The superluminous supernova SN 2017egm in the nearby galaxy NGC 3191: a metal-rich environment can support a typical SLSN evolution

At redshift z=0.03, the recently-discovered SN 2017egm is the nearest Type I superluminous supernova (SLSN) to date, and first near the center of a massive spiral galaxy (NGC 3191). Using SDSS spectra of NGC 3191, we find a metallicity ~2 Z$_\odot$ at the nucleus and ~1.3 Z$_\odot$ for a star forming region at a radial offset similar to SN 2017egm. Archival radio-to-UV photometry reveals a star-formation rate ~15 M$_\odot$ yr$^{-1}$ (with ~70% dust-obscured), which can account for a Swift X-ray detection, and stellar mass ~$10^{10.7}$ M$_\odot$. We model the early UV-optical light curves with a magnetar central-engine model, using the Bayesian light curve fitting tool MOSFiT. The fits indicate ejecta mass 2-4 M$_\odot$, spin period 4-6 ms, magnetic field (0.7-1.7)$\times 10^{14}$G, and kinetic energy 1-2 $\times10^{51}$ erg. These parameters are consistent with the overall distributions for SLSNe, modeled by Nicholl et al (2017), although the derived mass and spin are towards the low end, possibly indicating enhanced loss of mass and angular momentum before explosion. This has two implications: (i) SLSNe can occur at solar metallicity, although with a low fraction ~10%; and (ii) metallicity has at most a modest effect on their properties. Both conclusions are in line with results for long gamma-ray bursts. Assuming a monotonic rise gives an explosion date MJD $57889\pm1$. However, a short-lived excess in the data relative to the best-fitting models may indicate an early-time `bump'. If confirmed, SN 2017egm would be the first SLSN with a spectrum during the bump-phase; this shows the same O II lines seen at maximum light, which may be an important clue for explaining these bumps.Comment: Accepted for publication in ApJ

SN 2016iet: The Pulsational or Pair Instability Explosion of a Low Metallicity Massive CO Core Embedded in a Dense Hydrogen-Poor Circumstellar Medium

We present optical photometry and spectroscopy of SN 2016iet, an unprecedented Type I supernova (SN) at $z=0.0676$ with no obvious analog in the existing literature. The peculiar light curve has two roughly equal brightness peaks ($\approx -19$ mag) separated by 100 days, and a subsequent slow decline by 5 mag in 650 rest-frame days. The spectra are dominated by emission lines of calcium and oxygen, with a width of only $3400$ km s$^{-1}$, superposed on a strong blue continuum in the first year, and with a large ratio of $L_{\rm [Ca\,II]}/L_{\rm [O\,I]}\approx 4$ at late times. There is no clear evidence for hydrogen or helium associated with the SN at any phase. We model the light curves with several potential energy sources: radioactive decay, central engine, and circumstellar medium (CSM) interaction. Regardless of the model, the inferred progenitor mass near the end of its life (i.e., CO core mass) is $\gtrsim 55$ M$_\odot$ and up to $120$ M$_\odot$, placing the event in the regime of pulsational pair instability supernovae (PPISNe) or pair instability supernovae (PISNe). The models of CSM interaction provide the most consistent explanation for the light curves and spectra, and require a CSM mass of $\approx 35$ M$_\odot$ ejected in the final decade before explosion. We further find that SN 2016iet is located at an unusually large offset ($16.5$ kpc) from its low metallicity dwarf host galaxy ($Z\approx 0.1$ Z$_\odot$, $M\approx 10^{8.5}$ M$_\odot$), supporting the PPISN/PISN interpretation. In the final spectrum, we detect narrow H$\alpha$ emission at the SN location, likely due to a dim underlying galaxy host or an H II region. Despite the overall consistency of the SN and its unusual environment with PPISNe and PISNe, we find that the inferred properties of SN\,2016iet challenge existing models of such events.Comment: 26 Pages, 17 Figures, Submitted to Ap

The 20-m shuttle run: Assessment and interpretation of data in relation to youth aerobic fitness and health

Cardiorespiratory fitness (CRF) is a good summative measure of the body’s ability to perform continuous, rhythmic, dynamic, large-muscle group physical activity, and exercise. In children, CRF is meaningfully associated with health, independent of physical activity levels, and it is an important determinant of sports and athletic performance. Although gas-analyzed peak oxygen uptake is the criterion physiological measure of children’s CRF, it is not practical for population-based testing. Field testing offers a simple, cheap, practical alternative to gas analysis. The 20-m shuttle run test (20mSRT)—a progressive aerobic exercise test involving continuous running between 2 lines 20 m apart in time to audio signals—is probably the most widely used field test of CRF. This review aims to clarify the international utility of the 20mSRT by synthesizing the evidence describing measurement variability, validity, reliability, feasibility, and the interpretation of results, as well as to provide future directions for international surveillance. The authors show that the 20mSRT is an acceptable, feasible, and scalable measure of CRF and functional/exercise capacity, and that it has moderate criterion validity and high to very high reliability. The assessment is pragmatic, easily interpreted, and results are transferable to meaningful and understandable situations. The authors recommend that CRF, assessed by the 20mSRT, be considered as an international population health surveillance measure to provide additional insight into pediatric population health

Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog-responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wild-type Smo, and mutant forms of Smo, SmoM2, and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action.Chemistry and Chemical BiologyMolecular and Cellular BiologyStem Cell and Regenerative Biolog

The distant, galaxy cluster environment of the short GRB 161104A at z∼0.8z\sim 0.8 and a comparison to the short GRB host population

We present optical observations of the Swift short-duration gamma-ray burst (GRB) GRB 161104A and its host galaxy at $z=0.793 \pm 0.003$. We model the multiband photometry and spectroscopy with the stellar population inference code Prospector, and explore the posterior using nested sampling. We find that the mass-weighted age $t_m = 2.12^{+0.23}_{-0.21}$~Gyr, stellar mass $\log{(M/M_\odot)} = 10.21 \pm 0.04$, metallicity $\log{(Z/Z_\odot)} = 0.08^{+0.05}_{-0.06}$, dust extinction $A_V = 0.08^{+0.08}_{-0.05}$ mag, and the star formation rate $\text{SFR} = 9.9 \times 10^{-2} M_\odot$~yr$^{-1}$. These properties, along with a prominent 4000 Angstrom break and optical absorption lines classify this host as an early-type, quiescent galaxy. Using Dark Energy Survey galaxy catalogues, we demonstrate that the host of GRB 161104A resides on the outskirts of a galaxy cluster at $z\approx 0.8$, situated $\approx 1$ Mpc from the likely brightest cluster galaxy. We also present new modeling for 20 additional short GRB hosts ($\approx33\%$ of which are early-type galaxies), finding population medians of $\log(M/M_\odot) = 9.94^{+0.88}_{-0.98}$ and $t_m = 1.07^{+1.98}_{-0.67}$~Gyr ($68\%$ confidence). We further find that the host of GRB 161104A is more distant, less massive, and younger than the four other short GRB hosts known to be associated with galaxy clusters. Cluster short GRBs have faint afterglows, in the lower $\approx 11\%$ ($\approx 30\%$) of observed X-ray (optical) luminosities. We place a lower limit on the fraction of short GRBs in galaxy clusters versus those in the field of $\approx 5-13\%$, consistent with the fraction of stellar mass $\approx 10-20\%$ in galaxy clusters at redshifts $0.1 \leq z \leq 0.8$.Comment: 20 pages, 9 figures, ApJ: Vol. 904, No.

Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke

Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFβ1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB-431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFβ1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke. SIGNIFICANCE STATEMENT The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. We assessed whether microglial cells preserve neurovascular integrity after neonatal stroke. In neonatal rats, microglial depletion or pharmacological inhibition of TGFbr2/ALK5 signaling in microglia triggered hemorrhages in injured regions. The effect was not associated with additional changes in expression or intracellular redistribution of several tight junction proteins or collagen IV degradation induced by stroke. Consistent with observations in neonatal rats, microglial depletion in neonatal mice exacerbated stroke injury and induced hemorrhages. The effects were independent of infiltration of monocytes into injured regions. Thus, microglia protect neonatal brain from ischemia-induced hemorrhages, and this effect is consistent across two species

Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke

Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFβ1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB-431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFβ1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke. SIGNIFICANCE STATEMENT The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. We assessed whether microglial cells preserve neurovascular integrity after neonatal stroke. In neonatal rats, microglial depletion or pharmacological inhibition of TGFbr2/ALK5 signaling in microglia triggered hemorrhages in injured regions. The effect was not associated with additional changes in expression or intracellular redistribution of several tight junction proteins or collagen IV degradation induced by stroke. Consistent with observations in neonatal rats, microglial depletion in neonatal mice exacerbated stroke injury and induced hemorrhages. The effects were independent of infiltration of monocytes into injured regions. Thus, microglia protect neonatal brain from ischemia-induced hemorrhages, and this effect is consistent across two species

Selective Identification of Hedgehog Pathway Antagonists by Direct Analysis of Smoothened Ciliary Translocation

Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo’s actions. Smo ciliary translocation is inhibited by some pathway antagonists, while others promote ciliary accumulation, an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG and impaired by a mutation that generates a ligand-independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition and inhibited SmoM2 at concentrations similar to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies.Molecular and Cellular BiologyStem Cell and Regenerative Biolog