Sphingosine 1-phosphate receptor 4 promotes nonalcoholic steatohepatitis by activating NLRP3 inflammasome

BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n-octylphenyl)ethyl]-1,3-propanediol hydrochloride)-like sphingolipid-focused library. RESULTS: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4(++/-) mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domaincontainning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4(+/-) mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages

The Potential Economic Value of a Trypanosoma cruzi (Chagas Disease) Vaccine in Latin America

The substantial burden of Chagas disease, especially in Latin America, and the limitations of currently available treatment and control strategies have motivated the development of a Trypanosoma cruzi (T. cruzi) vaccine. Evaluating a vaccine's potential economic value early in its development can answer important questions while the vaccine's key characteristics (e.g., vaccine efficacy targets, price points, and target population) can still be altered. This can assist vaccine scientists, manufacturers, policy makers, and other decision makers in the development and implementation of the vaccine. We developed a computational economic model to determine the cost-effectiveness of introducing a T. cruzi vaccine in Latin America. Our results showed vaccination to be very cost-effective, in many cases providing both cost savings and health benefits, even at low infection risk and vaccine efficacy. Moreover, our study suggests that a vaccine may actually “pay for itself”, as even a relatively higher priced vaccine will generate net cost savings for a purchaser (e.g., a country's ministry of health). These findings support continued investments in and efforts toward the development of a human T. cruzi vaccine

Observation of Bs-Bsbar Oscillations

We report the observation of Bs-Bsbar oscillations from a time-dependent measurement of the Bs-Bsbar oscillation frequency Delta ms. Using a data sample of 1 fb^-1 of p-pbar collisions at sqrt{s}=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron, we find signals of 5600 fully reconstructed hadronic Bs decays, 3100 partially reconstructed hadronic Bs decays, and 61500 partially reconstructed semileptonic Bs decays. We measure the probability as a function of proper decay time that the Bs decays with the same, or opposite, flavor as the flavor at production, and we find a signal for Bs-Bsbar oscillations. The probability that random fluctuations could produce a comparable signal is 8 X 10^-8, which exceeds 5 sigma significance. We measure Delta ms = 17.77 +- 0.10 (stat) +- 0.07 (syst) ps^-1 and extract |Vtd/Vts| = 0.2060 +- 0.0007 (exp) + 0.0081 - 0.0060 (theor).Comment: 9 pages, 5 figures, submitted to Physical Review Letter

Epidemiology of severe pediatric adenovirus lower respiratory tract infections in Manitoba, Canada, 1991-2005

<p>Abstract</p> <p>Background</p> <p>Most pediatric adenovirus respiratory infections are mild and indistinguishable from other viral causes. However, in a few children, the disease can be severe and result in substantial morbidity. We describe the epidemiologic, clinical, radiologic features and outcome of adenovirus lower respiratory tract infections (LRTI) in Aboriginal and Non-Aboriginal children in Manitoba, Canada during the years 1991 and 2005.</p> <p>Methods</p> <p>This was a retrospective study of 193 children who presented to the department of pediatrics at Winnipeg Children's Hospital, Manitoba, Canada with LRTI and had a positive respiratory culture for adenovirus. Patients' demographics, clinical and radiologic features and outcomes were collected. Adenovirus serotype distributions and temporal associations were described. Approximate incidence comparisons (detection rates) of adenovirus LRTI among Aboriginal and Non-Aboriginal children were estimated with 95% confidence intervals.</p> <p>Results</p> <p>Adenovirus infections occurred throughout the year with clusters in the fall and winter. Serotypes 1 to 3 were the predominant isolates (two thirds of the cases). The infection was more frequent among Canadian Aboriginals, as illustrated in 2004, where its incidence in children 0-4 years old was 5.6 fold higher in Aboriginals (13.51 vs. 2.39 per 10,000, <it>p </it>< 0.000). There were no significant differences in length of hospitalization and use of ventilator assistance between the two groups (<it>p </it>> 0.185 and <it>p </it>> 0.624, respectively) nor across serotypes (<it>p </it>> 0.10 and <it>p </it>> 0.05, respectively). The disease primarily affected infants (median age, 9.5 months). Most children presented with bronchiolitis or pneumonia, with multi-lobar consolidations on the chest x-ray. Chronic (residual) changes were documented in 16 patients, with eight patients showing bronchiectasis on the chest computerized tomography scan.</p> <p>Conclusions</p> <p>Adenovirus infection is associated with significant respiratory morbidities, especially in young infants. The infection appears to be more frequent in Aboriginal children. These results justify a careful follow-up for children with adenovirus LRTI.</p

Measurement of the Dipion Mass Spectrum in X(3872) -> J/Psi Pi+ Pi- Decays

We measure the dipion mass spectrum in X(3872)--> J/Psi Pi+ Pi- decays using 360 pb-1 of pbar-p collisions at 1.96 TeV collected with the CDF II detector. The spectrum is fit with predictions for odd C-parity (3S1, 1P1, and 3DJ) charmonia decaying to J/Psi Pi+ Pi-, as well as even C-parity states in which the pions are from Rho0 decay. The latter case also encompasses exotic interpretations, such as a D0-D*0Bar molecule. Only the 3S1 and J/Psi Rho hypotheses are compatible with our data. Since 3S1 is untenable on other grounds, decay via J/Psi Rho is favored, which implies C=+1 for the X(3872). Models for different J/Psi-Rho angular momenta L are considered. Flexibility in the models, especially the introduction of Rho-Omega interference, enable good descriptions of our data for both L=0 and 1.Comment: 7 pages, 4 figures -- Submitted to Phys. Rev. Let

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

Search for Higgs Boson Decaying to b-bbar and Produced in Association with W Bosons in p-pbar Collisions at sqrt{s}=1.96 TeV

We present a search for Higgs bosons decaying into b-bbar and produced in association with W bosons in p-pbar collisions at sqrt{s}=1.96 TeV. This search uses 320 pb-1 of the dataset accumulated by the upgraded Collider Detector at Fermilab. Events are selected that have a high-transverse momentum electron or muon, missing transverse energy, and two jets, one of which is consistent with a hadronization of a b quark. Both the number of events and the dijet mass distribution are consistent with standard model background expectations, and we set 95% confidence level upper limits on the production cross section times branching ratio for the Higgs boson or any new particle with similar decay kinematics. These upper limits range from 10 pb for mH=110 GeV/c2 to 3 pb for mH=150 GeV/c2.Comment: 7 pages, 3 figures; updated title to published versio

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

Search for Second-Generation Scalar Leptoquarks in ppˉ\bm{p \bar{p}} Collisions at s\sqrt{s}=1.96 TeV

Results on a search for pair production of second generation scalar leptoquark in $p \bar{p}$ collisions at $\sqrt{s}$=1.96 TeV are reported. The data analyzed were collected by the CDF detector during the 2002-2003 Tevatron Run II and correspond to an integrated luminosity of 198 pb$^{-1}$. Leptoquarks (LQ) are sought through their decay into (charged) leptons and quarks, with final state signatures represented by two muons and jets and one muon, large transverse missing energy and jets. We observe no evidence for $LQ$ production and derive 95% C.L. upper limits on the $LQ$ production cross sections as well as lower limits on their mass as a function of $\beta$, where $\beta$ is the branching fraction for $LQ \to \mu q$.Comment: 9 pages (3 author list) 5 figure

Search for anomalous semileptonic decay of heavy flavor hadrons produced in association with a W boson at CDF II

We present a search for anomalous semileptonic decays of heavy flavor hadrons produced in association with a $W$ boson, in proton-antiproton collisions at sqrt{s}=1.96 TeV. We use 162 pb-1 of data collected with the CDF II detector at the Fermilab Tevatron Collider. We select events with one W boson and at least one jet with an identified secondary vertex. In the jets with a secondary vertex we look for a semileptonic decay to a muon. We compare the number of jets with both a secondary vertex and a semileptonic decay, and the kinematic properties of these jets, with the standard model expectation of W plus heavy flavor production and decay. No discrepancy is seen between the observation and the expectation, and we set limits on the production cross section of a B-like hadron with an anomalously high semileptonic branching ratio.Comment: 8 pages, 2 figures, submitted to PRD-RC; replaced to adjust the page forma