CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis

BACKGROUND: Resistance to anoikis, apoptosis triggered by a loss of cellular adhesion to the underlying extracellular matrix, is a hallmark of metastatic cancer. Previously we have shown re-establishment of CXCL12 expression in colorectal carcinoma cells inhibits metastasis by enhancing anoikis sensitivity. The objective of these studies was to define the signaling mechanisms regulating CXCL12-mediated anoikis. METHODOLOGY/PRINCIPAL FINDINGS: Adhesion, examined by crystal violet staining, immunofluorescence microscopy, and immunoblot analysis indicated decreased focal adhesion signaling corresponding with loss of adhesion in cells constitutively simulated by CXCL12. Loss of adhesion was inhibited by pertussis toxin treatment, indicating CXCL12 regulating anoikis through G(αi)-protein coupled receptors. Non-adherent HCT116 and HT29 colorectal carcinoma cells expressing CXCL12 exhibited enhanced anoikis sensitivity by propidium iodide staining, caspase activity assays, and immunoblot compared to GFP control cells. CXCL12 producing carcinomas cultured on poly-HEMA displayed heightened Bim and loss of Mcl-1 and Bcl-2 preceding cytochrome c release, and caspase-9 activation. RNAi knockdown of Bim reversed anoikis sensitivity of CXCL12-expressing cells and fostered increased soft-agar foci formation and hepatic tumors in an orthotopic mouse model of metastasis. CONCLUSIONS/SIGNIFICANCE: These data indicate CXCL12 provides a barrier to metastasis by increasing anoikis via activation of a Bim-mediated intrinsic apoptotic pathway. These results underscore the importance of retaining CXCL12 expression to sensitize colorectal carcinomas to anoikis and minimize tumor progression

In which shell-type SNRs should we look for gamma-rays and neutrinos from p-p collisions?

We present a simple analytic model for the various contributions to the non-thermal emission from shell type SNRs, and show that this model's results reproduce well the results of previous detailed calculations. We show that the \geq 1 TeV gamma ray emission from the shell type SNRs RX J1713.7-3946 and RX J0852.0-4622 is dominated by inverse-Compton scattering of CMB photons (and possibly infra-red ambient photons) by accelerated electrons. Pion decay (due to proton-proton collisions) is shown to account for only a small fraction, \lesssim10^-2, of the observed flux, as assuming a larger fractional contribution would imply nonthermal radio and X-ray synchrotron emission and thermal X-ray Bremsstrahlung emission that far exceed the observed radio and X-ray fluxes. Models where pion decay dominates the \geq 1 TeV flux avoid the implied excessive synchrotron emission (but not the implied excessive thermal X-ray Bremsstrahlung emission) by assuming an extremely low efficiency of electron acceleration, K_ep \lesssim 10^-4 (K_ep is the ratio of the number of accelerated electrons and the number of accelerated protons at a given energy). We argue that observations of SNRs in nearby galaxies imply a lower limit of K_ep \gtrsim 10^-3, and thus rule out K_ep values \lesssim 10^-4 (assuming that SNRs share a common typical value of K_ep). It is suggested that SNRs with strong thermal X-ray emission, rather than strong non-thermal X-ray emission, are more suitable candidates for searches of gamma rays and neutrinos resulting from proton-proton collisions. In particular, it is shown that the neutrino flux from the SNRs above is probably too low to be detected by current and planned neutrino observatories (Abridged).Comment: 13 pages, 1 figure, accepted for publication in JCAP, minor revision

