329 research outputs found
A novel role for proline- and acid-rich basic region leucine zipper (PAR bZIP) proteins in the transcriptional regulation of a BH3-only proapoptotic gene.
Proline- and acid-rich (PAR) basic region leucine zipper (bZIP) proteins thyrotroph embryonic factor (TEF), D-site-binding protein (DBP), and hepatic leukemia factor have been involved in neurotransmitter homeostasis and amino acid metabolism. Here we demonstrate a novel role for these proteins in the transcriptional control of a BH3-only gene. PAR bZIP proteins are able to transactivate the promoter of bcl-gS. This promoter is particularly responsive to TEF activation and is silenced by NFIL3, a repressor that shares the consensus binding site with PAR bZIP proteins. Consistently, transfection of TEF induces the expression of endogenous bcl-gS in cancer cells, and this induction is independent of p53. A naturally occurring variant of DBP (tDBP), lacking the transactivation domain, has been identified and shown to impede the formation of active TEF dimers in a competitive manner and to reduce the TEF-dependent induction of bcl-gS. Of note, treatment of cancer cells with etoposide induces TEF activation and promotes the expression of bcl-gS. Furthermore, blockade of bcl-gS or TEF expression by a small interfering RNA strategy or transfection with tDBP significantly reduces the etoposide-mediated apoptotic cell death. These findings represent the first described role for PAR bZIP proteins in the regulation of a gene involved in the execution of apoptosis
Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation
The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation
C2-phytoceramide perturbs lipid rafts and cell integrity in Saccharomyces cerevisiae in a sterol-dependent manner
Specific ceramides are key regulators of cell fate, and extensive studies aimed to develop therapies based on ceramide-induced cell death. However, the mechanisms regulating ceramide cytotoxicity are not yet fully elucidated. Since ceramides also regulate growth and stress responses in yeast, we studied how different exogenous ceramides affect yeast cells. C2-phytoceramide, a soluble form of phytoceramides, the yeast counterparts of mammalian ceramides, greatly reduced clonogenic survival, particularly in the G2/M phase, but did not induce autophagy nor increase apoptotic markers. Rather, the loss of clonogenic survival was associated with PI positive staining, disorganization of lipid rafts and cell wall weakening. Sensitivity to C2-phytoceramide was exacerbated in mutants lacking Hog1p, the MAP kinase homolog of human p38 kinase. Decreasing sterol membrane content reduced sensitivity to C2-phytoceramide, suggesting sterols are the targets of this compound. This study identified a new function of C2-phytoceramide through disorganization of lipid rafts and induction of a necrotic cell death under hypo-osmotic conditions. Since lipid rafts are important in mammalian cell signaling and adhesion, our findings further support pursuing the exploitation of yeast to understand the basis of synthetic ceramides' cytotoxicity to provide novel strategies for therapeutic intervention in cancer and other diseases.This work was supported by Fundacao para a Ciencia e Tecnologia through projects PTDC/BIA-BCM/69448/2006 and PEst-C/BIA/UI4050/2011, and fellowships to A. P. (SFRH/BPD/65003) and F. A. (SFRH/BD/80934/2011), as well as by FEDER through POFC - COMPETE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Charge separation relative to the reaction plane in Pb-Pb collisions at TeV
Measurements of charge dependent azimuthal correlations with the ALICE
detector at the LHC are reported for Pb-Pb collisions at TeV. Two- and three-particle charge-dependent azimuthal correlations in
the pseudo-rapidity range are presented as a function of the
collision centrality, particle separation in pseudo-rapidity, and transverse
momentum. A clear signal compatible with a charge-dependent separation relative
to the reaction plane is observed, which shows little or no collision energy
dependence when compared to measurements at RHIC energies. This provides a new
insight for understanding the nature of the charge dependent azimuthal
correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published
version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286
A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE
In this small note we are concerned with the solution of Forward-Backward
Stochastic Differential Equations (FBSDE) with drivers that grow quadratically
in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem
is a comparison result that allows comparing componentwise the signs of the
control processes of two different qgFBSDE. As a byproduct one obtains
conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio
Transverse sphericity of primary charged particles in minimum bias proton-proton collisions at , 2.76 and 7 TeV
Measurements of the sphericity of primary charged particles in minimum bias
proton--proton collisions at , 2.76 and 7 TeV with the ALICE
