Characterisation of the Mouse Vasoactive Intestinal Peptide Receptor Type 2 Gene, Vipr2, and Identification of a Polymorphic LINE-1-like Sequence That Confers Altered Promoter Activity

The VPAC(2) receptor is a seven transmembrane spanning G protein-coupled receptor for two neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). It has a distinct tissue-specific, developmental and inducible expression that underlies an important neuroendocrine role. Here, we report the characterisation of the gene that encodes the mouse VPAC(2) receptor (Vipr2), localisation of the transcriptional start site and functional analysis of the promoter region. The Vipr2 gene contains 12 introns within its protein-coding region and spans 68.6 kb. Comparison of the 5′ untranslated region sequences for cloned 5′-RACE products amplified from different tissues showed they all were contained within the same exon, with the longest extending 111 bp upstream of the ATG start site. Functional analysis of the 3.2-kb 5′-flanking region using sequentially deleted sequences cloned into a luciferase gene reporter vector revealed that this region is active as a promoter in mouse AtT20 D16:16 and rat GH4C1 cell lines. The core promoter is located within a 180-bp GC-rich region proximal to the ATG start codon and contains potential binding sites for Sp1 and AP2, but no TATA-box. Further upstream, in two out of three mice strains examined, we have discovered a 496-bp polymorphic DNA sequence that bears a significant identity to mouse LINE-1 DNA. Comparison of the promoter activity between luciferase reporter gene constructs derived from the BALB/c (which contains this sequence) and C57BL/6J (which lacks this sequence) Vipr2 promoter regions has shown three-fold difference in luciferase gene activity when expressed in mouse AtT20 D16:16 and αT3-1 cells, but not when expressed in the rat GH4C1 cells or in COS 7 cells. Our results suggest that the mouse Vipr2 gene may be differentially active in different mouse strains, depending on the presence of this LINE-1-like sequence in the promoter region

Multiparticle azimuthal correlations for extracting event-by-event elliptic and triangular flow in Au + Au collisions at sNN =200 GeV

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1<|η|<3 in Au + Au collisions at sNN=200 GeV, as a function of centrality. The multiparticle cumulant technique is used to obtain the elliptic flow coefficients v2{2},v2{4},v2{6}, and v2{8}, and triangular flow coefficients v3{2} and v3{4}. Using the small-variance limit, we estimate the mean and variance of the event-by-event v2 distribution from v2{2} and v2{4}. In a complementary analysis, we also use a folding procedure to study the distributions of v2 and v3 directly, extracting both the mean and variance. Implications for initial geometrical fluctuations and their translation into the final-state momentum distributions are discussed

Nonperturbative transverse-momentum-dependent effects in dihadron and direct photon-hadron angular correlations in p+p collisions at s =200 GeV

Dihadron and isolated direct photon-hadron angular correlations are measured in p+p collisions at s=200 GeV. The correlations are sensitive to nonperturbative initial-state and final-state transverse momenta kT and jT in the azimuthal nearly back-to-back region Δφ∼π. To have sensitivity to small transverse momentum scales, nonperturbative momentum widths of pout, the out-of-plane transverse-momentum component perpendicular to the trigger particle, are measured. In this region, the evolution of pout can be studied when several different hard scales are measured. These widths are used to investigate possible effects from transverse-momentum-dependent factorization breaking. When accounting for the longitudinal-momentum fraction of the away-side hadron with respect to the near-side trigger particle, the widths are found to increase with the hard scale; this is qualitatively similar to the observed behavior in Drell-Yan and semi-inclusive deep-inelastic scattering interactions, where factorization is predicted to hold. The momentum widths are also studied as a function of center-of-mass energy by comparing to previous measurements at s=510 GeV. The nonperturbative jet widths also appear to increase with s at a similar xT, which is qualitatively consistent to similar measurements in Drell-Yan interactions. Future detailed global comparisons between measurements of processes where transverse-momentum-dependent factorization is predicted to hold and be broken will provide further insight into the role of color in hadronic interactions

Nonperturbative-transverse-momentum broadening in dihadron angular correlations in sNN =200 GeV proton-nucleus collisions

