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Advanced in vitro and in silico models to explore mechanisms of deep vein thrombosis
Get PDFDeep vein thrombosis is a significant global medical issue associated with high levels of illness and death. Investigating DVT mechanisms and discovering innovative approaches for its prevention and treatment rely extensively on animal models; however, using animals in research is associated with technical and ethical challenges, which raise the critical need to create in vitro and in silico models that mimic the formation of thrombi in deep veins without relying on animals. Here, a microfluidics in-vitro method allows for the investigation of valve flexibility through an in-situ fabrication process, which provides independent control over the rigidity of valve leaflets and enables testing under pulsatile flow conditions. Symmetrical valves exhibit platelet accumulation on valve tips, while asymmetrical valves show platelet accumulation within the valve pocket. This model has been further developed by incorporating moving valve leaflets to replicate venous hydrodynamics alongside an endothelial cell monolayer. Employing a pulsatile flow, typical of veins, these experiments reveal that unstimulated human platelets, reconstituted with whole blood, accumulate on the luminal side of leaflet tips in proportion to leaflet flexibility. Thrombin-induced platelet activation results in robust accrual at leaflet tips. GPIbα-vWF interaction blockade abolishes platelet deposition. Histamine-induced endothelial stimulation prompts platelet accrual at the basal side of leaflets, illustrating human thrombi location and indicating a dependence on leaflet flexibility and GPIbα-vWF interaction. An in-silico model has also been developed to simulate particle agglomeration within elastic valves, replicating venous valve geometry and fluid dynamics. The findings support the hypothesis that fluid dynamics near the valve leaflets primarily drive clot formation.
These approaches combine experimental and numerical models to increase our understanding of DVT initiation phenomena, highlighting crucial aspects of thrombus formation. Also, It offers a feasible alternative to animal models in research
Determinants of early failure of dental implants
Get PDFIn modern dentistry, the use of osseointegrated dental implants is widely accepted as a valid treatment that can provide reliable rehabilitation for fully or partially edentulous patients. Efforts are continuously being made in the field of implant dentistry to further improve treatment outcomes and reduce failures.
There is a growing interest in improving treatment planning for dental implants, starting with tooth extraction techniques, as every dental implant procedure essentially begins with tooth extraction. In this context, minimally invasive vertical tooth extraction systems have been developed to reduce bone loss after tooth extraction and facilitate subsequent implant restoration.
This PhD project started with investigating the Benex vertical tooth extraction system. We developed an in vitro animal model system to replicate the clinical procedure of vertical tooth extraction using the Benex system. Using this model, we measured the axial forces associated with the tooth removal process. Furthermore, we examined potential modifications in the Benex vertical extraction technique that may increase the success rate of tooth extraction and reduce maximal extraction force and associated untoward sequelae. However, due to the impact of the COVID-19 pandemic and the subsequent closure of the laboratories, we could not pursue lab work further as planned. Furthermore, these unforeseen circumstances have disrupted the original plans for conducting clinical trials to determine the effectiveness of vertical tooth extraction using the Benex system in reducing the need for flap surgery and post-extraction alveolar bone loss. Therefore, we have made necessary adjustments to the work plan and have developed an alternative PhD plan to investigate risk factors for early implant failure.
The main aim of this thesis was to assess risk factors associated with early implant failure. Identifying and assessing the potential risk factors for early implant failure can be of great importance in predicting treatment outcomes. Furthermore, surgeons can make informed decisions to improve implant therapy outcomes by recognising high-risk conditions and adjusting treatment plans accordingly.
To achieve our aim, we first conducted a systematic review and meta-analysis to identify risk factors for early implant failure reported in the literature. We also investigated the statistical methods used to adjust for confounders in these studies. We found that studies frequently reported univariate analyses only, or, where adjustments for covariates were made, the selection of these variables was typically not based on a robust causal structure, which prevents a causal interpretation of the results. Therefore, we constructed a causal model using Directed Acyclic Graphs (DAGs), incorporating variables potentially related to early implant failure and defining their causal relationship based on available literature, expert knowledge, and plausible assumptions. This was done to make the underlying assumptions regarding the causal structure explicit and to guide covariate selection for the statistical models.
