The study of progesterone action in human myometrial explants

Study hypothesis: Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. Study finding: Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset. What is known already: Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. Study design, samples/materials, methods: Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. Main results and the role of chance: Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 μM P4 led to a reduction in interleukin-1 (IL-1) β-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. Limitations/reasons for caution: There is evidence of basal inflammation in the myometrial explant model. Wider implications of the findings: Myometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour. Large scale data: Data deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830

Circulating Citrate Is Associated with Liver Fibrosis in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is associated with mitochondrial damage. Circulating mitochondrial metabolites may be elevated in NAFLD but their associations with liver damage is not known. This study aimed to assess the association of key mitochondrial metabolites with the degree of liver fibrosis in the context of NAFLD and nonalcoholic steatohepatitis (NASH). Cross-sectional analyses were performed on two cohorts of biopsy-proven NAFLD and/or NASH subjects. The association of circulating mitochondrial metabolite concentrations with liver fibrosis was assessed using linear regression analysis. In the single-center cohort of NAFLD subjects (n = 187), the mean age was 54.9 ±13.0 years, 40.1% were female and 86.1% were White. Type 2 diabetes (51.3%), hypertension (43.9%) and obesity (72.2%) were prevalent. Those with high citrate had a higher proportion of moderate/significant liver fibrosis (stage F ≥ 2) (68.4 vs. 39.6%, p = 0.001) and advanced fibrosis (stage F ≥ 3) (31.6 vs. 13.6%, p = 0.01). Citrate was associated with liver fibrosis independent of age, sex, NAFLD activity score and metabolic syndrome (per 1 SD increase: β = 0.19, 95% CI: 0.03–0.35, p = 0.02). This association was also observed in a cohort of NASH subjects (n = 176) (β = 0.21, 95% CI: 0.07–0.36, p = 0.005). The association of citrate with liver fibrosis was observed in males (p = 0.005) but not females (p = 0.41). In conclusion, circulating citrate is elevated and associated with liver fibrosis, particularly in male subjects with NAFLD and NASH. Mitochondrial function may be a target to consider for reducing the progression of liver fibrosis and NASH.</p

Alternative Signature of TeV Strings

In string theory, it is well known that any hard scattering amplitude inevitably suffers exponential suppression. We demonstrate that, if the string scale is M_s < 2TeV, this intrinsically stringy behavior leads to a dramatic reduction in the QCD jet production rate with very high transverse momenta p_T > 2TeV at LHC. This suppression is sufficient to be observed in the first year of low-luminosity running. Our prediction is based on the universal behavior of string theory, and therefore is qualitatively model-independent. This signature is alternative and complementary to conventional ones such as Regge resonance (or string ball/black hole) production.Comment: a note added; version to appear in Phys. Rev. D; 11 pages, 1 eps figure, LaTeX2e; BibTeX with utphys style use

Energy loss in high energy heavy ion collisions from the Hydro+Jet model

We investigate the effect of energy loss of jets in high energy heavy ion collisions by using a full three-dimensional space-time evolution of a fluid combined with (mini-)jets that are explicitly evolved in space-time. In order to fit the pi^0 data for the Au+Au collisions at sqrt(s_{NN}) = 130 GeV, the space-time averaged energy loss dE/dx(tau <= 3 fm/c) = 0.36 GeV/fm is extracted within the model. It is found that most energy loss occurs at the very early time less than 2 fm/c in the QGP phase and that energy loss in the mixed phase is negligible within our parameterization for jet energy loss. This is a consequence of strong expansion of the system.Comment: 4 pages, 5 figures; one figure adde

Leading order analysis of neutrino induced dimuon events in the CHORUS experiment

