2,243 research outputs found

    Inter-individual variation of the human epigenome & applications

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    Graduate Catalog of Studies, 2023-2024

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    Distributed Ledger Technology (DLT) Applications in Payment, Clearing, and Settlement Systems:A Study of Blockchain-Based Payment Barriers and Potential Solutions, and DLT Application in Central Bank Payment System Functions

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    Payment, clearing, and settlement systems are essential components of the financial markets and exert considerable influence on the overall economy. While there have been considerable technological advancements in payment systems, the conventional systems still depend on centralized architecture, with inherent limitations and risks. The emergence of Distributed ledger technology (DLT) is being regarded as a potential solution to transform payment and settlement processes and address certain challenges posed by the centralized architecture of traditional payment systems (Bank for International Settlements, 2017). While proof-of-concept projects have demonstrated the technical feasibility of DLT, significant barriers still hinder its adoption and implementation. The overarching objective of this thesis is to contribute to the developing area of DLT application in payment, clearing and settlement systems, which is still in its initial stages of applications development and lacks a substantial body of scholarly literature and empirical research. This is achieved by identifying the socio-technical barriers to adoption and diffusion of blockchain-based payment systems and the solutions proposed to address them. Furthermore, the thesis examines and classifies various applications of DLT in central bank payment system functions, offering valuable insights into the motivations, DLT platforms used, and consensus algorithms for applicable use cases. To achieve these objectives, the methodology employed involved a systematic literature review (SLR) of academic literature on blockchain-based payment systems. Furthermore, we utilized a thematic analysis approach to examine data collected from various sources regarding the use of DLT applications in central bank payment system functions, such as central bank white papers, industry reports, and policy documents. The study's findings on blockchain-based payment systems barriers and proposed solutions; challenge the prevailing emphasis on technological and regulatory barriers in the literature and industry discourse regarding the adoption and implementation of blockchain-based payment systems. It highlights the importance of considering the broader socio-technical context and identifying barriers across all five dimensions of the social technical framework, including technological, infrastructural, user practices/market, regulatory, and cultural dimensions. Furthermore, the research identified seven DLT applications in central bank payment system functions. These are grouped into three overarching themes: central banks' operational responsibilities in payment and settlement systems, issuance of central bank digital money, and regulatory oversight/supervisory functions, along with other ancillary functions. Each of these applications has unique motivations or value proposition, which is the underlying reason for utilizing in that particular use case

    Graduate Catalog of Studies, 2023-2024

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    Inter-individual variation of the human epigenome & applications

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    Genome-wide association studies (GWAS) have led to the discovery of genetic variants influencing human phenotypes in health and disease. However, almost two decades later, most human traits can still not be accurately predicted from common genetic variants. Moreover, genetic variants discovered via GWAS mostly map to the non-coding genome and have historically resisted interpretation via mechanistic models. Alternatively, the epigenome lies in the cross-roads between genetics and the environment. Thus, there is great excitement towards the mapping of epigenetic inter-individual variation since its study may link environmental factors to human traits that remain unexplained by genetic variants. For instance, the environmental component of the epigenome may serve as a source of biomarkers for accurate, robust and interpretable phenotypic prediction on low-heritability traits that cannot be attained by classical genetic-based models. Additionally, its research may provide mechanisms of action for genetic associations at non-coding regions that mediate their effect via the epigenome. The aim of this thesis was to explore epigenetic inter-individual variation and to mitigate some of the methodological limitations faced towards its future valorisation.Chapter 1 is dedicated to the scope and aims of the thesis. It begins by describing historical milestones and basic concepts in human genetics, statistical genetics, the heritability problem and polygenic risk scores. It then moves towards epigenetics, covering the several dimensions it encompasses. It subsequently focuses on DNA methylation with topics like mitotic stability, epigenetic reprogramming, X-inactivation or imprinting. This is followed by concepts from epigenetic epidemiology such as epigenome-wide association studies (EWAS), epigenetic clocks, Mendelian randomization, methylation risk scores and methylation quantitative trait loci (mQTL). The chapter ends by introducing the aims of the thesis.Chapter 2 focuses on stochastic epigenetic inter-individual variation resulting from processes occurring post-twinning, during embryonic development and early life. Specifically, it describes the discovery and characterisation of hundreds of variably methylated CpGs in the blood of healthy adolescent monozygotic (MZ) twins showing equivalent variation among co-twins and unrelated individuals (evCpGs) that could not be explained only by measurement error on the DNA methylation microarray. DNA methylation levels at evCpGs were shown to be stable short-term but susceptible to aging and epigenetic drift in the long-term. The identified sites were significantly enriched at the clustered protocadherin loci, known for stochastic methylation in neurons in the context of embryonic neurodevelopment. Critically, evCpGs were capable of clustering technical and longitudinal replicates while differentiating young MZ twins. Thus, discovered evCpGs can be considered as a first prototype towards universal epigenetic fingerprint, relevant in the discrimination of MZ twins for forensic purposes, currently impossible with standard DNA profiling. Besides, DNA methylation microarrays are the preferred technology for EWAS and mQTL mapping studies. However, their probe design inherently assumes that the assayed genomic DNA is identical to the reference genome, leading to genetic artifacts whenever this assumption is not fulfilled. Building upon the previous experience analysing microarray data, Chapter 3 covers the development and benchmarking of UMtools, an R-package for the quantification and qualification of genetic artifacts on DNA methylation microarrays based on the unprocessed fluorescence intensity signals. These tools were used to assemble an atlas on genetic artifacts encountered on DNA methylation microarrays, including interactions between artifacts or with X-inactivation, imprinting and tissue-specific regulation. Additionally, to distinguish artifacts from genuine epigenetic variation, a co-methylation-based approach was proposed. Overall, this study revealed that genetic artifacts continue to filter through into the reported literature since current methodologies to address them have overlooked this challenge.Furthermore, EWAS, mQTL and allele-specific methylation (ASM) mapping studies have all been employed to map epigenetic variation but require matching phenotypic/genotypic data and can only map specific components of epigenetic inter-individual variation. Inspired by the previously proposed co-methylation strategy, Chapter 4 describes a novel method to simultaneously map inter-haplotype, inter-cell and inter-individual variation without these requirements. Specifically, binomial likelihood function-based bootstrap hypothesis test for co-methylation within reads (Binokulars) is a randomization test that can identify jointly regulated CpGs (JRCs) from pooled whole genome bisulfite sequencing (WGBS) data by solely relying on joint DNA methylation information available in reads spanning multiple CpGs. Binokulars was tested on pooled WGBS data in whole blood, sperm and combined, and benchmarked against EWAS and ASM. Our comparisons revealed that Binokulars can integrate a wide range of epigenetic phenomena under the same umbrella since it simultaneously discovered regions associated with imprinting, cell type- and tissue-specific regulation, mQTL, ageing or even unknown epigenetic processes. Finally, we verified examples of mQTL and polymorphic imprinting by employing another novel tool, JRC_sorter, to classify regions based on epigenotype models and non-pooled WGBS data in cord blood. In the future, we envision how this cost-effective approach can be applied on larger pools to simultaneously highlight regions of interest in the methylome, a highly relevant task in the light of the post-GWAS era.Moving towards future applications of epigenetic inter-individual variation, Chapters 5 and 6 are dedicated to solving some of methodological issues faced in translational epigenomics.Firstly, due to its simplicity and well-known properties, linear regression is the starting point methodology when performing prediction of a continuous outcome given a set of predictors. However, linear regression is incompatible with missing data, a common phenomenon and a huge threat to the integrity of data analysis in empirical sciences, including (epi)genomics. Chapter 5 describes the development of combinatorial linear models (cmb-lm), an imputation-free, CPU/RAM-efficient and privacy-preserving statistical method for linear regression prediction on datasets with missing values. Cmb-lm provide prediction errors that take into account the pattern of missing values in the incomplete data, even at extreme missingness. As a proof-of-concept, we tested cmb-lm in the context of epigenetic ageing clocks, one of the most popular applications of epigenetic inter-individual variation. Overall, cmb-lm offer a simple and flexible methodology with a wide range of applications that can provide a smooth transition towards the valorisation of linear models in the real world, where missing data is almost inevitable. Beyond microarrays, due to its high accuracy, reliability and sample multiplexing capabilities, massively parallel sequencing (MPS) is currently the preferred methodology of choice to translate prediction models for traits of interests into practice. At the same time, tobacco smoking is a frequent habit sustained by more than 1.3 billion people in 2020 and a leading (and preventable) health risk factor in the modern world. Predicting smoking habits from a persistent biomarker, such as DNA methylation, is not only relevant to account for self-reporting bias in public health and personalized medicine studies, but may also allow broadening forensic DNA phenotyping. Previously, a model to predict whether someone is a current, former, or never smoker had been published based on solely 13 CpGs from the hundreds of thousands included in the DNA methylation microarray. However, a matching lab tool with lower marker throughput, and higher accuracy and sensitivity was missing towards translating the model in practice. Chapter 6 describes the development of an MPS assay and data analysis pipeline to quantify DNA methylation on these 13 smoking-associated biomarkers for the prediction of smoking status. Though our systematic evaluation on DNA standards of known methylation levels revealed marker-specific amplification bias, our novel tool was still able to provide highly accurate and reproducible DNA methylation quantification and smoking habit prediction. Overall, our MPS assay allows the technological transfer of DNA methylation microarray findings and models to practical settings, one step closer towards future applications.Finally, Chapter 7 provides a general discussion on the results and topics discussed across Chapters 2-6. It begins by summarizing the main findings across the thesis, including proposals for follow-up studies. It then covers technical limitations pertaining bisulfite conversion and DNA methylation microarrays, but also more general considerations such as restricted data access. This chapter ends by covering the outlook of this PhD thesis, including topics such as bisulfite-free methods, third-generation sequencing, single-cell methylomics, multi-omics and systems biology.<br/

    LIPIcs, Volume 251, ITCS 2023, Complete Volume

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    LIPIcs, Volume 251, ITCS 2023, Complete Volum

    The 2023 terahertz science and technology roadmap

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    Terahertz (THz) radiation encompasses a wide spectral range within the electromagnetic spectrum that extends from microwaves to the far infrared (100 GHz–∼30 THz). Within its frequency boundaries exist a broad variety of scientific disciplines that have presented, and continue to present, technical challenges to researchers. During the past 50 years, for instance, the demands of the scientific community have substantially evolved and with a need for advanced instrumentation to support radio astronomy, Earth observation, weather forecasting, security imaging, telecommunications, non-destructive device testing and much more. Furthermore, applications have required an emergence of technology from the laboratory environment to production-scale supply and in-the-field deployments ranging from harsh ground-based locations to deep space. In addressing these requirements, the research and development community has advanced related technology and bridged the transition between electronics and photonics that high frequency operation demands. The multidisciplinary nature of THz work was our stimulus for creating the 2017 THz Science and Technology Roadmap (Dhillon et al 2017 J. Phys. D: Appl. Phys. 50 043001). As one might envisage, though, there remains much to explore both scientifically and technically and the field has continued to develop and expand rapidly. It is timely, therefore, to revise our previous roadmap and in this 2023 version we both provide an update on key developments in established technical areas that have important scientific and public benefit, and highlight new and emerging areas that show particular promise. The developments that we describe thus span from fundamental scientific research, such as THz astronomy and the emergent area of THz quantum optics, to highly applied and commercially and societally impactful subjects that include 6G THz communications, medical imaging, and climate monitoring and prediction. Our Roadmap vision draws upon the expertise and perspective of multiple international specialists that together provide an overview of past developments and the likely challenges facing the field of THz science and technology in future decades. The document is written in a form that is accessible to policy makers who wish to gain an overview of the current state of the THz art, and for the non-specialist and curious who wish to understand available technology and challenges. A such, our experts deliver a 'snapshot' introduction to the current status of the field and provide suggestions for exciting future technical development directions. Ultimately, we intend the Roadmap to portray the advantages and benefits of the THz domain and to stimulate further exploration of the field in support of scientific research and commercial realisation

    Investigating the learning potential of the Second Quantum Revolution: development of an approach for secondary school students

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    In recent years we have witnessed important changes: the Second Quantum Revolution is in the spotlight of many countries, and it is creating a new generation of technologies. To unlock the potential of the Second Quantum Revolution, several countries have launched strategic plans and research programs that finance and set the pace of research and development of these new technologies (like the Quantum Flagship, the National Quantum Initiative Act and so on). The increasing pace of technological changes is also challenging science education and institutional systems, requiring them to help to prepare new generations of experts. This work is placed within physics education research and contributes to the challenge by developing an approach and a course about the Second Quantum Revolution. The aims are to promote quantum literacy and, in particular, to value from a cultural and educational perspective the Second Revolution. The dissertation is articulated in two parts. In the first, we unpack the Second Quantum Revolution from a cultural perspective and shed light on the main revolutionary aspects that are elevated to the rank of principles implemented in the design of a course for secondary school students, prospective and in-service teachers. The design process and the educational reconstruction of the activities are presented as well as the results of a pilot study conducted to investigate the impact of the approach on students' understanding and to gather feedback to refine and improve the instructional materials. The second part consists of the exploration of the Second Quantum Revolution as a context to introduce some basic concepts of quantum physics. We present the results of an implementation with secondary school students to investigate if and to what extent external representations could play any role to promote students’ understanding and acceptance of quantum physics as a personal reliable description of the world

    Simultaneous Multiparametric and Multidimensional Cardiovascular Magnetic Resonance Imaging

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    Insights into temperature controls on rockfall occurrence and cliff erosion

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    A variety of environmental triggers have been associated with the occurrence of rockfalls however their role and relative significance remains poorly constrained. This is in part due to the lack of concurrent data on rockfall occurrence and cliff face conditions at temporal resolutions that mirror the variability of environmental conditions, and over durations for large enough numbers of rockfall events to be captured. The aim of this thesis is to fill this data gap, and then to specifically focus on the role of temperature in triggering rockfall that this data illuminates. To achieve this, a long-term multiannual 3D rockfall dataset and contemporaneous Infrared Thermography (IRT) monitoring of cliff surface temperatures has been generated. The approaches used in this thesis are undertaken at East Cliff, Whitby, which is a coastal cliff located in North Yorkshire, UK. The monitored section is ~ 200 m wide and ~65 m high, with a total cliff face area of ~9,592 m². A method for the automated quantification of rockfall volumes is used to explore data collected between 2017–2019 and 2021, with the resulting inventory including > 8,300 rockfalls from 2017–2019 and > 4,100 rockfalls in 2021, totalling > 12,400 number of rockfalls. The analysis of the inventory demonstrates that during dry conditions, increases in rockfall frequency are coincident with diurnal surface temperature fluctuations, notably at sunrise, noon and sunset in all seasons, leading to a marked diurnal pattern of rockfall. Statistically significant relationships are observed to link cliff temperature and rockfall, highlighting the response of rock slopes to absolute temperatures and changes in temperature. This research also shows that inclement weather constitutes the dominant control over the annual production of rockfalls but also quantifies the period when temperature controls are dominant. Temperature-controlled rockfall activity is shown to have an important erosional role, particularly in periods of iterative erosion dominated by small size rockfalls. As such, this thesis provides for the first high-resolution evidence of temperature controls on rockfall activity, cliff erosion and landform development
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