Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4

This paper describes a detailed structure activity relationship (SAR) analysis of the metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator, (-)-N-phenyl-7-(hydroxyimino)cyclopropa[b]-chromen-la-carboxamide (PHCCC). We have now developed compounds with improved potency and efficacy; in addition, compounds are presented that show selectivity for mGluR4 versus the other mGluR subtypes.

Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M-1) Antagonist In Vitro and In Vivo Probe

This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M-1). An M-1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M-1 versus M-4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective (>75-fold vs. M-2-M-5 and >10 mu M vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M-1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (Brain(AUC)/Plasma(AUC) of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/MLPCN probe molecule for studying and dissecting M-1 function.

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.

Optical and near-infrared coverage of SN 2004et: physical parameters and comparison with other Type IIP supernovae

We present new optical and near-infrared (NIR) photometry and spectroscopy of the Type IIP supernova (SN), SN 2004et. In combination with already published data, this provides one of the most complete studies of optical and NIR data for any Type IIP SN from just after explosion to +500 d. The contribution of the NIR flux to the bolometric light curve is estimated to increase from 15 per cent at explosion to around 50 per cent at the end of the plateau and then declines to 40 per cent at 300 d. SN 2004et is one of the most luminous IIP SNe which has been well studied and characterized, and with a luminosity of log L = 42.3 erg s-1 and a 56Ni mass of 0.06 +/- 0.04 M-circle dot, it is two times brighter than SN 1999em. We provide parametrized bolometric corrections as a function of time since explosion for SN 2004et and three other IIP SNe that have extensive optical and NIR data. These can be used as templates for future events in optical and NIR surveys without full wavelength coverage. We compare the physical parameters of SN 2004et with those of other well-studied IIP SNe and find that the kinetic energies span a range of 1050-1051 erg. We compare the ejected masses calculated from hydrodynamic models with the progenitor masses and limits derived from pre-discovery images. Some of the ejected mass estimates are significantly higher than the progenitor mass estimates, with SN 2004et showing perhaps the most serious mass discrepancy. With the current models, it appears difficult to reconcile 100 d plateau lengths and high expansion velocities with the low ejected masses of 5-6 M-circle dot implied from 7-8 M-circle dot progenitors. The nebular phase is studied using very late-time Hubble Space Telescope photometry, along with optical and NIR spectroscopy. The light curve shows a clear flattening at 600 d in the optical and the NIR, which is likely due to the ejecta impacting on circumstellar material. We further show that the [O i] 6300, 6364 A line strengths in the nebular spectra of four Type IIP SNe imply ejected oxygen masses of 0.5-1.5 M-circle dot.

SUPERNOVA 1996cr: SN 1987A's WILD COUSIN?

We report on new VLT optical spectroscopic and multiwavelength archival observations of SN 1996cr, a previously identified ultraluminous X-ray source known as Circinus galaxy X-2. Our optical spectrum confirms SN 1996cr as a bona fide Type IIn supernova, while archival imaging from the Anglo-Australian Telescope archive isolates the explosion date to between 1995 February 28 and 1996 March 16. SN 1996cr is one of the closest SNe (approximate to 3.8 Mpc) in the last several decades, and in terms of flux ranks among the brightest radio and X-ray SNe ever detected. The wealth of optical, X-ray, and radio observations that exist for this source provide relatively detailed constraints on its postexplosion expansion and progenitor history, including a preliminary angular size constraint from VLBI. Archival X-ray and radio data imply that the progenitor of SN 1996cr evacuated a large cavity just prior to exploding: the blast wave likely spent similar to 1-2 yr in relatively uninhibited expansion before eventually striking the dense circumstellar material which surrounds SN 1996cr. The X-ray and radio emission, which trace the progenitor mass-loss rate, have respectively risen by a factor of greater than or similar to 2 and remained roughly constant over the past 7 years. This behavior is reminiscent of the late rise of SN 1987A, but 1000 times more luminous and much more rapid to onset. SN 1996cr may likewise provide us with a younger example of SN 1978K and SN 1979C, both of which exhibit flat X-ray evolution at late times. Complex oxygen line emission hints at a possible concentric shell or ringlike structure. The discovery of SN 1996cr suggests that a substantial fraction of the closest SNe observed in the last several decades have occurred in wind-blown bubbles, and argues for the phenomena being widespread.

