Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). Here, we assess the impact of stress on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs) using subcellular fractionation with RNA sequencing and proteomics. Transient stress disrupts subcellular RNA and protein distributions, alters the RNA binding profile of SG- and ALS-relevant RBPs and recapitulates disease-associated molecular changes such as aberrant splicing of STMN2. Although neurotypical PSC-MNs re-establish a normal subcellular localization landscape upon recovery from stress, cells harboring ALS-linked mutations are intransigent and display a delayed-onset increase in neuronal cell death. Our results highlight subcellular molecular distributions as predictive features and underscore the utility of cellular stress as a paradigm to study ALS-relevant mechanisms

RELICS: The Reionization Lensing Cluster Survey and the Brightest High-z Galaxies

Massive foreground galaxy clusters magnify and distort the light of objects behind them, permitting a view into both the extremely distant and intrinsically faint galaxy populations. We present here the z ~ 6-8 candidate high-redshift galaxies from the Reionization Lensing Cluster Survey (RELICS), a Hubble and Spitzer Space Telescope survey of 41 massive galaxy clusters spanning an area of ≈200 arcmin². These clusters were selected to be excellent lenses, and we find similar high-redshift sample sizes and magnitude distributions as the Cluster Lensing And Supernova survey with Hubble (CLASH). We discover 257, 57, and eight candidate galaxies at z ~ 6, 7, and 8 respectively, (322 in total). The observed (lensed) magnitudes of the z ~ 6 candidates are as bright as AB mag ~23, making them among the brightest known at these redshifts, comparable with discoveries from much wider, blank-field surveys. RELICS demonstrates the efficiency of using strong gravitational lenses to produce high-redshift samples in the epoch of reionization. These brightly observed galaxies are excellent targets for follow-up study with current and future observatories, including the James Webb Space Telescope

Spectrum and Morphology of the Two Brightest Milagro Sources in the Cygnus Region: MGRO J2019+37 and MGRO J2031+41

The Cygnus region is a very bright and complex portion of the TeV sky, host to unidentified sources and a diffuse excess with respect to conventional cosmic-ray propagation models. Two of the brightest TeV sources, MGRO J2019+37 and MGRO J2031+41, are analyzed using Milagro data with a new technique, and their emission is tested under two different spectral assumptions: a power law and a power law with an exponential cutoff. The new analysis technique is based on an energy estimator that uses the fraction of photomultiplier tubes in the observatory that detect the extensive air shower. The photon spectrum is measured in the range 1 to 200 TeV using the last 3 years of Milagro data (2005-2008), with the detector in its final configuration. MGRO J2019+37 is detected with a significance of 12.3 standard deviations ($\sigma$), and is better fit by a power law with an exponential cutoff than by a simple power law, with a probability $>98$% (F-test). The best-fitting parameters for the power law with exponential cutoff model are a normalization at 10 TeV of $7^{+5}_{-2}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$, a spectral index of $2.0^{+0.5}_{-1.0}$ and a cutoff energy of $29^{+50}_{-16}$ TeV. MGRO J2031+41 is detected with a significance of 7.3$\sigma$, with no evidence of a cutoff. The best-fitting parameters for a power law are a normalization of $2.4^{+0.6}_{-0.5}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$ and a spectral index of $3.08^{+0.19}_{-0.17}$. The overall flux is subject to an $\sim$30% systematic uncertainty. The systematic uncertainty on the power law indices is $\sim$0.1. A comparison with previous results from TeV J2032+4130, MGRO J2031+41 and MGRO J2019+37 is also presented.Comment: 11 pages, 10 figure

RELICS: Reionization Lensing Cluster Survey

Large surveys of galaxy clusters with the Hubble and Spitzer Space Telescopes, including CLASH and the Frontier Fields, have demonstrated the power of strong gravitational lensing to efficiently deliver large samples of high-redshift galaxies. We extend this strategy through a wider, shallower survey named RELICS, the Reionization Lensing Cluster Survey. This survey, described here, was designed primarily to deliver the best and brightest high-redshift candidates from the first billion years after the Big Bang. RELICS observed 41 massive galaxy clusters with Hubble and Spitzer at 0.4-1.7um and 3.0-5.0um, respectively. We selected 21 clusters based on Planck PSZ2 mass estimates and the other 20 based on observed or inferred lensing strength. Our 188-orbit Hubble Treasury Program obtained the first high-resolution near-infrared images of these clusters to efficiently search for lensed high-redshift galaxies. We observed 46 WFC3/IR pointings (~200 arcmin^2) with two orbits divided among four filters (F105W, F125W, F140W, and F160W) and ACS imaging as needed to achieve single-orbit depth in each of three filters (F435W, F606W, and F814W). As previously reported by Salmon et al., we discovered 322 z ~ 6 - 10 candidates, including the brightest known at z ~ 6, and the most distant spatially-resolved lensed arc known at z ~ 10. Spitzer IRAC imaging (945 hours awarded, plus 100 archival) has crucially enabled us to distinguish z ~ 10 candidates from z ~ 2 interlopers. For each cluster, two HST observing epochs were staggered by about a month, enabling us to discover 11 supernovae, including 3 lensed supernovae, which we followed up with 20 orbits from our program. We delivered reduced HST images and catalogs of all clusters to the public via MAST and reduced Spitzer images via IRSA. We have also begun delivering lens models of all clusters, to be completed before the JWST GO call for proposals.Comment: 29 pages, 6 figures, submitted to ApJ. For reduced images, catalogs, lens models, and more, see relics.stsci.ed

Quantitative In Vivo Magnetic Resonance Spectroscopy Using Synthetic Signal Injection

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment