Stress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a highcontent screen to identify small molecules that alter SG properties in proliferative cells and human iPSC-derived motor neurons (iPS-MNs). One major class of active molecules contained extended planar aromatic moieties, suggesting a potential to intercalate in nucleic acids. Accordingly, we show that several hit compounds can prevent the RNA-dependent recruitment of the ALS-associated RNA-binding proteins (RBPs) TDP-43, FUS, and HNRNPA2B1 into SGs. We further demonstrate that transient SG formation contributes to persistent accumulation of TDP-43 into cytoplasmic puncta and that our hit compounds can reduce this accumulation in iPS-MNs from ALS patients. We propose that compounds with planar moieties represent a promising starting point to develop small-molecule therapeutics for treating ALS/FTD.

Progress in deep learning has spawned great successes in many engineering applications. As a prime example, convolutional neural networks, a type of feedforward neural networks, are now approaching -and sometimes even surpassing -human accuracy on a variety of visual recognition tasks. Here, however, we show that these neural networks and their recent extensions struggle in recognition tasks where co-dependent visual features must be detected over long spatial ranges. We introduce a visual challenge, Pathfinder, and describe a novel recurrent neural network architecture called the horizontal gated recurrent unit (hGRU) to learn intrinsic horizontal connections -both within and across feature columns. We demonstrate that a single hGRU layer matches or outperforms all tested feedforward hierarchical baselines including state-of-the-art architectures with orders of magnitude more parameters.

Skeletal muscle contractions are initiated by an increase in Ca 2+ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca 2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca 2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca 2+ in internal stores, which is consistent with increased SR luminal Ca 2+ . These findings define critical roles for Stac3 in EC coupling and human disease.zebrafish | skeletal muscle | excitation-contraction coupling | dihydropyridine receptor | Native American myopathy