An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity

Caspases are key mediators in liver inflammation and apoptosis. In the present study we provide evidence that a nitric oxide (NO) derivative of ursodeoxycholic acid (UDCA), NCX-1000 ([2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester]), protects against liver damage in murine models of autoimmune hepatitis induced by i.v. injection of Con A or a Fas agonistic antibody, Jo2. Con A administration causes CD4+ T lymphocytes to accumulate in the liver and up-regulates FasL expression, resulting in FasL-mediated cytotoxicity. Cotreating mice with NCX-1000, but not with UDCA, protected against liver damage induced by Con A and Jo2, inhibited IL-1β, IL-18, and IFN-γ release and caspase 3, 8, and 9 activation. Studies on HepG2 cells demonstrated that NCX-1000, but not UDCA, directly prevented multiple caspase activation induced by Jo2. Incubating HepG2 cells with NCX-1000 resulted in intracellular NO formation and a DTT-reversible inhibition of proapoptotic caspases, suggesting that cysteine S-nitrosylation was the main mechanism responsible for caspase inhibition. Collectively, these data suggest that NCX-1000 protects against T helper 1-mediated liver injury by inhibiting both the proapoptotic and the proinflammatory branches of the caspase superfamily.

NCX-1000, a NO-releasing derivative of ursodeoxycholic acid, selectively delivers NO to the liver and protects against development of portal hypertension

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.

Cellular mechanisms for the formation of a soluble form derivative of T-cell receptor alpha chain by suppressor T cells.

Upon stimulation with anti-CD3, suppressor T-cell (Ts) hybridomas and homologous transfectants of T-cell receptor a (TCRalpha) cDNA in the T-cell hybridoma formed a 55-kDa TCRalpha chain derivative that bound both the monoclonal anti-TCRalpha chain and polyclonal antibodies against glycosylation inhibiting factor (GIF). The peptide is a subunit of antigen-specific suppressor T-cell factor (TsF), and is considered to be a posttranslationally-formed conjugate of TCRalpha chain with GIF peptide. The TCRalpha derivative is synthesized by the transfectant after stimulation with anti-CD3, and not derived from TCR present on the cell surface. Stimulation of the stable homologous transfectants with anti-CD3 induced translocation of the 13-kDa GIF peptide into endoplasmic reticulum (ER). When a helper Ts hybridoma or a stable transfectant of the same TCRalpha cDNA in a helper cell-derived TCRalpha- clone was stimulated with anti-CD3, translocation of GIF peptide was not detected, and these cells failed to secrete a TCRalpha derivative. However, further transfection of a chimeric cDNA encoding a procalcitonin-GIF fusion protein into the helper cell-derived stable transfectant of TCRalpha cDNA resulted in translocation of the GIF protein and formation of bioactive 55-kDa GIF. The results indicated that translocation of GIF peptide through ER is unique for Ts cells, and that this process is essential for the formation/secretion of the soluble form derivative of TCRalpha chain by T cells.

On the origin of the order Artiodactyla.

The first known members of the order Artiodactyla appeared suddenly throughout the Holarctic region at the beginning of the Eocene. They are characterized by distinctive cursorial skeletal specializations. Owing to their abrupt appearance and the lack of transitional forms, the origin of the order is problematic. Descent from a "condylarth," specifically the arctocyonid Chriacus, has been suggested based on dental resemblances, but until now postcranial anatomy seemed to preclude close relationship between Arctocyonidae and Artiodactyla. A middle Paleocene specimen of a small arctocyonid (?Chriacus) reported here is much more similar to the oldest artiodactyl, Diacodexis, in the derived condition of the hindlimb, reviving the possibility that Artiodactyla evolved from an arctocyonid.

Stars and brown dwarfs in the σ Orionis cluster (Research Note) III. OSIRIS/GTC low-resolution spectroscopy of variable sources

Context. Although many studies have been performed so far, there are still dozens of low-mass stars and brown dwarfs in the young σ Orionis open cluster without detailed spectroscopic characterisation. Aims. We look for unknown strong accretors and disc hosts that were undetected in previous surveys. Methods. We collected low-resolution spectroscopy (R ~ 700) of ten low-mass stars and brown dwarfs in σ Orionis with OSIRIS at the Gran Telescopio Canarias under very poor weather conditions. These objects display variability in the optical, infrared, Hα, and/or X-rays on time scales of hours to years. We complemented our spectra with optical and near-/mid-infrared photometry. Results. For seven targets, we detected lithium in absorption, identified Hα, the calcium doublet, and forbidden lines in emission, and/or determined spectral types for the first time. We characterise in detail a faint, T Tauri-like brown dwarf with an 18 h-period variability in the optical and a large Hα equivalent width of –125  ±  15 Å, as well as two M1-type, X-ray-flaring, low-mass stars, one with a warm disc and forbidden emission lines, the other with a previously unknown cold disc with a large inner hole. Conclusions. New unrevealed strong accretors and disc hosts, even below the substellar limit, await discovery among the list of known σ Orionis stars and brown dwarfs that are variable in the optical and have no detailed spectroscopic characterisation yet.

