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Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300
(2017)
Nonsteroidal anti-inflammatory drugs are the most widely used medicine to treat pain and inflammation, and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. HDAC inhibition (HDACi) with the pan-HDAC inhibitor, vorinostat, attenuated prostaglandin (PG)E2 generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE2 synthesis, microsomal PGE synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-sequencing analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. In conclusion, HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.
Die Einführung von Patient Blood Management (PBM) führt zu einem Paradigmenwechsel bezüglich Erkennen und Therapie der Anämie und zeigt Maßnahmen auf um die Entstehung einer Anämie zu verhindern. PBM unterstützt den Arzt im Entscheidungsdilemma zwischen positiver Wirkung und nachteiligen Nebenwirkungen von Bluttransfusionen. Mit PBM wird der Blutverbrauch deutlich reduziert und die Nebenwirkungen gesenkt. Nicht nur die therapeutischen Maßnahmen, sondern auch die diagnostischen PBM Maßnahmen im Labor führen zu einer relevanten Verringerung des Blutvolumens. PBM Studienergebnisse zeigen eine signifikant Reduktion der Morbidität und Mortalität und die Verbesserung des Patienten- Outcome. Ein weiterer positiver Nebeneffekt ist Schonung von Ressourcen in allen beteiligten Bereichen, welches zu einer relevanten Kostenreduktion und Steigerung der Wirtschaftlichkeit führt. Zusätzlich sensibilisiert das PBM bezüglich des Vorliegens, der Entwicklung und der Therapie einer anämischen Situation sowie den Umgang mit der kostbaren Ressource Blut. Die Bedeutung des PBM wird mittlerweile von der Industrie auch für das Labor unterstützt; für den Bereich POCT ist das PBM jedoch bisher noch nicht adäquat technisch realisiert.
The yeast Rcf1 protein is a member of the conserved family of proteins termed the hypoxia-induced gene (domain) 1 (Hig1 or HIGD1) family. Rcf1 interacts with components of the mitochondrial oxidative phosphorylation system, in particular the cytochrome bc1 (complex III)-cytochrome c oxidase (complex IV) supercomplex (termed III-IV) and the ADP/ATP carrier proteins. Rcf1 plays a role in the assembly and modulation of the activity of complex IV; however, the molecular basis for how Rcf1 influences the activity of complex IV is currently unknown. Hig1 type 2 isoforms, which include the Rcf1 protein, are characterized in part by the presence of a conserved motif, (Q/I)X3(R/H)XRX3Q, termed here the QRRQ motif. We show that mutation of conserved residues within the Rcf1 QRRQ motif alters the interactions between Rcf1 and partner proteins and results in the destabilization of complex IV and alteration of its enzymatic properties. Our findings indicate that Rcf1 does not serve as a stoichiometric component, i.e. as a subunit of complex IV, to support its activity. Rather, we propose that Rcf1 serves to dynamically interact with complex IV during its assembly process and, in doing so, regulates a late maturation step of complex IV. We speculate that the Rcf1/Hig1 proteins play a role in the incorporation and/or remodeling of lipids, in particular cardiolipin, into complex IV and. possibly, other mitochondrial proteins such as ADP/ATP carrier proteins.
In this proceeding, we study the dynamical evolution of the sigma field within the framework of Langevin dynamics. We find that, as the system evolves in the critical regime, the magnitudes and signs of the cumulants of sigma field, C3 and C4, can be dramatically different from the equilibrated ones due to the memory effects near Tc. For the dynamical evolution across the 1st order phase transition boundary, the supercooling effect leads the sigma field to be widely distributed in the thermodynamical potential, which largely enhances the cumulants C3, C4, correspondingly.
Starting from IP-Glasma initial conditions, we investigate the effects of bulk pressure on low mass dilepton production at the Relativistic Heavy Ion Collider (RHIC) and the Large Hadron Collider (LHC) energies. Though thermal dilepton is affected by the presence of both bulk and shear viscosity, whether or not these effects can be measured depends on the dilepton “cocktail” contribution to the the low mass dilepton . Combining the thermal and “cocktail” dileptons, the effects of bulk viscosity on total dilepton is investigated.
The first study of ϕ-meson production in p-Pb collisions at forward and backward rapidity, at a nucleon-nucleon centre-of-mass energy sNN−−−√=5.02~TeV, has been performed with the ALICE apparatus at the LHC. The ϕ-mesons have been identified in the dimuon decay channel in the transverse momentum (pT) range 1<pT<7 GeV/c, both in the p-going (2.03<y<3.53) and the Pb-going (−4.46<y<−2.96) directions, where y stands for the rapidity in the nucleon-nucleon centre-of-mass, the integrated luminosity amounting to 5.01±0.19~nb−1 and 5.81±0.20~nb−1, respectively, for the two data samples. Differential cross sections as a function of transverse momentum and rapidity are presented. The forward-backward ratio for ϕ-meson production is measured for 2.96<|y|<3.53, resulting in a ratio ∼0.5 with no significant pT dependence within the uncertainties. The pT dependence of the ϕ nuclear modification factor RpPb exhibits an enhancement up to a factor 1.6 at pT = 3-4 GeV/c in the Pb-going direction. The pT dependence of the ϕ-meson cross section in pp collisions at s√ = 2.76 TeV, which is used to determine a reference for the p-Pb results, is also presented here for 1<pT<5 GeV/c and 2.5<y<4 for a 78±3~nb−1 integrated luminosity sample.
The first study of ϕ-meson production in p-Pb collisions at forward and backward rapidity, at a nucleon-nucleon centre-of-mass energy sNN−−−√=5.02~TeV, has been performed with the ALICE apparatus at the LHC. The ϕ-mesons have been identified in the dimuon decay channel in the transverse momentum (pT) range 1<pT<7 GeV/c, both in the p-going (2.03<y<3.53) and the Pb-going (−4.46<y<−2.96) directions, where y stands for the rapidity in the nucleon-nucleon centre-of-mass, the integrated luminosity amounting to 5.01±0.19~nb−1 and 5.81±0.20~nb−1, respectively, for the two data samples. Differential cross sections as a function of transverse momentum and rapidity are presented. The forward-backward ratio for ϕ-meson production is measured for 2.96<|y|<3.53, resulting in a ratio ∼0.5 with no significant pT dependence within the uncertainties. The pT dependence of the ϕ nuclear modification factor RpPb exhibits an enhancement up to a factor 1.6 at pT = 3-4 GeV/c in the Pb-going direction. The pT dependence of the ϕ-meson cross section in pp collisions at s√ = 2.76 TeV, which is used to determine a reference for the p-Pb results, is also presented here for 1<pT<5 GeV/c and 2.5<y<4 for a 78±3~nb−1 integrated luminosity sample.
The production of beauty hadrons was measured via semi-leptonic decays at mid-rapidity with the ALICE detector at the LHC in the transverse momentum interval 1<pT<8 GeV/c in minimum-bias p-Pb collisions at sNN−−−√=5.02 TeV and in 1.3<pT<8 GeV/c in the 20% most central Pb-Pb collisions at sNN−−−√=2.76 TeV. The pp reference spectra at s√=5.02 TeV and s√=2.76 TeV, needed for the calculation of the nuclear modification factors RpPb and RPbPb, were obtained by a pQCD-driven scaling of the cross section of electrons from beauty-hadron decays measured at s√=7 TeV. In the pT interval 3<pT<8 GeV/c a suppression of the yield of electrons from beauty-hadron decays is observed in Pb-Pb compared to pp collisions. Towards lower pT, the RPbPb values increase with large systematic uncertainties. The RpPb is consistent with unity within systematic uncertainties and is well described by theoretical calculations that include cold nuclear matter effects in p-Pb collisions. The measured RpPb and these calculations indicate that cold nuclear matter effects are small at high transverse momentum also in Pb-Pb collisions. Therefore, the observed reduction of RPbPb below unity at high pT may be ascribed to an effect of the hot and dense medium formed in Pb-Pb collisions.
The production of beauty hadrons was measured via semi-leptonic decays at mid-rapidity with the ALICE detector at the LHC in the transverse momentum interval 1<pT<8 GeV/c in minimum-bias p-Pb collisions at sNN−−−√=5.02 TeV and in 1.3<pT<8 GeV/c in the 20% most central Pb-Pb collisions at sNN−−−√=2.76 TeV. The pp reference spectra at s√=5.02 TeV and s√=2.76 TeV, needed for the calculation of the nuclear modification factors RpPb and RPbPb, were obtained by a pQCD-driven scaling of the cross section of electrons from beauty-hadron decays measured at s√=7 TeV. In the pT interval 3<pT<8 GeV/c a suppression of the yield of electrons from beauty-hadron decays is observed in Pb-Pb compared to pp collisions. Towards lower pT, the RPbPb values increase with large systematic uncertainties. The RpPb is consistent with unity within systematic uncertainties and is well described by theoretical calculations that include cold nuclear matter effects in p-Pb collisions. The measured RpPb and these calculations indicate that cold nuclear matter effects are small at high transverse momentum also in Pb-Pb collisions. Therefore, the observed reduction of RPbPb below unity at high pT may be ascribed to an effect of the hot and dense medium formed in Pb-Pb collisions.
In two-particle angular correlation measurements, jets give rise to a near-side peak, formed by particles associated to a higher pT trigger particle. Measurements of these correlations as a function of pseudorapidity (Δη) and azimuthal (Δφ) differences are used to extract the centrality and pT dependence of the shape of the near-side peak in the pT range 1<pT< 8 GeV/c in Pb-Pb and pp collisions at sNN−−−√ = 2.76 TeV. A combined fit of the near-side peak and long-range correlations is applied to the data and the peak shape is quantified by the variance of the distributions. While the width of the peak in the Δφ direction is almost independent of centrality, a significant broadening in the Δη direction is found from peripheral to central collisions. This feature is prominent for the low pT region and vanishes above 4 GeV/c. The widths measured in peripheral collisions are equal to those in pp in the Δφ direction and above 3 GeV/c in the Δη direction. Furthermore, for the 10\% most central collisions and 1<pT,assoc< 2 GeV/c, 1<pT,trig< 3 GeV/c a departure from a Gaussian shape is found: a depletion develops around the centre of the peak. The results are compared to AMPT model simulations as well as other theoretical calculations indicating that the broadening and the development of the depletion is connected to the strength of radial and longitudinal flow.