Novel insights into pancreatic β-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in INS-1E insulinoma cells.

Work in our lab is supported by the Medical Research Council [New Investigator Research Grant G1100165 to CA] and Plymouth University [PhD studentship to JB] The final version of record is available at http://www.biochemj.org/bj/456/bj4560417.htmHigh circulating glucose and non-esterified (free) fatty acid levels can cause pancreatic β-cell failure. The molecular mechanisms of this β-cell glucolipotoxicity are yet to be established conclusively. In the present paper we report on the involvement of mitochondrial dysfunction in fatty-acid-induced β-cell failure. We have used state-of-the-art extracellular flux technology to functionally probe mitochondrial energy metabolism in intact INS-1E insulinoma cells in real-time. We show that 24-h palmitate exposure at high glucose attenuates the glucose-sensitivity of mitochondrial respiration and lowers coupling efficiency of glucose-stimulated oxidative phosphorylation. These mitochondrial defects coincide with an increased level of ROS (reactive oxygen species), impaired GSIS (glucose-stimulated insulin secretion) and decreased cell viability. Palmitate lowers absolute glucose-stimulated respiration coupled to ATP synthesis, but does not affect mitochondrial proton leak. Palmitate is not toxic when administered at low glucose unless fatty acid β-oxidation is inhibited. Palmitoleate, on the other hand, does not affect mitochondrial respiration, ROS levels, GSIS or cell viability. Although palmitoleate protects against the palmitate-induced ROS increase and cell viability loss, it does not protect against respiratory and insulin secretory defects. We conclude that mitochondrial dysfunction contributes to fatty-acid-induced GSIS impairment, and that glucolipotoxic cell viability and GSIS phenotypes are mechanistically distinct

Herschel-PACS Measurements of Nitrogen Enrichment in Nebulae around Wolf-Rayet Stars

For three nebulae that have early-WN Wolf-Rayet exciting stars, NGC 6888, WR 8 and Abell 48, we have obtained Herschel-PACS line scans of the [N III] 57 um and [O III] 88 micron lines, along with the 122 and 205 micron lines of [N II]. From the former two lines we have derived N$^{2+}$/O$^{2+}$ abundance ratios, equal to the overall N/O ratio under a wide range of nebular conditions. We find that all of the nebulae observed possess significant nitrogen enrichment, with derived N/O ratios greater than solar. The two nebulae with massive Wolf-Rayet exciting stars, NGC 6888 and WR8 are found to have N/O ratios that are enhanced by factors of 7 - 10 relative to the solar N/O ratio, consistent with an origin as material ejected just before the onset of the Wolf-Rayet phase. The other nebula, Abell 48, has recently been reclassified as a member of the rare class of three planetary nebulae that have early-WN central stars and are not of Peimbert Type I. We derive a nebular N/O ratio for it that is a factor of 4 enhanced relative to solar and slightly above the range of N/O values that have been measured for the other three members of its [WN] planetary nebula class.Comment: 11 pages, 5 figures, MNRAS accepte

The dust and gas content of the Crab Nebula

We have constructed MOCASSIN photoionization plus dust radiative transfer models for the Crab Nebula core-collapse supernova (CCSN) remnant, using either smooth or clumped mass distributions, in order to determine the chemical composition and masses of the nebular gas and dust. We computed models for several different geometries suggested for the nebular matter distribution but found that the observed gas and dust spectra are relatively insensitive to these geometries, being determined mainly by the spectrum of the pulsar wind nebula which ionizes and heats the nebula. Smooth distribution models are ruled out since they require 16-49 Msun of gas to fit the integrated optical nebular line fluxes, whereas our clumped models re quire 7.0 Msun of gas. A global gas-phase C/O ratio of 1.65 by number is derived, along with a He/H number ratio of 1.85, neither of which can be matched by current CCSN yield predictions. A carbonaceous dust composition is favoured by the observed gas-phase C/O ratio: amorphous carbon clumped model fits to the Crab's Herschel and Spitzer infrared spectral energy distribution imply the presence of 0.18-0.27 Msun of dust, corresponding to a gas to dust mass ratio of 26-39. Mixed dust chemistry models can also be accommodated, comprising 0.11-0.13 Msun of amorphous carbon and 0.39-0.47 Msun of silicates. Power-law grain size distributions with mass distributions that are weighted towards the largest grain radii are derived, favouring their longer-term survival when they eventually interact with the interstellar medium. The total mass of gas plus dust in the Crab Nebula is 7.2 +/- 0.5 Msun, consistent with a progenitor star mass of 9 Msun.Comment: Accepted in Ap

OH+^+ emission from cometary knots in planetary nebulae

We model the molecular emission from cometary knots in planetary nebulae (PNe) using a combination of photoionization and photodissociation region (PDR) codes, for a range of central star properties and gas densities. Without the inclusion of ionizing extreme ultraviolet (EUV) radiation, our models require central star temperatures $T_*$ to be near the upper limit of the range investigated in order to match observed H$_2$ and OH$^+$ surface brightnesses consistent with observations - with the addition of EUV flux, our models reproduce observed OH$^+$ surface brightnesses for $T_* \ge 100 \, {\rm kK}$. For $T_* < 80 \, {\rm kK}$, the predicted OH$^+$ surface brightness is much lower, consistent with the non-detection of this molecule in PNe with such central star temperatures. Our predicted level of H$_2$ emission is somewhat weaker than commonly observed in PNe, which may be resolved by the inclusion of shock heating or fluorescence due to UV photons. Some of our models also predict ArH$^+$ and HeH$^+$ rotational line emission above detection thresholds, despite neither molecule having been detected in PNe, although the inclusion of photodissociation by EUV photons, which is neglected by our models, would be expected to reduce their detectability.Comment: Accepted by MNRAS, 11 pages, 15 figures. Author accepted manuscript. Accepted on 24/04/18. Deposited on 27/04/1

Three-Dimensional Ionisation, Dust RT and Chemical Modelling of Planetary Nebulae

The assumption of spherical symmetry is not justified for the vast majority of PNe. The interpretation of spatially-resolved observations cannot rely solely on the application of 1D codes, which may yield incorrect abundances determinations resulting in misleading conclusions. The 3D photoionisation code MOCASSIN (Monte CAarlo SimulationS of ionised Nebulae) is designed to remedy these shortcomings. The 3D transfer of both primary and secondary radiation is treated self-consistently without the need of approximations. The code was benchmarked and has been applied to the study of several PNe. The current version includes a fully self-consistent radiative transfer treatment for dust grains mixed within the gas, taking into account the microphysics of dust-gas interactions within the geometry-independent Monte Carlo transfer. The new code provides an excellent tool for the self-consistent analysis of dusty ionised regions showing asymmetries and/or density and chemical inhomogeneities. Work is currently in progress to incorporate the processes that dominate the thermal balance of photo-dissociation regions (PDRs), as well as the formation and destruction processes for all the main molecular species.Comment: 3 pages, to appear in Proc. IAU Symp. 234, Planetary Nebulae in Our Galaxy and Beyond (3-7 Apr 2006), eds. M.J. Barlow & R.H. Mendez (Cambridge Univ. Press

3D Photoionisation Modelling of NGC 6302

We present a three-dimensional photoionisation and dust radiative transfer model of NGC 6302, an extreme, high-excitation planetary nebula. We use the 3D photoionisation code Mocassin} to model the emission from the gas and dust. We have produced a good fit to the optical emission-line spectrum, from which we derived a density distribution for the nebula. A fit to the infrared coronal lines places strong constraints on the properties of the unseen ionising source. We find the best fit comes from using a 220,000 K hydrogen-deficient central star model atmosphere, indicating that the central star of this PN may have undergone a late thermal pulse. We have also fitted the overall shape of the ISO spectrum of NGC 6302 using a dust model with a shallow power-law size distribution and grains up to 1.0 micron in size. To obtain a good fit to the infrared SED the dust must be sufficiently recessed within the circumstellar disk to prevent large amounts of hot dust at short wavelengths, a region where the ISO spectrum is particularly lacking. These and other discoveries are helping to unveil many properties of this extreme object and trace it's evolutionary history.Comment: 8 pages, 4 figures; for the proceedings of "Asymmetric Planetary Nebuale IV," R. L. M. Corradi, A. Manchado, N. Soker ed

A study of the drooped leading edge airfoil

Wind tunnel tests were conducted to examine various aspects of the drooped-leading edge airfoil which reduces the tendency for an airplane to enter a spin after stall occurs. Three baseline models were used for tests of two dimensional models: NACA 0015, 0014.6, and 0014.2. The 14.6% and 14.2% models were derived from NACA 0015 sections by increasing the chord and matching the profiles aft section. Force, balance data (lift, drag, pitching moment) were obtained for each model at a free-steam Reynold's number of 2.66 x 10 to the 6th power/m. In addition, oil flow visualization tests were performed at various angles of attack. An existing NACA 64 sub 1 A211 airfoil was used in a second series of tests. The leading edge flap was segmented in three parts which allowed various baseline/drooped leading edge configurations to be tested. Force balance and flow visualization tests were completer at chord Renolds numbers of 0.44 x 10 to the 6th power, 1.4 x 10 to the 6th power, and 2.11 x 10 to the 6th power. Test results are included