Early Life Determinants of Metabolic and Reproductive Health

Events in early life have consistently been associated with health outcomes in later life. The ‘developmental origins’ theory first hypothesised that adverse conditions in-utero can lead to physiological adaptations in the developing foetus which have long lasting influences on health. This concept has been extended to early childhood and adolescence, whereby exposures during critical periods of development can impact health throughout the life course of an individual. In particular, a secular trend for a decreasing age of puberty onset has been linked to the global increases in prevalence of cardio-metabolic diseases and cancer. It has been suggested that childhood obesity and lifetime sex hormone exposure may act as key mediating factors in this relationship. As the prevalence of obesity continues to rise globally and consequent comorbidities place an increasing burden on healthcare systems, understanding the mechanisms that link early life events to later life health have become of increasing importance. While environmental exposures are often cited as being highly influential on growth and development, the role of genetics has become gradually more apparent in recent years. This has been aided by the availability of increasingly large data resources. Genetic studies have shown that many developmental traits are highly heritable and share genetic determinants with metabolic and reproductive health outcomes. In this thesis I use data from large-scale, population-based resources to further elucidate the role of genetic and epigenetic factors in explaining observed associations between developmental traits and later life metabolic and reproductive health. I begin by examining the genetic aetiology of puberty timing in men, a key stage of sexual development which is understudied compared to women. I identify 29 novel genes involved in the control of puberty timing, implicating new biological pathways and demonstrate genetic correlations between earlier age of puberty and adverse health in adulthood. I then expand on the theme of genetic discovery by conducting genome-wide association studies (GWAS) for reproductive traits in the UK Biobank study. These outcomes have important societal and public health impacts but many have not previously been investigated from a genetic perspective. I identify over 800 variant-trait associations, highlighting genomic regions with highly pleiotropic influences on a diverse range of reproductive traits. This data is then leveraged to construct a framework for conducting phenome-wide association studies (PheWAS), which is used to explore the extent to which both BMI and sex hormone exposure act as mediating factors to explain the link between earlier puberty and heightened reproductive health risks. I go on to examine mechanisms linking early life markers of development to adult health. I investigate the association between weight at birth and body composition in adulthood, determining that foetal and maternal-specific genetic determinants of birth weight have differential influences on fat and lean mass distribution. Downstream analyses suggest that these operate through distinct biological pathways, adding to our understanding of the association between low birth weight and poor health. Finally, I conduct an epigenome-wide association study (EWAS) as a complementary approach to GWAS for both BMI and puberty timing to identify additional genomic loci associated with both traits. Using EWAS data I present evidence for a casual epigenetic effect on puberty timing, functioning through both BMI-mediated and independent pathways. The findings from this thesis contribute to the understanding of the genetic determinants of early life developmental processes and their relationship with later health, which have important implications for the improvement of individualised disease prevention and management

Companions to peculiar red giants: HR 363 and HR 1105

Recent IUE observations of two Tc-deficient S-type peculiar red giants that are also spectroscopic binaries, HR 363 and HR 1105 are reported. A 675 min SWP exposure of HR 363 shows emission lines of O I 1304 and Si II 1812 and a trace of continuum. Compared to the M giants, the far UV flux may be relatively larger, indicating a possible contribution from a white dwarf companion, but no high temperature emission lines are seen to indicate that this is an interacting system where mass-transfer recently occurred. However, HR 1105 appears to have a highly variable UV companion. In 1982, no UV flux was discerned for this system, but by 1986 C IV was strong, increasing by a factor of 3 in 1987 with prominent lines of Si III, C III, O III, Si IV, and N V. Using orbital parameters, these observations are consistent with high activity occuring when the side of the S-star primary illuminated by the companion faces the Earth, but since the IUE data were taken over 3 orbits, a secular change in the UV component cannot be excluded

Observational Results of a Multi-Telescope Campaign in Search of Interstellar Urea [(NH2_2)2_2CO]

In this paper, we present the results of an observational search for gas phase urea [(NH$_2$)$_2$CO] observed towards the Sgr B2(N-LMH) region. We show data covering urea transitions from $\sim$100 GHz to 250 GHz from five different observational facilities: BIMA, CARMA, the NRAO 12 m telescope, the IRAM 30 m telescope, and SEST. The results show that the features ascribed to urea can be reproduced across the entire observed bandwidth and all facilities by best fit column density, temperature, and source size parameters which vary by less than a factor of 2 between observations merely by adjusting for telescope-specific parameters. Interferometric observations show that the emission arising from these transitions is cospatial and compact, consistent with the derived source sizes and emission from a single species. Despite this evidence, the spectral complexity, both of (NH$_2$)$_2$CO and of Sgr B2(N), makes the definitive identification of this molecule challenging. We present observational spectra, laboratory data, and models, and discuss our results in the context of a possible molecular detection of urea.Comment: 38 pages, 9 Figures, accepted in the Astrophysical Journa

Cold-formed steel profiled decks topped with cementitious structural panels to enable fast floor construction of residential buildings

High efficiency floor systems satisfying structural and serviceability performance and providing ease of construction could significantly impact the quality and cost of buildings. Many of the traditional floor systems require cast-in-place concrete and most of the new floor systems are proprietary, resulting in additional costs. The FastFloor Residential project explores a new type of floor system that is non-proprietary and uses existing components to make a simple efficient design without any cast-in-place concrete. The prototype design uses two cold-formed steel profiled decks connected with self-drilling screws to form a cellular deck and topped with cementitious structural panels. Through a series of twelve four-point bending tests, the impact of fully and partially composite deck-to-structural panel connections are explored. This paper investigates how the deck and structural panel interaction impacts capacity, stiffness, and failure mode of the prototype floor system. The results have shown that using the structural panels could increase the ultimate strength up to 50%.Testing on a FastFloor Residential prototype has provided promising results. The structural panel and use of a close fastener spacing both show significant increase in capacity above steel only response. There is, however, significant analysis and testing that needs to be completed to make more significant conclusions regarding serviceability, strength, and the use of the prototype in diaphragms

Aeroheating Testing and Predictions for Project Orion CEV at Turbulent Conditions

An investigation of the aeroheating environment of the Project Orion Crew Exploration Vehicle was performed in the Arnold Engineering Development Center Hypervelocity Wind Tunnel No. 9 Mach 8 and Mach 10 nozzles and in the NASA Langley Research Center 20 - Inch Mach 6 Air Tunnel. Heating data were obtained using a thermocouple-instrumented approx.0.035-scale model (0.1778-m/7-inch diameter) of the flight vehicle. Runs were performed in the Tunnel 9 Mach 10 nozzle at free stream unit Reynolds numbers of 1x10(exp 6)/ft to 20x10(exp 6)/ft, in the Tunnel 9 Mach 8 nozzle at free stream unit Reynolds numbers of 8 x 10(exp 6)/ft to 48x10(exp 6)/ft, and in the 20-Inch Mach 6 Air Tunnel at free stream unit Reynolds numbers of 1x10(exp 6)/ft to 7x10(exp 6)/ft. In both facilities, enthalpy levels were low and the test gas (N2 in Tunnel 9 and air in the 20-Inch Mach 6) behaved as a perfect-gas. These test conditions produced laminar, transitional and turbulent data in the Tunnel 9 Mach 10 nozzle, transitional and turbulent data in the Tunnel 9 Mach 8 nozzle, and laminar and transitional data in the 20- Inch Mach 6 Air Tunnel. Laminar and turbulent predictions were generated for all wind tunnel test conditions and comparisons were performed with the experimental data to help define the accuracy of computational method. In general, it was found that both laminar data and predictions, and turbulent data and predictions, agreed to within less than the estimated 12% experimental uncertainty estimate. Laminar heating distributions from all three data sets were shown to correlate well and demonstrated Reynolds numbers independence when expressed in terms of the Stanton number based on adiabatic wall-recovery enthalpy. Transition onset locations on the leeside centerline were determined from the data and correlated in terms of boundary-layer parameters. Finally turbulent heating augmentation ratios were determined for several body-point locations and correlated in terms of the boundary-layer momentum Reynolds number

Experimental Investigation of Project Orion Crew Exploration Vehicle Aeroheating in AEDC Tunnel 9

An investigation of the aeroheating environment of the Project Orion Crew Entry Vehicle has been performed in the Arnold Engineering Development Center Tunnel 9. The goals of this test were to measure turbulent heating augmentation levels on the heat shield and to obtain high-fidelity heating data for assessment of computational fluid dynamics methods. Laminar and turbulent predictions were generated for all wind tunnel test conditions and comparisons were performed with the data for the purpose of helping to define uncertainty margins for the computational method. Data from both the wind tunnel test and the computational study are presented herein

Sea ice thickness and elastic properties from the analysis of multimodal guided wave propagation measured with a passive seismic array

Field data are needed for a better understanding of sea ice decline in the context of climate change. The rapid technological and methodological advances of the last decade have led to a reconsideration of seismic methods in this matter. In particular, passive seismology has filled an important gap by removing the need to use active sources. We present a seismic experiment where an array of 247 geophones was deployed on sea ice, in the Van Mijen fjord near Sveagruva (Svalbard). The array is a mix of 1C and 3C stations with sampling frequencies of 500 and 1000 Hz. They recorded continuously the ambient seismic field in sea ice between 28 February and 26 March 2019. Data also include active acquisitions on 1 and 26 March with a radar antenna, a shaker unit, impulsive sources, and artificial sources of seismic noise. This data set is of unprecedented quality regarding sea ice seismic monitoring, as it also includes thousands of microseismic events recorded each day. By combining passive seismology approaches with specific array processing methods, we demonstrate that the multimodal dispersion curves of sea ice can be calculated without an active source and then used to infer sea ice properties. We calculated an ice thickness, Young's modulus, and Poisson's ratio with values h=543 cm, E=3.90.15 GPa, and nu=0.340.02 on 1 March, and h=583 cm, E=4.4 +/- 0.15 GPa, and nu=0.32 +/- 0.02 on 5 March. These values are consistent with in situ field measurements and observations.Peer reviewe

Concert recording 2017-11-05d

[Track 1]. Quatour pour Saxophones. Overture Brillante / Pierre Max Dubois -- [Track 2]. Arrivée de la Reine de Sabbat / G.F. Handel -- [Track 3]. Recitation book. Broken heart: Der du bist drei in Einigkeit / David Maslanka -- [Track 4]. Stemming+ / Nigel Wood -- [Track 5]. Capriol suite. Basse danse Pavane Tordion Bransles Pieds-en-l\u27air Mattachins / Peter Warlock arranged by R. Stevens -- [Track 6]. Carnival / Karen Street

Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual’s genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases