A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.Intracellular antibodies are tools that can be used directly for target validation by interfering with properties like protein-protein interactions. An alternative use of intracellular antibodies in drug discovery is developing small-molecule surrogates using antibody-derived (Abd) technology. We previously used this strategy with an in vitro competitive surface plasmon resonance method that relied on high-affinity antibody fragments to obtain RAS-binding compounds. We now describe a novel implementation of the Abd method with a cell-based intracellular antibody-guided screening method that we have applied to the chromosomal translocation protein LMO2. We have identified a chemical series of anti-LMO2 Abd compounds that bind at the same LMO2 location as the inhibitory anti-LMO2 intracellular antibody combining site. Intracellular antibodies could therefore be used in cell-based screens to identify chemical surrogates of their binding sites and potentially be applied to any challenging proteins, such as transcription factors that have been considered undruggable.Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD (n = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet (n = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.Oceanic transform faults, a key element of plate tectonics, represent the first-order discontinuities along mid-ocean ridges, host large earthquakes, and induce extreme thermal gradients in lithosphere. However, the thermal structure along transform faults and its effects on earthquake generation are poorly understood. Here we report the presence of a 10- to 15-kilometer-thick in-depth band of microseismicity in 10 to 34 kilometer depth range associated with a high-temperature (700° to 900°C) mantle below the brittle lithosphere along the Romanche mega transform fault in the equatorial Atlantic Ocean. The occurrence of the shallow 2016 moment magnitude 7.1 supershear rupture earthquake and these deep microearthquakes indicate that although large earthquakes occur in the upper brittle lithosphere, a substantial amount of deformation is accommodated in the semibrittle mylonitic mantle that resides at depths below the 600°C isotherm. We also observe a rapid westward deepening of this band of seismicity indicating a strong lateral heterogeneity.Cells in vivo generate mechanical traction on the surrounding 3D extracellular matrix (ECM) and neighboring cells. Such traction and biochemical cues may remodel the matrix, e.g., increase stiffness, which, in turn, influences cell functions and forces. This dynamic reciprocity mediates development and tumorigenesis. Currently, there is no method available to directly quantify single-cell forces and matrix remodeling in 3D. Here, we introduce a method to fulfill this long-standing need. We developed a high-resolution microfabricated sensor that hosts a 3D cell-ECM tissue formed by self-assembly. This sensor measures cell forces and tissue stiffness and can apply mechanical stimulation to the tissue. We measured single and multicellular force dynamics of fibroblasts (3T3), human colon (FET) and lung (A549) cancer cells, and cancer-associated fibroblasts (CAF05) with 1-nN resolution. Single cells show notable force fluctuations in 3D. FET/CAF coculture system, mimicking cancer tumor microenvironment, increased tissue stiffness by three times within 24 hours.Current sea-level projections are based on climate models in which the effects of ocean eddies are parameterized. Here, we investigate the effect of ocean eddies on global mean sea-level rise (GMSLR) projections, using climate model simulations. Explicitly resolving ocean eddies leads to a more realistic Southern Ocean temperature distribution and volume transport. These quantities control the rate of basal melt, which eventually results in Antarctic mass loss. In a model with resolved ocean eddies, the Southern Ocean temperature changes lead to a smaller Antarctic GMSLR contribution compared to the same model in which eddies are parameterized.  https://www.selleckchem.com/products/daratumumab.html  As a result, the projected GMSLR is about 25% lower at the end of this century in the eddying model. Relatively small-scale ocean eddies can hence have profound large-scale effects and consequently affect GMSLR projections.