Characterising the gas and dust in protoplanetary discs around Herbig stars

This thesis contains a study of the circumstellar discs around intermediate mass stars. Through observational data and protoplanetary disc modelling, the physical structure and composition of protoplanetary discs are investigated with regards to their capacity for planet formation. In-depth analysis of millimetre-wavelength interferometric observations are carried out on the circumstellar environment of two Herbig stars. Firstly, the distribution of gas and dust in the gas-rich, potentially planet-hosting disc of HD100546 is characterised. Using ALMA observations of 1.3mm continuum and CO isotopologues tracing the disc midplane, estimates of disc mass are calculated, constraints on the size of dust grains inferred and evidence for midplane counterparts to scattered light features are identified. Secondly, an analysis of the more evolved circumstellar disc around Herbig star HD141569 is made in order to investigate the mass content of the disc and inform the debate as to its evolutionary stage. New ALMA observations presented in this thesis and new midplane structures in the gas and dust that support an intermediary stage of evolution between the protoplanetary disc and debris disc regimes. Finally, modelling of the pre-main sequence evolution of stars across the stellar mass range at which exoplanet detections peak is combined with Monte Carlo radiative transfer and modelling of the evolution of midplane gas and dust in order to study the impact of stellar evolution on the midplanes of protoplanetary discs. Variations in midplane temperature profles result in different locations of key snowlines in the disc, which in turn produces variations in the molecular composition of the local disc. The results quantify how snowline locations depend on stellar luminosity evolution. This modelling procedure is applied to the system of HR8799 in order to put constraints on the time and location within the disc at which wide-orbit planets could have formed based on their atmospheric C/O ratio. The results support an early formation time, within around 1 Myr, for the carbon-rich exoplanet HR8799b

A Candidate Brightest Proto-Cluster Galaxy at z = 3.03

We report the discovery of a very bright (m_R = 22.2) Lyman break galaxy at z = 3.03 that appears to be a massive system in a late stage of merging. Deep imaging reveals multiple peaks in the brightness profile with angular separations of ~0.''8 (~25 h^-1 kpc comoving). In addition, high signal-to-noise ratio rest-frame UV spectroscopy shows evidence for ~5 components based on stellar photospheric and ISM absorption lines with a velocity dispersion of sigma ~460 km s^-1 for the three strongest components. Both the dynamics and high luminosity, as well as our analysis of a LCDM numerical simulation, suggest a very massive system with halo mass M ~ 10^13 M_solar. The simulation finds that all halos at z = 3 of this mass contain sub-halos in agreement with the properties of these observed components and that such systems typically evolve into M ~ 10^14 M_solar halos in groups and clusters by z = 0. This discovery provides a rare opportunity to study the properties and individual components of z ~ 3 systems that are likely to be the progenitors to brightest cluster galaxies.Comment: 14 pages, 3 figures, submitted to ApJ Letter

Current Conditions Risk Assessment for the 300-FF-5 Groundwater Operable Unit

This report updates a baseline risk assessment for the 300 Area prepared in 1994. The update includes consideration of changes in contaminants of interest and in the environment that have occurred during the period of interim remedial action, i.e., 1996 to the present, as well as the sub-regions, for which no initial risk assessments have been conducted. In 1996, a record of decision (ROD) stipulated interim remedial action for groundwater affected by releases from 300 Area sources, as follows: (a) continued monitoring of groundwater that is contaminated above health-based levels to ensure that concentrations continue to decrease, and (b) institutional controls to ensure that groundwater use is restricted to prevent unacceptable exposure to groundwater contamination. In 2000, the groundwater beneath the two outlying sub-regions was added to the operable unit. In 2001, the first 5-year review of the ROD found that the interim remedy and remedial action objectives were still appropriate, although the review called for additional characterization activities. This report includes a current conditions baseline ecological and human health risk assessment using maximum concentrations in the environmental media of the 300-FF-5 Operable Unit and downstream conditions at the City of Richland, Washington. The scope for this assessment includes only current measured environmental concentrations and current use scenarios. Future environmental concentrations and future land uses are not considered in this assessment