The PHENIX collaboration has measured high-pT dihadron correlations in p+p, p+Al, and p+Au collisions at sNN=200 GeV. The correlations arise from inter- and intrajet correlations and thus have sensitivity to nonperturbative effects in both the initial and final states. The distributions of pout, the transverse-momentum component of the associated hadron perpendicular to the trigger hadron, are sensitive to initial- and final-state transverse momenta. These distributions are measured multidifferentially as a function of xE, the longitudinal momentum fraction of the associated hadron with respect to the trigger hadron. The near-side pout widths, sensitive to fragmentation transverse momentum, show no significant broadening between p+Au, p+Al, and p+p. The away-side nonperturbative pout widths are found to be broadened in p+Au when compared to p+p; however, there is no significant broadening in p+Al compared to p+p collisions. The data also suggest that the away-side pout broadening is a function of Ncoll, the number of binary nucleon-nucleon collisions, in the interaction. The potential implications of these results with regard to initial- and final-state transverse-momentum broadening and energy loss of partons in a nucleus, among other nuclear effects, are discussed

Measurements of μμ pairs from open heavy flavor and Drell-Yan in p+p collisions at s =200 GeV

PHENIX reports differential cross sections of μμ pairs from semileptonic heavy-flavor decays and the Drell-Yan production mechanism measured in p+p collisions at s=200 GeV at forward and backward rapidity (1.2<|η|<2.2). The μμ pairs from cc, bb, and Drell-Yan are separated using a template fit to unlike- and like-sign muon pair spectra in mass and pT. The azimuthal opening angle correlation between the muons from cc and bb decays and the pair-pT distributions are compared to distributions generated using pythia and powheg models, which both include next-to-leading order processes. The measured distributions for pairs from cc are consistent with pythia calculations. The cc data present narrower azimuthal correlations and softer pT distributions compared to distributions generated from powheg. The bb data are well described by both models. The extrapolated total cross section for bottom production is 3.75±0.24(stat)±0.500.35(syst)±0.45(global) [μb], which is consistent with previous measurements at the Relativistic Heavy Ion Collider in the same system at the same collision energy and is approximately a factor of 2 higher than the central value calculated with theoretical models. The measured Drell-Yan cross section is in good agreement with next-to-leading-order quantum-chromodynamics calculations

Measurement of charm and bottom production from semileptonic hadron decays in p+p collisions at s =200 GeV

Measurements of the differential production of electrons from open-heavy-flavor hadrons with charm- and bottom-quark content in p+p collisions at s=200 GeV are presented. The measurements proceed through displaced-vertex analyses of electron tracks from the semileptonic decay of charm and bottom hadrons using the PHENIX silicon-vertex detector. The relative contribution of electrons from bottom decays to inclusive heavy-flavor-electron production is found to be consistent with fixed-order-plus-next-to-leading-log perturbative-QCD calculations within experimental and theoretical uncertainties. These new measurements in p+p collisions provide a precision baseline for comparable forthcoming measurements in A+A collisions

Hyperexcitability of the local cortical circuit in mouse models of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a neurogenetic disorder associated with epilepsy, intellectual disabilities, and autistic behaviors. These neurological symptoms result from synaptic dysregulations, which shift a balance between excitation and inhibition. To decipher the synaptic substrate of hyperexcitability, we examined pan-neuronal Tsc1 knockout mouse and found a reduction in surface expression of a GABA receptor (GABAR) subunit but not AMPA receptor (AMPAR) subunit. Using electrophysiological recordings, we found a significant reduction in the frequency of GABAR-mediated miniature inhibitory postsynaptic currents (GABAR-mIPSCs) but not AMPAR-mediated miniature excitatory postsynaptic currents (AMPAR-mEPSCs) in layer 2/3 pyramidal neurons. To determine a subpopulation of interneurons that are especially vulnerable to the absence of TSC1 function, we also analyzed two strains of conditional knockout mice targeting two of the prominent interneuron subtypes that express parvalbumin (PV) or somatostatin (SST). Unlike pan-neuronal knockout mice, both interneuron-specific Tsc-1 knockout mice did not develop spontaneous seizures and grew into adults. Further, the properties of AMPAR-mEPSCs and GABAR-mIPSCs were normal in both Pv-Cre and Sst-Cre x Tsc1fl/fl knockout mice. These results indicate that removal of TSC1 from all neurons in a local cortical circuit results in hyperexcitability while connections between pyramidal neurons and interneurons expressing PV and SST are preserved in the layer 2/3 visual cortex. Our study suggests that another inhibitory cell type or a combination of multiple subtypes may be accountable for hyperexcitability in TSC. Keywords: Tuberous sclerosis complex; E/I balance; AMPA receptor; GABA receptor; Autism; Epilepsy; mTOR pathwa

Potential use of COX-2–aromatase inhibitor combinations in breast cancer

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer