Competitive-Binding Based Optical DNA Mapping - From Bacterial Plasmids to the Human Genome

Significant advances within the field of DNA sequencing have allowed us to study DNA at a level of detail that was previously impossible. However, dynamic genomic regions with a high degree of structural variations, while being linked to disease in humans and increased resistance to antibiotics, are still challenging to characterize. Furthermore, DNA sequencing for bacterial diagnostics and detection of resistance genes is presently hampered by the excessive lead times associated with the overall complexity of the applied methods.This Thesis describes the development of novel assays based on optical DNA mapping, which, although studying DNA at a lower resolution, is capable of rapid processing of significantly larger DNA fragments compared to sequencing. The fluorescent labeling in the assays presented here relies on competitive DNA binding between the emissive YOYO-1 and the sequence-specific, non-emissive, netropsin. The labeled DNA is then stretched in nanofluidic channels and imaged using fluorescence microscopy, enabling extraction of coarse-grained sequence information from ultralong DNA molecules at the single-molecule level.The results demonstrate how competitive binding-based optical DNA mapping can be used to characterize and trace bacterial DNA, responsible for the spread of antibiotic resistance. The mapped bacterial DNA can also be used to identify bacterial species in complex mixtures and directly from clinical samples. Additionally, so-called long-range sequence information of the human genome can be obtained, with possible future applications including detection of disease-related structural variations and epigenetic profiling

Does Form follow Function? Connecting Function Modelling and Geometry Modelling for Design Space Exploration

The aerospace industry, representative of industries developing complex products, faces challenges from changes in user behaviour, legislation, environmental policy. Meeting these challenges will require the development of radically new products. Radically new technologies and solutions need to be explored, investigated, and integrated into existing aerospace component architectures. The currently available design space exploration (DSE) methods, mainly based around computer-aided design (CAD) modelling, do not provide sufficient support for this exploration. These methods often lack a representation of the product’s architecture in relation to its design rationale (DR)—they do not illustrate how form follows function. Hence, relations between different functions and solutions, as well as how novel ideas relate to the legacy design, are not captured. In particular, the connection between a product’s function and the embodiment of its solution is not captured in the applied product modelling approaches, and can therefore not be used in the product development process.To alleviate this situation, this thesis presents a combined function and geometry-modelling approach with automated generation of CAD models for variant concepts. The approach builds on enhanced function means (EF-M) modelling for representation of the design space and the legacy design’s position in it. EF-M is also used to capture novel design solutions and reference them to the legacy design’s architecture. A design automation (DA) approach based on modularisation of the CAD model, which in turn is based on the functional decomposition of the product concepts, is used to capture geometric product information. A combined function-geometry object model captures the relations between functions, solutions, and geometry. This allows for CAD models of concepts based on alternative solutions to be generated.The function- and geometry-exploration (FGE) approach has been developed and tested in collaboration with an aerospace manufacturing company. A proof-of-concept tool implementing the approach has been realised. The approach has been validated for decomposition, innovation, and embodiment of new concepts in multiple studies involving three different aerospace suppliers. Application of FGE provides knowledge capture and representation, connecting the teleological and geometric aspects of the product. Furthermore, it supports the exploration of increasingly novel solutions, enabling the coverage of a wider area of the design space.The connection between the modelling domains addresses a research gap for the “integration of function architectures with CAD models”.While the FGE approach has been tested in laboratory environments as well as in applied product development projects, further development is needed to refine CAD integration and user experience and integrate additional modelling domains

Perceptual Differences for Modifications of the Elevation of Early Room Reflections

Acoustic room responses usually comprise components that propagate in non-horizontal directions. Oftentimes, audio capture and reproduction systems are not capable of maintaining such elevation information reliably hence it is important to understand their perceptual significance when auralizing rooms. This work investigates the ability of the human hearing system to distinguish between early reflections with different elevation angles by performing loudspeaker- and headphone-based listening experiments using manipulated spatial room impulse responses. The results show that changing the elevation of a strong early reflection can lead to clearly perceivable differences and factors that influence the detectability are identified. Projecting all elevated reflections of a spatial room impulse response with no very prominent ceiling reflection to the horizontal plane showed no perceivable differences

Perceptual Differences for Modifications of the Elevation of Early Room Reflections

Acoustic room responses usually comprise components that propagate in non-horizontal directions. Oftentimes, audio capture and reproduction systems are not capable of maintaining such elevation information reliably hence it is important to understand their perceptual significance when auralizing rooms. This work investigates the ability of the human hearing system to distinguish between early reflections with different elevation angles by performing loudspeaker- and headphone-based listening experiments using manipulated spatial room impulse responses. The results show that changing the elevation of a strong early reflection can lead to clearly perceivable differences and factors that influence the detectability are identified. Projecting all elevated reflections of a spatial room impulse response with no very prominent ceiling reflection to the horizontal plane showed no perceivable differences

Perceptions and Attitudes to a Terrorist Shock: Evidence from the UK

The emergence of transnational terrorism in Western countries has raised the debate about security measures, some of which could constrain civil liberties. This is the first paper that uses terrorist attacks (on 7th July, 2005 in London) as an exogenous source of variation to study the dynamics of risk perceptions and its impact on the readiness to trade off civil liberties for enhanced security. In this framework we show that the willingness to trade off security for liberties is dramatically affected by changes in individual risk assessments brought on after a terrorist attack, and document the extent of its persistence

Terrorism Risk Concern in Europe

We explore whether differences of terrorism risk perception across all European countries reflect their underlying differences in terrorism risk, which we decompose into a long term and innovation component. We employ longitudinal country-level data on terrorism risk concern and our modeling approach is motivated by the Bayesian framework. We conclude that the observed risk perception variation is significantly explained by the long term terrorism countries face, while the cyclical part of terrorism activity does not affect risk perception

A quantitative taxonomy of human hand grasps

Background: A proper modeling of human grasping and of hand movements is fundamental for robotics, prosthetics, physiology and rehabilitation. The taxonomies of hand grasps that have been proposed in scientific literature so far are based on qualitative analyses of the movements and thus they are usually not quantitatively justified. Methods: This paper presents to the best of our knowledge the first quantitative taxonomy of hand grasps based on biomedical data measurements. The taxonomy is based on electromyography and kinematic data recorded from 40 healthy subjects performing 20 unique hand grasps. For each subject, a set of hierarchical trees are computed for several signal features. Afterwards, the trees are combined, first into modality-specific (i.e. muscular and kinematic) taxonomies of hand grasps and then into a general quantitative taxonomy of hand movements. The modality-specific taxonomies provide similar results despite describing different parameters of hand movements, one being muscular and the other kinematic. Results: The general taxonomy merges the kinematic and muscular description into a comprehensive hierarchical structure. The obtained results clarify what has been proposed in the literature so far and they partially confirm the qualitative parameters used to create previous taxonomies of hand grasps. According to the results, hand movements can be divided into five movement categories defined based on the overall grasp shape, finger positioning and muscular activation. Part of the results appears qualitatively in accordance with previous results describing kinematic hand grasping synergies. Conclusions: The taxonomy of hand grasps proposed in this paper clarifies with quantitative measurements what has been proposed in the field on a qualitative basis, thus having a potential impact on several scientific fields

Connecting functional and geometrical representations to support the evaluation of design alternatives for aerospace components

Novel product concepts are often down-selected in favour of the incremental development of available designs. This can be attributed to the fact that for the development of a new product, simulations and analysis based on high-fidelity CAD models are required, which are expensive to create. To solve this problem, the use of a function model (FM) as intermediate step between ideation and embodiment is suggested. The approach has been examined in a case study with an aerospace company for the development of a turbine rear assembly, using multiple workshops and interviews with practitioners from the company. A multitude of novel solutions, even extending the functionality of the legacy design, were captured. The FM approach proved to support the representation, analysis, and configuration of 102 different concepts. Although supported by the FM model, the embodiment still showed to be a bottle neck for further development. The subsequent interviews with practitioners showed that the benefits of the approach were seen, but experienced as too complex. Further work will concern a more systematic connection between the FM and CAD model, in order to automate of the embodiment process