BIRC6 mediates imatinib resistance independently of Mcl-1

© 2017 Okumu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Baculoviral IAP repeat containing 6 (BIRC6) is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related proteins that inhibit apoptosis. BIRC6 has been implicated in drug resistance in several different human cancers, however mechanisms regulating BIRC6 have not been extensively explored. Our phosphoproteomic analysis of an imatinib-resistant chronic myelogenous leukemia (CML) cell line (MYL-R) identified increased amounts of a BIRC6 peptide phosphorylated at S480, S482, and S486 compared to imatinib-sensitive CML cells (MYL). Thus we investigated the role of BIRC6 in mediating imatinib resistance and compared it to the well-characterized anti-apoptotic protein, Mcl-1. Both BIRC6 and Mcl-1 were elevated in MYL-R compared to MYL cells. Lentiviral shRNA knockdown of BIRC6 in MYL-R cells increased imatinib-stimulated caspase activation and resulted in a ~20-25-fold increase in imatinib sensitivity, without affecting Mcl-1. Treating MYL-R cells with CDK9 inhibitors decreased BIRC6 mRNA, but not BIRC6 protein levels. By contrast, while CDK9 inhibitors reduced Mcl-1 mRNA and protein, they did not affect imatinib sensitivity. Since the Src family kinase Lyn is highly expressed and active in MYL-R cells, we tested the effects of Lyn inhibition on BIRC6 and Mcl-1. RNAi-mediated knockdown or inhibition of Lyn (dasatinib/ponatinib) reduced BIRC6 protein stability and increased caspase activation. Inhibition of Lyn also increased formation of an N-terminal BIRC6 fragment in parallel with reduced amount of the BIRC6 phosphopeptide, suggesting that Lyn may regulate BIRC6 phosphorylation and stability. In summary, our data show that BIRC6 stability is dependent on Lyn, and that BIRC6 mediates imatinib sensitivity independently of Mcl-1 or CDK9. Hence, BIRC6 may be a novel target for the treatment of drugresistant CML where Mcl-1 or CDK9 inhibitors have failed

On-disk coronal rain

Small and elongated, cool and dense blob-like structures are being reported with high resolution telescopes in physically different regions throughout the solar atmosphere. Their detection and the understanding of their formation, morphology and thermodynamical characteristics can provide important information on their hosting environment, especially concerning the magnetic field, whose understanding constitutes a major problem in solar physics. An example of such blobs is coronal rain, a phenomenon of thermal non- equilibrium observed in active region loops, which consists of cool and dense chromospheric blobs falling along loop-like paths from coronal heights. So far, only off-limb coronal rain has been observed and few reports on the phenomenon exist. In the present work, several datasets of on-disk H{\alpha} observations with the CRisp Imaging SpectroPolarimeter (CRISP) at the Swedish 1-m Solar Telescope (SST) are analyzed. A special family of on-disk blobs is selected for each dataset and a statistical analysis is carried out on their dynamics, morphology and temperatures. All characteristics present distributions which are very similar to reported coronal rain statistics. We discuss possible interpretations considering other similar blob-like structures reported so far and show that a coronal rain interpretation is the most likely one. Their chromospheric nature and the projection effects (which eliminate all direct possibility of height estimation) on one side, and their small sizes, fast dynamics, and especially, their faint character (offering low contrast with the background intensity) on the other side, are found as the main causes for the absence until now of the detection of this on-disk coronal rain counterpart.Comment: 18 pages, 10 figures. Accepted for Solar Physic

Electrostatic and electrokinetic contributions to the elastic moduli of a driven membrane

We discuss the electrostatic contribution to the elastic moduli of a cell or artificial membrane placed in an electrolyte and driven by a DC electric field. The field drives ion currents across the membrane, through specific channels, pumps or natural pores. In steady state, charges accumulate in the Debye layers close to the membrane, modifying the membrane elastic moduli. We first study a model of a membrane of zero thickness, later generalizing this treatment to allow for a finite thickness and finite dielectric constant. Our results clarify and extend the results presented in [D. Lacoste, M. Cosentino Lagomarsino, and J. F. Joanny, Europhys. Lett., {\bf 77}, 18006 (2007)], by providing a physical explanation for a destabilizing term proportional to \kps^3 in the fluctuation spectrum, which we relate to a nonlinear ($E^2$) electro-kinetic effect called induced-charge electro-osmosis (ICEO). Recent studies of ICEO have focused on electrodes and polarizable particles, where an applied bulk field is perturbed by capacitive charging of the double layer and drives flow along the field axis toward surface protrusions; in contrast, we predict "reverse" ICEO flows around driven membranes, due to curvature-induced tangential fields within a non-equilibrium double layer, which hydrodynamically enhance protrusions. We also consider the effect of incorporating the dynamics of a spatially dependent concentration field for the ion channels.Comment: 22 pages, 10 figures. Under review for EPJ

Phi meson production in Au+Au and p+p collisions at sqrt (s)=200 GeV

We report the STAR measurement of Phi meson production in Au+Au and p+p collisions at sqrt (s)=200 GeV. Using the event mixing technique, the Phi spectra and yields are obtained at mid-rapidity for five centrality bins in Au+Au collisions and for non-singly-diffractive p+p collisions. It is found that the Phi transverse momentum distributions from Au+Au collisions are better fitted with a single-exponential while the p+p spectrum is better described by a double-exponential distribution. The measured nuclear modification factors indicate that Phi production in central Au+Au collisions is suppressed relative to peripheral collisions when scaled by the number of binary collisions. The systematics of versus centrality and the constant Phi/K- ratio versus beam species, centrality, and collision energy rule out kaon coalescence as the dominant mechanism for Phi production.Comment: 6 pages, 3 figures, submitted to Phys. Rev. Let

Azimuthal anisotropy at RHIC: the first and fourth harmonics

We report the first observations of the first harmonic (directed flow, v_1), and the fourth harmonic (v_4), in the azimuthal distribution of particles with respect to the reaction plane in Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC). Both measurements were done taking advantage of the large elliptic flow (v_2) generated at RHIC. From the correlation of v_2 with v_1 it is determined that v_2 is positive, or {\it in-plane}. The integrated v_4 is about a factor of 10 smaller than v_2. For the sixth (v_6) and eighth (v_8) harmonics upper limits on the magnitudes are reported.Comment: 6 pages with 3 figures, as accepted for Phys. Rev. Letters The data tables are at http://www.star.bnl.gov/central/publications/pubDetail.php?id=3

Pion, kaon, proton and anti-proton transverse momentum distributions from p+p and d+Au collisions at sNN=200\sqrt{s_{NN}} = 200 GeV

Identified mid-rapidity particle spectra of $\pi^{\pm}$, $K^{\pm}$, and $p(\bar{p})$ from 200 GeV p+p and d+Au collisions are reported. A time-of-flight detector based on multi-gap resistive plate chamber technology is used for particle identification. The particle-species dependence of the Cronin effect is observed to be significantly smaller than that at lower energies. The ratio of the nuclear modification factor ($R_{dAu}$) between protons $(p+\bar{p})$ and charged hadrons ($h$) in the transverse momentum range $1.2<{p_{T}}<3.0$ GeV/c is measured to be $1.19\pm0.05$(stat)$\pm0.03$(syst) in minimum-bias collisions and shows little centrality dependence. The yield ratio of $(p+\bar{p})/h$ in minimum-bias d+Au collisions is found to be a factor of 2 lower than that in Au+Au collisions, indicating that the Cronin effect alone is not enough to account for the relative baryon enhancement observed in heavy ion collisions at RHIC.Comment: 6 pages, 4 figures, 1 table. We extended the pion spectra from transverse momentum 1.8 GeV/c to 3. GeV/

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Experimental and Theoretical Challenges in the Search for the Quark Gluon Plasma: The STAR Collaboration's Critical Assessment of the Evidence from RHIC Collisions

We review the most important experimental results from the first three years of nucleus-nucleus collision studies at RHIC, with emphasis on results from the STAR experiment, and we assess their interpretation and comparison to theory. The theory-experiment comparison suggests that central Au+Au collisions at RHIC produce dense, rapidly thermalizing matter characterized by: (1) initial energy densities above the critical values predicted by lattice QCD for establishment of a Quark-Gluon Plasma (QGP); (2) nearly ideal fluid flow, marked by constituent interactions of very short mean free path, established most probably at a stage preceding hadron formation; and (3) opacity to jets. Many of the observations are consistent with models incorporating QGP formation in the early collision stages, and have not found ready explanation in a hadronic framework. However, the measurements themselves do not yet establish unequivocal evidence for a transition to this new form of matter. The theoretical treatment of the collision evolution, despite impressive successes, invokes a suite of distinct models, degrees of freedom and assumptions of as yet unknown quantitative consequence. We pose a set of important open questions, and suggest additional measurements, at least some of which should be addressed in order to establish a compelling basis to conclude definitively that thermalized, deconfined quark-gluon matter has been produced at RHIC.Comment: 101 pages, 37 figures; revised version to Nucl. Phys.

Single Spin Asymmetry ANA_N in Polarized Proton-Proton Elastic Scattering at s=200\sqrt{s}=200 GeV

We report a high precision measurement of the transverse single spin asymmetry $A_N$ at the center of mass energy $\sqrt{s}=200$ GeV in elastic proton-proton scattering by the STAR experiment at RHIC. The $A_N$ was measured in the four-momentum transfer squared $t$ range $0.003 \leqslant |t| \leqslant 0.035$ \GeVcSq, the region of a significant interference between the electromagnetic and hadronic scattering amplitudes. The measured values of $A_N$ and its $t$-dependence are consistent with a vanishing hadronic spin-flip amplitude, thus providing strong constraints on the ratio of the single spin-flip to the non-flip amplitudes. Since the hadronic amplitude is dominated by the Pomeron amplitude at this $\sqrt{s}$, we conclude that this measurement addresses the question about the presence of a hadronic spin flip due to the Pomeron exchange in polarized proton-proton elastic scattering.Comment: 12 pages, 6 figure