A high-fluence fusion neutron source

A conceptual design of a D-T fusion facility for continuous production of 14-MeV neutron wall loading from 5 to 10 MW/m/sup 2/ at the plasma surface is presented. In this design, D-T neutrons are produced in a linear, two-component plasma formed by neutral beam irradiation of a fully ionized warm plasma target. The beam energy, which is deposited in the center, is transferred to the warm plasma mainly by electron drag and is conducted along the target plasma column to end regions where it is absorbed in neutral gas at high pressure. The target plasma is operated in a regime where electron thermal conduction along the column is the controlling energy-loss process. The loss rate is minimized by adjusting the diameter and length of the plasma column. A substantial gradient in T/sub e/ along the column results in recombination of the plasma to gas in the end-regions before impact on the end walls. The resultant hot gas is cooled by contact with large-area heat exchangers. In this way, the large steady-state heat load from the injected neutral beams is diffused and removed at tolerable heat flux levels. The reacting plasma is essentially an extrapolation of the 2XIIB high-..beta.. plasma to higher magnetic field, ion energy, and density. 12 refs., 4 figs

Identification of an allosteric binding site for RORγt inhibition

RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors

Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases

The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.FWN – Publicaties zonder aanstelling Universiteit Leide