Gamma Rays from Star Formation in Clusters of Galaxies

Star formation in galaxies is observed to be associated with gamma-ray emission. The detection of gamma rays from star-forming galaxies by the Fermi Large Area Telescope (LAT) has allowed the determination of a functional relationship between star formation rate and gamma-ray luminosity (Ackermann et. al. 2012). Since star formation is known to scale with total infrared (8-1000 micrometers) and radio (1.4 GHz) luminosity, the observed infrared and radio emission from a star-forming galaxy can be used to quantitatively infer the galaxy's gamma-ray luminosity. Similarly, star forming galaxies within galaxy clusters allow us to derive lower limits on the gamma-ray emission from clusters, which have not yet been conclusively detected in gamma rays. In this study we apply the relationships between gamma-ray luminosity and radio and IR luminosities derived in Ackermann et. al. 2012 to a sample of galaxy clusters from Ackermann et. al. 2010 in order to place lower limits on the gamma-ray emission associated with star formation in galaxy clusters. We find that several clusters have predicted lower limits on gamma-ray emission that are within an order of magnitude of the upper limits derived in Ackermann et. al. 2010 based on non-detection by Fermi-LAT. Given the current gamma-ray limits, star formation likely plays a significant role in the gamma-ray emission in some clusters, especially those with cool cores. We predict that both Fermi-LAT over the course of its lifetime and the future Cherenkov Telescope Array will be able to detect gamma-ray emission from star-forming galaxies in clusters.Comment: 17 pages, 2 figures, 2 tables. Minor revisions made to match version accepted to Ap

Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome

Donnai-Barrow syndrome (DBS) is an autosomal-recessive disorder characterized by multiple pathologies including malformation of forebrain and eyes, as well as resorption defects of the kidney proximal tubule. The underlying cause of DBS are mutations in LRP2, encoding the multifunctional endocytic receptor megalin. Here, we identified a unique missense mutation R3192Q of LRP2 in an affected family that may provide novel insights into the molecular causes of receptor dysfunction in the kidney proximal tubule and other tissues affected in DBS. Using patient-derived induced pluripotent stem cell lines we generated neuroepithelial and kidney cell types as models of the disease. Using these cell models, we documented the inability of megalinR3192Q to properly discharge ligand and ligand-induced receptor decay in lysosomes. Thus, mutant receptors are aberrantly targeted to lysosomes for catabolism, essentially depleting megalin in the presence of ligand in this affected family

Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson’s disease, STEM-PD

Cell replacement therapies for Parkinson’s disease (PD) based on transplantation of pluripotent stem cell-derived dopaminergic neurons are now entering clinical trials. Here, we present quality, safety, and efficacy data supporting the first-in-human STEM-PD phase I/IIa clinical trial along with the trial design. The STEM-PD product was manufactured under GMP and quality tested in vitro and in vivo to meet regulatory requirements. Importantly, no adverse effects were observed upon testing of the product in a 39-week rat GLP safety study for toxicity, tumorigenicity, and biodistribution, and a non-GLP efficacy study confirmed that the transplanted cells mediated full functional recovery in a pre-clinical rat model of PD. We further observed highly comparable efficacy results between two different GMP batches, verifying that the product can be serially manufactured. A fully in vivo-tested batch of STEM-PD is now being used in a clinical trial of 8 patients with moderate PD, initiated in 2022

Searching for Primordial Black Holes in the Radio and X-Ray Sky

We model the accretion of gas onto a population of massive primordial black holes in the Milky Way, and compare the predicted radio and X-ray emission with observational data. We show that under conservative assumptions on the accretion process, the possibility that ${\cal O}(10) \, M_\odot$ primordial black holes can account for all of the dark matter in the Milky Way is excluded at $5\sigma$ by a comparison with a VLA radio catalog at $1.4$ GHz, and at $\simeq 40\sigma$ by a comparison with a Chandra X-ray catalog ($0.5 - 8$ keV). We argue that this method can be used to identify such a population of primordial black holes with more sensitive future radio and X-ray surveys.Comment: 5 pages, 2 figure

Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.Peer reviewe