Assigning function to genome wide association study variants associated with complex gastrointestinal disease

PhDThe genome‐wide association study era has identified numerous loci associated with many common polygenic diseases. The next challenge is to identify the functional consequences of these variants and elicit how they impact on disease risk. Using a combination of protein based assays, large scale microarrays and high‐throughput generation sequencing platforms this thesis aims to identify the functional effects of disease loci, with particular focus on Crohn’s disease and coeliac disease, two common complex gastrointestinal diseases. Variants located within the Interleukin 23 receptor are associated with both susceptibility and protection from Crohn’s disease, a debilitating chronic inflammatory disease of the bowel. A study was undertaken to investigate the effect of these variants, at the mRNA as well as the protein level, on both cytokine and receptor levels. Coeliac disease is a dietary intolerance to the gluten component of wheat, barley and rye and has an estimated prevalence of approximately 1%. Genome‐wide association studies have identified eight genomic different loci as associated with coeliac disease but none have been functionally characterised. To investigate the effect that genotype has on gene transcript levels, a genetical genomics study was undertaken in patients with coeliac disease generating results with relevance to a range of autoimmune disorders. Before disease based effects can be identified, it is first important to fully characterise the normal human transcriptome and methylome. To this end CD4 + T cells were studied using novel high‐throughput sequencing techniques, with the aim of providing some insight into novel genomic properties that may illuminate current and future disease associated loci. Given the base pair resolution approach of high‐throughput sequencing, a novel method of assaying for SNP effects on gene expression was developed. This allele specific method, using whole transcriptome sequencing, is capable of identifying alterations in transcript expression on a genome‐wide scale

Decision making for net zero policy design and climate action:Considerations for improving translation at the research-policy interface: A UK Carbon Dioxide Removal Case Study

The impacts of climate change on society and the natural environment are being experienced now, with extreme weather events increasing in frequency and severity across the globe. To keep the Paris Agreement's ambition of limiting warming to 1.5ºC above pre-industrial levels there is now also a need to establish and scale a new sector to remove CO2 at Giga-tonne scale for over a century. Despite this mounting evidence and warnings, current climate policy in the UK and globally falls far short of achieving the required reductions in CO2 emissions or establishment of a new removal sector needed to stave off the risks posed by climate change. Some of the science on climate risk is abundant and well evidenced, but the policy response is lacking in effectiveness. Other evidence to design policy, such as Carbon Dioxide Removal (CDR), is fraught with deep uncertainty. Why are the plethora of scientific evidence, assessments and decision support tools available to decision and policymakers not always translating into effective climate-net zero policy action? How can emergent evidence be brought in introduced to shape new sectors such as CDR? What are the capacity gaps? Through a combination of literature review, interviews and UK policy workshops over 17 months these are some of the questions that this contribution sought insight. We set out three recommendations for policymakers and other stakeholders, including academic researchers and third sector organisations, to address the identified gaps associated with translating climate risk and net zero decision support into effective climate policy: Enhance collaboration between decision-makers, policymakers, analysts, researchers, and other stakeholders to co-develop and co-design operational climate risk assessments and policies, relevant to context. Identify the research and capacity gaps around climate risk decision-making under uncertainty, and work with stakeholders across the decision value chain to ensure those gaps are addressed. Co-create effective translation mechanisms to embed decision-support tools into policy better, employing a participatory approach to ensure inclusion of diverse values and viewpoints. It is fundamental that there is improvement in our understanding about how we can make good decisions and operationalise them, rather than simply focus on further research on the climate risk and net zero problem

Decision making for net zero policy design and climate action:Considerations for improving translation at the research-policy interface: A UK Carbon Dioxide Removal Case Study

The impacts of climate change on society and the natural environment are being experienced now, with extreme weather events increasing in frequency and severity across the globe. To keep the Paris Agreement's ambition of limiting warming to 1.5ºC above pre-industrial levels there is now also a need to establish and scale a new sector to remove CO2 at Giga-tonne scale for over a century. Despite this mounting evidence and warnings, current climate policy in the UK and globally falls far short of achieving the required reductions in CO2 emissions or establishment of a new removal sector needed to stave off the risks posed by climate change. Some of the science on climate risk is abundant and well evidenced, but the policy response is lacking in effectiveness. Other evidence to design policy, such as Carbon Dioxide Removal (CDR), is fraught with deep uncertainty. Why are the plethora of scientific evidence, assessments and decision support tools available to decision and policymakers not always translating into effective climate-net zero policy action? How can emergent evidence be brought in introduced to shape new sectors such as CDR? What are the capacity gaps? Through a combination of literature review, interviews and UK policy workshops over 17 months these are some of the questions that this contribution sought insight. We set out three recommendations for policymakers and other stakeholders, including academic researchers and third sector organisations, to address the identified gaps associated with translating climate risk and net zero decision support into effective climate policy: Enhance collaboration between decision-makers, policymakers, analysts, researchers, and other stakeholders to co-develop and co-design operational climate risk assessments and policies, relevant to context. Identify the research and capacity gaps around climate risk decision-making under uncertainty, and work with stakeholders across the decision value chain to ensure those gaps are addressed. Co-create effective translation mechanisms to embed decision-support tools into policy better, employing a participatory approach to ensure inclusion of diverse values and viewpoints. It is fundamental that there is improvement in our understanding about how we can make good decisions and operationalise them, rather than simply focus on further research on the climate risk and net zero problem

A short diastereoselective total synthesis of (±)-vibralactone

A total synthesis of the (±)-vibralactone has been achieved in 11 steps and 16% overall yield from malonic acid. Key steps include a highly diastereoselective allylation of an α-formyl ester containing an all carbon α-quaternary center, a Pd-catalyzed deallylative β-lactonization, and an aldehyde-selective Wacker oxidation of a terminal alkene

Design, Development, and In-flight Testing of a Pointer/tracker for In-flight Experiments to Measure Aero-optical Effects over a Scaled Turret

We address the design, development, and testing of a pointer/tracker as a probe beam for the purpose of making high-speed, aero-optical measurements of the flow over a scaled beam director turret. The tracker uses retro-reflection of the probe beam off of a Reflexite annulus surrounding the turret. The constraints of the design required a near-total-commercial off the shelf system that could be quickly installed and removed in a rented aircraft. Baseline measurements of environmental vibrations are used to predict pointing performance; mitigation of line-of-sight jitter on the probe beam is achieved through passive isolation and the design of relay optics. Accommodation of ambient light is made with the use of wavelength filters and track algorithms. Postanalysis of measured data is compared to design estimates

A Candidate Substellar Companion to HR 7329

We present the discovery of a candidate substellar companion from a survey of nearby, young stars with the NICMOS coronagraph on the Hubble Space Telescope. The H ~ 12 mag object was discovered approximately 4" from the young A0V star HR 7329. Using follow-up spectroscopy from STIS, we derive a spectral type between M7V and M8V with an effective temperature of ~ 2600 K. We estimate that the probability of a chance alignment with a foreground dwarf star of this nature is ~ 10^(-8) and therefore suggest the object (HR 7329B) is physically associated with HR 7329 with a projected separation of 200 AU. Current brown dwarf cooling models indicate a mass of less than 50 Jupiter masses for HR 7329B based on age estimates of < 30 Myr for HR7329A.Comment: 8 pages LATEX, 5 ps figures, accepted for Ap

Level Eulerian Posets

The notion of level posets is introduced. This class of infinite posets has the property that between every two adjacent ranks the same bipartite graph occurs. When the adjacency matrix is indecomposable, we determine the length of the longest interval one needs to check to verify Eulerianness. Furthermore, we show that every level Eulerian poset associated to an indecomposable matrix has even order. A condition for verifying shellability is introduced and is automated using the algebra of walks. Applying the Skolem--Mahler--Lech theorem, the ${\bf ab}$-series of a level poset is shown to be a rational generating function in the non-commutative variables ${\bf a}$ and ${\bf b}$. In the case the poset is also Eulerian, the analogous result holds for the ${\bf cd}$-series. Using coalgebraic techniques a method is developed to recognize the ${\bf cd}$-series matrix of a level Eulerian poset

Confirming the Primarily Smooth Structure of the Vega Debris Disk at Millimeter Wavelengths

Clumpy structure in the debris disk around Vega has been previously reported at millimeter wavelengths and attributed to concentrations of dust grains trapped in resonances with an unseen planet. However, recent imaging at similar wavelengths with higher sensitivity has disputed the observed structure. We present three new millimeter wavelength observations that help to resolve the puzzling and contradictory observations. We have observed the Vega system with the Submillimeter Array (SMA) at a wavelength of 880 μm and an angular resolution of 5"; with the Combined Array for Research in Millimeter-wave Astronomy (CARMA) at a wavelength of 1.3 mm and an angular resolution of 5"; and with the Green Bank Telescope (GBT) at a wavelength of 3.3 mm and angular resolution of 10". Despite high sensitivity and short baselines, we do not detect the Vega debris disk in either of the interferometric data sets (SMA and CARMA), which should be sensitive at high significance to clumpy structure based on previously reported observations. We obtain a marginal (3σ) detection of disk emission in the GBT data; the spatial distribution of the emission is not well constrained.We analyze the observations in the context of several different models, demonstrating that the observations are consistent with a smooth, broad, axisymmetric disk with inner radius 20–100 AU and width ≾50 AU. The interferometric data require that at least half of the 860 μm emission detected by previous single-dish observations with the James Clerk Maxwell Telescope be distributed axisymmetrically, ruling out strong contributions from flux concentrations on spatial scales of ≾100 AU. These observations support recent results from the Plateau de Bure Interferometer indicating that previous detections of clumpy structure in the Vega debris disk were spurious

Hubble Space Telescope Ultraviolet Spectroscopy of Fourteen Low-Redshift Quasars

We present low-resolution ultraviolet spectra of 14 low redshift (z<0.8) quasars observed with HST/STIS as part of a Snap project to understand the relationship between quasar outflows and luminosity. By design, all observations cover the CIV emission line. Nine of the quasars are from the Hamburg-ESO catalog, three are from the Palomar-Green catalog, and one is from the Parkes catalog. The sample contains a few interesting quasars including two broad absorption line (BAL) quasars (HE0143-3535, HE0436-2614), one quasar with a mini-BAL (HE1105-0746), and one quasar with associated narrow absorption (HE0409-5004). These BAL quasars are among the brightest known (though not the most luminous) since they lie at z<0.8. We compare the properties of these BAL quasars to the z1.4 Large Bright Quasar samples. By design, our objects sample luminosities in between these two surveys, and our four absorbed objects are consistent with the v ~ L^0.62 relation derived by Laor & Brandt (2002). Another quasar, HE0441-2826, contains extremely weak emission lines and our spectrum is consistent with a simple power-law continuum. The quasar is radio-loud, but has a steep spectral index and a lobe-dominated morphology, which argues against it being a blazar. The unusual spectrum of this quasar resembles the spectra of the quasars PG1407+265, SDSSJ1136+0242, and PKS1004+13 for which several possible explanations have been entertained.Comment: Uses aastex.cls, 21 pages in preprint mode, including 6 figures and 2 tables; accepted for publication in The Astronomical Journal (projected vol 133