HIF-1 alpha-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

© 2014 Landes Bioscience. PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re-localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease

X-ray properties of early-type stars in the Tarantula Nebula from T-ReX

We reassess the historical L-X/L-Bol relation for early-type stars from a comparison between T-ReX, the Chandra ACIS X-ray survey of the Tarantula Nebula in the Large Magellanic Cloud (LMC), and contemporary spectroscopic analysis of massive stars obtained primarily from VLT/FLAMES, VLT/MUSE, and HST/STIS surveys. For 107 sources in common (some host to multiple stars), the majority of which are bolometrically luminous (40 per cent exceed 10(6)L(circle dot)), we find an average log L-X/L-Bol = -6.90 +/- 0.65. Excluding extreme systems Mk 34 (WN5h+WN5h), R140a (WC4+WN6+), and VFTS 399 (O9 IIIn+?), plus four WR sources with anomalously hard X-ray components (R130, R134, 8135, Mk 53) and 10 multiple sources within the spatially crowded core of R136a, log L-X/L-Bol = -7.00 +/- 0.49, in good agreement with Galactic OB stars. No difference is found between single and binary systems, nor between O, Of/WN, and WR stars, although there does appear to be a trend towards harder X-ray emission from O dwarfs, through O (super)giants, Of/WN stars, and WR stars. The majority of known OB stars in the Tarantula are not detected in the T-ReX point source catalogue, so we have derived upper limits for all undetected OB stars for which log L-Bol/L-circle dot \u3e= 5.0. A survival analysis using detected and upper limit log L-X/L-Bol values indicates no significant difference between luminous O stars in the LMC and the Carina Nebula. This analysis suggests that metallicity does not strongly influence L-X/L-Bol. Plasma temperatures for single, luminous O stars in the Tarantula ((kT(m)) over bar = 1.0 key) are higher than counterparts in Carina ((kT(m)) over bar = 0.5 keV)

Chandra ACIS Survey of M33 (ChASeM33): The enigmatic X-ray emission from IC131

We present the first X-ray analysis of the diffuse hot ionized gas and the point sources in IC131, after NGC604 the second most X-ray luminous giant HII region in M33. The X-ray emission is detected only in the south eastern part of IC131 (named IC131-se) and is limited to an elliptical region of ~200pc in extent. This region appears to be confined towards the west by a hemispherical shell of warm ionized gas and only fills about half that volume. Although the corresponding X-ray spectrum has 1215 counts, it cannot conclusively be told whether the extended X-ray emission is thermal, non-thermal, or a combination of both. A thermal plasma model of kT_e=4.3keV or a single power law of Gamma=2.1 fit the spectrum equally well. If the spectrum is purely thermal (non-thermal), the total unabsorbed X-ray luminosity in the 0.35-8keV energy band amounts to L_X = 6.8(8.7)x10^35erg/s. Among other known HII regions IC131-se seems to be extreme regarding the combination of its large extent of the X-ray plasma, the lack of massive O stars, its unusually high electron temperature (if thermal), and the large fraction of L_X emitted above 2keV (~40-53%). A thermal plasma of ~4keV poses serious challenges to theoretical models, as it is not clear how high electron temperatures can be produced in HII regions in view of mass-proportional and collisionless heating. If the gas is non-thermal or has non-thermal contributions, synchrotron emission would clearly dominate over inverse Compton emission. It is not clear if the same mechanisms which create non-thermal X-rays or accelerate CRs in SNRs can be applied to much larger scales of 200pc. In both cases the existing theoretical models for giant HII regions and superbubbles do not explain the hardness and extent of the X-ray emission in IC131-se.Comment: 28 pages, 7 figures and 2 tables. Accepted for publication in ApJ. For a high resolution version of the paper see http://hea-www.harvard.edu/vlp_m33_public/publications.htm

Dealing with large and volatile capital flows and the role of the IMF

The last decade has been characterised by the pronounced volatility of capital flows. While cross-border capital flows can have many benefits for both advanced and emerging market economies, they may also carry risks, which require appropriate policy responses. Disentangling the push from the pull factors driving capital flows is key to designing appropriate policies to deal with them. Strong institutions, sound fundamentals and a large domestic investor base tend to shield economies from adverse global conditions and attract less volatile types of capital. However, when the policy space for using traditional macroeconomic policies is limited, countries may also turn to macroprudential and capital flow management policies in a pragmatic manner. The IMF can play an important role in helping countries to deal with capital flows, through its surveillance and lending policy and through international cooperation

Detection of the second eclipsing high mass X-ray binary in M 33

Chandra data of the X-ray source [PMH2004] 47 were obtained in the ACIS Survey of M 33 (ChASeM33) in 2006. During one of the observations, the source varied from a high state to a low state and back, in two other observations it varied from a low state to respectively intermediate states. These transitions are interpreted as eclipse ingress and egresses of a compact object in a high mass X-ray binary system. The phase of mid eclipse is given by HJD 2453997.476+-0.006, the eclipse half angle is 30.6+-1.2 degree. Adding XMM-Newton observations of [PMH2004] 47 in 2001 we determine the binary period to be 1.732479+-0.000027 d. This period is also consistent with ROSAT HRI observations of the source in 1994. No short term periodicity compatible with a rotation period of the compact object is detected. There are indications for a long term variability similar to that detected for Her X-1. During the high state the spectrum of the source is hard (power law spectrum with photon index ~0.85) with an unabsorbed luminosity of 2E37 erg/cm2/s (0.2-4.5 keV). We identify as an optical counterpart a V ~ 21.0mag star with T_eff > 19000 K, log(g) > 2.5. CFHT optical light curves for this star show an ellipsoidal variation with the same period as the X-ray light curve. The optical light curve together with the X-ray eclipse can be modeled by a compact object with a mass consistent with a neutron star or a black hole in a high mass X-ray binary. However, the hard power law X-ray spectrum favors a neutron star as the compact object in this second eclipsing X-ray binary in M 33. Assuming a neutron star with a canonical mass of 1.4 M_sun and the best fit companion temperature of 33000 K, a system inclination i = 72 degree and a companion mass of 10.9 M_sun are implied.Comment: 19 pages, 9 figures, ApJ accepte

A newly recognized very young supernova remnant in M83

As part of a spectroscopic survey of supernova remnant candidates in M83 using the Gemini-South telescope and Gemini Multi-Object Spectrograph, we have discovered one object whose spectrum shows very broad lines at Hα, [O I] λλ6300, 6363, and [O III] λλ4959, 5007, similar to those from other objects classified as "late time supernovae". Although six historical supernovae have been observed in M83 since 1923, none were seen at the location of this object. Hubble Space Telescope (HST) Wide Field Camera 3 images show a nearly unresolved emission source, while Chandra and ATCA data reveal a bright X-ray source and nonthermal radio source at the position. Objects in other galaxies showing similar spectra are only decades post-supernova, which raises the possibility that the supernova that created this object occurred during the last century but was missed. Using photometry of nearby stars from the HST data, we suggest the precursor was at least 17 M ☉, and the presence of broad Hα in the spectrum makes a type II supernova likely. The supernova must predate the 1983 Very Large Array radio detection of the object. We suggest examination of archival images of M83 to search for evidence of the supernova event that gave rise to this object, and thus provide a precise age

Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant