Excision of Titin's Cardiac Pevk Spring Element Abolishes PKCα-Induced Increases in Myocardial Stiffness

Protein Kinase C-alpha (PKCalpha) was recently reported to increase myocardial stiffness, an effect that was proposed to be due to phosphorylation of two highly conserved sites (S11878 and S12022) within the proline-gluatamic acid-valine-lysine (PEVK) rich spring element of titin. To test this proposal we investigated the effect of PKCalpha on phosphorylation and passive stiffness in a mouse model lacking the titin exons that contain these two phosphorylation sites, the PEVK knockout (KO). We used skinned, gelsolin-extracted, left ventricular, myocardium from wildtype and PEVK KO mice. Consistent with previous work we found that PKCalpha increased passive stiffness in the WT myocardium by 27 +/-6%. Importantly, this effect was completely abolished in KO myocardium. In addition, increases in the elastic and viscous moduli at a wide range of frequencies (properties important in diastolic filling) following PKCalpha incubation (27 +/-3% and 20 +/-4%, respectively) were also ablated in the KO. Back phosphorylation assays showed that titin phosphorylation following incubation with PKCalpha was significantly reduced by 36+/-12% in skinned PEVK KO myocardial tissues. The remaining phosphorylation in the KO suggests that PKCalpha sites exist in the titin molecule outside the PEVK region; these sites are not involved in increasing passive stiffness. Our results firmly support that the PEVK region of cardiac titin is phosphorylated by PKCalpha and that this increases passive tension. Thus, the PEVK spring element is the critical site of PKCalpha's involvement in passive myocardial stiffness

SOST Inhibits Prostate Cancer Invasion.

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings

An application of bayesian networks to antiterrorism risk management for military planners

Abstrac

CFHTLenS: Co-evolution of galaxies and their dark matter haloes

Galaxy-galaxy weak lensing is a direct probe of the mean matter distribution around galaxies. The depth and sky coverage of the CFHT Legacy Survey yield statistically significant galaxy halo mass measurements over a much wider range of stellar masses ($10^{8.75}$ to $10^{11.3} M_{\odot}$) and redshifts ($0.2 < z < 0.8$) than previous weak lensing studies. At redshift $z \sim 0.5$, the stellar-to-halo mass ratio (SHMR) reaches a maximum of $4.0\pm0.2$ percent as a function of halo mass at $\sim 10^{12.25} M_{\odot}$. We find, for the first time from weak lensing alone, evidence for significant evolution in the SHMR: the peak ratio falls as a function of cosmic time from $4.5 \pm 0.3$ percent at $z \sim 0.7$ to $3.4 \pm 0.2$ percent at $z \sim 0.3$, and shifts to lower stellar mass haloes. These evolutionary trends are dominated by red galaxies, and are consistent with a model in which the stellar mass above which star formation is quenched "downsizes" with cosmic time. In contrast, the SHMR of blue, star-forming galaxies is well-fit by a power law that does not evolve with time. This suggests that blue galaxies form stars at a rate that is balanced with their dark matter accretion in such a way that they evolve along the SHMR locus. The redshift dependence of the SHMR can be used to constrain the evolution of the galaxy population over cosmic time.Comment: 18 pages, MNRAS, in pres

Constraining dark matter halo properties using lensed SNLS supernovae

This paper exploits the gravitational magnification of SNe Ia to measure properties of dark matter haloes. The magnification of individual SNe Ia can be computed using observed properties of foreground galaxies and dark matter halo models. We model the dark matter haloes of the galaxies as truncated singular isothermal spheres with velocity dispersion and truncation radius obeying luminosity dependent scaling laws. A homogeneously selected sample of 175 SNe Ia from the first 3-years of the Supernova Legacy Survey (SNLS) in the redshift range 0.2 < z < 1 is used to constrain models of the dark matter haloes associated with foreground galaxies. The best-fitting velocity dispersion scaling law agrees well with galaxy-galaxy lensing measurements. We further find that the normalisation of the velocity dispersion of passive and star forming galaxies are consistent with empirical Faber-Jackson and Tully-Fisher relations, respectively. If we make no assumption on the normalisation of these relations, we find that the data prefer gravitational lensing at the 92 per cent confidence level. Using recent models of dust extinction we deduce that the impact of this effect on our results is very small. We also investigate the brightness scatter of SNe Ia due to gravitational lensing. The gravitational lensing scatter is approximately proportional to the SN Ia redshift. We find the constant of proportionality to be B = 0.055 +0.039 -0.041 mag (B < 0.12 mag at the 95 per cent confidence level). If this model is correct, the contribution from lensing to the intrinsic brightness scatter of SNe Ia is small for the SNLS sample.Comment: 11 pages, 7 figures, accepted for publication in MNRA

The gas distribution in the outer regions of galaxy clusters

We present the analysis of a local (z = 0.04 - 0.2) sample of 31 galaxy clusters with the aim of measuring the density of the X-ray emitting gas in cluster outskirts. We compare our results with numerical simulations to set constraints on the azimuthal symmetry and gas clumping in the outer regions of galaxy clusters. We exploit the large field-of-view and low instrumental background of ROSAT/PSPC to trace the density of the intracluster gas out to the virial radius. We perform a stacking of the density profiles to detect a signal beyond r200 and measure the typical density and scatter in cluster outskirts. We also compute the azimuthal scatter of the profiles with respect to the mean value to look for deviations from spherical symmetry. Finally, we compare our average density and scatter profiles with the results of numerical simulations. As opposed to some recent Suzaku results, and confirming previous evidence from ROSAT and Chandra, we observe a steepening of the density profiles beyond \sim r500. Comparing our density profiles with simulations, we find that non-radiative runs predict too steep density profiles, whereas runs including additional physics and/or treating gas clumping are in better agreement with the observed gas distribution. We report for the first time the high-confidence detection of a systematic difference between cool-core and non-cool core clusters beyond \sim 0.3r200, which we explain by a different distribution of the gas in the two classes. Beyond \sim r500, galaxy clusters deviate significantly from spherical symmetry, with only little differences between relaxed and disturbed systems. We find good agreement between the observed and predicted scatter profiles, but only when the 1% densest clumps are filtered out in the simulations. [Abridged]Comment: The data for the average profiles and individual clusters can be downloaded at: http://www.isdc.unige.ch/~deckert/newsite/The_Planck_ROSAT_project.htm

CFHTLenS: co-evolution of galaxies and their dark matter haloes

Galaxy-galaxy weak lensing is a direct probe of the mean matter distribution around galaxies. The depth and sky coverage of the Canada-France-Hawaii Telescope Legacy Survey yield statistically significant galaxy halo mass measurements over a much wider range of stellar masses (108.75 to 1011.3 M⊙) and redshifts (0.2<z<0.8) than previous weak lensing studies. At redshift z∼0.5, the stellar-to-halo mass ratio (SHMR) reaches a maximum of 4.0±0.2 per cent as a function of halo mass at ∼1012.25 M⊙. We find, for the first time from weak lensing alone, evidence for significant evolution in the SHMR: the peak ratio falls as a function of cosmic time from 4.5±0.3 per cent at z∼0.7 to 3.4±0.2 per cent at z∼0.3, and shifts to lower stellar mass haloes. These evolutionary trends are dominated by red galaxies, and are consistent with a model in which the stellar mass above which star formation is quenched ‘downsizes' with cosmic time. In contrast, the SHMR of blue, star-forming galaxies is well fitted by a power law that does not evolve with time. This suggests that blue galaxies form stars at a rate that is balanced with their dark matter accretion in such a way that they evolve along the SHMR locus. The redshift dependence of the SHMR can be used to constrain the evolution of the galaxy population over cosmic tim

CFHTLenS: the environmental dependence of galaxy halo masses from weak lensing

We use weak gravitational lensing to analyse the dark matter haloes around satellite galaxies in galaxy groups in the Canada–France–Hawaii Telescope Lensing Survey (CFHTLenS) data set. This data set is derived from the Canada–France–Hawaii Telescope Legacy Survey Wide survey, and encompasses 154 deg^2 of high-quality shape data. Using the photometric redshifts, we divide the sample of lens galaxies with stellar masses in the range 10^(9)–10^(10.5) M_⊙ into those likely to lie in high-density environments (HDE) and those likely to lie in low-density environments (LDE). Through comparison with galaxy catalogues extracted from the Millennium Simulation, we show that the sample of HDE galaxies should primarily (∼61 per cent) consist of satellite galaxies in groups, while the sample of LDE galaxies should consist of mostly (∼87 per cent) non-satellite (field and central) galaxies. Comparing the lensing signals around samples of HDE and LDE galaxies matched in stellar mass, the lensing signal around HDE galaxies clearly shows a positive contribution from their host groups on their lensing signals at radii of ∼500–1000 kpc, the typical separation between satellites and group centres. More importantly, the subhaloes of HDE galaxies are less massive than those around LDE galaxies by a factor of 0.65 ± 0.12, significant at the 2.9σ level. A natural explanation is that the haloes of satellite galaxies are stripped through tidal effects in the group environment. Our results are consistent with a typical tidal truncation radius of ∼40 kpc

Child Sponsorship as Development Education in the Northern Classroom

This chapter explores the ethical dilemmas, and potential harm done when child sponsorship NGOs market sponsorship to children in school settings. Arguing that child sponsorship functions as a form of development education in the northern classroom, this chapter points to the potential for CS marketing strategies to infantalise and demean the poor, through a well-intentioned lens of paternalism. The chapter calls for greater commitment to global citizenship education in the crowded curriculum of secondary education and provides key questions (after Andreotti, 2012) for NGO marketing staff to consider in their public communication