The host galaxies and black-hole:galaxy mass ratios of luminous quasars at z~4

We present and analyse the deepest, high-quality Ks-band images ever obtained of luminous quasars at z~4, in an attempt to determine the basic properties of their host galaxies less than 1 Gyr after the first recorded appearance of black holes with Mbh > 10^9 Msol. To maximise the robustness of our results we have carefully selected two SDSS quasars at z~4. These quasars are representative of the most luminous quasars known at this epoch but they also, crucially, lie within 40 arcsec of comparably-bright foreground stars (required for accurate PSF definition), and have redshifts which ensure line-free Ks-band imaging. The data were obtained in excellent seeing (<0.4-arcsec) at the ESO VLT with integration times of ~5.5 hours per source. Via carefully-controlled separation of host-galaxy and nuclear light, we estimate the luminosities and stellar masses of the host galaxies, and set constraints on their half-light radii. The quasar host galaxies have K-band luminosities similar to radio galaxies at comparable redshifts, suggesting that these quasar hosts are also among the most massive galaxies in existence at this epoch. However, the quasar hosts are a factor ~5 smaller than the host galaxies of luminous low-redshift quasars. We estimate the stellar masses of the z~4 host galaxies to lie in the range 2-10x10^11 Msol, and use the CIV emission line in the Sloan spectra to estimate the masses of their black holes. The results imply a black-hole:host-galaxy mass ratio Mbh:Mgal~0.01-0.05. This is an order of magnitude higher than typically seen in the low-redshift Universe, and is consistent with existing evidence for a systematic growth in this mass ratio with increasing redshift, at least for objects selected as powerful AGN.Comment: 10 pages, 6 figure

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket

Reactivation of Kaposi's sarcoma-associated herpesvirus by natural products from Kaposi's sarcoma endemic regions

Kaposi’s sarcoma (KS) and its causative agent, Kaposi’s sarcoma associated herpesvirus (KSHV/HHV-8), a gamma2 herpesvirus, have distinctive geographical distributions that are largely unexplained. We propose the “oncoweed” hypothesis to explain these differences, namely that environmental cofactors present in KS endemic regions cause frequent reactivation of KSHV in infected subjects, leading to increased viral shedding and transmission leading to increased prevalence of KSHV infection as well as high viral load levels and antibody titers. Reactivation also plays a role in the pathogenesis of KSHV-associated malignancies. To test this hypothesis, we employed an in vitro KSHV reactivation assay that measured increases in KSHV viral load in KSHV infected primary effusion lymphoma (PEL) cells and screened aqueous natural product extracts from KS endemic regions. Of 4,842 extracts from 38 countries, 184 (5%) caused KSHV reactivation. Extracts that caused reactivation came from a wide variety of plant families, and extracts from Africa, where KSHV is highly prevalent, caused the greatest level of reactivation. Time course experiments were performed using 28 extracts that caused the highest levels of reactivation. The specificity of the effects on viral replication was examined using transcriptional profiling of all viral mRNAs. The array data indicated that the natural extracts caused an ordered cascade of lytic replication similar to that seen after induction with synthetic activators. These in vitro data provide support for the “oncoweed” hypothesis by demonstrating basic biological plausibility

Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell–mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR–HLA-B*4405EENLLDFVRF complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes

Mutation-Specific RAS Oncogenicity Explains NRAS Codon 61 Selection in Melanoma

N-RAS mutation at codon 12, 13 or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an N-RasQ61R knock-in allele to similarly designed K-RasG12D and N-RasG12D alleles. With concomitant p16INK4a inactivation, K-RasG12D or N-RasQ61R expression efficiently promoted melanoma in vivo, whereas N-RasG12D did not. Additionally, N-RasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of N-RasQ61R and N-RasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, N-RasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity and increased stability when compared to N-RasG12D. This work identifies a faithful model of human N-RAS mutant melanoma, and suggests that the increased melanomagenecity of N-RasQ61R over N-RasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways