The PI3K pathway regulates endochondral bone growth through control of hypertrophic chondrocyte differentiation

<p>Abstract</p> <p>Background</p> <p>The majority of our bones develop through the process of endochondral ossification that involves chondrocyte proliferation and hypertrophic differentiation in the cartilage growth plate. A large number of growth factors and hormones have been implicated in the regulation of growth plate biology, however, less is known about the intracellular signaling pathways involved. PI3K/Akt has been identified as a major regulator of cellular proliferation, differentiation and death in multiple cell types.</p> <p>Results and Discussion</p> <p>Employing an organ culture system of embryonic mouse tibiae and LY294002, a pharmacological inhibitor of PI3K, we show that inhibition of the pathway results in significant growth reduction, demonstrating that PI3K is required for normal endochondral bone growth <it>in vitro</it>. PI3K inhibition reduces the length of the proliferating and particularly of the hypertrophic zone. Studies with organ cultures and primary chondrocytes in micromass culture show delayed hypertrophic differentiation of chondrocytes and increased apoptosis in the presence of LY294002. Surprisingly, PI3K inhibition had no strong effect on IGF1-induced bone growth, but partially blocked the anabolic effects of C-type natriuretic peptide.</p> <p>Conclusion</p> <p>Our data demonstrate an essential role of PI3K signaling in chondrocyte differentiation and as a consequence of this, in the endochondral bone growth process.</p

FIREBALL: Instrument pointing and aspect reconstruction

The Faint Intergalactic Redshifted Emission Balloon (FIREBALL) had its first scientific flight in June 2009. The instrument is a 1 meter class balloon-borne telescope equipped with a vacuum-ultraviolet integral field spectrograph intended to detect emission from the inter-galactic medium at redshifts 0.3 < z < 1.0. The scientific goals and the challenging environment place strict constraints on the pointing and tracking systems of the gondola. In this manuscript we briefly review our pointing requirements, discuss the methods and solutions used to meet those requirements, and present the aspect reconstruction results from the first successful scientific flight

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Augmented cardiac growth hormone signaling contributes to cardiomyopathy following genetic disruption of the cardiomyocyte circadian clock

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the hypothesis that the cardiomyopathy observed following cardiomyocyte circadian clock disruption may be secondary to chronic activation of cardiac GH/IGF1 signaling. Here, we report that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit increased cardiac GH sensitivity, as evidenced by augmented GH-induced STAT5 phosphorylation (relative to littermate controls) in the heart (but not in the liver). Moreover

Hypervelocity Stars from the Andromeda Galaxy

Hypervelocity stars (HVSs) discovered in the Milky Way (MW) halo are thought to be ejected from near the massive black hole (MBH) at the galactic centre. In this paper we investigate the spatial and velocity distributions of the HVSs which are expected to be similarly produced in the Andromeda galaxy (M31). We consider three different HVS production mechanisms: (i) the disruption of stellar binaries by the galactocentric MBH; (ii) the ejection of stars by an in-spiraling intermediate mass black hole; and (iii) the scattering of stars off a cluster of stellar-mass black holes orbiting around the MBH. While the first two mechanisms would produce large numbers of HVSs in M31, we show that the third mechanism would not be effective in M31. We numerically calculate 1.2*10^6 trajectories of HVSs from M31 within a simple model of the Local Group and hence infer the current distribution of these stars. Gravitational focusing of the HVSs by the MW and the diffuse Local Group medium leads to high densities of low mass (~ solar mass) M31 HVSs near the MW. Within the virialized MW halo, we expect there to be of order 1000 HVSs for the first mechanism and a few hundred HVSs for the second mechanism; many of these stars should have distinctively large approach velocities (< -500 km/s). In addition, we predict ~5 hypervelocity RGB stars within the M31 halo which could be identified observationally. Future MW astrometric surveys or searches for distant giants could thus find HVSs from M31.Comment: 14 pages, 6 figures, changed to match version accepted by MNRA

SPIRITS 16tn in NGC 3556: A heavily obscured and low-luminosity supernova at 8.8 Mpc

We present the discovery by the SPitzer InfraRed Intensive Transients Survey (SPIRITS) of a likely supernova (SN) in NGC 3556 at only 8.8 Mpc, which, despite its proximity, was not detected by optical searches. A luminous infrared (IR) transient at $M_{[4.5]} = -16.7$ mag (Vega), SPIRITS 16tn is coincident with a dust lane in the inclined, star-forming disk of the host. Using IR, optical, and radio observations, we attempt to determine the nature of this event. We estimate $A_V \approx$ 8 - 9 mag of extinction, placing it among the three most highly obscured IR-discovered SNe to date. The [4.5] light curve declined at a rate of 0.013 mag day$^{-1}$, and the $[3.6] - [4.5]$ color grew redder from 0.7 to $\gtrsim$ 1.0 mag by 184.7 days post discovery. Optical/IR spectroscopy shows a red continuum, but no clearly discernible features, preventing a definitive spectroscopic classification. Deep radio observations constrain the radio luminosity of SPIRITS 16tn to $L_{\nu} \lesssim 10^{24}$ erg s$^{-1}$ Hz$^{-1}$ between 3 - 15 GHz, excluding many varieties of radio core-collapse SNe. A type Ia SN is ruled out by the observed red IR color, and lack of features normally attributed to Fe-peak elements in the optical and IR spectra. SPIRITS 16tn was fainter at [4.5] than typical stripped-envelope SNe by $\approx$ 1 mag. Comparison of the spectral energy distribution to SNe II suggests SPIRITS 16tn was both highly obscured, and intrinsically dim, possibly akin to the low-luminosity SN 2005cs. We infer the presence of an IR dust echo powered by a peak luminosity of the transient of $5 \times 10^{40}$ erg s$^{-1} < L_{\mathrm{peak}} < 4\times10^{43}$ erg s$^{-1}$, consistent with the observed range for SNe II. This discovery illustrates the power of IR surveys to overcome the compounding effects of visible extinction and optically sub-luminous events in completing the inventory of nearby SNe.Comment: 25 pages, 10 figures, submitted to Ap

AERO & VISTA: Demonstrating HF Radio Interferometry with Vector Sensors

AERO (Auroral Emission Radio Observer) and VISTA (Vector Interferometry Space Technology using AERO) are recently selected NASA HTIDeS CubeSat missions for terrestrial auroral science and radio interferometric technology demonstration. The AERO and VISTA CubeSats both host vector sensing antenna systems providing advanced electromagnetic capabilities. Together, they will provide the first in-space demonstration of interferometric imaging, beamforming, and nulling using electromagnetic vector sensors at low frequencies (100 kHz –15 MHz). A key goal of the joint missions’ technology demonstration is to validate theoretical sensor performance modeling indicating that interferometric arrays composed of vector sensors will be able to maintain sensitivity even in the presence of terrestrial interference. If validated in flight, this capability would relax the requirement that space-based low frequency interferometers be placed far from the Earth (e.g. lunar orbit), and the closer communications range will significantly increase the data volume returned from space-based radio telescope systems. The two-spacecraft AERO+VISTA mission will address the auroral science goals of AERO (Erickson et al. 2018, SSC18) while adding three additional technology demonstration goals enabled by the second CubeSat, VISTA

Experimental study of the role of physicochemical surface processing on the IN ability of mineral dust particles

During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influence of various surface modifications on the ice nucleating ability of Arizona Test Dust (ATD) particles in the immersion freezing mode. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤T≤−28 °C. The pure ATD particles nucleated ice over a broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T>−35 °C) and a slight increase in the second branch (T≤−35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. The strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor and the resulting significant reductions in IN potential are of importance for atmospheric ice cloud formation. Our findings suggest that the IN concentration can decrease by up to one order of magnitude for the conditions investigated

Suzaku X-ray Spectra and Pulse Profile Variations during the Superorbital Cycle of LMC X-4

We present results from spectral and temporal analyses of Suzaku and RXTE observations of the high mass X-ray binary LMC X-4. Using the full 13 years of available RXTE/ASM data, we apply the ANOVA and Lomb normalized Periodogram methods to obtain an improved superorbital period measurement of 30.32 +/- 0.04 days. The phase-averaged X-ray spectra from Suzaku observations during the high state of the superorbital period can be modeled in the 0.6--50 keV band as the combination of a power-law with Gamma ~ 0.6 and a high-energy cutoff at ~ 25 keV, a blackbody with kT_BB ~ 0.18 keV, and emission lines from Fe K_alpha, O VIII, and Ne IX (X Lyalpha). Assuming a distance of 50 kpc, The source has luminosity L_X ~ 3 x 10^38 ergs s^-1 in the 2--50 keV band, and the luminosity of the soft (blackbody) component is L_BB ~ 1.5 x 10^37 ergs s^-1. The energy resolved pulse profiles show single-peaked soft (0.5-1 keV) and hard (6-10 keV) pulses but a more complex pattern of medium (2-10 keV) pulses; cross-correlation of the hard with the soft pulses shows a phase shift that varies between observations. We interpret these results in terms of a picture in which a precessing disk reprocesses the hard X-rays and produces the observed soft spectral component, as has been suggested for the similar sources Her X-1 and SMC X-1.Comment: 13 emulateapj pages, 11 figures, 4 tables; accepted for publication in Ap