Doctor of Philosophy

dissertationThe main concern of human population genetics is to identify and describe genetic differences between groups of people. These differences give insight into the evolutionary processes and unique histories that have shaped these populations. A better understanding of human genetic diversity will lead to a better understanding of the biological systems that underly human phenotypic diversity. Here I explore three processes which have led to population differentiation in modern humans. First, I examine how differential disease risk across continents may have (or may not have) led to differences in allele frequencies immune-related genes. Second, I describe a method for discovering genomic regions in admixed populations that appear more similar to one parent population than the other. This method highlights regions which may have very recently been under selection in these populations. And finally, using the same method I attempt to discern regions of the genome in modern humans that may have been shaped by archaic admixture

Design of a Ballistically-Launched Foldable Multirotor

The operation of multirotors in crowded environments requires a highly reliable takeoff method, as failures during takeoff can damage more valuable assets nearby. The addition of a ballistic launch system imposes a deterministic path for the multirotor to prevent collisions with its environment, as well as increases the multirotor’s range of operation and allows deployment from an unsteady platform. In addition, outfitting planetary rovers or entry vehicles with such deployable multirotors has the potential to greatly extend the data collection capabilities of a mission. A proof-of-concept multirotor aircraft has been developed, capable of transitioning from a ballistic launch configuration to a fully controllable flight configuration in midair after launch. The transition is accomplished via passive unfolding of the multirotor arms, triggered by a nichrome burn wire release mechanism. The design is 3D printable, launches from a three-inch diameter barrel, and has sufficient thrust to carry a significant payload. The system has been fabricated and field tested from a moving vehicle up to 50mph to successfully demonstrate the feasibility of the concept and experimentally validate the design’s aerodynamic stability and deployment reliability

Design and Autonomous Stabilization of a Ballistically Launched Multirotor

Aircraft that can launch ballistically and convert to autonomous, free flying drones have applications in many areas such as emergency response, defense, and space exploration, where they can gather critical situational data using onboard sensors. This paper presents a ballistically launched, autonomously stabilizing multirotor prototype (SQUID, Streamlined Quick Unfolding Investigation Drone) with an onboard sensor suite, autonomy pipeline, and passive aerodynamic stability. We demonstrate autonomous transition from passive to vision based, active stabilization, confirming the ability of the multirotor to autonomously stabilize after a ballistic launch in a GPS denied environment.Comment: Accepted to 2020 International Conference on Robotics and Automatio

Design and Autonomous Stabilization of a Ballistically-Launched Multirotor

Aircraft that can launch ballistically and convert to autonomous, free-flying drones have applications in many areas such as emergency response, defense, and space exploration, where they can gather critical situational data using onboard sensors. This paper presents a ballistically-launched, autonomously-stabilizing multirotor prototype (SQUID - Streamlined Quick Unfolding Investigation Drone) with an onboard sensor suite, autonomy pipeline, and passive aerodynamic stability. We demonstrate autonomous transition from passive to vision-based, active stabilization, confirming the multirotor’s ability to autonomously stabilize after a ballistic launch in a GPS-denied environment

Design and Autonomous Stabilization of a Ballistically-Launched Multirotor

Aircraft that can launch ballistically and convert to autonomous, free-flying drones have applications in many areas such as emergency response, defense, and space exploration, where they can gather critical situational data using onboard sensors. This paper presents a ballistically-launched, autonomously-stabilizing multirotor prototype (SQUID - Streamlined Quick Unfolding Investigation Drone) with an onboard sensor suite, autonomy pipeline, and passive aerodynamic stability. We demonstrate autonomous transition from passive to vision-based, active stabilization, confirming the multirotor’s ability to autonomously stabilize after a ballistic launch in a GPS-denied environment

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease