cometadata/datacite-rtg-text-other-reclassification-records huggingface dataset:
Single base resolution analysis of DNA methylation in a rat model of crescentic glomerulonephritis
Creators: name: Oates, Thomas
Publisher: name: Imperial College London
Year: 2014

description: Crescentic glomerulonephritis (CRGN) is a significant cause of renal failure in humans and often has an autoimmune aetiology. The Wistar-Kyoto (WKY) rat has a marked susceptibility to CRGN, whilst the Lewis (Lew) rat is resistant, making this a useful model system to study molecular mechanisms underlying the disease. Previous work has demonstrated the importance of macrophages in CRGN and defined some of the genetic determinants underlying CRGN susceptibility. Given emerging data linking epigenetic modifications to both macrophage activation and autoimmune diseases, I hypothesized that variation in DNA methylation in macrophages could contribute to susceptibility to glomerulonephritis in the WKY rat. This thesis investigated this hypothesis using both experimental and bioinformatic approaches. Experimental methods including locus-specific sequencing of differentially expressed genes and unbiased whole genome sequencing allowed investigation of variability in DNA methylation between the two rat strains. Further analyses of methylation in the pathogenesis of CRGN was achieved by both in vivo experiments in WKY rats and in vitro work on cultured macrophages using an inhibitor of DNA methylation. Bioinformatic analysis of sequencing and transcriptional data allowed examination of the affect of DNA methylation on gene expression in rat macrophages, and histone and transcription factor binding site data were used to explore the interaction of methylation and distant gene regulatory sequences. Whole genome shotgun bisulfite sequencing revealed that WKY bone marrow-derived macrophages were generally less methylated than Lew, and more than 13,000 CpG dinucleotides were robustly differentially methylated between the two strains. Multiplexed PCR sequencing was used to verify whole genome methylation signatures. At the genome-wide level, the relationship between methylation and expression was complex but my analyses suggested that differentially methylated CpGs might be enriched at distant gene regulatory elements. These data offer evidence of an association between DNA methylation and susceptibility to CRGN and therefore impart a basis for understanding the distinct genes, pathways and gene regulatory elements that could underlie this association.
Using mathematical models to characterize HIV epidemics for the design of HIV prevention strategies
Creators: name: Mishra, Sharmistha
Publisher: name: Imperial College London
Year: 2014

description: Since 2000, we have been trying to characterize and classify HIV epidemics to guide the strategic design of HIV prevention policies and focus HIV programmes and resource allocation by a regions’ epidemic type. We have used arbitrary thresholds of HIV prevalence across different risk-groups in a given population, ‘static’ mathematical models and classical epidemiological measures of the population attributable fraction that do not account for chains of transmission. As a result, these traditional approaches could be missing the underlying transmission dynamics and the role of key populations – such as female sex workers and their clients – on HIV spread. In this thesis, I build on a growing paradigm shift on how we should re-classify HIV epidemics based on the epidemiological features that lead to HIV emergence and persistence (i.e. the ‘epidemic drivers’ that influence the basic reproductive ratio, R0). I examine the extent to which our traditional approaches have been underestimating the contribution of sex work to HIV spread and likely misclassifying epidemic type by developing dynamic mathematical models of HIV transmission and simulating a large number of plausible ‘synthetic’ HIV epidemics. I then develop – as proofof- concept- a novel algorithm to diagnose epidemic type using these synthetic epidemics and glean the key epidemiological data that would be most useful to help distinguish between ‘epidemic drivers’, and therefore would be most useful to collect as part of HIV surveillance and future empirical research.
Quantifying the impact of infection by Batrachochytrium dendrobatidis on montane populations of Alytes obstetricans
Creators: name: Clare, Frances Cherry
Publisher: name: Imperial College London
Year: 2014

description: This thesis aims to assess the population-level risk posed by Batrachochytrium dendrobatidis (Bd), a pathogen responsible for worldwide declines and extinctions, to the amphibians of a series of infected Pyrenean Lakes. The principle focus was on the common midwife toad (Alytes obstetricans), which, in parts of its range has suffered population declines and even local extinction as a result of exposure to Bd. Infection severity thresholds may play an important role in the risk of decline a population faces, but such thresholds are only useful if individual-level infection estimates are accurate. I found that widely-used data obtained via epidermal swabs are not accurate indications of the full infection burden of an individual, as assessed by a novel full-skin digest procedure I developed (Chapter Three). Swab-based infection thresholds should therefore be applied with caution. However, infection intensity in dead and moribund individuals was significantly higher than that of visually healthy individuals, suggesting that infection severity is an important predictor of mortality. Population monitoring is necessary for understanding whether long-term infection translates into changes to host population size. I used capture-mark-recapture (CMR) techniques on larval A. obstetricans and found evidence of possible disease-induced declines in two populations, but an increase in abundance in another, suggesting that the pathogen may exist in an endemic state in some host populations (Chapter Four). To assess disease-induced mortality across populations, I compared mortality rates monitored in laboratory-held individuals, to those estimated in the field (Chapter Five). This highlighted inter-site differences within my study populations and provided evidence of host persistence with low-level Bd infection. The presence of hosts in the field with low-level infection may indicate host population persistence is possible. To broaden my thesis from a single host to the amphibian community, I analysed temporal data on infection in three species within a single focal lake (Chapter Six). I show that environmental effects may affect the prevalence of infection in two sympatric species, suggesting infection is likely influenced by biotic and abiotic variables and may change over time. Overall, these data lend valuable insights into not only the individual level responses to infection, but that of the population and even begin to elucidate community level effects. These data will be useful in developing conservation policy for these, and other, Alytes populations.
Studies on mechanisms of enterocutaneous fistula healing
Creators: name: Rahbour, Goher
Publisher: name: Imperial College London
Year: 2013

description: This thesis reviewed and investigated several aspects of the management of enterocutaneous fistula (ECF). The best management of ECF, particularly complex fistulas, is in specialist units where there is a multidisciplinary structured approach. Surgical management of ECF at St. Mark’s National Intestinal Failure Unit is safe and improving over time. The highest incidence of ECF development occurs following abdominal surgery particularly in the presence of Crohn’s disease. The audit confirmed this in our unit. A retrospective audit of our unit revealed the majority of patients underwent definitive surgery. There were improved overall healing rates following both surgery and conservative management in the current cohort, with also improvement in the 30 day post fistula resection mortality compared with a previous series at our unit. Multivariate analysis revealed co-morbidity, source of referral and aetiology had significant associations with ECF healing. This thesis has included the first study and design of a scoring system for predicting ECF healing. The scoring systems devised were both validated. They can provide further information to aid clinical management and decision making for the multidisciplinary team and predict the possible long term outcome for patients at external institutions. Meta-analyses of randomised control trials has revealed somatostatin and octreotide increase the likelihood of fistula closure, reducing the time to fistula closure, and neither has an effect on mortality. 5 Immunological studies revealed an increased on-going production of cytokines, in particular TNF-α, in non-IBD ECF compared with control terminal ileum tissue. The data may provide evidence for the potential use of anti-TNF-α agents in the treatment of non-IBD ECF. A future pilot study has been designed with the aim to identify a potential novel therapy for patients with persistent enterocutaneous fistula not associated with inflammatory bowel disease. Any positive findings would equate to a major medical advance with a new use for anti-TNF-α agents.
Additional file 1 of Incomplete immune reconstitution and its predictors in people living with HIV in Wuhan, China
Creators: name: Zhang, Wenyuan
name: Yan, Jisong
name: Luo, Hong
name: Wang, Xianguang
name: Ruan, Lianguo
Publisher: name: figshare
Year: 2023
Subjects: subject: Medicine
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Mathematical Sciences not elsewhere classified
subject: Science Policy

description: Additional file 1: Supplementary table 1. Sensitivity analysis in imputation for missing data. Supplementary table 2. Univariable and multivariable logistic regression analysis of the training set. Supplementary Figure 1. Flow diagram of participants selection. Abbreviations: INRs, immunologic non responders; VL, viral load ; ART, antiretroviral therapy.
‘compiacimento di purgattissimo conoscimento’ – Performing Gesualdo in Mid-Seventeenth Century Rome
Creators: name: Kirnbauer, Martin
Publisher: name: Terebinto Edizioni
Year: 2019

description: The title of the article contains two elements: a citation (referring, of course, to Carlo Gesualdo, the then and today praised madrigal composer) and a statement worth discussing, namely that Gesualdo's music was not only known and studied in the 17th century, but that his music was also still performed (at least at a certain time and place). Roman documents from the middle of the 17th century illustrate interesting aspects of performance practice of Gesualdo's madrigals, especially concerning his notorious use of many accidentals, which I call 'vieltönig' (using verbatim 'many pitches') and which is more fully investigated in a recent publication (Martin Kirnbauer, Vieltönige Musik – Spielarten chromatischer und enharmonischer Musik in Rom in der ersten Hälfte des 17. Jahrhunderts, Basel 2013). Based on this I would like to argue that especially Gesualdo's madrigals formed the core of a distinguished repertory, which lead to later so-called 'madrigali al tavolino'.
The role of cohesin in regulating early steps of cellular differentiation and reprogramming
Creators: name: Mello Cintra L Muller, Thias
Publisher: name: Imperial College London
Year: 2013

description: The cohesion protein complex is critical for sister chromatid cohesion and proper chromosome segregation in cycling cells and has additional roles in gene regulation and chromatin organisation. Particularly, cohesin has been implicated in regulating genes critical for maintaining pluripotency in embryonic stem (ES) cells. Here I ask whether cohesin regulates gene expression during early stages of ES cell differentiation and the reprogramming of somatic cells towards pluripotency. In order to dissociate the role of cohesin in gene expression from cohesin’s essential functions during the cell cycle I have established genetic approaches to conditionally delete cohesion in ES cells and in somatic cells. By depleting cohesin in ES cells my results reinforce the suggested role of cohesin in pluripotency maintenance, but also show that cohesin removal preferentially leads to mesoderm and neuroectoderm differentiation. In addition, data presented here suggest that cohesin is required for the silencing of X-inactivating genes that occurs during the differentiation of female ES cells. To explore the role of cohesin in reprogramming I used experimental heterokaryons generated by fusing ES cells and somatic cells. In this system, the re-expression of ES-specific genes in somatic cell nuclei occurs in the absence of cell division, thereby obviating the need for cohesin for cell division-related functions. Interestingly, by depleting cohesion in ES cells I found that cohesin is not required for the ability of ES cells to induce reprogramming of somatic cells. Instead, cohesin depletion enhanced their reprogramming ability to re-activate the expression of pluripotency markers in somatic cells, possibly by a mechanism that involves the up-regulation of the reprogramming factor c-Myc. In contrast, somatic cells require cohesin to be reprogrammed. Cohesin-depleted somatic cells were unable to re-activate pluripoency markers and failed to silence lineage-specific somatic genes after fusion. Finally, ongoing experiments to establish a rapid and reversible system for proteolytic cleavage of cohesion in mammalian cells, will contribute to understand the mechanisms by which cohesin regulates gene expression in cellular differentiation and reprogramming.
Evidence for separable networks for auditory and visual attention
Creators: name: Braga, Rodrigo
Publisher: name: Imperial College London
Year: 2014

description: The research reported in this thesis investigated the neural systems involved in auditory attention, and in particular how these may differ from those recruited for visual attention. One current leading theory of attentional control postulates that a single frontoparietal network (the ‘dorsal attention network’ or DAN) subserves top-down attention to all sensory modalities. However, there is an abundance of published evidence which contradicts this claim (which is discussed herein). This thesis reports the results of three studies. In the first study, I investigated auditory attention whilst controlling for crossmodal and executive factors which may have confounded the interpretation of previous studies. In the second study, I investigated whether another crossmodal factor, the control of eye movements, may also have contributed to the controversy regarding auditory attention. Lastly, I investigated whether some regions of the brain contain multiple overlapping signals, a finding which could explain how a cortical region might display ‘amodal’ properties, and participate in multiple cognitive functions simultaneously. As a whole, this thesis provides evidence that the DAN is a predominantly visuospatial attention network whose recruitment during auditory attention reflects indirect crossmodal mechanisms rather than the direct modulation of auditory information. In addition, this thesis provides evidence that a candidate frontotemporal network, which links executive regions of the prefrontal cortex with temporal auditory association areas, subserves top-down attention to non-spatial auditory features.
Helicase activation mechanisms during initiation of DNA replication
Creators: name: Tognetti, Silvia
Publisher: name: Imperial College London
Year: 2014

description: This thesis provides new insights into the recruitment mechanisms of factors to replicative origins that are important for helicase activation during initiation of DNA replication in budding yeast. DNA replication origins are recognised by the Origin Recognition Complex (ORC), which recruits, during late M-phase, Cdc6, Cdt1 and MCM2-7 to form a pre-replication complex (pre-RC). MCM2-7 represents the core of the eukaryotic replicative helicase, but it is inactive within the pre-RC. In early S-phase, the pre-RC is converted into the pre-initiation complex (pre-IC), leading to stable Cdc45/GINS/MCM2-7 (CMG) complex formation and helicase activation. This process depends on the recruitment of a series of factors (Sld3, Cdc45, Sld2, Sld7, Dpb11…) and is regulated by kinases (DDK and S-CDK) but their specific function and mechanism of action is largely unknown. A systematic pairwise interaction analysis was performed using purified and in vitro translated proteins from Saccharomyces cerevisiae in order to understand how these factors interact with each other and MCM2-7, allowing helicase loading and activation. During this study a new network of interactions was identified, which is required for the stable recruitment of Cdc45 to MCM2-7. This was concomitant with the in vitro reconstitution of Cdc45 loading with purified proteins, which described Sld2, in addition to Sld3, as Cdc45 loading factor. Moreover, the Mcm2 subunit of the MCM2-7 hexamer was identified as a central player in Cdc45 recruitment, representing a binding surface for Sld2, Sld3 and Cdc45. The interaction sites in these proteins were mapped and mutants were generated to disrupt the formation of the complex containing Cdc45. The results obtained in this work constitute a comprehensive overview on the interactions occurring during pre-RC, and CMG formation. Additionally, they provide important details on the mechanisms leading to helicase activation and contribute to the understanding of this still poorly defined step of DNA replication.
Das Ausmass an Agilität bei OneOPES
Creators: name: Toikander, Nuna
Publisher: name: Fachhochschule Nordwestschweiz FHNW
Year: 2020
Subjects: Agilität
agiles Mindset
Vertrauen
Verantwortung
Hierarchie
Kommunikation
selbstorganisierte Teams
Entscheidungen
agile Entscheidungen

description: Das Thema Agilität ist hoch im Trend und viele Unternehmen streben eine agile Arbeitsweise an. Zu diesen Unternehmen gehört auch die Organisationseinheit «Operativer Einkauf und Systeme» der SBB AG. Diese Bachelorarbeit untersucht, wo sich diese Organisationseinheit im Hinblick auf ihre Agilität befindet und ob Entscheidungen agil getroffen werden. Dafür wurden elf halbstandardisierte Interviews mit sieben Führungspersonen und vier Mitarbeitenden ohne einer Führungsfunktion durchgeführt. Die Ergebnisse zeigen auf, dass gewisse Eigenschaften der Agilität vorhanden sind. Das Ausmass an Agilität ist jedoch nicht derart ausgeprägt, sodass die Organisationseinheit bereits komplett agil strukturiert wäre oder es von heute auf morgen sein könnte. Weniger agil scheint die Organisationseinheit allerdings hinsichtlich ihrer momentanen Entscheidungskultur zu sein.
Ausgestaltung eines Assistenzprozesses im sozio-technischen Umfeld am Beispiel eines Produktions-Planungs-Prozesses
Creators: name: Waldburger, Raoul
name: Stauffacher, Christoph
Publisher: name: Fachhochschule Nordwestschweiz FHNW
Year: 2021
Subjects: subject: Assitance Systems
subject: Business Engineering
subject: PPS
subject: 658 - General Management

description: In the context of the Smart Recommender System for Medium Sized Entreprises SRS-4-MSE project of the Institute of Business Engineering IBE of the University of Applied Sciences Northwestern Switzerland FHNW, this thesis investigates the main success factors for the design of effective and efficient assistance systems in socio-technical environments. By following the SRS-4-MSE, concrete implications are sought that can be derived for this project from the work presented here. For this purpose, the questions of how a good planning process is defined and what an assistance system is, are explored. How a self-learning assistance system has to be designed, so that the human being learns as well as the machine, and how a planning process with an assistance system can be designed. The main results of this project work can be divided into the areas of planning process and assistance system and assigned to the respective levels according to PTO. In the area of planning process these are: Understanding about process as a key factor (people), monitoring of processes as a basis for decision making (technology), processes have to be continuously adapted to their environment (organization). Regarding assistance systems, these are: Humans must understand technology (people), the "right" use of technology is to be decided (technology), role distribution between humans and machines must be clarified (organization). From this, 19 key insights could be derived, which form the basis for the assistance process. This in turn covers the entire course from design to optimization of an assistance system in a planning process in five phases: Requirements & Design, Introduction, Application, Control and Need for Action.
Molecular mechanism of transdermal co-delivery of interferon-alpha protein with gold nanoparticle – a molecular dynamics study
Creators: name: Gupta, Rakesh
name: Kashyap, Nishi
name: Rai, Beena
Publisher: name: Taylor & Francis
Year: 2017
Subjects: subject: Biophysics
subject: Biochemistry
subject: Space Science
subject: 29999 Physical Sciences not elsewhere classified
subject: FOS: Physical sciences
subject: Medicine
subject: Molecular Biology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: Developmental Biology
subject: Computational Biology

description: The transdermal route provides numerous advantages over conventional drug delivery routes. However, passive delivery of large molecules such as proteins through the skin is challenging due to its barrier function. Therefore, to design a successful formulation, molecular interaction of these proteins with constituent molecules present in the skin responsible for its barrier function, is necessary. In this study, we have shown through extensive computer simulations that the therapeutic protein, interferon alpha (INF), can be co-delivered through the skin using the gold nanoparticle. We carried out both steered (umbrella sampling) and unrestrained coarse-grained molecular dynamics simulation to show the molecular mechanism of absorption/permeation of protein on/through skin layer in the absence/presence of gold nanoparticle. According to the steered simulations, when INF was taken alone, the free energy minimum was observed at the head group of the skin layer, whereas, when co-delivered with AuNP, it was observed in the interior of the bilayer. Unrestrained simulations have also shown that INF was adsorbed on the skin lipid bilayer head group, while in presence of AuNP, it first complexed with the AuNP and then breached the barrier. The MD simulations thus established the transdermal delivery as a possible pathway for delivery of INF protein.
title: Préface_Les Secrets du menuisier-ébéniste
Creators: name: AmateurS
Publisher: name: NAKALA - https://nakala.fr (Huma-Num - CNRS)
publisherIdentifier: https://ror.org/04ces3204
publisherIdentifierScheme: ROR
Year: 2020

description: Préface
description: ID_PARA_00690
Deciphering the link and direction between attention-deficit/hyperactivity disorder symptoms and obesity: Common behavioural or prenatal pathways?
Creators: name: Khalife, Natasha
Publisher: name: Imperial College London
Year: 2014

description: Growing evidence suggests an association between attention-deficit/hyperactivity disorder (ADHD) and obesity, although very little is understood about the nature of this link. The aims of this thesis were to examine the following aspects of the ADHD-obesity association: (1) the directionality of the link from childhood to adolescence, (2) behavioural mediators during childhood and adolescence, and (3) prenatal risk factors common for both disorders. Participants were from the Northern Finland Birth Cohort (NFBC) 1986 (N=9479). Data were obtained on pregnancy and birth factors, and child/adolescent mental health, obesity, and lifestyle factors. Regression analyses showed that ADHD symptoms significantly predicted obesity, rather than in the opposite direction, from childhood to adolescence. Mediation analyses examined potential underlying behavioural factors – physical activity and binge-eating, and showed that physical inactivity mediated the longitudinal ADHD symptom-obesity association. Further, there was a bidirectional, longitudinal association between physical inactivity and ADHD symptoms. ADHD and obesity may share common prenatal risk factors, including prenatal exposure to cortisol. This was studied using a quasi-experimental approach by examining the impact of prenatal exposure to synthetic glucocorticoids (sGC). Results from propensity-score and mixed-effects methods showed that prenatal sGC increased the risk for general psychiatric disturbance and inattention symptoms, but not obesity, in childhood. Placental size may represent another common prenatal contributing factor; placental size was positively associated with behaviour problems, including ADHD symptoms, in child and adolescent boys, but was not associated with obesity. This thesis addresses important unexplored aspects of the association between ADHD and obesity, and provides insight into risk factors for both disorders. The direction of the association was driven from ADHD symptoms to obesity, and physical inactivity was a behavioural mediator underlying the link. Although there was no evidence that both disorders share common prenatal risk, prenatal sGC and placental size were positively associated with ADHD symptoms.
The relationship between HIV, vulnerability, and school education in eastern Zimbabwe
Creators: name: Pufall, Erica Lynne
Publisher: name: Imperial College London
Year: 2014

description: HIV severely affects children in sub-Saharan Africa. It is important to understand not only the effects of HIV on children, but also how to mitigate them and prevent future infections, with education as one possible avenue. This thesis investigates associations between HIV and education in youth participating in the Manicaland HIV/STD Prevention Project in eastern Zimbabwe from 1998 to 2011. In the first HIV prevalence survey from a general population sample of Zimbabwean children (aged 2-17 from 2009-2011), HIV prevalence was 2.1%, and was primarily due to mother-to-child transmission. Antiretroviral therapy coverage was low (<25%) and driven by a lack of diagnosis. Therefore, increased testing and diagnosis should be a priority to improve the outlook of HIV-positive children in this population. Providing context for my detailed analyses of education, I show that although education has increased over time in Zimbabwe, it suffered during the economic turmoil of the 2000s, and females consistently achieve lower education levels than males. Increasing education is important because children with educated parents are more likely to be educated themselves, and education appears to be protective against HIV, particularly for females. Conversely, orphanhood is associated with poorer educational outcomes and substance use, which is associated with higher levels of sexual risk behaviours. School enrolment, however, mitigates these effects and is associated with lower levels of substance use and risky sex. Thus, I illustrate one pathway through which education may decrease HIV risk. Moving beyond problems to their solutions, I demonstrate that schools can impact on the education and wellbeing of vulnerable children: high quality schools were associated with better education outcomes and higher wellbeing, suggesting that schools are well placed to improve children’s lives. The findings of this thesis suggest how education can support HIV-affected children and play a role in decreasing HIV in sub-Saharan Africa.
The maternal and fetal inflammatory response in normal pregnancy and fetal growth restriction: An ultrasound, flow-cytometry and immunoassay study
Creators: name: Mullins, Edward William Samuel
Publisher: name: Imperial College London
Year: 2014

description: The fetal vascular phenotype in fetal growth restriction (FGR) is significantly altered, with affected fetuses appearing to have relatively more dilated vessels with increased proportional blood flow to the head and neck arteries. This concurs with the concept of ‘brain sparing’ in FGR, but sets it in the context of a globally altered fetal circulatory system. The data presented in this thesis suggest that there are subtle alterations in the maternal antenatal inflammatory cytokine and chemokine profile in FGR. In FGR cord blood there appears to be a mixed inflammatory picture. Cord blood monocytes from FGR samples demonstrate priming towards anti-inflammatory profile with increased levels of IL-10 whilst in blood samples from neonates on day 1 of life there is evidence of a more pro-inflammatory set of cytokines. Subsequent to this, there is a persistent increase in IL-8 in samples from FGR infants collected at 6 weeks of age. The marked difference from cord blood to day 1 cytokines suggests a response of the FGR infant to delivery and their post-natal environment. Maternal blood samples at delivery from pregnancies with FGR show decreased pro-inflammatory chemokines and IL-10. In addition, maternal antenatal IL-2 and MIP1α correlate positively and MMP-9 negatively with fetal vessel diameter (per kg) after correction for gestation and pre-eclampsia. Although maternal post-natal samples show few significant differences, there is positive correlation of IL-17 and negative correlation of sIL-6ra with the severity of FGR in cord blood. This suggests that chronic inflammation mediated by IL-17 and altered IL-6 signaling are possibly associated with the processes which impair fetal growth. The overall findings indicate that FGR fetuses and infants have a syndrome of vascular and inflammatory perturbation which could be factors influencing the short and long-term sequelae of these individuals.
Optimising the outcome of neuromodulation for faecal incontinence and constipation
Creators: name: Thomas, Gregory
Publisher: name: Imperial College London
Year: 2014

description: This thesis begins with a summary of the general management of faecal incontinence and constipation. This is followed by a review of the literature to support the use of neuromodulation for these conditions. The first study reports the effect of alteration of pulse width and frequency on sacral nerve stimulation for constipation. The next study investigates the outcome of transcutaneous stimulation of the sacrum for faecal incontinence. The outcome of pudendal nerve stimulation is reported for those who have failed to improve with sacral nerve stimulation. Lastly the effect of unilateral transcutaneous posterior tibial nerve stimulation is studied and applied to bilateral stimulation.
Haloacetic acids in public drinking water and risk of adverse birth outcomes in the Born in Bradford cohort
Creators: name: Edwards, Susan
Publisher: name: Imperial College London
Year: 2014

description: Disinfection of drinking water is vital to protect the public against disease. However disinfectants such as chlorine react with organic matter in drinking water to produce a wide range of chemical disinfection by-products (DBPs) of potential health concern including haloacetic acids (HAAs). This thesis is an epidemiologic analysis investigating the relationship between prenatal exposure to HAAs in drinking water and adverse birth outcomes in “Born in Bradford”, a large multi-ethnic prospective birth cohort study based in Bradford, England. It focuses on the understudied and as yet unregulated HAAs which are the second most prevalent class of chlorination DBPs in UK drinking waters. To assess exposure, area-level concentrations to three select HAAs (measured in drinking water samples newly collected for this study, modelled in time and space, and weighted to each cohort woman’s specific trimester of pregnancy by postcode of residence) were combined with individual water consumption information collected via questionnaire at recruitment to the cohort. Despite the benefits of state-of-the-art exposure metrics and a large sample size, this study does not find any significant patterns of association between prenatal exposure to HAAs and either birth weight, being born term low birth weight or small-for-gestational age. Water consumption over the course of late pregnancy was further studied in a subset of cohort women. A small but significant increase in water consumption was reported, bearing in mind that both behaviour change over the third trimester of pregnancy and measurement error likely contributed to this effect. This research addresses some of the limitations of previous DBP studies in terms of exposure assessment and birth outcome definitions, and uniquely evaluates the variability of individual water consumption over time. It also identifies areas for future research and examines the importance of HAAs and birth weight-based outcomes in the larger research context.
Epigenetic reprogramming and DNA demethylation
Creators: name: Bagci, Hakan
Publisher: name: Imperial College London
Year: 2014

description: Embryonic development begins with fertilization of the egg, a progressive process that gives rise to the zygote and subsequently to the formation of somatic tissues. Normally once cells acquire a fate, it is stably maintained. Conversion back to a multipotent state occurs rarely in-vivo, but can be achieved experimentally by inducing ‘reprogramming’. In this study I am looking at the epigenetic mechanisms that underlie reprogramming and, in particular, DNA methylation and demethylation. To address this I am taking advantage of the cellular fusion system. Fusion of pluripotent cells with differentiated cells results in the formation of transient heterokaryon and hybrid cells, where the somatic partner is efficiently reprogrammed. This gives me the opportunity to monitor early and late events in pluripotent conversion, in which global remodelling of chromatin and changes in DNA methylation occur. Here, I examine changes in DNA methylation that are induced at imprinted loci and pluripotency-associated genes when somatic cells are fused with either mouse embryonic stem (ES) or embryonic germ (EG) cells. I focus on defining the factors and order of events that accompany reprogramming. I show that acquisition of pluripotency is an early process occurring at the heterokaryon stage, and is followed by imprint erasure later in hybrids. However reprogramming of imprinting is only induced by EG, but not ES cells, and it requires sequential steps of 5-methylcytosine oxidation mediated by Tet proteins and nucleotide exchange upon several rounds of DNA synthesis. I provide evidence that Tet proteins are dispensable for pluripotent reprogramming using CRISPR-Cas9 genome editing to abrogate the expression of both Tet1 and Tet2. This result suggests that either DNA demethylation can occur without TET activity (implying a redundancy with other demethylating agents and routes), or that DNA demethylation is not required for inducing pluripotency. Finally, I describe how CRISPR/Cas9 approaches were used to demonstrate that non-canonical Wnt signalling components are downstream targets of JARID2 in ES cells.
Quantitative assessment and functional correlates of cardiac mechanics and energetics in newborn infants
Creators: name: Finnemore, Anna
Publisher: name: Imperial College London
Year: 2014

description: Introduction: As preterm birth and survival rates continue to rise, circulatory failure remains a leading cause of mortality and morbidity. Structural and functional variations in circulatory physiology within the preterm population have been described, secondary to pre and post natal factors. This study applied magnetic resonance imaging techniques to assess cardiac function; analysed suitable techniques for indexing functional parameters by body size and applied a novel method of body composition quantification to investigate the impact of varying growth patterns on cardiac measures. Methods: Steady state free precession MRI imaging was used to analyse cardiac function in 78 preterm neonates. Analysis techniques were validated by comparison to phase contrast measures in 40 infants. Current methods of indexing for body size were compared. A modified DIXON whole body MRI scan utilising chemical shift was validated in phantoms and in vivo and successfully applied to 20 infants to assess adipose tissue content. Results: Validation of acquisition and analysis techniques demonstrated an acceptable level of accuracy. Functional measures indexed by body weight generally decreased with increasing corrected gestational age but patterns were altered when indexed by body surface area. Allometric transformation did not significantly improve correlation between size and function. Full body MDIXON scans demonstrated variations in body fat percentage of between 15 and 25%. Indexing cardiac function by lean body mass gave differing trends to total weight. Conclusions: Analysis of cardiac function in preterm neonates using MRI can be used to describe normative ranges and causes of variation for functional parameters. However, until an appropriate indexing technique for body size can be determined, the impact of pre and post natal factors cannot be fully understood. Analysis of body composition using MRI imaging may present a new indexing technique and allow us to investigate the effects of different growth patterns on cardiac function.
Identification of genes involved in reprogramming-induced senescence
Creators: name: Beolchi, Patrizia
Publisher: name: Imperial College London
Year: 2014

description: Senescence is a state of irreversible growth arrest first described in human fibroblasts when they undergo serial passage in vitro. Senescence can also occur in response to different stresses, such as replicative exhaustion, DNA damage or overexpression of oncogenes. The growth arrest associated with senescence is implemented by the activation of the p53/p21Cip1 and p16INK4a/Rb pathways. The expression in somatic cells of a combination of pluripotency-associated transcription factors, Oct4, Sox2, Klf4 and cMyc (OSKM) has been shown to generate embryonic stem cell-like cells termed induced pluripotent stem cells (iPSCs). iPSCs have brought new expectations to the study of stem cell biology, drugs development and regenerative medicine. However, the overall low efficiency of the reprogramming and its slow kinetics suggest that there might be barriers limiting the derivation of iPSCs. The expression of the reprogramming factors in normal somatic cells has been shown to activate the p53 and p16INK4a pathways, triggering a senescence response that limits the cells available to be reprogrammed, in what has been called reprogramming induced-senescence (RIS). Our aim is to identify modulators of RIS. We hypothesized that this could help not just to improve the efficiency of generation of iPSCs but could also help to clarify the link between tumour suppressor pathways, pluripotency and de-differentiation. To this end, we carried out a screen to identify shRNAs whose expression bypass the growth arrest imposed by the four reprogramming factors in IMR90 human primary fibroblasts. We screened a genome-wide shRNA library and took advantage of next generation sequencing (NGS) to detect the relative enrichment of shRNAs. We shortlisted 68 genes to validate their ability to bypass the OSKM-induced arrest. Of those, 8 genes consistently rescued the growth arrest in independent experiments. We performed a preliminary characterisation of IFIH1 and IGSF4D. The long-term goal would be to expand the characterisation of these candidates, assess whether they might also have a role in oncogene and replicative induced senescence and investigate whether they affect the efficiency of reprogramming to iPSCs. In addition, conducting a secondary screen with the top candidates shortlisted from the primary screen could contribute to the identification of additional genes that affect reprogramming and senescence.
Mechanisms of cohesin mediated regulation of gene expression
Creators: name: Gupta, Preksha
Publisher: name: Imperial College London
Year: 2014

description: The cohesin complex is essential for proper sister chromatid segregation during cell division and post-replicative DNA repair. Cohesin is also important for the regulation of gene expression. However, the mechanisms by which cohesin impacts gene expression remain incompletely understood. Owing to its vital role in cell division and DNA repair, loss of cohesin can indirectly impact gene expression programme in cycling cells. Thus, in order to investigate cohesin’s role in gene regulation, a conditional knockout system was used which allowed rapid depletion of the cohesin subunit RAD21 and avoided secondary stress-induced effects on gene expression. Acute depletion of cohesin in mouse embryonic stem (ES) cells did not lead to a global collapse in pluripotency. Instead, the impact of cohesin depletion was limited to about 600 genes and was locus-specific in terms of direction of deregulation. A subset of deregulated genes was selected based on the positioning of cis-regulatory elements and relevance to the pluripotent state and the role of cohesin in mediating long-range interactions was analysed using chromosome conformation capture (3C). Interestingly, cohesin binding, DNA looping and transcriptional changes were not always correlated. At some of the loci tested, these interactions were maintained after removal of cohesin, questioning models where cohesin regulates gene expression solely by mediating long-range interactions. One of the pluripotency factors affected by cohesin depletion in ES cells was Myc. Experiments analysing the expression of Myc showed that it was post-transcriptionally upregulated, specifically in cohesin deficient ES cells growing in defined media supplemented with ERK and GSK3β inhibitors (2i media). Further investigation revealed that contrary to the previously reported downregulation of Myc upon cohesin depletion, cohesin was not essential for Myc expression in various cell types. In separate experiments, I investigated if cohesin was required for the transcriptional activation of a silent gene in response to extracellular stimuli. Results from IFNγ induction of cohesin deficient non-cycling mouse embryonic fibroblasts (MEFs) showed that cohesin was important for the activation of MHC class II genes and their master regulator Ciita. The expression of MHC class I genes and the associated regulatory factors remained unaffected by cohesin depletion. Further evidence is provided for the involvement of cohesin in regulating transcription by modulating RNA polymerase processivity and through the action of PTIP subunit of the MLL complexes. Altogether my work gives an insight into the role of cohesin in mediating long-range DNA interactions important for regulation of gene expression and explores novel mechanisms of gene activation by cohesin.
Consumers (Dis)Preference for Bitterness in Extra Virgin Olive Oil: A Field Experiment
Creators: name: Caracciolo, Francesco
name: Cavallo, Carla
name: Del Giudice, Teresa
name: Panico, Teresa
name: Vecchio, Riccardo
name: Cicia, Gianni
Publisher: name: International Journal on Food System Dynamics
Year: 2020
Subjects: in-store experiment; real choices; sensory panel; taste preferences; willingness to pay

description: Globally, bitterness in food is not a preferred attribute by consumers, for several reasons. In the case of Extra Virgin Olive Oil its presence is fundamental as it is a healthiness indicator, being strictly linked to the antioxidant content. The current study aimed to assess the extent of Italian consumers’ preferences for bitterness taste of Extra Virgin Olive Oil. Real choices made by shoppers at the store shelf of a hypermarket were recorded and then compared with the selected Extra Virgin Olive Oil sensory profiles evaluated by a professional panel. Findings reveal that bitterness exerts a negative willingness to pay equal to -1.18 €/liter. Furthermore, consumers tend to overestimate the perception of Extra Virgin Olive Oil bitterness compared to sensory experts. Results provide new evidences of consumer preferences for sweet sensory profile of Extra Virgin Olive Oil and bitter aversion.
description: International Journal on Food System Dynamics, Vol 11, No 1 (2020)
Statistical Methods in Metabolomics
Creators: name: Muncey, Harriet Jane
Publisher: name: Imperial College London
Year: 2014

description: Metabolomics lies at the fulcrum of the system biology ‘omics’. Metabolic profiling offers researchers new insight into genetic and environmental interactions, responses to pathophysi- ological stimuli and novel biomarker discovery. Metabolomics lacks the simplicity of a single data capturing technique; instead, increasingly sophisticated multivariate statistical techniques are required to tease out useful metabolic features from various complex datasets. In this work, two major metabolomics methods are examined: Nuclear Magnetic Resonance (NMR) Spec- troscopy and Liquid Chromatography-Mass Spectrometry (LC-MS). MetAssimulo, an 1H-NMR metabolic-profile simulator, was developed in part by this author and is described in the Chap- ter 2. Peak positional variation is a phenomenon occurring in NMR spectra that complicates metabolomic analysis so Chapter 3 focuses on modelling the effect of pH on peak position. Analysis of LC-MS data is somewhat more complex given its 2-D structure, so I review existing pre-processing and feature detection techniques in Chapter 4 and then attempt to tackle the issue from a Bayesian viewpoint. A Bayesian Partition Model is developed to distinguish chro- matographic peaks representing useful features from chemical and instrumental interference and noise. Another of the LC-MS pre-processing problems, data binning, is also explored as part of H-MS: a pre-processing algorithm incorporating wavelet smoothing and novel Gaussian and Exponentially Modified Gaussian peak detection. The performance of H-MS is compared alongside two existing pre-processing packages: apLC-MS and XCMS.
The association between Chlamydia trachomatis and pelvic inflammatory disease: findings from observational studies
Creators: name: Davies, Bethan
Publisher: name: Imperial College London
Year: 2014

description: Estimates of the cost-effectiveness of chlamydia control interventions are highly sensitive to the risk of progression from genital chlamydia infection to pelvic inflammatory disease (PID). There is no consensus for the risk of PID following asymptomatic chlamydia infections detected through population-based testing. The aim of this thesis is to generate improved estimates of this risk of PID that can be used to parameterise mathematical models and inform chlamydia control policy. We have determined the risk of PID following a positive chlamydia test in three cohorts: a small historic prospective clinical cohort of sex workers (Praed Street Project (PSP)); a large population-based retrospective cohort from Manitoba, Canada established for this research; and a large nationally representative retrospective cohort from Denmark. The risk of PID was higher in women with a positive chlamydia test compared to women who tested negative (PSP: adjusted hazard ratio (AHR) 2.03 (95%CI 0.75-5.49); Manitoba: 1.55 (95%CI 1.43-1.70); Denmark: 1.42 (95%CI 1.32-1.53)). There was heterogeneity in this risk: 13-23% higher following a repeat infection; up to four-fold higher in younger women (Manitoba: AHR 4.55 (95%CI 3.59-5.78) in 12-15 compared to 30-40 years); two-fold higher following previous gonorrhoea (PSP: 2.28 (95%CI 1.14-4.56)). The increased risk following a positive test lasted considerably longer than the likely duration of infection and fewer than 10% of PID diagnoses within 12 months of a test could be attributed to a positive result. This suggests that there are other important causes of PID. Individual-based risks of progression that capture this heterogeneity may improve the accuracy of estimates from mathematical models and therefore their utility to policy makers. Further research is needed to fully characterise the aetiology of PID to inform the design of chlamydia control interventions. In the meantime, interventions should focus on young women and those at risk of repeat chlamydia infection.