Water Ice, Silicate, and Polycyclic Aromatic Hydrocarbon Emission Featuresin the Infrared Space Observatory Spectrum of the Carbon-richPlanetary Nebula CPD –56°8032*

Combined Infrared Space Observatory Short-Wavelength Spectrometer and Long-Wavelength Spectrometer spectroscopy is presented of the late WC-type planetary nebula nucleus CPD -56°8032 and its carbon-rich nebula. The extremely broad coverage (2.4-197 μm) enables us to recognize the clear and simultaneous presence of emission features from both oxygen- and carbon-rich circumstellar materials. Removing a smooth continuum highlights bright emission bands characteristic of polycyclic aromatic hydrocarbons in the 3-14 μm region, bands from crystalline silicates longward of 18 μm, and the 43 and 62 μm bands of crystalline water ice. We discuss the probable evolutionary state and history of this unusual object in terms of (a) a recent transition from an O-rich to a C-rich outflow following a helium shell flash or (b) a carbon-rich nebular outflow encountering an O-rich comet cloud

Blueschist from the Mariana forearc records long-lived residence of material in the subduction channel

From ca. 50 Ma to present, the western Pacific plate has been subducting under the Philippine Sea plate, forming the oceanic Izu-Bonin-Mariana (IBM) subduction system. It is the only known location where subduction zone products are presently being transported to the surface by serpentinite-mud volcanoes. A large serpentine mud “volcano” forms the South Chamorro Seamount and was successfully drilled by ODP during Leg 195. This returned mostly partially serpentinized harzburgites enclosed in serpentinite muds. In addition, limited numbers of small (1 mm–1 cm) fragments of rare blueschists were also discovered. U–Pb dating of zircon and rutile from one of these blueschist clasts give ages of 51.1 ± 1.2 Ma and 47.5 ± 2.0 Ma, respectively. These are interpreted to date prograde high-pressure metamorphism. Mineral equilibria modelling of the blueschist clast suggests the mineral assemblage formed at conditions of ∼1.6 GPa and ∼590 °C. We interpret that this high-pressure assemblage formed at a depth of ∼50 km within the subduction channel and was subsequently exhumed and entrained into the South Chamorro serpentinite volcano system at depths of ∼27 km. Consequently, we propose that the material erupted from the South Chamarro Seamount may be sampling far greater depths within the Mariana subduction system than previously thought. The apparent thermal gradient implied by the pressure–temperature modelling (∼370 °C/GPa) is slightly warmer than that predicted by typical subduction channel numerical models and other blueschists worldwide. The age of the blueschist suggests it formed during the arc initiation stages of the proto-Izu-Bonin-Mariana arc, with the P–T conditions recording thermally elevated conditions during initial stages of western Pacific plate subduction. This indicates the blueschist had prolonged residence time in the stable forearc as the system underwent east-directed rollback. The Mariana blueschist shows that subduction products can remain entrained in subduction channels for many millions of years prior to exhumation

Post-supereruption recovery at Toba Caldera

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ~74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14 C, zircon U-Th crystallization and (U-Th)/He ages show resurgence commenced at 69.7±4.5 ka and continued until at least ~2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions

The Galactic Plane at faint X-ray fluxes - I: Properties and characteristics of the X-ray source population

We investigate the serendipitous X-ray source population revealed in XMM-Newton observations targeted in the Galactic Plane within the region 315<l<45 and |b|<2.5 deg. Our study focuses on a sample of 2204 X-ray sources at intermediate to faint fluxes, which were detected in a total of 116 XMM fields and are listed in the 2XMMi catalogue. We characterise each source as spectrally soft or hard on the basis of whether the bulk of the recorded counts have energies below or above 2 keV and find that the sample divides roughly equally (56%:44%) into these soft and hard categories. The X-ray spectral form underlying the soft sources may be represented as either a power-law continuum with Gamma~2.5 or a thermal spectrum with kT~0.5 keV, with N_H ranging from 10^{20-22} cm^{-2}. For the hard sources, a significantly harder continuum form is likely, i.e., Gamma~1 with N_H=10^{22-24} cm^{-2}. For ~50% of the hard sources, the inferred column density is commensurate with the total Galactic line-of-sight value; many of these sources will be located at significant distances across the Galaxy implying a hard band luminosity L_X>10^{32} erg/s, whereas some will be extragalactic interlopers. >90% of the soft sources have potential NIR (2MASS and/or UKIDSS) counterparts inside their error circles, consistent with the dominant soft X-ray source population being relatively nearby coronally-active stars. These stellar counterparts are generally brighter than J=16, a brightness cutoff which corresponds to the saturation of the X-ray coronal emission at L_X=10^{-3} L_{bol}. In contrast, the success rate in finding likely IR counterparts to the hard X-ray sample is no more than ~15% down to J=16 and ~25% down to J=20, set against a rapidly rising chance coincidence rate. The make-up of the hard X-ray source population, in terms of the known classes of accreting and non-accreting systems, remains uncertain.Comment: 17 pages, 17 figures, accepted for publication in MNRA

Late Silurian zircon U–Pb ages from the Ludlow and Downton bone beds, Welsh Basin, UK

The Ludlow Bone Bed (Welsh Basin) is a critical stratigraphic horizon and contains a rich assemblage of fish scales. Units above provide insights into the early evolution of animal and plant life. The bed has not yet been radioisotopically dated. Here, we report 207 secondary ion mass spectrometry (SIMS) ages from 102 zircon (ZrSiO4) grains from the Ludlow (n = 2) and stratigraphically higher Downton (n = 1) bone beds. SIMS ages are middle Ordovician (471.6 ± 20.7 Ma) to late Devonian (375.7 ± 14.6 Ma, 238U–206Pb, ±1σ analytical uncertainty). Cathodoluminescence images show that the youngest ages appear affected by alteration. Chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-ID-TIMS) U–Pb geochronology was utilized to improve precision. Detrital zircon grains from Downton yield 424.91 ± 0.34/0.42/0.63 Ma and from Ludlow 424.85 ± 0.32/0.41/0.62 Ma (n = 5 each, 238U–206Pb, ±2σ analytical, tracer or systematic uncertainty). These ages provide a maximum deposition age. Results overlap the basal Přídolí age (423.0 ± 2.3 Ma) in its stratotype (Požáry Section, Reporyje, Prague, Czech Republic). The Ludlow Bone Bed marks the base of the local Downton Group, which has previously been correlated with the base of the Přídolí Series. The CA-ID-TIMS ages are older than those for other land arthropod-bearing sediments, such as the Cowie Harbour Fish Bed and Rhynie Chert.© 2020 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/ licenses/by/4.0/). Published by The Geological Society of London. Publishing disclaimer: www.geolsoc.org.uk/pub_ethic

Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850

Notch-induced T cell development requires phosphoinositide-dependent kinase 1

Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development

The topology of plasminogen binding and activation on the surface of human breast cancer cells

The urokinase-dependent activation of plasminogen by breast cancer cells plays an important role in metastasis. We have previously shown that the metastatic breast cancer cell line MDA-MB-231 over-expresses urokinase and binds and efficiently activates plasminogen at the cell surface compared to non-metastatic cells. The aim of this study was to further characterise plasminogen binding and determine the topology of cell surface-bound plasminogen in terms of its potential for activation. The lysine-dependent binding of plasminogen at 4°C to MDA-MB-231 cells was stable and resulted in an activation-susceptible conformation of plasminogen. Topologically, a fraction of bound plasminogen was co-localised with urokinase on the surfaces of MDA-MB-231 cells where it could be activated to plasmin. At 37°C plasmin was rapidly lost from the cell surface. Apart from actin, other candidate plasminogen receptors were either not expressed or did not co-localise with plasminogen at the cell surface. Thus, based on co-localisation with urokinase, plasminogen binding is partitioned into two functional pools on the surface of MDA-MB-231 cells. In conclusion, these results shed further light on the functional organisation of the plasminogen activation cascade on the surface of a metastatic cancer cell. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

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