11,423 research outputs found

    Inter-individual variation of the human epigenome & applications

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    Explainable AI models for predicting drop coalescence in microfluidics device

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    In the field of chemical engineering, understanding the dynamics and probability of drop coalescence is not just an academic pursuit, but a critical requirement for advancing process design by applying energy only where it is needed to build necessary interfacial structures, increasing efficiency towards Net Zero manufacture. This research applies machine learning predictive models to unravel the sophisticated relationships embedded in the experimental data on drop coalescence in a microfluidics device. Through the deployment of SHapley Additive exPlanations values, critical features relevant to coalescence processes are consistently identified. Comprehensive feature ablation tests further delineate the robustness and susceptibility of each model. Furthermore, the incorporation of Local Interpretable Model-agnostic Explanations for local interpretability offers an elucidative perspective, clarifying the intricate decision-making mechanisms inherent to each model’s predictions. As a result, this research provides the relative importance of the features for the outcome of drop interactions. It also underscores the pivotal role of model interpretability in reinforcing confidence in machine learning predictions of complex physical phenomena that are central to chemical engineering applications

    Tipping Points and Early Warning Signals in the Climate-Carbon System

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    This is a thesis about tipping points and early warning signals. The tipping points investigated are related to various components of the climate-carbon system. In contrast, the work on early warning signals has more generic applications, however in this thesis they are analysed in the context of the climate-carbon system. The thesis begins with an introduction to the climate-carbon system as well as a discussion of tipping points in the Earth system. Then a more mathematical summary of tipping points and early warning signals is given. An investigation into the ‘compost bomb’ is undertaken, in which the spatial structure of soils is accounted for. It is found that a hot summer could cause a compost bomb. The effect of biogeochemical heating on the stability of the global carbon cycle is investigated and it is found to play only a small role. The potential for instabilities in the climate-carbon cycle is further investigated when the dynamic behaviour of the ocean carbon cycle is accounted for. It is found that some CMIP6 models may be close to having an unstable carbon cycle. Spatial early warning signals are investigated in the context of more rapidly forced systems. It is found that spatial early warning signals perform better when the system is rapidly forced compared with time series based early warning signals. The typical assumptions about white noise made when using early warning signals are also studied. It is found that time correlated noise may mask the early warning signal. It is shown that a spectral analysis can avoid this problem.European Commissio

    Uncertainty quantification for random domains using periodic random variables

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    We consider uncertainty quantification for the Poisson problem subject to domain uncertainty. For the stochastic parameterization of the random domain, we use the model recently introduced by Kaarnioja et al. (SIAM J. Numer. Anal., 2020) in which a countably infinite number of independent random variables enter the random field as periodic functions. We develop lattice quasi-Monte Carlo (QMC) cubature rules for computing the expected value of the solution to the Poisson problem subject to domain uncertainty. These QMC rules can be shown to exhibit higher order cubature convergence rates permitted by the periodic setting independently of the stochastic dimension of the problem. In addition, we present a complete error analysis for the problem by taking into account the approximation errors incurred by truncating the input random field to a finite number of terms and discretizing the spatial domain using finite elements. The paper concludes with numerical experiments demonstrating the theoretical error estimates

    Nernst-Planck-Gaussian modelling of electrodiffusional recovery from ephaptic excitation between mammalian cardiomyocytes

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    Introduction: In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na+ from, creating a negative potential within, ephaptic spaces between the participating membranes, activating the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete recovery of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time.Materials and Methods: Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na+], [Cl−], and the consequent Gaussian charge differences and membrane potential recovery patterns following a ΔV∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles.Results: Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm-2, experimentally reported radii a = 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance w = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na+] = 153.1 mM and [Cl−] = 145.8 mM, respective diffusion coefficients DNa = 1.3 × 109 and DCl = 2 × 109 nm2s-1. Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δt≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented a and w-dependent ionic concentration differences adapting Gauss’s flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying a, and DNa and DCl markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying w exerted minimal effects.Conclusion: We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies in vivo background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery

    Application and reduction of a nonlinear hyperelastic wall model capturing ex vivo relationships between fluid pressure, area, and wall thickness in normal and hypertensive murine left pulmonary arteries

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    Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel–Gasser–Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure–area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease

    Sperm Quality and Cryopreservation in Teleost: Effect of Seminal Plasma Component and Climate Change

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    [ES] La selección de gametos de alta calidad es un requisito indispensable a tener en cuenta en los programas de reproduccion asistida. El desarrollo de herramientas biotecnológicas como la criopreservación de gametos, juega un papel importante en la producción acuicola y en la formación de bancos de germoplasma, que contribuiran luego en la mejora genética de las poblaciónes de peces, principalmente aquellas en peligro y que pudieran estar más afectadas ante futuros cambios climáticos. En la primera fase de esta tesis realizada en la Unesp, se trabajó con una especie neotropical de elevada importancia económica para la region Suramericana. La segunda fase realizada en la UPV se trabajó con la Anguila europea (Anguilla anguilla), una especie clasificada en la Lista Roja de la (UICN) como especie "en peligro crítico de extinción". En la primera fase se buscó caracterizar la composición bioquímica del plasma y las características seminales de la especie para evaluar las posibles relaciones entre estos parámetros. El plasma seminal estuvo principalmente compuesto por iones de sodio (Na+) y dentro de los componentes orgánicos sobresalieron las proteínas totales y la glucosa. A través del análisis de componentes principales (PCA) se observó que la motilidad tenía una fuerte correlación positiva con el tiempo de motilidad, la concentración de espermatozoides y las proteínas totales. Estos análisis sirvieron de base para la creación de una solución diluyente utilizada posteriormente en la sustancia crioprotectora. Luego se determinó la influencia del plasma seminal como constituyente de la solución crioprotectora en la criopreservación de semen de P. reticulatum. Se utilizaron tres tratamientos: glucosa 5% + metanol 10% (T1), a este crioprotector se le agregó 30% de plasma seminal natural (T2) y 30% de plasma seminal artificial en base a los resultados de los componentes bioquímicos del plasma determinados para la especie en el experimento anterior (T3). Se evaluaron parámetros de motilidad espermática, capacidad fecundante del semen criopreservado, así como fragmentación del ADN. El tratamiento T1 resultó con los mejores valores de motilidad seguido del T2, y la capacidad fertilizante de estos dos tratamientos fue similar al control, sin embargo, el tratamiento T2 mostró menos daño en el ADN. Mediante el PCA se demostró que T1 tenía una mejor relación positiva con la fertilidad y la motilidad total y progresiva. Finalmente, evaluamos las estructuras de las subpoblaciones espermáticas en cada uno de los tratamientos utilizados. Mediante análisis multivariado en dos etapas, fue posible determinar tres subpoblaciones espermáticas en el semen crioconservado de la especie, SP1 (rápido-lineal), SP2 (rápido-no lineal) y SP3 (lento-lineal). T1 presentó el mayor porcentaje de SP1, siendo confirmado por la efectividad en la protección de las células de este tratamiento en el proceso de criopreservación de la especie. En la segunda fase que se está llevó a cabo en la UPV, el objetivo general fue determinar el efecto de la temperatura y el pH del agua de mar sobre la motilidad de los espermatozoides en la Anguila europea. Se determinó que el bajo pH del agua de mar (6.5-7.4) disminuyó la motilidad de los espermatozoides de anguila en comparación con el control (pH= 8.2). Cuando estudiamos el efecto combinado del pH del plasma seminal artificial y el pH de ASW (7.8 y 8.2), no encontramos diferencias estadísticas en la motilidad y cinética de los espermatozoides en relación con el pH del plasma seminal artificial, pero sí el pH del agua de mar. Se encontraron valores más altos de motilidad total (MOT), FA(rápidos) y ME (médios) con un pH de 8.2 que con un pH de 7.8. En contraste, la temperatura del agua de mar no afectó los parámetros de motilidad de los espermatozoides o la longevidad de los espermatozoides en el contexto del cambio climático.[CA] La selecció de gàmetes d'alta qualitat és un requisit indispensable a tenir en compte en els programes de reproducció assistida. El desenvolupament d'eines biotecnològiques com la criopreservació de gàmetes, juga un paper important en la producció aqüicola i en la formació de bancs de germoplasma, que contribuiran després a la millora genètica de les població de peixos, principalment aquelles en perill i que poguessin estar més afectades davant de futurs canvis climàtics. A la primera fase d'aquesta tesi realitzada a la Unesp, es va treballar amb una espècie neotropical d'elevada importància econòmica per a la regió sud-americana. La segona fase realitzada a la UPV es va treballar amb l'Anguilla europea (Anguilla anguilla), una espècie classificada a la Llista Vermella de la (UICN) com a espècie "en perill crític d'extinció". A la primera fase es va buscar caracteritzar la composició bioquímica del plasma i les característiques seminals de l'espècie per avaluar les possibles relacions entre aquests paràmetres. El plasma seminal va estar principalment compost per ions de sodi (Na+) i dins dels components orgànics van sobresortir les proteïnes totals i la glucosa. A través de l'anàlisi de components principals (PCA), es va observar que la motilitat tenia una forta correlació positiva amb el temps de motilitat, la concentració d'espermatozoides i les proteïnes totals. Aquestes anàlisis van servir de base per a la creació d'una solució diluent utilitzada posteriorment a la substància crioprotectora. Després es va determinar la influència del plasma seminal com a constituent de la solució crioprotectora en la criopreservació de semen de P. reticulatum. Es van utilitzar tres tractaments: glucosa 5% + metanol 10% (T1), a aquest crioprotector se li va afegir 30% de plasma seminal natural (T2) i 30% de plasma seminal artificial sobre la base dels resultats dels components bioquímics del plasma determinats per a l'espècie a l'experiment anterior (T3). S'avaluaren paràmetres de motilitat espermàtica, capacitat fecundant del semen criopreservat, així com fragmentació de l'ADN. El tractament T1 va resultar amb els millors valors de motilitat seguit del T2, i la capacitat fertilitzant d'aquests dos tractaments va ser similar al control, però el tractament T2 va mostrar menys mal a l'ADN. Mitjançant el PCA es va demostrar que T1 tenia una millor relació positiva amb la fertilitat i la motilitat total i progressiva. Finalment, avaluem les estructures de les subpoblacions espermàtiques a cadascun dels tractaments utilitzats. Mitjançant anàlisi multivariada en dues etapes, va ser possible determinar tres subpoblacions espermàtiques en el semen crioconservat de l'espècie, SP1 (ràpid-lineal), SP2 (ràpid-no lineal) i SP3 (lent-lineal). T1 va presentar el percentatge més gran de SP1, i va ser confirmat per l'efectivitat en la protecció de les cèl·lules d'aquest tractament en el procés de criopreservació de l'espècie. A la segona fase que es va dur a terme a la UPV, l'objectiu general va ser determinar l'efecte de la temperatura i el pH de l'aigua de mar sobre la motilitat dels espermatozoides a l'Anguila europea. Es va determinar que el pH baix de l'aigua de mar (6.5-7.4) va disminuir la motilitat dels espermatozoides d'anguila en comparació del control (pH= 8.2). Quan estudiem l'efecte combinat del pH del plasma seminal artificial i el pH d'ASW (7.8 i 8.2), no trobem diferències estadístiques en la motilitat i la cinètica dels espermatozoides en relació amb el pH del plasma seminal artificial, però sí el pH de l'aigua de mar. Es van trobar valors més alts de motilitat total (MOT), FA(ràpids) i ME (metges) amb un pH de 8.2 que amb un pH de 7.8. En contrast, la temperatura de l'aigua de mar no va afectar els paràmetres de motilitat dels espermatozous o la longevitat dels espermatozous en el context del canvi climàtic.[EN] The selection of high-quality gametes is an essential requirement to take into account in assisted reproduction programs. The development of biotechnological tools such as cryopreservation of gametes plays an important role in aquaculture production and in the formation of germplasm banks, which will later contribute to the genetic improvement of fish populations, mainly those in danger and that could be more affected by future climate changes. In the first phase of this thesis carried out at Unesp, we worked with a neotropical species of high economic importance for the South American region. The second phase carried out at the UPV worked with the European Eel (Anguilla anguilla), a species classified on the (IUCN) Red List as a "critically endangered" species. In the first phase, we sought to characterize the biochemical composition of the plasma and the seminal characteristics of the species to evaluate the possible relationships between these parameters. The seminal plasma was mainly composed of sodium ions (Na+) and within the organic components, total proteins and glucose stood out. Through principal component analysis (PCA) it was observed that motility had a strong positive correlation with motility time, sperm concentration and total proteins. These analyzes served as the basis for the creation of a diluent solution later used in the cryoprotective substance. Then the influence of seminal plasma as a constituent of the cryoprotectant solution in the cryopreservation of P. reticulatum semen was determined. Three treatments were used: 5% glucose + 10% methanol (T1), 30% natural seminal plasma (T2) and 30% artificial seminal plasma were added to this cryoprotectant based on the results of the determined biochemical components of the plasma. for the species in the previous experiment (T3). Parameters of sperm motility, fertilizing capacity of cryopreserved semen, as well as DNA fragmentation were evaluated. Treatment T1 resulted with the best motility values followed by T2, and the fertilizing capacity of these two treatments was similar to the control, however, treatment T2 showed less DNA damage. Using PCA, it was shown that T1 had a better positive relationship with fertility and total and progressive motility. Finally, we evaluated the structures of the sperm subpopulations in each of the treatments used. Through two-stage multivariate analysis, it was possible to determine three sperm subpopulations in the cryopreserved semen of the species, SP1 (fast-linear), SP2 (fast-nonlinear) and SP3 (slow-linear). T1 presented the highest percentage of SP1, being confirmed by the effectiveness in protecting the cells of this treatment in the cryopreservation process of the species. In the second phase that is being carried out at the UPV, the general objective was to determine the effect of temperature and pH of seawater on sperm motility in the European Eel. It was determined that the low pH of seawater (6.5-7.4) decreased the motility of eel sperm compared to the control (pH= 8.2). When we studied the combined effect of the pH of the artificial seminal plasma and the pH of ASW (7.8 and 8.2), we did not find statistical differences in the motility and kinetics of the sperm in relation to the pH of the artificial seminal plasma, but we did find the pH of the water of sea Higher values of total motility (MOT), FA (fast) and ME (medium) were found at a pH of 8.2 than at a pH of 7.8. In contrast, seawater temperature did not affect sperm motility parameters or sperm longevity in the context of climate change.I also thank the Coordination for the Improvement of Higher Education Personnel (CAPES/PROEX) (N° 88887.302629/2018-00), National Council for Scientific, Technological Development CNPq (N° 200452/2022-3) and the Brazilian fostering agencies Foundation for Research Support of the State of Sao Paulo FAPESP (N° 2020/15020-0), for its financial support in Brazil. In Spain, the ThinkInAzul programme, supported by the Spanish Ministry of Science and Innovation (MCIN) with funding from the European Union NextGenerationEU (PRTR-C17.I1) and the Generalitat Valenciana (THINKINAZUL/2021/012) to SEASPERM, which has made it possible the preparation of this work. To the AUIP (Ibero-American Postgraduate University Association) for the Academic Mobility scholarship between Institutions Associated with the AUIP 2022Padilla Sánchez, M. (2023). Sperm Quality and Cryopreservation in Teleost: Effect of Seminal Plasma Component and Climate Change [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/20154

    Weak-Instrument and Pleiotropy-Robust Methods for Mendelian randomisation, with Applications to Mental Health

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    This PhD dissertation focused on developing and applying new methods for Mendelian Randomisation (MR), a technique that uses genetic variants as instrumental variables in order to assess causal effects of exposures on health outcomes. The major focus of the applied research is psychiatric research and mental health, with a range of analyses that address the topic of causal risk factors for depression with the use of these genetics-informed methods. The first contribution of this dissertation is the development of new methods for pleiotropy-robust MR by leveraging sex specificity of phenotypes. These methods allow for more accurate and robust estimation of causal effects by cancelling out potential pleiotropic effects of genetic instruments. The second contribution is a new method for appraising high-dimensional correlated variables in multivariable MR. This method allows for the inclusion of multiple correlated variables as exposures in MR analyses, through a transformation to groups of exposures that have attractive statistical properties and biological meaning. Finally, the dissertation provides an applied analysis of how inflammation and BMI affect a range of depression phenotypes with cutting-edge methods. This analysis replicates previous results on the harmful effects of overweight on mood and challenges the independent effect of inflammation as proxied by CRP. The introduction of the dissertation is divided into two parts. The first part provides a walkthrough of the epidemiological concepts of bias, randomisation, and causal inference with observational data. The second part is a specific introduction to MR, including its underlying assumptions and limitations, as well as detailed discussion of developments that make it more robust. Overall, this dissertation contributes new methods and applied analyses to the field of MR, with potential implications for researchers and practitioners

    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/

    Evaluating the sustainability and resiliency of local food systems

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    With an ever-rising global population and looming environmental challenges such as climate change and soil degradation, it is imperative to increase the sustainability of food production. The drastic rise in food insecurity during the COVID-19 pandemic has further shown a pressing need to increase the resiliency of food systems. One strategy to reduce the dependence on complex, vulnerable global supply chains is to strengthen local food systems, such as by producing more food in cities. This thesis uses an interdisciplinary, food systems approach to explore aspects of sustainability and resiliency within local food systems. Lifecycle assessment (LCA) was used to evaluate how farm scale, distance to consumer, and management practices influence environmental impacts for different local agriculture models in two case study locations: Georgia, USA and England, UK. Farms were grouped based on urbanisation level and management practices, including: urban organic, peri-urban organic, rural organic, and rural conventional. A total of 25 farms and 40 crop lifecycles were evaluated, focusing on two crops (kale and tomatoes) and including impacts from seedling production through final distribution to the point of sale. Results were extremely sensitive to the allocation of composting burdens (decomposition emissions), with impact variation between organic farms driven mainly by levels of compost use. When composting burdens were attributed to compost inputs, the rural conventional category in the U.S. and the rural organic category in the UK had the lowest average impacts per kg sellable crop produced, including the lowest global warming potential (GWP). However, when subtracting avoided burdens from the municipal waste stream from compost inputs, trends reversed entirely, with urban or peri-urban farm categories having the lowest impacts (often negative) for GWP and marine eutrophication. Overall, farm management practices were the most important factor driving environmental impacts from local food supply chains. A soil health assessment was then performed on a subset of the UK farms to provide insight to ecosystem services that are not captured within LCA frameworks. Better soil health was observed in organically-farmed and uncultivated soils compared to conventionally farmed soils, suggesting higher ecosystem service provisioning as related to improved soil structure, flood mitigation, erosion control, and carbon storage. However, relatively high heavy metal concentrations were seen on urban and peri-urban farms, as well as those located in areas with previous mining activity. This implies that there are important services and disservices on farms that are not captured by LCAs. Zooming out from a focus on food production, a qualitative methodology was used to explore experiences of food insecurity and related health and social challenges during the COVID-19 pandemic. Fourteen individuals receiving emergency food parcels from a community food project in Sheffield, UK were interviewed. Results showed that maintaining food security in times of crisis requires a diverse set of individual, household, social, and place-based resources, which were largely diminished or strained during the pandemic. Drawing upon social capital and community support was essential to cope with a multiplicity of hardship, highlighting a need to develop community food infrastructure that supports ideals of mutual aid and builds connections throughout the food supply chain. Overall, this thesis shows that a range of context-specific solutions are required to build sustainable and resilient food systems. This can be supported by increasing local control of food systems and designing strategies to meet specific community needs, whilst still acknowledging a shared global responsibility to protect ecosystem, human, and planetary health
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