A self-optimised approach to synthesising DEHiBA for advanced nuclear reprocessing, exploiting the power of machine-learning

In an effort to advance the development of hydrometallurgical reprocessing of used nuclear fuel across the globe, this work sets out to explore and identify an optimised, cost effective pathway to synthesise the ligand DEHiBA (N,N-di-(2-ethylhexyl)isobutyramide). Currently, very few chemical suppliers stock and distribute this specialist ligand, designed for selective uranium chelation and extraction from nuclear fuel. The current high cost of DEHiBA therefore restricts access to essential large-scale testing of this promising ligand designed to advance nuclear reprocessing. This work utilises an automated flow reactor platform for the efficient optimisation of four synthetic routes to DEHiBA. These optimisations focus on optimising cost, reagent efficiency, yield, and productivity target functions by exploiting the power of machine-learning algorithms for rapid process development. Ultimately, we have identified an efficient and cost-effective solvent-free route to DEHiBA from isobutyric anhydride and di-2-ethylhexylamine for 99%, at a purity of 76%, and a process mass intensity of 1.29 g g−1, whilst alternative conditions demonstrated productivities >75 kg L−1 h−1, all whilst maintaining a high level of process control with outlet temperatures not exceeding 35 °C

T cell shape and function is orchestrated by a network of T polarity proteins

Loss of polarity is one of the earliest hallmarks of epithelial neoplasia and leads to aberrant communication between the epithelial cell and its microenvironment. Understanding how deregulation of polarity occurs and how it may contribute to tumour formation is a new and unexplored area of cancer research. Genetic screens in Drosophila have identified scribble, discs large (dlg) and lethal giant larvae (lgl) as key epithelial polarity regulators with mutation in any of these genes resulting in loss of polarity, overproliferation and multilayering of epithelial cells leading to 3D-tumourous overgrowth, and in the presence of activated Ras, invasion and metastasis. We have recently described the human homologue of Scribble and demonstrated using complementation studies in Drosophila that expression of human Scribble can also regulate polarity and proliferation. Evidence from cancer patients suggests that Scribble and Dlg could act as a tumour suppressor in some epithelial cancers with, in many cases, low levels of Scribble or Dlg correlating with increased tumour invasiveness and malignancy. We have undertaken a detailed functional analysis of Scribble in mammalian epithelial cells and mice mutant for Scribble and uncovered a critical role for Scribble in the regulation of epithelial polarity required for directed migration during development and wound healing in vivo. In addition, we show that impaired human Scribble can function together with activated Ras to lead to increased invasion and tumourigenesis. Therefore, Scribble can act to promote or inhibit migration dependent on the cellular context. We propose that Scribble and other polarity regulators may be key signalling molecules involved in a new pathway regulating epithelial tumour progression in mammals