We present a leading order QCD analysis of a sample of neutrino induced charged-current events with two muons in the final state originating in the lead-scintillating fibre calorimeter of the CHORUS detector. The results are based on a sample of 8910 neutrino and 430 antineutrino induced opposite-sign dimuon events collected during the exposure of the detector to the CERN Wide Band Neutrino Beam between 1995 and 1998. % with $E_{\mu 1},E_{\mu 2} > 5$ GeV and $Q^2 > 3$ GeV$^2$ collected %between 1995 and 1998. The analysis yields a value of the charm quark mass of \mc = (1.26\pm 0.16 \pm 0.09) \GeVcc and a value of the ratio of the strange to non-strange sea in the nucleon of $\kappa = 0.33 \pm 0.05 \pm 0.05$, improving the results obtained in similar analyses by previous experiments.Comment: Submitted to Nuclear Physics

Partial Wave Analysis of J/ψ→γ(K+K−π+π−)J/\psi \to \gamma (K^+K^-\pi^+\pi^-)

BES data on $J/\psi \to \gamma (K^+K^-\pi^+\pi^-)$ are presented. The $K^*\bar K^*$ contribution peaks strongly near threshold. It is fitted with a broad $0^{-+}$ resonance with mass $M = 1800 \pm 100$ MeV, width $\Gamma = 500 \pm 200$ MeV. A broad $2^{++}$ resonance peaking at 2020 MeV is also required with width $\sim 500$ MeV. There is further evidence for a $2^{-+}$ component peaking at 2.55 GeV. The non-$K^*\bar K^*$ contribution is close to phase space; it peaks at 2.6 GeV and is very different from $K^{*}\bar{K^{*}}$.Comment: 15 pages, 6 figures, 1 table, Submitted to PL

Photoproduction of D∗±D^{*\pm} mesons associated with a leading neutron

The photoproduction of $D^{*\pm} (2010)$ mesons associated with a leading neutron has been observed with the ZEUS detector in $ep$ collisions at HERA using an integrated luminosity of 80 pb$^{-1}$. The neutron carries a large fraction, {$x_L>0.2$}, of the incoming proton beam energy and is detected at very small production angles, {$\theta_n<0.8$ mrad}, an indication of peripheral scattering. The $D^*$ meson is centrally produced with pseudorapidity {$|\eta| 1.9$ GeV}, which is large compared to the average transverse momentum of the neutron of 0.22 GeV. The ratio of neutron-tagged to inclusive $D^*$ production is $8.85\pm 0.93({\rm stat.})^{+0.48}_{-0.61}({\rm syst.})\%$ in the photon-proton center-of-mass energy range {$130 <W<280$ GeV}. The data suggest that the presence of a hard scale enhances the fraction of events with a leading neutron in the final state.Comment: 28 pages, 4 figures, 2 table

Observation of isolated high-E_T photons in deep inelastic scattering

First measurements of cross sections for isolated prompt photon production in deep inelastic ep scattering have been made using the ZEUS detector at the HERA electron-proton collider using an integrated luminosity of 121 pb^-1. A signal for isolated photons in the transverse energy and rapidity ranges 5 < E_T^gamma < 10 GeV and -0.7 < eta^gamma < 0.9 was observed for virtualities of the exchanged photon of Q^2 > 35 GeV^2. Cross sections are presented for inclusive prompt photons and for those accompanied by a single jet in the range E_T^jet \geq 6 GeV and -1.5 \leq eta^jet < 1.8. Calculations at order alpha^3alpha_s describe the data reasonably well.Comment: 16 pages, 5 figure

Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed

Search for contact interactions, large extra dimensions and finite quark radius in ep collisions at HERA

A search for physics beyond the Standard Model has been performed with high-Q^2 neutral current deep inelastic scattering events recorded with the ZEUS detector at HERA. Two data sets, e^+ p \to e^+ X and e^- p \to e^- X, with respective integrated luminosities of 112 pb^-1 and 16 pb^-1, were analyzed. The data reach Q^2 values as high as 40000 GeV^2. No significant deviations from Standard Model predictions were observed. Limits were derived on the effective mass scale in eeqq contact interactions, the ratio of leptoquark mass to the Yukawa coupling for heavy leptoquark models and the mass scale parameter in models with large extra dimensions. The limit on the quark charge radius, in the classical form factor approximation, is 0.85 10^-16 cm.Comment: 28 pages, 4 figures, accepted for publication in Physics Letters