An Analysis of U.S. Air Force Policy and Installation CO2 Emissions to Determine Best Practices for the Implementation of Executive Order 13514

United States Air Force (USAF) energy policy is a measured but aggressive response to federal energy policy guidance. Previous USAF efforts, like those of the federal government, focused primarily on energy intensity reduction, cost, and BTU savings, and in certain cases have resulted in facility greenhouse gas (GHG) emission reductions. The USAF now faces the challenge of integrating GHG reduction goals and inventory requirements set forth in Executive Order 13514. Using USAF reported energy consumption data, facility GHG emission estimates have been synthesized to identify trends and elucidate existing energy best practices to be applied as part of overarching USAF GHG mitigation efforts and to highlight areas of possible concern for the integration of EO 13514 into operational USAF policy.

A compact difference scheme for numerical solutions of second order dual-phase-lagging models of microscale heat transfer

Dual-phase-lagging (DPL) models constitute a family of non-Fourier models of heat conduction that allow for the presence of time lags in the heat flux and the temperature gradient. These lags may need to be considered when modeling microscale heat transfer, and thus DPL models have found application in the last years in a wide range of theoretical and technical heat transfer problems. Consequently, analytical solutions and methods for computing numerical approximations have been proposed for particular DPL models in different settings. In this work, a compact difference scheme for second order DPL models is developed, providing higher order precision than a previously proposed method. The scheme is shown to be unconditionally stable and convergent, and its accuracy is illustrated with numerical examples.

Cardipeltis; an early Devonian agnathan of the order Heterostraci / Robert H. Denison.

v.16:no.4(1966)

Die Gestaltung der Globalität. Schlüsselwörter der sozialen Ordnung (II) = The design of the global order: the keywords of social order. ZEI Discussion Paper C215, 2013

No abstract.

Die proto-konstitutionelle Etablierung der europäischen Innenpolitik, Rückblick und Ausblick auf Bedingungen föderaler Ordnung in Europa = The proto-constitutional establishment of European domestic policy. Review and outlook on conditions of federal order in Europe. ZEI Discussion Paper C225, 2014

ZEI Director Prof. Ludger Kühnhardt recalls the leading ideas of federalism as territorial equivalent for political pluralism. Celebrating the 80th anniversary of Bonn historian and political scientist Prof. Dr. Hans-Peter Schwarz, he reflects on the emerging EU domestic policies in ZEI Discussion Paper C 225.

System Costs of Variable Renewable Energy in the European Union. Bruges European Economic Policy (BEEP) Briefings 37/2015

To shift to a low-carbon economy, the EU has been encouraging the deployment of variable renewable energy sources (VRE). However, VRE lack of competitiveness and their technical specificities have substantially raised the cost of the transition. Economic evaluations show that VRE life-cycle costs of electricity generation are still today higher than those of conventional thermal power plants. Member States have consequently adopted dedicated policies to support them. In addition, Ueckerdt et al. (2013) show that when integrated to the power system, VRE induce supplementary not-accounted-for costs. This paper first exposes the rationale of EU renewables goals, the EU targets and current deployment. It then explains why the LCOE metric is not appropriate to compute VRE costs by describing integration costs, their magnitude and their implications. Finally, it analyses the consequences for the power system and policy options. The paper shows that the EU has greatly underestimated VRE direct and indirect costs and that policymakers have failed to take into account the burden caused by renewable energy and the return of State support policies. Indeed, induced market distortions have been shattering the whole power system and have undermined competition in the Internal Energy Market. EU policymakers can nonetheless take full account of this negative trend and reverse it by relying on competition rules, setting-up a framework to collect robust EU-wide data, redesigning the architecture of the electricity system and relying on EU regulators.

Investigation of the flow over simple bodies at Mach numbers of the order of 20 /

"It is shown that adequate means are available for calculating inviscid direct and induced pressures on simple axisymmetric bodies at zero angle of attack. The extent to which viscous effects can alter these predictions is indicated. It is also shown that inviscid induced pressures can significantly affect the stability of blunt, two-dimensional flat wings at low angles of attack. However, at high angles of attack, the inviscid induced pressure effects are negligible."