the following chemical transformation through sequential heterolytic (H+) and homolytic (H•) cleavage of the two O-H bonds. The R3P-OH radical intermediate provides an ideal platform to mimic the reactivity of a "free" hydrogen atom that can be directly transferred to various π-systems to give H-adduct C-radicals, which are eventually reduced by a thiol cocatalyst leading to overall transfer hydrogenation of π-systems, with the two H-atoms of water ending up in the product. The driving force is the strong P-O bond formed in the phosphine oxide byproduct. Hydrogenation of alkenes, arenes and hetero(arenes) will be investigated, also addressing stereoselective reductions using chiral H-donors. Deuteration and tritiation with D2O and T2O as formal reductants will be explored. Experimental studies will be supported by DFT calculations throughout the studies. Polar effects exerted by the H-donors will be studied, which will allow the design of more complex intramolecular and intermolecular reductive cascade reactions comprising C-C bond forming steps. Reactivity of the novel R3P-OH radicals towards various functionalities will be systematically investigated and the reactive functional groups then incorporated into cascade reactions. Atom-economic radical H-transfer isomerization reactions that proceed with P-based catalysts will be developed. Finally, photoactive P-compounds will be used as mediators for water activation in hydrogen atom transfer radical chemistry.

Human Papillomavirus Type 16 (HPV16), the paradigm cancer-causing HPV type, is a small, nonenveloped, DNA virus characterized by its complex life cycle coupled to differentiation of squamous epithelia. Due to this complexity, how HPV16 infects cells is an understudied field of research. Our previous work to define the cellular pathways that are hijacked for initial infection revealed uptake by a novel endocytosis mechanism, and the requirement for mitosis for nuclear delivery. Our findings indicated that nuclear envelope breakdown was required to access the nuclear space, and that the virus associated with mitotic chromatin during metaphase. This prolonged mitosis, a process beneficiary for infection. The viral L2 protein as part of incoming viruses mimics this on its own. The aim of this proposal is to reveal how HPV16 differentially modulates or takes advantage of the mitotic machinery for nuclear import in cells, tissues or during aging, and whether malignant cellular consequences arise. On the viral side, we will define the minimal properties of L2 to mediate association with cell chromatin and mitosis prolongation. On the cellular side, we will identify the protein(s) that mediate recruitment, and how it occurs in a detailed temporal/spatial manner. To elucidate the mechanism of mitotic prolongation and consequences thereof, we will identify which regulatory complex of mitosis is targeted, how it is induced, and whether it causes DNA damage or segregation errors. Finally, we will ascertain the influence of tissue differentiation and aging on this process. Using systems biology, proteomics, virology, cell biology, biochemistry, and a wide range of microscopy approaches we will unravel the complex interactions between HPV and the host cell mitosis machinery. In turn, as viruses often serve as valuable tools to study cell function, this work is likely to uncover new insights into how cells spatially and temporally regulate mitosis in differentiation and aging.

Bone is one of the most common organs for solid tumour metastasis. 75% of patients with late-stage breast cancer develop recurrence in bone. Current treatments are palliative, leaving this condition incurable, with an unmet need to identify new therapies. Inflammation is an important player in cancer. My pilot data show that depletion of a specific immune cell type, neutrophils, impairs bone metastasis in vivo, suggesting that neutrophils have tumour-supporting functions. However, the role of neutrophils in the metastatic bone niche remains largely unexplored, it is unknown whether they contribute to the seeding or the expansion phase of bone metastasis and if tumour cells regulate neutrophil plasticity, therefore skewing the balance towards pro-tumourigenic neutrophil subsets. I hypothesise that neutrophils acquire pro-tumourigenic phenotypes when in close proximity to cancer cells and support metastatic progression by regulating the tumour niche. By using a liposoluble fluorescent protein expressed by cancer cells, neighbouring neutrophils will be characterised: Neutrophil subsets will be identified by spectral cytometry, their transcriptomic signature analysed using RNA sequencing and their pro-tumourigenic role functionally assessed in vitro and in vivo. By employing a combination of MALDI-MSI and multiplex antibody-based imaging, neutrophil-cancer cell interactome will be established in order to identify candidate molecular mechanisms regulating neutrophil pro-tumourigenic functions. By using in vivo models of neutrophil extracellular traps (NETs) blockade, neutropenia, neutrophilia and enhanced neutrophil retention in the bone marrow, neutrophil candidate mechanisms shaping the metastatic niche will be determined. Dissecting the molecular mechanisms regulating pro-tumourigenic neutrophil subsets is fundamental to identify novel means of inhibiting bone metastasis without affecting neutrophil critical functions in inflammation.