Optical and infrared spectroscopy of the type IInSN1998S: days 3-127

We present contemporary optical and infrared spectroscopic observations of the type IIn SN 1998S covering the period between 3 and 127 days after discovery. During the first week the spectra are characterized by prominent broad H, He and C III/N III emission lines with narrow peaks, superimposed on a very blue continuum (T similar to 24 000 K). In the following two weeks the C III/N III emission vanished, together with the broad emission components of the H and He lines. Broad, blueshifted absorption components appeared in the spectra. The temperature of the continuum also dropped to similar to 14000 K. By the end of the first month the spectrum comprised broad, blueshifted absorptions in H, He, Si II, Fe II and Sc II. By day 44, broad emission components in H and He reappeared in the spectra. These persisted to as late as days similar to 100-130, becoming increasingly asymmetric. We agree with Leonard et al. that the broad emission lines indicate interaction between the ejecta and circumstellar material (CSM) emitted by the progenitor. We also agree that the progenitor of SN 1998S appears to have gone through at least two phases of mass-loss, giving rise to two CSM zones. Examination of the spectra indicates that the inner zone extended to less than or equal to 90 au, while the outer CSM extended from 185 an to over 1800 au.

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.

Discovery of Main-Belt Comet P/2006 VW139 by Pan-STARRS 1

The main-belt asteroid (300163) 2006 VW139 (later designated P/2006 VW139) was discovered to exhibit comet-like activity by the Pan-STARRS1 (PS1) survey telescope using automated point-spread-function analyses performed by PS1's Moving Object Processing System. Deep follow-up observations show both a short (~10'') antisolar dust tail and a longer (~60'') dust trail aligned with the object's orbit plane, similar to the morphology observed for another main-belt comet (MBC), P/2010 R2 (La Sagra), and other well-established comets, implying the action of a long-lived, sublimation-driven emission event. Photometry showing the brightness of the near-nucleus coma remaining constant over ~30 days provides further evidence for this object's cometary nature, suggesting it is in fact an MBC, and not a disrupted asteroid. A spectroscopic search for CN emission was unsuccessful, though we find an upper limit CN production rate of Q CN 100 Myr, while a search for a potential asteroid family around the object reveals a cluster of 24 asteroids within a cutoff distance of 68 m s-1. At 70 m s-1, this cluster merges with the Themis family, suggesting that it could be similar to the Beagle family to which another MBC, 133P/Elst-Pizarro, belongs.

Langmuir probe measurements of plasma parameters in the late stages of a laser ablated plume

A simple Langmuir probe technique has been used to measure the electron density, electron temperature, and plasma potential in the late stages (>5 mu s) of a laser ablated plasma plume. In the plasma, formed following 248 nm laser irradiation of a copper target, in vacuum at a laser fluence of 2.5 J cm(-2), electron densities of similar to 10(18) m(-3) and temperatures of similar to 0.5 eV were measured. These values are comparable with those reported previously using Faraday cup detectors and optical emission spectroscopy, respectively. (C) 1997 American Institute of Physics.

Discovery and evolving history of two genetically related but phenotypically different viruses, porcine circoviruses 1 and 2

Porcine circoviruses (PCVs) belong to the genus Circovirus, family Circoviridae. and are the smallest non-enveloped, single stranded, negative sense, circular DNA viruses that replicate autonomously in mammalian cells. Two types of PCV have been characterised, PCV1 and PCV2 and these two viruses show 83% sequence identity at open reading frame (ORF) 1 and 67% identity at ORF2. PCV1 is a nonpathogenic virus of pigs. In contrast, PCV2 has emerged as a major pathogen of swine around the world. The discovery of PCV1 and how the subsequent studies on this virus eventually led to the recognition and characterisation of PCV2, and the disease scenarios associated with PCV2, serve as a model of how multidisciplinary collaboration among field veterinarians, diagnosticians and researchers can lead to the rapid characterisation and control of a globally important emerging disease. (C) 2011 Elsevier B.V. All rights reserved.