detector at the LHC are presented. The observable is linearized to be collinear
safe and is measured in the plane perpendicular to the beam direction using
primary charged tracks with GeV/c in . The
mean sphericity as a function of the charged particle multiplicity at
mid-rapidity () is reported for events with different
scales ("soft" and "hard") defined by the transverse momentum of the leading
particle. In addition, the mean charged particle transverse momentum versus
multiplicity is presented for the different event classes, and the sphericity
distributions in bins of multiplicity are presented. The data are compared with
calculations of standard Monte Carlo event generators. The transverse
sphericity is found to grow with multiplicity at all collision energies, with a
steeper rise at low , whereas the event generators show the
opposite tendency. The combined study of the sphericity and the mean with multiplicity indicates that most of the tested event generators
produce events with higher multiplicity by generating more back-to-back jets
resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with
tune PERUGIA-2011 exhibits a noticeable improvement in describing the data,
compared to the other tested generators.Comment: 21 pages, 9 captioned figures, 3 tables, authors from page 16,
published version, figures from
http://aliceinfo.cern.ch/ArtSubmission/node/308
Effective Rheology of Bubbles Moving in a Capillary Tube
We calculate the average volumetric flux versus pressure drop of bubbles
moving in a single capillary tube with varying diameter, finding a square-root
relation from mapping the flow equations onto that of a driven overdamped
pendulum. The calculation is based on a derivation of the equation of motion of
a bubble train from considering the capillary forces and the entropy production
associated with the viscous flow. We also calculate the configurational
probability of the positions of the bubbles.Comment: 4 pages, 1 figur
Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at TeV
The inclusive transverse momentum () distributions of primary
charged particles are measured in the pseudo-rapidity range as a
function of event centrality in Pb-Pb collisions at
TeV with ALICE at the LHC. The data are presented in the range
GeV/ for nine centrality intervals from 70-80% to 0-5%.
The Pb-Pb spectra are presented in terms of the nuclear modification factor
using a pp reference spectrum measured at the same collision
energy. We observe that the suppression of high- particles strongly
depends on event centrality. In central collisions (0-5%) the yield is most
suppressed with at -7 GeV/. Above
GeV/, there is a significant rise in the nuclear modification
factor, which reaches for GeV/. In
peripheral collisions (70-80%), the suppression is weaker with almost independently of . The measured nuclear
modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12,
published version, figures at
http://aliceinfo.cern.ch/ArtSubmission/node/284
Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at TeV
The elliptic, , triangular, , and quadrangular, , azimuthal
anisotropic flow coefficients are measured for unidentified charged particles,
pions and (anti-)protons in Pb-Pb collisions at TeV
with the ALICE detector at the Large Hadron Collider. Results obtained with the
event plane and four-particle cumulant methods are reported for the
pseudo-rapidity range at different collision centralities and as a
function of transverse momentum, , out to GeV/.
The observed non-zero elliptic and triangular flow depends only weakly on
transverse momentum for GeV/. The small dependence
of the difference between elliptic flow results obtained from the event plane
and four-particle cumulant methods suggests a common origin of flow
fluctuations up to GeV/. The magnitude of the (anti-)proton
elliptic and triangular flow is larger than that of pions out to at least
GeV/ indicating that the particle type dependence persists out
to high .Comment: 16 pages, 5 captioned figures, authors from page 11, published
version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186
Elliptic flow of charged particles in Pb-Pb collisions at 2.76 TeV
We report the first measurement of charged particle elliptic flow in Pb-Pb
collisions at 2.76 TeV with the ALICE detector at the CERN Large Hadron
Collider. The measurement is performed in the central pseudorapidity region
(||<0.8) and transverse momentum range 0.2< < 5.0 GeV/. The
elliptic flow signal v, measured using the 4-particle correlation method,
averaged over transverse momentum and pseudorapidity is 0.087 0.002
(stat) 0.004 (syst) in the 40-50% centrality class. The differential
elliptic flow v reaches a maximum of 0.2 near = 3
GeV/. Compared to RHIC Au-Au collisions at 200 GeV, the elliptic flow
increases by about 30%. Some hydrodynamic model predictions which include
viscous corrections are in agreement with the observed increase.Comment: 10 pages, 4 captioned figures, published version, figures at
http://aliceinfo.cern.ch/ArtSubmission/node/389
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