Mutations in the RNA-binding protein roquin-1 are known to result in humoral autoimmunity. Heissmeyer and colleagues show that MALT1 cleavage of roquin and regnase-1 downstream of TCR signaling releases cooperatively repressed targets to promote T H 17 cell differentiation
Recovery, recrystallization and grain growth are among the most important metallurgical heat treatment processes to soften cold worked metals and design desired microstructures and textures. Specifically the reduction in grain size can be efficiently achieved by recrystallization. While plastic cold working increases the stored energy of metals, mainly through dislocation accumulation, recovery and specifically recrystallization lead to it reduction. While recovery describes the gradual re-ordering and annihilation of the stored dislocations, primary recrystallization proceeds discontinuously by the formation and motion of high angle grain boundaries which discontinuously sweep the deformation substructure. Grain growth describes the process of competitive capillary driven coarsening of the average grain size. This chapter reviews the main mechanisms, lattice defects, and driving forces associated with recovery, recrystallization and grain growth and provides an introduction to the simulation of these phenomena.
Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.
