Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity

Phosphorylation of estrogen receptor-α (ERα) at specific residues in transcription activation function 1 (AF-1) can stimulate ERα activity in a ligand-independent manner. This has led to the proposal that AF-1 phosphorylation and the consequent increase in ERα activity could contribute to resistance to endocrine therapies in breast cancer patients. Previous studies have shown that serine 118 (S118) in AF-1 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) in a ligand-independent manner. Here, we show that serines 104 (S104) and 106 (S106) are also phosphorylated by MAPK in vitro and upon stimulation of MAPK activity in vivo. Phosphorylation of S104 and S106 can be inhibited by the MAP-erk kinase (MEK)1/2 inhibitor U0126 and by expression of kinase-dead Raf1. Further, we show that, although S118 is important for the stimulation of ERα activity by the selective ER modulator 4-hydroxytamoxifen (OHT), S104 and S106 are also required for the agonist activity of OHT. Acidic amino acid substitution of S104 or S106 stimulates ERα activity to a greater extent than the equivalent substitution at S118, suggesting that phosphorylation at S104 and S106 is important for ERα activity. Collectively, these data indicate that the MAPK stimulation of ERα activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ERα at these sites may contribute to resistance to tamoxifen in breast cancer

Investigation of top mass measurements with the ATLAS detector at LHC

Several methods for the determination of the mass of the top quark with the ATLAS detector at the LHC are presented. All dominant decay channels of the top quark can be explored. The measurements are in most cases dominated by systematic uncertainties. New methods have been developed to control those related to the detector. The results indicate that a total error on the top mass at the level of 1 GeV should be achievable.Comment: 47 pages, 40 figure

Analyses of multiplicity distributions with \eta_c and Bose-Einstein correlations at LHC by means of generalized Glauber-Lachs formula

Using the negative binomial distribution (NBD) and the generalized Glauber-Lachs (GGL) formula, we analyze the data on charged multiplicity distributions with pseudo-rapidity cutoffs \eta_c at 0.9, 2.36, and 7 TeV by ALICE Collaboration and at 0.2, 0.54, and 0.9 TeV by UA5 Collaboration. We confirm that the KNO scaling holds among the multiplicity distributions with \eta_c = 0.5 at \sqrt{s} = 0.2\sim2.36 TeV and estimate the energy dependence of a parameter 1/k in NBD and parameters 1/k and \gamma (the ratio of the average value of the coherent hadrons to that of the chaotic hadrons) in the GGL formula. Using empirical formulae for the parameters 1/k and \gamma in the GGL formula, we predict the multiplicity distributions with \eta_c = 0.5 at 7 and 14 TeV. Data on the 2nd order Bose-Einstein correlations (BEC) at 0.9 TeV by ALICE Collaboration and 0.9 and 2.36 TeV by CMS Collaboration are also analyzed based on the GGL formula. Prediction for the 3rd order BEC at 0.9 and 2.36 TeV are presented. Moreover, the information entropy is discussed

Event by Event Analysis and Entropy of Multiparticle Systems

The coincidence method of measuring the entropy of a system, proposed some time ago by Ma, is generalized to include systems out of equilibrium. It is suggested that the method can be adapted to analyze multiparticle states produced in high-energy collisions.Comment: 13 pages, 2 figure

Inhibition of Striatal Soluble Guanylyl Cyclase-cGMP Signaling Reverses Basal Ganglia Dysfunction and Akinesia in Experimental Parkinsonism

There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinson's disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD.The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP.We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP.Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD

Climacteric Lowers Plasma Levels of Platelet-Derived Microparticles: A Pilot Study in Pre-versus Postmenopausal Women

Background: Climacteric increases the risk of thrombotic events by alteration of plasmatic coagulation. Up to now, less is known about changes in platelet-(PMP) and endothelial cell-derived microparticles (EMP). Methods: In this prospective study, plasma levels of microparticles (MP) were compared in 21 premenopausal and 19 postmenopausal women. Results: No altered numbers of total MP or EMP were measured within the study groups. However, the plasma values of CD61-exposing MP from platelets/megakaryocytes were higher in premenopausal women (5,364 x 10(6)/l, range 4,384-17,167) as compared to postmenopausal women (3,808 x 10(6)/l, range 2,009-8,850; p = 0.020). This differentiation was also significant for the subgroup of premenopausal women without hormonal contraceptives (5,364 x 10(6)/l, range 4,223-15,916; p = 0.047; n = 15). Furthermore, in premenopausal women, higher plasma levels of PMP exposing CD62P were also present as compared to postmenopausal women (288 x 10(6)/l, range 139-462, vs. 121 x 10(6)/l, range 74-284; p = 0.024). This difference was also true for CD63+ PMP levels (281 x 10(6)/l, range 182-551, vs. 137 x 10(6)/l, range 64-432; p = 0.015). Conclusion: Climacteric lowers the level of PMP but has no impact on the number of EMP in women. These data suggest that PMP and EMP do not play a significant role in enhancing the risk of thrombotic events in healthy, postmenopausal women. Copyright (C) 2012 S. Karger AG, Base

Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation.

Brain injury elicits a systemic acute-phase response (APR), which is responsible for co-ordinating the peripheral immunological response to injury. To date, the mechanisms responsible for signalling the presence of injury or disease to selectively activate responses in distant organs were unclear. Circulating endogenous extracellular vesicles (EVs) are increased after brain injury and have the potential to carry targeted injury signals around the body. Here, we examined the potential of EVs, isolated from rats after focal inflammatory brain lesions using IL-1β, to activate a systemic APR in recipient naïve rats, as well as the behavioural consequences of EV transfer. Focal brain lesions increased EV release, and, following isolation and transfer, the EVs were sequestered by the liver where they initiated an APR. Transfer of blood-borne EVs from brain-injured animals was also enough to suppress exploratory behaviours in recipient naïve animals. EVs derived from brain endothelial cell cultures treated with IL-1β also activated an APR and altered behaviour in recipient animals. These experiments reveal that inflammation-induced circulating EVs derived from endothelial cells are able to initiate the APR to brain injury and are sufficient to generate the associated sickness behaviours, and are the first demonstration that EVs are capable of modifying behavioural responses

p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells.

Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression. This occurs through the induction of p21 (CDKN1A) and the recruitment of the repressive DREAM complex to the A3B gene promoter, such that loss of p53 through mutation, or human papilloma virus-mediated inhibition, prevents recruitment of the complex, thereby causing elevated A3B expression and cytosine deaminase activity in cancer cells. As p53 is frequently mutated in cancer, our findings provide a mechanism by which p53 loss can promote cancer mutagenesis

A Quasi-Model-Independent Search for New Physics at Large Transverse Momentum

We apply a quasi-model-independent strategy ("Sleuth") to search for new high p_T physics in approximately 100 pb^-1 of ppbar collisions at sqrt(s) = 1.8 TeV collected by the DZero experiment during 1992-1996 at the Fermilab Tevatron. Over thirty-two e mu X, W+jets-like, Z+jets-like, and 3(lepton/photon)X exclusive final states are systematically analyzed for hints of physics beyond the standard model. Simultaneous sensitivity to a variety of models predicting new phenomena at the electroweak scale is demonstrated by testing the method on a particular signature in each set of final states. No evidence of new high p_T physics is observed in the course of this search, and we find that 89% of an ensemble of hypothetical similar experimental runs would have produced a final state with a candidate signal more interesting than the most interesting observed in these data.Comment: 28 pages, 17 figures. Submitted to Physical Review