Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice

BACKGROUND & AIMS: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis. METHODS: We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS: After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor kappaB, degradation of inhibitor of kappaB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor kappaB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection. CONCLUSIONS: In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage

Limits on Anomalous WWgamma and WWZ Couplings

Limits on the anomalous WWgamma and WWZ couplings are presented from a simultaneous fit to the data samples of three gauge boson pair final states in pbar-p collisions at sqrt(s)=1.8 TeV: Wgamma production with the W boson decaying to enu or munu, W boson pair production with both of the W bosons decaying to enu or munu, and WW or WZ production with one W boson decaying to enu and the other W boson or the Z boson decaying to two jets. Assuming identical WWgamma and WWZ couplings, 95 % C.L. limits on the anomalous couplings of -0.30<Delta kappa<0.43 (lambda = 0) and -0.20<lambda<0.20 (Delta kappa = 0) are obtained using a form factor scale Lambda = 2.0 TeV. Limits found under other assumptions on the relationship between the WWgamma and WWZ couplings are also presented.Comment: 13 pages, 3 figures, submitted to Physical Review

Search for Top Squark Pair Production in the Dielectron Channel

This report describes the first search for top squark pair production in the channel stop_1 stopbar_1 -> b bbar chargino_1 chargino_1 -> ee+jets+MEt using 74.9 +- 8.9 pb^-1 of data collected using the D0 detector. A 95% confidence level upper limit on sigma*B is presented. The limit is above the theoretical expectation for sigma*B for this process, but does show the sensitivity of the current D0 data set to a particular topology for new physics.Comment: Five pages, including three figures, submitted to PRD Brief Report

Direct Measurement of the Top Quark Mass at D0

We determine the top quark mass m_t using t-tbar pairs produced in the D0 detector by \sqrt{s} = 1.8 TeV p-pbar collisions in a 125 pb^-1 exposure at the Fermilab Tevatron. We make a two constraint fit to m_t in t-tbar -> b W^+bbar W^- final states with one W boson decaying to q-qbar and the other to e-nu or mu-nu. Likelihood fits to the data yield m_t(l+jets) = 173.3 +- 5.6 (stat) +- 5.5 (syst) GeV/c^2. When this result is combined with an analysis of events in which both W bosons decay into leptons, we obtain m_t = 172.1 +- 5.2 (stat) +- 4.9 (syst) GeV/c^2. An alternate analysis, using three constraint fits to fixed top quark masses, gives m_t(l+jets) = 176.0 +- 7.9 (stat) +- 4.8 (syst) GeV/C^2, consistent with the above result. Studies of kinematic distributions of the top quark candidates are also presented.Comment: 43 pages, 53 figures, 33 tables. RevTeX. Submitted to Phys. Rev.

Spin Correlation in tt-bar Production from pp-bar Collisions at sqrt(s)=1.8 TeV

The D0 collaboration has performed a study of spin correlation in tt-bar production for the process tt-bar to bb-bar W^+W^-, where the W bosons decay to e-nu or mu-nu. A sample of six events was collected during an exposure of the D0 detector to an integrated luminosity of approximately 125 pb^-1 of sqrt{s}=1.8 TeV pp-bar collisions. The standard model (SM) predicts that the short lifetime of the top quark ensures the transmission of any spin information at production to the tt-bar decay products. The degree of spin correlation is characterized by a correlation coefficient k. We find that k>-0.25 at the 68% confidence level, in agreement with the SM prediction of k=0.88.Comment: Submitted to PRL, Added references, minor changes to tex

Measurement of the Top Quark Mass Using Dilepton Events

The D0 collaboration has performed a measurement of the top quark mass based on six candidate events for the process t tbar -> b W+ bbar W-, where the W bosons decay to e nu or mu nu. This sample was collected during an exposure of the D0 detector to an integrated luminosity of 125 pb^-1 of sqrt(s)=1.8 TeV p-pbar collisions. We obtain mt = 168.4 +- 12.3 (stat) +- 3.7 (sys) GeV/c^2, consistent with the measurement obtained using single-lepton events. Combination of the single-lepton and dilepton results yields mt = 172.0 +- 7.5 GeV/c^2.Comment: 12 pages, 3 figure

Search for First Generation Scalar Leptoquark Pairs in ppbar Collisions at sqrt(s)=1.8 TeV

We have searched for first generation scalar leptoquark (LQ) pairs in the enu+jets channel using ppbar collider data (integrated luminosity= 115 pb^-1) collected by the DZero experiment at the Fermilab Tevatron during 1992-96. The analysis yields no candidate events. We combine the results with those from the ee+jets and nunu+jets channels to obtain 95% confidence level (CL) upper limits on the LQ pair production cross section as a function of mass and of beta, the branching fraction to a charged lepton. Comparing with the next-to-leading order theory, we set 95% CL lower limits on the LQ mass of 225, 204, and 79 GeV/c^2 for beta=1, 1/2, and 0, respectively.Comment: 14 pages, 4 figures, submitted to Physical Review Letters Replaced to correct visitor addresse

Search for Charge 1/3 Third Generation Leptoquarks in pbarp Collisions at sqrt(s)=1.8 TeV

We report on a search for charge 1/3 third generation leptoquarks (LQ) produced in pbarp collisions at sqrt(s) = 1.8 TeV using the D0 detector at Fermilab. Third generation leptoquarks are assumed to be produced in pairs and to decay to a tau neutrino and a b quark with branching fraction B. We place upper limits on sigma(pbarp to LQbarLQ)xB^2 as a function of the leptoquark mass M_LQ. Assuming B =1, we exclude at the 95% confidence level third generation scalar leptoquarks with M_LQ<94 GeV/c^2, and third generation vector leptoquarks with M_LQ<216 GeV/c^2 (M_LQ<148 GeV/c^2) assuming Yang-Mills (anomalous) coupling.Comment: 6 pages, 3 figure

Measurement of Dijet Angular Distributions and Search for Quark Compositeness

We have measured the dijet angular distribution in $\sqrt{s}$=1.8 TeV $p\bar{p}$ collisions using the D0 detector. Order $\alpha^{3}_{s}$ QCD predictions are in good agreement with the data. At 95% confidence the data exclude models of quark compositeness in which the contact interaction scale is below 2 TeV.Comment: 11 pages, Latex, 3 postscript figure

Search for a Fourth Generation Charge -1/3 Quark via Flavor Changing Neutral Current Decay

We report on a search for pair production of a fourth generation charge -1/3 quark (b') in pbar p collisions at sqrt(s) = 1.8 TeV at the Fermilab Tevatron using an integrated luminosity of 93 pb^-1. Both quarks are assumed to decay via flavor changing neutral currents (FCNC). The search uses the signatures gamma + 3 jets + mu-tag and 2 gamma + 2 jets. We see no significant excess of events over the expected background. We place an upper limit on the production cross section times branching fraction that is well below theoretical expectations for a b' quark decaying exclusively via FCNC for b' quark masses up to m(Z) + m(b).Comment: Eleven pages, two postscript figures, submitted to Physical Review Letter