Correction for founder effects in host-viral association studies via principal components

Viruses such as HIV and Hepatitis C (HCV) replicate rapidly and with high transcription error rates, which may facilitate their escape from immune detection through the encoding of mutations at key positions within human leukocyte antigen (HLA)-specific peptides, thus impeding T-cell recognition. Large-scale population-based host-viral association studies are conducted as hypothesis-generating analyses which aim to determine the positions within the viral sequence at which host HLA immune pressure may have led to these viral escape mutations. When transmission of the virus to the host is HLA-associated, however, standard tests of association can be confounded by the viral relatedness of contemporarily circulating viral sequences, as viral sequences descended from a common ancestor may share inherited patterns of polymorphisms, termed 'founder effects'. Recognizing the correspondence between this problem and the confounding of case-control genome-wide association studies by population stratification, we adapt methods taken from that field to the analysis of host-viral associations. In particular, we consider methods based on principal components analysis within a logistic regression framework motivated by alternative formulations in the Frisch-Waugh-Lovell Theorem. We demonstrate via simulation their utility in detecting true host-viral associations whilst minimizing confounding by associations generated by founder effects. The proposed methods incorporate relatively robust, standard statistical procedures which can be easily implemented using widely available software, and provide alternatives to the more complex computer intensive methods often implemented in this area

Does the X-ray outflow quasar PDS 456 have a UV outflow at 0.3c?

The quasar PDS 456 (at redshift ~0.184) has a prototype ultra-fast outflow (UFO) measured in X-rays. This outflow is highly ionized with relativistic speeds, large total column densities log N_H(cm^-2) > 23, and large kinetic energies that could be important for feedback to the host galaxy. A UV spectrum of PDS 456 obtained with the Hubble Space Telescope in 2000 contains one well-measured broad absorption line (BAL) at ~1346A (observed) that might be Ly-alpha at v ~ 0.06c or NV 1240 at v ~ 0.08c. However, we use photoionisation models and comparisons to other outflow quasars to show that these BAL identifications are problematic because other lines that should accompany them are not detected. We argue that the UV BAL is probably CIV 1549 at v ~ 0.30c. This would be the fastest UV outflow ever reported, but its speed is similar to the X-ray outflow and its appearance overall is similar to relativistic UV BALs observed in other quasars. The CIV BAL identification is also supported indirectly by the tentative detection of another broad CIV line at v ~ 0.19c. The high speeds suggest that the UV outflow originates with the X-ray UFO crudely 20 to 30 r_g from the central black hole. We speculate that the CIV BAL might form in dense clumps embedded in the X-ray UFO, requiring density enhancements of only >0.4 dex compared clumpy structures already inferred for the soft X-ray absorber in PDS 456. The CIV BAL might therefore be the first detection of low-ionisation clumps proposed previously to boost the opacities in UFOs for radiative driving.Comment: in press with MNRA

Remarkable Spectral Variability of PDS 456

We report on the highest to date signal-to-noise-ratio X-ray spectrum of the luminous quasar PDS 456, as obtained during two XMM-Newton orbits in September 2007. The present spectrum is considerably different from several previous X-ray spectra recorded for PDS 456 since 1998. The ultra-high-velocity outflow seen as recently as February 2007 is not detected in absorption. Conversely, a significant reflection component is detected. The reflection model suggests the reflecting medium may be outflowing at a velocity v/c = -0.06 +/- 0.02. The present spectrum is analyzed in the context of the previous ones in an attempt to understand all spectra within the framework of a single model. We examine whether an outflow with variable partial covering of the X-ray source along the line of sight that also reflects the source from other lines of sight can explain the dramatic variations in the broad-band spectral curvature of PDS 456. It is established that absorption plays a major role in shaping the spectrum of other epochs, while the 2007 XMM-Newton spectrum is dominated by reflection, and the coverage of the source by the putative outflow is small (< 20%).Comment: submitted to Ap

Imprints of a high velocity wind on the soft x-ray spectrum of PG 1211+143

An extended XMM-Newton observation of the luminous narrow line Seyfert galaxy PG 1211+143 in 2014 has revealed a more complex high velocity wind, with components distinguished in velocity, ionization level, and column density. Here we report soft x-ray emission and absorption features from the ionized outflow, finding counterparts of both high velocity components, v ~ 0.129c and v ~ 0.066c, recently identified in the highly ionized Fe K absorption spectrum. The lower ionization of the co-moving soft x-ray absorbers imply a distribution of higher density clouds embedded in the main outflow, while much higher column densities for the same flow component in the hard x-ray spectra suggest differing sight lines to the continuum x-ray source.Comment: 8 pages, 5 figures, 4 tables; Accepted for publication in MNRA

The role of stress and dietary micronutrients in fish health

The overall theme of this thesis has been the study of the effects of well known and potentially novel stressors on fish health and how some of these may be modulated by dietary supplements of micronutrients, using both in vitro and in vivo analysis. In vitro experiments with cultured fish cells (EPC-A1, GFSk-S1) evaluated the potential of niacin and selenium to reduce cytotoxicity and genomic instability (DNA damage) induced by ultraviolet radiation exposure, following assay validation with reference toxins. Whilst cytotoxicity was determined by the neutral red retention (NRR) assay, genomic stability was evaluated by either a standard or modified version of the single cell gel electrophoresis (SCGE) or 'Comet' assay. Niacin as nicotinamide (NAM) significantly reduced levels of UVB induced DNA damage (single strand breaks). Selenium supplements, as sodium selenite or seleno-L-methionine also showed a protective effect against H202, UVA and UVB induced cytotoxicity and oxidative DNA damage. An additional in vitro study was carried out to identify environmental nanoparticles as a potential novel source of stress for fish. Titanium dioxide (Ti02) nanoparticle exposure to GFSk-81 cells caused dose-dependent increases in cytotoxicity (NRR assay) and oxidative DNA damage (Comet assay). These effects were exacerbated by combined exposures of Ti02 with UVA. Electron spin resonance (ESR) and spin trapping suggested that Ti02 induced oxidative stress may be primarily due to the production of hydroxyl radicals (OH). Two in vivo experiments were carried out in order to evaluate the effects of husbandry stress (netting and confinement stress) on antioxidant capacity, immune function and genomic stability in trout (Oncorhynchus mykiss) and carp (Cyprinus carpio) , In both studies on trout and carp, certain health parameters were shown to be sensitive to husbandry stress, and may be useful biomarkers of stress in future studies. Total antioxidant capacity (TAC) was reduced in both carp and trout after stress. Respiratory burst capacity of blood leukocytes was also affected by stress but differently in carp than in trout. In carp, husbandry stress apparently stimulated the production of free radicals by leukocytes whereas in trout it was suppressed. In trout, stress was also shown to increase oxidative DNA damage, as measured by the Comet assay. Health parameters that appeared not to be significantly affected by husbandry stress in this study include SOD activity, ALP activity, red blood cell fragility and complement activity (for carp only). In the second experiment on carp, a 10 week feeding trial was also conducted prior to stress induction to evaluate the potential modulatory effects of selenium, zinc and vitamin E on any husbandry induced stress effects observed. Health parameters were also evaluated pre stress in order to elicit any effects of micronutrient supplementation on health parameters in unstressed fish. Selenium supplementation significantly increased glutathione peroxidase activity post stress, but not pre stress, indicating an increased requirement of selenium in stressed fish. No other differences were observed between dietary treatments for any parameter measured either pre stress or post stress, indicating that levels of selenium, zinc and vitamin E were probably sufficient in the control diet. Further work is needed to enhance our understanding on the interaction between, and the role of, stress and dietary micronutrients in fish health using a suite of assays to monitor all aspects of fish health, both in vitro and in vivo.The Waltham Centre for Pet Nutritio

Multinuclear NMR Investigations of Local Structure, Distortions and Redox Mechanisms in Layered Lithium Ion Battery Cathode Materials