Evidence of a Curved Synchrotron Spectrum in the Supernova Remnant SN 1006

A joint spectral analysis of some Chandra ACIS X-ray data and Molonglo Observatory Synthesis Telescope radio data was performed for 13 small regions along the bright northeastern rim of the supernova remnant SN 1006. These data were fitted with a synchrotron radiation model. The nonthermal electron spectrum used to compute the photon emission spectra is the traditional exponentially cut off power law, with one notable difference: The power-law index is not a constant. It is a linear function of the logarithm of the momentum. This functional form enables us to show, for the first time, that the synchrotron spectrum of SN 1006 seems to flatten with increasing energy. The effective power-law index of the electron spectrum is 2.2 at 1 GeV (i.e., radio synchrotron-emitting momenta) and 2.0 at about 10 TeV (i.e., X-ray synchrotron-emitting momenta). This amount of change in the index is qualitatively consistent with theoretical models of the amount of curvature in the proton spectrum of the remnant. The evidence of spectral curvature implies that cosmic rays are dynamically important instead of being "test" particles. The spectral analysis also provides a means of determining the critical frequency of the synchrotron spectrum associated with the highest-energy electrons. The critical frequency seems to vary along the northeastern rim, with a maximum value of 1.1e17 (0.6e17 - 2.1e17) Hz. This value implies that the electron diffusion coefficient can be no larger than a factor of ~4.5-21 times the Bohm diffusion coefficient if the velocity of the forward shock is in the range 2300-5000 km/s. Since the coefficient is close to the Bohm limit, electrons are accelerated nearly as fast as possible in the regions where the critical frequency is about 1.0e17 Hz.Comment: 41 pages, 8 figures, accepted by Ap

Nonthermal Emission from a Supernova Remnant in a Molecular Cloud

In evolved supernova remnants (SNRs) interacting with molecular clouds, such as IC 443, W44, and 3C391, a highly inhomogeneous structure consisting of a forward shock of moderate Mach number, a cooling layer, a dense radiative shell and an interior region filled with hot tenuous plasma is expected. We present a kinetic model of nonthermal electron injection, acceleration and propagation in that environment and find that these SNRs are efficient electron accelerators and sources of hard X- and gamma-ray emission. The energy spectrum of the nonthermal electrons is shaped by the joint action of first and second order Fermi acceleration in a turbulent plasma with substantial Coulomb losses. Bremsstrahlung, synchrotron, and inverse Compton radiation of the nonthermal electrons produce multiwavelength photon spectra in quantitative agreement with the radio and the hard emission observed by ASCA and EGRET from IC 443. We distinguish interclump shock wave emission from molecular clump shock wave emission accounting for a complex structure of molecular cloud. Spatially resolved X- and gamma- ray spectra from the supernova remnants IC 443, W44, and 3C391 as might be observed with BeppoSAX, Chandra XRO, XMM, INTEGRAL and GLAST would distinguish the contribution of the energetic lepton component to the gamma-rays observed by EGRET.Comment: 14 pages, 4 figure, Astrophysical Journal, v.538, 2000 (in press

Self-Similar Collisionless Shocks

Observations of gamma-ray burst afterglows suggest that the correlation length of magnetic field fluctuations downstream of relativistic non-magnetized collisionless shocks grows with distance from the shock to scales much larger than the plasma skin depth. We argue that this indicates that the plasma properties are described by a self-similar solution, and derive constraints on the scaling properties of the solution. For example, we find that the scaling of the characteristic magnetic field amplitude with distance from the shock is B \propto D^{s_B} with -1<s_B<=0, that the spectrum of accelerated particles is dn/dE \propto E^{-2/(s_B+1)}, and that the scaling of the magnetic correlation function is \propto x^{2s_B} (for x>>D). We show that the plasma may be approximated as a combination of two self-similar components: a kinetic component of energetic particles and an MHD-like component representing "thermal" particles. We argue that the latter may be considered as infinitely conducting, in which case s_B=0 and the scalings are completely determined (e.g. dn/dE \propto E^{-2} and B \propto D^0). Similar claims apply to non- relativistic shocks such as in supernova remnants, if the upstream magnetic field can be neglected. Self-similarity has important implications for any model of particle acceleration and/or field generation. For example, we show that the diffusion function in the angle \mu of momentum p in diffusive shock acceleration models must satisfy D_{\mu\mu}(p,D) = D^{-1}D'_{\mu\mu}(p/D), and that a previously suggested model for the generation of large scale magnetic fields through a hierarchical merger of current-filaments should be generalized. A numerical experiment testing our analysis is outlined (Abridged).Comment: 16 pages, 1 figure, accepted for publication in Ap

The X-ray Emissions from the M87 Jet: Diagnostics and Physical Interpretation

We reanalyze the deep Chandra observations of the M87 jet, first examined by Wilson & Yang (2002). By employing an analysis chain that includes image deconvolution, knots HST-1 and I are fully separated from adjacent emission. We find slight but significant variations in the spectral shape, with values of $\alpha_x$ ranging from $\sim 1.2-1.6$. We use VLA radio observations, as well as HST imaging and polarimetry data, to examine the jet's broad-band spectrum and inquire as to the nature of particle acceleration in the jet. As shown in previous papers, a simple continuous injection model for synchrotron-emitting knots, in which both the filling factor, $f_{acc}$, of regions within which particles are accelerated and the energy spectrum of the injected particles are constant, cannot account for the X-ray flux or spectrum. Instead, we propose that $f_{acc}$ is a function of position and energy and find that in the inner jet, $f_{acc} \propto E_\gamma^{-0.4 \pm 0.2} \propto E_e^{-0.2 \pm 0.1}$, and in knots A and B, $f_{acc} \propto E_\gamma^{-0.7 \pm 0.2} \propto E_e^{-0.35 \pm 0.1}$, where $E_\gamma$ is the emitted photon energy and and $E_e$ is the emitting electron energy. In this model, the index $p$ of the injected electron energy spectrum ($n(E_{e}) \propto E_{e}^{-p}$) is $p=2.2$ at all locations in the jet, as predicted by models of cosmic ray acceleration by ultrarelativistic shocks. There is a strong correlation between the peaks of X-ray emission and minima of optical percentage polarization, i.e., regions where the jet magnetic field is not ordered. We suggest that the X-ray peaks coincide with shock waves which accelerate the X-ray emitting electrons and cause changes in the direction of the magnetic field; the polarization is thus small because of beam averaging.Comment: Accepted for publication in ApJ; 21 pages, 9 figures, 2 tables; abstract shortened for astro-ph; Figures 1, 7 and 8 at reduced resolutio

Factors associated with attendee adherence to COVID-19 guidance during the 2021 DCMS Events Research Programme Phase 1

As part of the DCMS Events Research Programme 2021, we surveyed and interviewed attendees of the FA Cup Semi-Final (18th April), Carabao Cup Final (25th April), the FA Cup Final (15th May), the Snooker World Championship (17th April – 3rd May) and Sefton Park music event (2nd May) to examine attendee experiences of the events, perceptions of the COVID-19 guidance, and factors most associated with self-reported adherence

When non-activists care: group efficacy mediates the effect of social identification and perceived instability on the legitimacy of collective action

In recent years, multiple social movements have emerged around the world. In addition, public surveys indicate the highest recorded levels of support for protest. In this context of acceptance of collective action, we examine the role of non-activists in the legitimacy of social movements, as this ‘passive’ support can contribute to social change. Given that antecedents of legitimacy have been neglected in the literature, we carried out a survey (N = 605) among a general sample of the population in Chile to shed light on this issue. We found that social identification with movements and perceived instability predicted the perceived legitimacy of protests by social movements, and that both variables had only indirect effects, through group efficacy. This suggests that perceiving social movements as able to achieve success can lead non-activists to perceive their actions as legitimate, highlighting the importance to movements of being seen to be effective

Efficiency of Nonlinear Particle Acceleration at Cosmic Structure Shocks

We have calculated the evolution of cosmic ray (CR) modified astrophysical shocks for a wide range of shock Mach numbers and shock speeds through numerical simulations of diffusive shock acceleration (DSA) in 1D quasi- parallel plane shocks. The simulations include thermal leakage injection of seed CRs, as well as pre-existing, upstream CR populations. Bohm-like diffusion is assumed. We model shocks similar to those expected around cosmic structure pancakes as well as other accretion shocks driven by flows with upstream gas temperatures in the range $T_0=10^4-10^{7.6}$K and shock Mach numbers spanning $M_s=2.4-133$. We show that CR modified shocks evolve to time-asymptotic states by the time injected particles are accelerated to moderately relativistic energies (p/mc \gsim 1), and that two shocks with the same Mach number, but with different shock speeds, evolve qualitatively similarly when the results are presented in terms of a characteristic diffusion length and diffusion time. For these models the time asymptotic value for the CR acceleration efficiency is controlled mainly by shock Mach number. The modeled high Mach number shocks all evolve towards efficiencies $\sim 50$%, regardless of the upstream CR pressure. On the other hand, the upstream CR pressure increases the overall CR energy in moderate strength shocks ($M_s \sim {\rm a few}$). (abridged)Comment: 23 pages, 12 ps figures, accepted for Astrophysical Journal (Feb. 10, 2005