Heteroreceptor complexes formed by dopamine D1, histamine H3 and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D , histamine H , and N-methylD-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by coimmunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H receptor agonists, via negative cross-talk, and H receptor antagonists, via cross-antagonism, decreased D receptor agonist signaling determined by ERK1/2 or Akt phosphorylation and counteracted D receptormediated excitotoxic cell death. Both D and H receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D -H receptor heteromer function. Likely due to heteromerization, H receptors act as allosteric regulator for D and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D or H receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D -H -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H receptor antagonists reduced NMDA or D receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H receptor antagonists reverted the toxicity induced by ß -amyloid peptide. Thus, histamine H receptors in D -H -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration

A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog–Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog–Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2–Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.

Measurement of Lifetime and Decay-Width Difference in B0s -> J/psi phi Decays

We measure the mean lifetime, tau=2/(Gamma_L+Gamma_H), and the width difference, DeltaGamma=Gamma_L-Gamma_H, of the light and heavy mass eigenstates of the B0s meson, B0sL and B0sH, in B0s -> J/psi phi decays using 1.7 fb^-1 of data collected with the CDF II detector at the Fermilab Tevatron ppbar collider. Assuming CP conservation, a good approximation for the B0s system in the Standard Model, we obtain DeltaGamma = 0.076^+0.059_-0.063 (stat.) +- 0.006 (syst.) ps^-1 and tau = 1.52 +- 0.04 (stat.) +- 0.02 (syst.) ps, the most precise measurements to date. Our constraints on the weak phase and DeltaGamma are consistent with CP conservation. Dedicated to the memory of our dear friend and colleague, Michael P. Schmid

Limits on Anomalous Triple Gauge Couplings in ppbar Collisions at sqrt{s}=1.96 TeV

We present a search for anomalous triple gauge couplings (ATGC) in WW and WZ boson production. The boson pairs are produced in ppbar collisions at sqrt{s}=1.96 TeV, and the data sample corresponds to 350 pb-1 of integrated luminosity collected with the CDF II detector at the Fermilab Tevatron. In this search one W decays to leptons, and the other boson (W or Z) decays hadronically. Combining with a previously published CDF measurement of Wgamma boson production yields ATGC limits of -0.18 < lambda < 0.17 and -0.46 < Delta kappa < 0.39 at the 95% confidence level, using a cut-off scale Lambda=1.5 TeV.Comment: 7 pages, 3 figures. Submitted to Phys. Rev.

Search for Pair Production of Scalar Top Quarks Decaying to a tau Lepton and a b Quark in ppbar Collisions at sqrt{s}=1.96 TeV

We search for pair production of supersymmetric top quarks (~t_1), followed by R-parity violating decay ~t_1 -> tau b with a branching ratio beta, using 322 pb^-1 of ppbar collisions at sqrt{s}=1.96 TeV collected by the CDF II detector at Fermilab. Two candidate events pass our final selection criteria, consistent with the standard model expectation. We set upper limits on the cross section sigma(~t_1 ~tbar_1)*beta^2 as a function of the stop mass m(~t_1). Assuming beta=1, we set a 95% confidence level limit m(~t_1)>153 GeV/c^2. The limits are also applicable to the case of a third generation scalar leptoquark (LQ_3) decaying LQ_3 -> tau b.Comment: 7 pages, 2 eps figure

Forward-Backward Asymmetry in Top Quark Production in ppbar Collisions at sqrt{s}=1.96 TeV

Reconstructable final state kinematics and charge assignment in the reaction ppbar->ttbar allows tests of discrete strong interaction symmetries at high energy. We define frame dependent forward-backward asymmetries for the outgoing top quark in both the ppbar and ttbar rest frames, correct for experimental distortions, and derive values at the parton-level. Using 1.9/fb of ppbar collisions at sqrt{s}=1.96 TeV recorded with the CDF II detector at the Fermilab Tevatron, we measure forward-backward top quark production asymmetries in the ppbar and ttbar rest frames of A_{FB,pp} = 0.17 +- 0.08 and A_{FB,tt} = 0.24 +- 0.14.Comment: 7 pages, 2 figures, submitted to Phys.Rev.Lett, corrected references and change of tex

Measurement of the W+W−W^+W^- Production Cross Section and Search for Anomalous WWγWW\gamma and WWZWWZ Couplings in ppˉp \bar p Collisions at s=1.96\sqrt{s} = 1.96 TeV

This Letter describes the current most precise measurement of the $W$ boson pair production cross section and most sensitive test of anomalous $WW\gamma$ and $WWZ$ couplings in $p \bar p$ collisions at a center-of-mass energy of 1.96 TeV. The $WW$ candidates are reconstructed from decays containing two charged leptons and two neutrinos, where the charged leptons are either electrons or muons. Using data collected by the CDF II detector from 3.6 fb$^{-1}$ of integrated luminosity, a total of 654 candidate events are observed with an expected background contribution of $320 \pm 47$ events. The measured total cross section is $\sigma (p \bar p \to W^+ W^- + X) = 12.1 \pm 0.9 \textrm{(stat)} ^{+1.6}_{-1.4} \textrm{(syst)}$ pb, which is in good agreement with the standard model prediction. The same data sample is used to place constraints on anomalous $WW\gamma$ and $WWZ$ couplings.Comment: submitted to Phys. Rev. Let

Elongation of very long-chain (>C24) fatty acids in Clarias gariepinus: Cloning, functional characterization and tissue expression of elovl4 elongases

Elongation of very long-chain fatty acid 4 (Elovl4) proteins participate in the biosynthesis of very long-chain (&gt;C24) saturated and polyunsaturated fatty acids (FA). Previous studies have shown that fish possess two different forms of Elovl4, termed Elovl4a and Elovl4b. The present study aimed to characterize both molecularly and functionally two elovl4 cDNA from the African catfish Clarias gariepinus. The results confirmed that C. gariepinus possessed two elovl4-like elongases with high homology to two previously characterized Elovl4 from Danio rerio, and thus they were termed accordingly as Elovl4a and Elovl4b. The C. gariepinus Elovl4a and Elovl4b have open reading frames (ORF) of 945 and 915 base pairs, respectively, encoding putative proteins of 314 and 304 amino acids, respectively. Functional characterization in yeast showed both Elovl4 enzymes have activity towards all the PUFA substrates assayed (18:4n-3, 18:3n-6, 20:5n-3, 20:4n-6, 22:5n-3, 22:4n-6 and 22:6n-3), producing elongated products of up to C36. Moreover, the C. gariepinus Elovl4a and Elovl4b were able to elongate very long-chain saturated FA (VLC-SFA) as denoted by increased levels of 28:0 and longer FA in yeast transformed with elovl4 ORF compared to control yeast. These results confirmed that C. gariepinus Elovl4 play important roles in the biosynthesis of very long-chain FA. Tissue distribution analysis of elovl4 mRNAs showed both genes were widely expressed in all tissues analyzed, with high expression of elovl4a in pituitary and brain, whereas female gonad and pituitary had the highest expression levels for elovl4b

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente