WASP-39b: a highly inflated Saturn-mass planet orbiting a late G-type star

We present the discovery of WASP-39b, a highly inflated transiting Saturn-mass planet orbiting a late G-type dwarf star with a period of 4.055259 +/- 0.000008 d, Transit Epoch T-0 = 2 455 342.9688 +/- 0.0002 (HJD), of duration 0.1168 +/- 0.0008 d. A combined analysis of the WASP photometry, high-precision follow-up transit photometry, and radial velocities yield a planetary mass of M-pl = 0.28 +/- 0.03 M-J and a radius of R-pl = 1.27 +/- 0.04 R-J, resulting in a mean density of 0.14 +/- 0.02 rho(J). The stellar parameters are mass M-star = 0.93 +/- 0.03 M-circle dot, radius R-star = 0.895 +/- 0.23 R-circle dot, and age 9(-4)(+3) Gyr. Only WASP-17b and WASP-31b have lower densities than WASP-39b, although they are slightly more massive and highly irradiated planets. From our spectral analysis, the metallicity of WASP-39 is measured to be [Fe/H] = -0.12 +/- 0.1 dex, and we find the planet to have an equilibrium temperature of 1116(-32)(+33) K. Both values strengthen the observed empirical correlation between these parameters and the planetary radius for the known transiting Saturn-mass planets.

Nanodosimetric effects of gold nanoparticles in megavoltage radiation therapy

Background and purpose: The addition of gold nanoparticles (GNPs) to tumours leads to an increase in dose due to their high density and energy absorption coefficient, making it a potential radiosensitiser. However, experiments have observed radiosensitisations significantly larger than the increase in dose alone, including at megavoltage energies where gold's relative energy absorption is lowest. This work investigates whether GNPs create dose inhomogeneities on a sub-cellular scale which combine with non-linear dose dependence of cell survival to be the source of radiosensitisation at megavoltage energies.

Correlating Alpine glaciation with Adriatic sea-level changes through lake and alluvial stratigraphy

We compare lake and alluvial stratigraphy along a frame connecting the southern Alpine foothills and the Adriatic Sea, with the aim of matching the effects of Alpine glaciation and sea-level changes on sedimentation during the last glacial cycle. The palynostratigraphy of Lake Fimon provided proxies for regional vegetation and climate change and was coupled with sediment petrography, loss on ignition and magnetic susceptibility, disentangling alluvial phases from fluvioglacial activity related to culminations of the southeastern Alpine glaciers. The Fimon area was not reached by alluvial fans during the penultimate glacial maximum, nor by the sea transgression during the last interglacial, but a closed lake soon developed at the Eemian onset due to enhanced rainfall. Sea-level fall at glacial inception triggered the entrenchment of the drainage network in the plain reaching the outer Fimon Basin. Slow aggradation, but no sign of fluvioglacial activity, lasted to 38.2 +/- 1.45 cal. ka BP, when a major forest withdrawal took place, coeval to the spread of alluvial fans. By 27.5 perpendicular to 0.5 cal. ka BP the Fimon Basin was dammed by the Brenta outwash system. The main step of of forest recovery commenced at around (15.8) cal. ka BP, when apex trenching of the outwash fans was triggered by the glacier's decay. Copyright (C) 2011 John Wiley & Sons, Ltd.

Isoprenylation of the G protein gamma subunit is both necessary and sufficient for beta gamma dimer-mediated stimulation of phospholipase C

We have previously shown that isoprenylation and/or additional pest-translational processing of the G protein gamma(1) subunit carboxyl terminus is required for beta(1) gamma(1) subunit stimulation of phospholipase C-beta(2) (PLC beta(2)) [Dietrich, A., Meister, M., Brazil, D., Camps, M., & Gierschik, P. (1994) Eur. J. Biochem. 219, 171-178]. To examine whether isoprenylation of the gamma(1) subunit alone is sufficient for beta(1) gamma(1)-mediated PLC beta(2) stimulation or whether any of the two subsequent modifications, proteolytic removal of the carboxyl-terminal tripeptide and/or carboxylmethylation, is required for this effect, nonisoprenylated recombinant beta(1) gamma(1) dimers were produced in baculovirus-infected insect cells, purified to near homogeneity, and then isoprenylated in vitro using purified recombinant protein farnesyltransferase. Analysis of the beta(1) gamma(1) dimer after in vitro farnesylation by reversed phase high-performance liquid chromatography followed by delayed extraction matrix-assisted laser desorption/ionization mass spectrometry confirmed that the gamma(1) subunit was carboxyl-terminally farnesylated but not proteolyzed and carboxylmethylated. Functional reconstitution of in vitro-farnesylated beta(1) gamma(1) dimers with a recombinant PLC beta(2) isozyme revealed that farnesylation rendered recombinant nonisoprenylated beta(1) gamma(1) dimers capable of stimulating PLC beta(2) and that the degree of this stimulation was only approximately 45% lower for in vitro-farnesylated beta(1) gamma(1) dimers than for fully modified native beta(1) gamma(1) purified from bovine retinal rod outer segments. Taken together, these results suggest that isoprenylation of the gamma subunit is both necessary and sufficient for beta gamma dimer-mediated stimulation of phospholipase C.

Late Pleistocene history of turbidite sedimentation in a submarine canyon off the northern Great Barrier Reef, Australia

Cores from slopes east of the Great Barrier Reef (GBR) challenge traditional models for sedimentation on tropical mixed siliciclastic-carbonate margins. However, satisfactory explanations of sediment accumulation on this archetypal margin that include both hemipelagic and turbidite sedimentation remain elusive, as submarine canyons and their role in delivering coarse-grained turbidite deposits, are poorly understood. Towards addressing this problem we investigated the shelf and canyon system bordering the northern Ribbon Reefs and reconstructed the history of turbidite deposition since the Late Pleistocene. High-resolution bathymetric and seismic data show a large paleo-channel system that crosses the shelf before connecting with the canyons via the inter-reef passages between the Ribbon Reefs. High-resolution bathymetry of the canyon axis reveals a complex and active system of channels, sand waves, and local submarine landslides. Multi-proxy examination of three cores from down the axis of the canyon system reveals 18 turbidites and debrites, interlayered with hemipelagic muds, that are derived from a mix of shallow and deep sources. Twenty radiocarbon ages indicate that siliciclastic-dominated and mixed turbidites only occur prior to 31 ka during Marine Isotope Stage (MIS) 3, while carbonate-dominated turbidites are well established by 11 ka in MIS1 until as recently as 1.2 ka. The apparent lack of siliciclastic-dominated turbidites and presence of only a few carbonate-dominated turbidites during the MIS2 lowstand are not consistent with generic models of margin sedimentation but might also reflect a gap in the turbidite record. These data suggest that turbidite sedimentation in the Ribbon Reef canyons, probably reflects the complex relationship between the prolonged period (> 25 ka) of MIS3 millennial sea level changes and local factors such as the shelf, inter-reef passage depth, canyon morphology and different sediment sources. On this basis we predict that the spatial and temporal patterns of turbidite sedimentation could vary considerably along the length of the GBR margin.

Late-Holocene marine radiocarbon reservoir correction (Delta R) for the west coast of South Africa

In order to calibrate radiocarbon ages based on samples with a marine carbon component it is important to know the marine carbon reservoir correction or Delta R value. This study measured the Delta R on both known-age pre-bomb marine shells and paired marine and terrestrial samples from two regions on the west coast of South Africa: the southwestern Cape and Namaqualand. Pooling the data by region produces Delta R values that are similar enough to use a west coast weighted mean Delta R of 146 +/- 85 C-14 years to correctly calibrate marine shell or mixed marine and terrestrial C-14 ages. There are however temporal differences in Delta R throughout the Holocene, which we compare with proxy data for upwelling and sea surface temperatures.

The Respiratory Syncytial Virus G Protein Conserved Domain Induces a Persistent and Protective Antibody Response in Rodents

Respiratory syncytial virus (RSV) is an important cause of severe upper and lower respiratory disease in infants and in the elderly. There are 2 main RSV subtypes A and B. A recombinant vaccine was designed based on the central domain of the RSV-A attachment G protein which we had previously named G2Na (aa130–230). Here we evaluated immunogenicity, persistence of antibody (Ab) response and protective efficacy induced in rodents by: (i) G2Na fused to DT (Diphtheria toxin) fragments in cotton rats. DT fusion did not potentiate neutralizing Ab responses against RSV-A or cross-reactivity to RSV-B. (ii) G2Nb (aa130–230 of the RSV-B G protein) either fused to, or admixed with G2Na. G2Nb did not induce RSV-B-reactive Ab responses. (iii) G2Na at low doses. Two injections of 3 µg G2Na in Alum were sufficient to induce protective immune responses in mouse lungs, preventing RSV-A and greatly reducing RSV-B infections. In cotton rats, G2Na-induced RSV-reactive Ab and protective immunity against RSV-A challenge that persisted for at least 24 weeks. (iv) injecting RSV primed mice with a single dose of G2Na/Alum or G2Na/PLGA [poly(D,L-lactide-co-glycolide]. Despite the presence of pre-existing RSV-specific Abs, these formulations effectively boosted anti-RSV Ab titres and increased Ab titres persisted for at least 21 weeks. Affinity maturation of these Abs increased from day 28 to day 148. These data indicate that G2Na has potential as a component of an RSV vaccine formulation.

HIF-2alpha Associated Familial Erythrocytosis Supports the PHD2-HIF2-alpha-VHL Axis as the Major Regulator of Erythropoietin Production

Transcriptionally erythropoietin (Epo) synthesis is tightly regulated by the hypoxia inducible factor (HIF), which is composed of one alpha and one beta subunit that are constitutively expressed. The beta subunit is non-variable, but three different alpha subunits give rise to three isoforms of HIF. The alpha subunit is proteasomally regulated in the presence of oxygen by hydroxylation of the proline in the LXXLAP motif of the oxygen dependent degradation (ODD) domain of HIFalpha, catalysed by members of the prolyl hydroxylase domain (PHD) family of enzymes. This allows the von Hippel Lindau (VHL) protein to associate with the alpha subunit, which is subsequently tagged with ubiquitin and degraded by the proteasome. Any defect in the oxygen sensing pathway that allows the alpha subunit to escape proteasomal regulation leads to elevated expression of HIF target genes.

Recently mutations in both VHL and PHD2 have been identified in a cohort of patients with erythrocytosis, but no mutations were found in the ODD domain of HIF1alpha. Instead, investigation of the homologous region in HIF-2alpha revealed four different mutations, Pro534Leu, Met535Val, Gly537Arg and Gly537Trp in seven individuals/families. Affected individuals presented at a young age with elevated serum Epo. Several individuals have a clinical history of thrombosis, but no evidence of a von Hippel Lindau-like syndrome.

To define how the four mutations relate to the erythrocytosis phenotype functional assays were performed in vitro. Binding of PHD2 to the four HIF-2alpha mutants was impaired to varying degrees, with both the Gly537 mutants showing the greatest reduction. The association of VHL with the hydroxylated Met535Val mutant peptide was similar to wild type HIF- 2alpha, but was decreased in the other three HIF-2alpha mutants. Expression of three HIF- 2alpha target genes, adrenomedullin, NDRG1 and VEGF, was significantly up-regulated in cells stably transfected with the mutants under normoxia compared to wild type HIF-2alpha. Mutations in the ODD domain of HIF-2alpha disrupt proteasomal regulation by reducing the association with PHD2 and hence hydroxylation. Furthermore the binding of VHL is also impaired, even when HIF-2alpha is hydroxylated. Examination of the three-dimensional structure of hydroxylated HIF-1alpha bound to VHL confirms that amino acids close to site of hydroxylation (Pro-531 in isoform 2) are important for this association. These observations, together with recent studies utilising murine models of erythrocytosis, support the PHD2-HIF-2alpha-VHL axis as the major regulator of erythropoietin.

Cell type-dependent uptake, localization, and cytotoxicity of 1.9 nm gold nanoparticles

Background: This follow-up study aims to determine the physical parameters which govern the differential radiosensitization capacity of two tumor cell lines and one immortalized normal cell line to 1.9 nm gold nanoparticles. In addition to comparing the uptake potential, localization, and cytotoxicity of 1.9 nm gold nanoparticles, the current study also draws on comparisons between nanoparticle size and total nanoparticle uptake based on previously published data.

Methods: We quantified gold nanoparticle uptake using atomic emission spectroscopy and imaged intracellular localization by transmission electron microscopy. Cell growth delay and clonogenic assays were used to determine cytotoxicity and radiosensitization potential, respectively. Mechanistic data were obtained by Western blot, flow cytometry, and assays for reactive oxygen species.

Results: Gold nanoparticle uptake was preferentially observed in tumor cells, resulting in an increased expression of cleaved caspase proteins and an accumulation of cells in sub G1 phase. Despite this, gold nanoparticle cytotoxicity remained low, with immortalized normal cells exhibiting an LD50 concentration approximately 14 times higher than tumor cells. The surviving fraction for gold nanoparticle-treated cells at 3 Gy compared with that of untreated control cells indicated a strong dependence on cell type in respect to radiosensitization potential.

Conclusion: Gold nanoparticles were most avidly endocytosed and localized within cytoplasmic vesicles during the first 6 hours of exposure. The lack of significant cytotoxicity in the absence of radiation, and the generation of gold nanoparticle-induced reactive oxygen species provide a potential mechanism for previously reported radiosensitization at megavoltage energies.