Lithium ion (Li ion) battery technology has enabled a complete revolution in consumer electronics and is beginning to have a similar impact on transport. Increased adoption of electric vehicles is essential to reduce anthropogenic carbon emissions and combat climate change. For vehicular applications, improvements in specific and volumetric capacity are desirable, if they can be achieved without sacrificing safety, cost or cyclability. The redox mechanisms of many of the cathode materials with the highest capacities, particularly the “Li-excess” family, are poorly understood however, and such materials typically show accelerated degradation that makes commercial implementation impractical. Solid state NMR is a powerful tool to study local structure and ^{6/7}Li NMR has been used extensively to probe many aspects of local structure and dynamics in Li-ion batteries. Less commonly studied nuclei, such as ^{59}Co and ^{17}O can also offer complementary information, although their implementation and interpretation can be challenging. In this thesis the local structure, distortions and delithiation behaviours of two intriguing compounds are investigated: LiNi_{0.8}Co_{0.15}Al_{0.05}O_{2} (NCA)—a commercial cathode material with complex redox behaviour—and Li_2RuO_3—a model compound for the highly promising Li excess family of compounds. Firstly, the structure of pristine NCA is characterised. The complex dynamics of the Ni^{3+} Jahn-Teller (JT) distortion are probed using ^7Li, ^{17}O, ^{27}Al and ^{59}Co NMR spectroscopies and, by comparison with the expected statistical distribution of environments, a model emerges in which the JT distortions are dynamically disordered but the average structure is weighted towards thermodynamically favoured arrangements. This study is then extended to electrochemically delithiated NCA samples, which reveals enhanced Li mobility on delithiation from variable temperature (VT) ^7Li NMR measurements. Using an extension of the statistical model employed for the pristine material, the lineshapes are modelled and hopping rates for Li are estimated. At the onset of fast Li motion, two populations of Li are observed, indicating heterogeneous delithiation; this may suggest a kinetic origin for the reaction heterogeneity and poor first cycle coulombic efficiency observed in NCA. Finally, the redox mechanisms and electronic structure of NCA are investigated. ^{59}Co NMR reveals a population of Co^{3+} is present at the end of charge, demonstrating a deviation from the conventional cation redox model. The unintuitive evolution of the ^{59}Co peak position further reveals an evolution of the Co^{3+} electronic structure which is consistent with the observed long-range structural changes. Li^{2}RuO^{3} and its doped analogues are commonly employed as model compounds to understand redox mechanisms in Li excess cathode materials. Despite its single redox centre and well-ordered Ru-layer, ^7Li and ^{17}O NMR, along with magnetic susceptibility measurements confirm that that the Ru^{4+} ions form dimers and the effect of dimerisation on the observed ^{17}O NMR shifts is elucidated. The dimers, which are ordered at room temperature, lose their long-range ordering above 260 °C when Li_2RuO_3 undergoes a phase transition. This phase transition is characterised using laser-heated VT NMR and the changes observed, via ^7Li and ^{17}O NMR, reflect the changes in susceptibility and confirm the room temperature assignments. The changes in the structure, dimerisation of Ru and electronic structure in Li_2RuO_3 on delithiation are then investigated, which have implications for the understanding of the redox mechanisms in this highly studied compound and other Li-excess compounds. Notably, it is found that the Ru-dimerisation, which is highly influential in the pristine material, appears to remain throughout the discharging process.I thank the North East Center for Chemical Energy Storage (NECCES), an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under award DE-SC0012583 for funding

Sensitivity of LDEF foil analyses using ultra-low background germanium vs. large NaI(Tl) multidimensional spectrometers

Cobalt foils and stainless steel samples were analyzed for induced Co-60 activity with both an ultra-low background germanium gamma-ray spectrometer and with a large NaI(Tl) multidimensional spectrometer, both of which use electronic anticoincidence shielding to reduce background counts resulting from cosmic rays. Aluminum samples were analyzed for Na-22. The results, in addition to the relative sensitivities and precisions afforded by the two methods, are presented

Economics is becoming an elite subject for elite UK universities

UK universities have had to become much more responsive to changes in the pattern of demand and compete with one another for different revenue streams. James Johnston and Alan Reeves ask how this has played out in relation to the undergraduate economics degree, finding that new universities have retreated from offering economics programmes even as student numbers rose substantially. The authors argue that the role of research evaluation exercises cannot be ignored in this development and that there is a widening gulf between new and old universities. Moreover, the study of economics is being restricted along class lines, with students from disadvantaged backgrounds more likely to attend new universities and thus less likely to have access to economics programmes