The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Development of automated turf testing equipment for playing surfaces

[Abstract]: Research has shown that a significant percentage of sporting injuries can be attributed to the sporting surface. The most serious of these injuries require surgery, for example, to correct knee ligament damage, a condition which involves expensive procedures and lengthy post-operative rehabilitation. The responsibility for meeting the costs of these injuries is not restricted to the player or the team; there is an unnecessary burden on society in terms of overtaxing an already encumbered health system. A correlation between knee injuries and the traction properties of the sporting surface has been identified by Dr John Orchard, a recognised expert in Australia for sporting injuries. Turf traction referred to in this thesis is a term relating to the shoe and sporting surface interface and reflects the maximum amount of torque a studded sporting shoe can impart on the surface before the integrity of the surface is compromised. Current equipment to measure turf traction properties has limited accuracy and repeatability. This thesis reports the development of a device which measures turf traction with improved accuracy, repeatability and operator safety in comparison with existing commercially-available equipment. The design described in this thesis comprises a rotating ground-engaging ‘foot’ driven by a DC motor to provide the required torque for traction measurement, and this torque is continuously monitored using a load cell via an idler sprocket in the drive train. A digital load indicator displays and transmits torque data, and a programmable controller automates the test sequence. A permanently-installed laptop computer analyses, displays and records the traction data. The mechanical design includes a chassis which provides convenient movement across a playing surface and also convenient transport between sporting surfaces. The design automates only those measurement processes that require a high degree of accuracy and repeatability. Non-critical actions are operated manually to maximise simplicity and minimise development costs. Commercially available technology is used wherever possible within the design to eliminate specialist maintenance skills or knowledge. Software was developed to analyse, display and record the traction data and produce a traction profile which is unique for this type of equipment. A full patent has been granted on the device (encompassing function, design and performance) to facilitate commercial development by the Queensland Department of Primary Industries and Fisheries. An evaluation of the accuracy and repeatability of this machine is described and several experiments were undertaken to analyse its ability to compare and differentiate turf species from the traction results. For torque measurements within the expected operating range of 50 to 100 Nm a maximum error of ±1.28% has been established. It is demonstrated that the device meets the design objectives of accuracy, repeatability and operational safety. It has been used within a national Horticulture Australia project to determine best practices for sustainable and safe playing surface of Australian Football League sports fields

Assessing grain crop attributes using digital imagery acquired from a low-altitude remote controlled aircraft

Considerable research has already been conducted using satellite and aerial imagery to observe cropping areas. However, these imagery platforms have limitations: repeatability, cloud cover, cost and poor spatial resolution. The aim of this study was to investigate the potential of detecting and mapping grain crop attributes using digital imagery acquired from a low-altitude remote controlled aircraft (RCA). The study utilised a digital camera (Kodak DC3200, 1 megapixel, 24-bit) mounted on a RCA of a high-wing cabin-design model of balsa wood construction with a 2m wingspan. The platform was powered by a 10 cc 4-stroke glow fuel (methanol) motor and has a payload of approximately 750g. Preliminary images were acquired on 8 February 2003, over sorghum crop fields (151°54′, –27°40′) 15 km south of Toowoomba, Queensland. The images were captured at approximately 120 m (400 ft) above the ground. Information contained in the images captured include: • canopy density (high and low leaf area index)—due to differences in soil-type, moisture/nutrient status, etc. • other land cover types (grass, soil, asphalt, etc.) • unplanted areas—due to planting misses, germination problems and tree influences. • micro-relief (topography) • fence lines, posts and other infrastructure. The information that this platform-sensor system can provide is potentially useful for many precision agriculture applications and farm planning in general. More work is being conducted that includes the use of infrared filter, geometric correction, multi-temporal acquisition, and the use of video camera