Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

<p>Abstract</p> <p>Background-</p> <p>Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission.</p> <p>Results-</p> <p>In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice.</p> <p>Conclusions-</p> <p>Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.</p

Endogenous Morphine Levels Are Increased in Sepsis: A Partial Implication of Neutrophils

BACKGROUND: Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis. METHODOLOGY: The presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. mu opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested. PRINCIPAL FINDINGS: We confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca(2+). LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca(2+). LPS treatment increased mu opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine. CONCLUSIONS: Our results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils

X-ray Absorption Near-Edge Structure calculations with pseudopotentials. Application to K-edge in diamond and alpha-quartz

We present a reciprocal-space pseudopotential scheme for calculating X-ray absorption near-edge structure (XANES) spectra. The scheme incorporates a recursive method to compute absorption cross section as a continued fraction. The continued fraction formulation of absorption is advantageous in that it permits the treatment of core-hole interaction through large supercells (hundreds of atoms). The method is compared with recently developed Bethe-Salpeter approach. The method is applied to the carbon K-edge in diamond and to the silicon and oxygen K-edges in alpha-quartz for which polarized XANES spectra were measured. Core-hole effects are investigated by varying the size of the supercell, thus leading to information similar to that obtained from cluster size analysis usually performed within multiple scattering calculations.Comment: 11 pages, 4 figure

Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.publishedVersio

Measurement of CP Asymmetries and Branching Fractions in Charmless Two-Body B-Meson Decays to Pions and Kaons

We present improved measurements of CP-violation parameters in the decays $B^0 \to \pi^+ \pi^-$, $B^0 \to K^+ \pi^-$, and $B^0 \to \pi^0 \pi^0$, and of the branching fractions for $B^0 \to \pi^0 \pi^0$ and $B^0 \to K^0 \pi^0$. The results are obtained with the full data set collected at the $\Upsilon(4S)$ resonance by the BABAR experiment at the PEP-II asymmetric-energy $B$ factory at the SLAC National Accelerator Laboratory, corresponding to $467 \pm 5$ million $B\bar B$ pairs. We find the CP-violation parameter values and branching fractions $S_{\pi^+\pi^-} = -0.68 \pm 0.10 \pm 0.03, C_{\pi^+\pi^-} = -0.25 \pm 0.08 \pm 0.02, A_{K^-\pi^+} = -0.107 \pm 0.016 ^{+0.006}_{-0.004}, C_{\pi^0\pi^0} = -0.43 \pm 0.26 \pm 0.05, Br(B^0 \to \pi^0 \pi^0) = (1.83 \pm 0.21 \pm 0.13) \times 10^{-6}, Br(B^0 \to K^0 \pi^0) = (10.1 \pm 0.6 \pm 0.4) \times 10^{-6},$ where in each case, the first uncertainties are statistical and the second are systematic. We observe CP violation with a significance of 6.7 standard deviations for $B^0 \to\pi^+\pi^-$ and 6.1 standard deviations for $B^0 \to K^+ \pi^-$, including systematic uncertainties. Constraints on the Unitarity Triangle angle $\alpha$ are determined from the isospin relations among the $B \to \pi\pi$ rates and asymmetries. Considering only the solution preferred by the Standard Model, we find $\alpha$ to be in the range $[71^\circ,109^\circ]$ at the 68% confidence level.Comment: 18 pages, 11 postscript figures, submitted to Phys. Rev.

Measurement of Branching Fractions and Rate Asymmetries in the Rare Decays B -> K(*) l+ l-

In a sample of 471 million BB events collected with the BABAR detector at the PEP-II e+e- collider we study the rare decays B -> K(*) l+ l-, where l+ l- is either e+e- or mu+mu-. We report results on partial branching fractions and isospin asymmetries in seven bins of di-lepton mass-squared. We further present CP and lepton-flavor asymmetries for di-lepton masses below and above the J/psi resonance. We find no evidence for CP or lepton-flavor violation. The partial branching fractions and isospin asymmetries are consistent with the Standard Model predictions and with results from other experiments.Comment: 16 pages, 14 figures, accepted by Phys. Rev.

First Observation of CP Violation in B0->D(*)CP h0 Decays by a Combined Time-Dependent Analysis of BaBar and Belle Data

We report a measurement of the time-dependent CP asymmetry of B0->D(*)CP h0 decays, where the light neutral hadron h0 is a pi0, eta or omega meson, and the neutral D meson is reconstructed in the CP eigenstates K+ K-, K0S pi0 or K0S omega. The measurement is performed combining the final data samples collected at the Y(4S) resonance by the BaBar and Belle experiments at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain ( 471 +/- 3 ) x 10^6 BB pairs recorded by the BaBar detector and ( 772 +/- 11 ) x 10^6, BB pairs recorded by the Belle detector. We measure the CP asymmetry parameters -eta_f S = +0.66 +/- 0.10 (stat.) +/- 0.06 (syst.) and C = -0.02 +/- 0.07 (stat.) +/- 0.03 (syst.). These results correspond to the first observation of CP violation in B0->D(*)CP h0 decays. The hypothesis of no mixing-induced CP violation is excluded in these decays at the level of 5.4 standard deviations.Comment: 9 pages, 2 figures, submitted to Physical Review Letter

Cross Sections for the Reactions e+e- --> K+ K- pi+pi-, K+ K- pi0pi0, and K+ K- K+ K- Measured Using Initial-State Radiation Events

We study the processes e+e- --> K+ K- pi+pi-gamma, K+ K- pi0pi0gamma, and K+ K- K+ K-gamma, where the photon is radiated from the initial state. About 84000, 8000, and 4200 fully reconstructed events, respectively, are selected from 454 fb-1 of BaBar data. The invariant mass of the hadronic final state defines the \epem center-of-mass energy, so that the K+ K- pi+pi- data can be compared with direct measurements of the e+e- --> K+ K- pi+pi- reaction. No direct measurements exist for the e+e- --> K+ K-pi0pi0 or e+e- --> K+ K-K+ K- reactions, and we present an update of our previous result with doubled statistics. Studying the structure of these events, we find contributions from a number of intermediate states, and extract their cross sections. In particular, we perform a more detailed study of the e+e- --> phi(1020)pipigamma reaction, and confirm the presence of the Y(2175) resonance in the phi(1020) f0(980) and K+K-f0(980) modes. In the charmonium region, we observe the J/psi in all three final states and in several intermediate states, as well as the psi(2S) in some modes, and measure the corresponding product of branching fraction and electron width.Comment: 35 pages, 42 figure

Measurement of B(B-->X_s {\gamma}), the B-->X_s {\gamma} photon energy spectrum, and the direct CP asymmetry in B-->X_{s+d} {\gamma} decays

The photon spectrum in B --> X_s {\gamma} decay, where X_s is any strange hadronic state, is studied using a data sample of (382.8\pm 4.2) \times 10^6 e^+ e^- --> \Upsilon(4S) --> BBbar events collected by the BABAR experiment at the PEP-II collider. The spectrum is used to measure the branching fraction B(B --> X_s \gamma) = (3.21 \pm 0.15 \pm 0.29 \pm 0.08)\times 10^{-4} and the first, second, and third moments = 2.267 \pm 0.019 \pm 0.032 \pm 0.003 GeV,, )^2> = 0.0484 \pm 0.0053 \pm 0.0077 \pm 0.0005 GeV^2, and )^3> = -0.0048 \pm 0.0011 \pm 0.0011 \pm 0.0004 GeV^3, for the range E_\gamma > 1.8 GeV, where E_{\gamma} is the photon energy in the B-meson rest frame. Results are also presented for narrower E_{\gamma} ranges. In addition, the direct CP asymmetry A_{CP}(B --> X_{s+d} \gamma) is measured to be 0.057 \pm 0.063. The spectrum itself is also unfolded to the B-meson rest frame; that is the frame in which theoretical predictions for its shape are made.Comment: 37 pages, 19 postscript figures, submitted to Phys. Rev. D. No analysis or results have changed from previous version. Some changes to improve clarity based on interactions with Phys. Rev. D referees, including one new Figure (Fig. 13), and some minor wording/punctuation/spelling mistakes fixe

Study of Upsilon(3S,2S) -> eta Upsilon(1S) and Upsilon(3S,2S) -> pi+pi- Upsilon(1S) hadronic trasitions

We study the Upsilon(3S,2S)->eta Upsilon(1S) and Upsilon(3S,2S)->pi+pi- Upsilon(1S) transitions with 122 million Upsilon(3S) and 100 million Upsilon(2S) mesons collected by the BaBar detector at the PEP-II asymmetric energy e+e- collider. We measure B[Upsilon(2S)->eta Upsilon(1S)]=(2.39+/-0.31(stat.)+/-0.14(syst.))10^-4 and Gamma[Upsilon(2S)->eta Upsilon(1S)]/Gamma[Upsilon(2S)-> pi+pi- Upsilon(1S)]=(1.35+/-0.17(stat.)+/-0.08(syst.))10^-3. We find no evidence for Upsilon(3S)->eta Upsilon(1S) and obtain B[Upsilon(3S)->eta Upsilon(1S)]<1.0 10^-4 and Gamma[Upsilon(3S)->eta Upsilon(1S)]/Gamma[Upsilon(3S)->pi+pi- Upsilon(1S)]<2.3 10^-3 as upper limits at the 90% confidence level. We also provide improved measurements of the Upsilon(2S) - Upsilon(1S) and Upsilon(3S) - Upsilon(1S) mass differences, 562.170+/-0.007(stat.)+/-0.088(syst.) MeV/c^2 and 893.813+/-0.015(stat.)+/-0.107(syst.) MeV/c^2 respectively.Comment: 8 pages, 16 encapsulated postscript figures, submitted to Phys.Rev.