The Jülich HBS Project for accelerator based neutron sources

The Jülich Centre for Neutron Science is working on the project to develop, design and demonstrate anaccelerator driven high-brilliance neutron source (HBS) as an efficient and cost-effective alternative tocurrent low- and medium-flux reactor and spallation sources. The HBS comprises a high current protonacceleratorwith an energy of 70 MeV and a beam current of 100 mA, a compact neutron target of 100 kWpower, sophisticated cold and thermal moderator systems and an optimized neutron transport system toprovide thermal and cold neutrons with high brilliance for a full suite of epithermal, thermal and coldinstruments.The project offers construction of a scalable neutron source fora user facility with open access and serviceaccording to the various and changing demand of its communities. Embedded within an internationalcollaboration with partners from Germany, Europe and Japan the Jülich HBS project offers best flexiblesolutions to the scientific and industrial users. The overall conceptual design of HBS was published in arecent report.We will present the current status of the project, progress and next steps regarding accelerator, target,moderators and beam delivery development, milestones and the vision for the realization of such a facility

Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling

Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine