Krygerlindsay0333

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.Aminoglycoside antibiotics target the ribosome and induce mistranslation, yet which translation errors induce bacterial cell death is unclear. The analysis of cellular proteins by quantitative mass spectrometry shows that bactericidal aminoglycosides induce not only single translation errors, but also clusters of errors in full-length proteins in vivo with as many as four amino acid substitutions in a row. The downstream errors in a cluster are up to 10,000-fold more frequent than the first error and independent of the intracellular aminoglycoside concentration. The prevalence, length, and composition of error clusters depends not only on the misreading propensity of a given aminoglycoside, but also on its ability to inhibit ribosome translocation along the mRNA. Error clusters constitute a distinct class of misreading events in vivo that may provide the predominant source of proteotoxic stress at low aminoglycoside concentration, which is particularly important for the autocatalytic uptake of the drugs.Sea-level budgets account for the contributions of processes driving sea-level change, but are predominantly focused on global-mean sea level and limited to the 20th and 21st centuries. Here we estimate site-specific sea-level budgets along the U.S. Atlantic coast during the Common Era (0-2000 CE) by separating relative sea-level (RSL) records into process-related signals on different spatial scales. Regional-scale, temporally linear processes driven by glacial isostatic adjustment dominate RSL change and exhibit a spatial gradient, with fastest rates of rise in southern New Jersey (1.6 ± 0.02 mm yr-1). Regional and local, temporally non-linear processes, such as ocean/atmosphere dynamics and groundwater withdrawal, contributed between -0.3 and 0.4 mm yr-1 over centennial timescales. The most significant change in the budgets is the increasing influence of the common global signal due to ice melt and thermal expansion since 1800 CE, which became a dominant contributor to RSL with a 20th century rate of 1.3 ± 0.1 mm yr-1.Dislocation glide is a general deformation mode, governing the strength of metals. Via discrete dislocation dynamics and molecular dynamics simulations, we investigate the strain rate and dislocation density dependence of the strength of bulk copper and aluminum single crystals. An analytical relationship between material strength, dislocation density, strain rate and dislocation mobility is proposed, which agrees well with current simulations and published experiments. Results show that material strength displays a decreasing regime (strain rate hardening) and then increasing regime (classical forest hardening) as the dislocation density increases. Accordingly, the strength displays universally, as the strain rate increases, a strain rate-independent regime followed by a strain rate hardening regime. All results are captured by a single scaling function, which relates the scaled strength to a coupling parameter between dislocation density and strain rate. Such coupling parameter also controls the localization of plasticity, fluctuations of dislocation flow and distribution of dislocation velocity.The remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. selleck chemicals Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning of Drosophila memory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement of orion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in the Drosophila developing brain.Geomagnetic substorms are a global magnetospheric reconfiguration, during which energy is abruptly transported to the ionosphere. Central to this are the auroral electrojets, large-scale ionospheric currents that are part of a larger three-dimensional system, the substorm current wedge. Many, often conflicting, magnetospheric reconfiguration scenarios have been proposed to describe the substorm current wedge evolution and structure. SuperMAG is a worldwide collaboration providing easy access to ground based magnetometer data. Here we show application of techniques from network science to analyze data from 137 SuperMAG ground-based magnetometers. We calculate a time-varying directed network and perform community detection on the network, identifying locally dense groups of connections. Analysis of 41 substorms exhibit robust structural change from many small, uncorrelated current systems before substorm onset, to a large spatially-extended coherent system, approximately 10 minutes after onset. We interpret this as strong indication that the auroral electrojet system during substorm expansions is inherently a large-scale phenomenon and is not solely due to many meso-scale wedgelets.