To assess potential risk factors for early implant failure, we conducted a retrospective cohort study using data from the European Centres for Dental Implantology (ECDI) database. This study included 150,896 implants placed in 63,414 patients between 2010 and 2022. First, we performed a descriptive analysis of all variables to gain an overview of the dataset and identify its strengths and limitations. Then, we analysed the data by creating multilevel mixed-effects logistic regression models for each potential risk factor for early implant failure. The covariate adjustment sets used in these models were selected based on our previously proposed causal model. We found that certain factors have a causal association with early implant failure. These factors are male sex, cigarette smoking, immediate implant placement, low primary stability, using narrow and short implants, placing implants in upper molar and lower anterior sites, poor bone quality, insufficient alveolar bone height, bone augmentation, and transmucosal healing mode. We did not find an association of age and diabetes mellitus with early implant failure
Maps, Mongols and the neoclassical moment: north-east Asia in thirteenth-century mappaemundi
Get PDFThis thesis explores the construction and reception of North-East Asia on three thirteenth-century mappaemundi (Christian world maps) – the Ebstorf, Psalter and Hereford maps – assessing their creation, symbolism and developments across a century of new threats from and new knowledge about Asia. The thesis comprises two thematic and three chronological, map-focused chapters and presents three main interrelated arguments about how the maps’ makers understood and used this region. Firstly, in a period of challenges from Mongol invasions and losses in the Christian Levant, the mappaemundi consistently present a morally and culturally flawed North-East Asia which champions and consoles Latin Christianity by comparison. Secondly, the mappaemundi can be understood as neoclassical; the cartographers used antique Roman sources but, rather than simply copying these older texts’ information wholesale, the maps’ makers creatively adapted classical knowledge to suit medieval ends, a process which included omissions of both antique and contemporary information. Thirdly, the mappaemundi exhibit change and historical contingency across the century. The barbarian lands of Scythia on the Hereford mappamundi, drawn c.1300, are extensive, fierce and bordering on Europe; conversely, earlier maps have a small, peripheral Scythia. The thesis presents the Mongol invasions as the catalyst for change here, the cartographers acknowledging the seismic changes in geographical thought while accommodating the Mongols within a comfortable formula.
To develop these arguments, the thesis analyses the construction and symbolism of important constituent themes of North-East Asia: urbanism (deliberately minimised in Asia), barbarianism and the apocalyptic Gog and Magog, each of which contributed to a savage, morally flawed land. In sum, the thesis argues that these propagandistic mappaemundi were, in their depiction of North-East Asia, more creative and historically sensitive than has previously been suggested. The cartographers displayed authorial agency in adapting old and new material to create maps which suited the demands and contexts of their day, creating a specifically cartographical North-East Asia to assert Christian supremacy against a range of contemporary challenges
The role of Tropomyosins and their Isoforms in Urothelial Carcinoma of Bladder ('TropICana-B')
No full textHigh throughput sequencing has informed molecular pathology for classification of urothelial bladder cancer (BC). Noting the prominence of ‘biomarkers’, they may be a key tool to avoid impaired quality of life (QoL) for patients undergoing investigation and surveillance for BC. This is predicated on the practicality of implementing such tests as a point-of-care (POC) urine-based test. It can potentially aid in early detection and diagnosis and facilitate screening pathways of patients prior to the development of T1 disease. Altered transcriptional events generate tropomyosin (TPM) isoforms that appear to have selective upregulation in the presence of BC. They are stable coiled-coil dimers, resistant to degradation and can be found in urine. We created a multistep verification model to assess the biomarker potential of TPM isoforms for detection of BC, incorporating sequencing techniques and wet lab experiments.
IsoTPM, a bespoke bioinformatics pipeline was created to identify upregulated TPM isoforms that contributed to overall gene expression by exploring short-read RNA sequences from 6 datasets: Cancer Cell Line Encyclopaedia (CCLE n=26, BC cell lines), West Midlands Bladder Cancer Prognosis Program (BCPP n=85, non-muscle-invasive), The Cancer Genome Atlas (TCGA n=414, muscle-invasive), a paracancerous dataset (GEO Accession GSE133624 n=29), University of York (n=8, bladder stroma and urothelium) and Genotype Tissue Expression (GTEx n=7, benign). Coupled with targeted long-read sequencing, we evaluated the expression of these target TPM isoforms in BCPP archived tissues and BC cell lines (n=96). Experimental validation of in silico analyses was performed on the top candidates (Tpm1.4, Tpm1.7, Tpm4.2 and Tpm 4.1). Isoform specific primer-pairs with probe-based multiplex qPCR assay was created to measure ‘relative’ isoform expression. Preliminary assay testing was performed on urine supernatants from cancer patients and those with benign urological conditions to define its potential as a urine-based test.
We found 2 pairs of isoforms with strong disease diagnostic value (p-value: 0.031, 9.18e-06). Furthermore, our qPCR assay showed a 1.41-fold increase in relative isoform expression in cancer vs benign conditions (p-value: 0.00312, n=28). Our assay can effectively predict the presence of BC when compared to other benign bladder conditions (AUC= 0.82).
We have pioneered the use of relative isoform usage as a diagnostic urine-based-assay for detection of BC. Currently available detection kits utilize mutation/ methylation-based techniques incorporating molecular adaptations at the gene-level but cannot evaluate isoform expression which constitutes an additional layer of information indicative of gene expression to understand the mechanisms of carcinogenesis.
Translational Relevance:
With the use of isoform evaluation and differences found in expression levels, a urine-based-diagnostic test can be utilized for creation of a point-of-care test to triage patients for further investigations, if required, via referral to the haematuria pathway, decreasing the unnecessary need for undergoing flexible cystoscopy as a first-line investigation for identifying bladder cancer
The role of Gremlin-1 in metabolic dysfunction-associated steatotic liver disease
Get PDFMetabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD) is an increasing global health problem that is tightly linked to the rising prevalence of obesity and the metabolic syndrome. Hepatocellular lipid accumulation and lipotoxic injury prompt a chronic inflammatory response (metabolic dysfunction-associated steatohepatitis, MASH) that culminates with the activation of hepatic stellate cells (HSCs) and subsequent hepatic fibrogenesis. Liver fibrosis is the most prominent determinant of prognosis in patients with MASH but currently there are no treatments available that target hepatic fibrogenesis directly.
Gremlin-1 has been implicated in liver fibrosis in MASH via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that while Gremlin-1 was upregulated in human and rat MASH fibrosis, restricted to a small subpopulation of myofibroblasts, neutralisation of Gremlin- 1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Lentiviral overexpression of Gremlin-1 in the hepatic stellate cell line LX-2 and primary HSCs led to changes in BMP-related gene expression, which did not translate into increased fibrogenesis. Furthermore, Gremlin-1 bound to heparin with high affinity, which appeared to prevent Gremlin-1 from entering the systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Gremlin-1 also had no effect on hepatic endothelial cell activation and showed no significant expression changes in monocyte-derived macrophages.
Through an integrated analysis of bulk RNA sequencing data sets of human liver fibrosis and in vitro-activated hepatic stellate cells, we identified the activin and myostatin antagonist follistatin-like 3 (FSTL3) as strongly associated with hepatic fibrogenic responses. FSTL3 was upregulated in the HSC cell line LX-2 in response to transforming growth factor beta (TGFβ)1 and activin A, and in the hepatocyte cell line HepG2 in response to activin A. Inhibition of FSTL3 by siRNA-mediated knockdown altered fibrogenic gene expression in LX-2 cells and increased lipolytic gene expression in HepG2 cells, which translated into reduced hepatocellular lipid accumulation.
Overall, these findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting. The activin and myostatin inhibitor FSTL3 however seems to be involved in hepatic stellate cell activation and hepatocellular steatosis and warrants further investigation as a therapeutic target in liver fibrosis and MASH in particular
Luminescent ruthenium on gold nanoparticles; novel DNA probes for cancer theranostics
Get PDFRuthenium (II) polypyridyl complexes have been extensively investigated for cancer research as imaging probes or as therapeutic drug due to their photothermal stability, large stoke shifts, relatively long lifetimes, and potential anticancer activity. To overcome issues of solubility and delivery, gold nanoparticles (AuNPs) have emerged as nano carriers due to their relative chemical inertness, large surface area with possibilities of functionalisation as well as their unique multimodal imaging properties due to their surface plasmon resonance and electron density. Three ruthenium (II) complexes carrying DNA intercalating groups (RuPhenL1, RuPhenL2 and RuDppzL2) were successfully attached onto the surface of 13 nm and 25 nm gold nanoparticles. Luminescence studies of Au.RuPhenL1 and Au.RuPhenL2 revealed enhancement of the ruthenium luminescence lifetime upon attachment to gold nanoparticles by considering the type of ancillary ligands around the metal in combination with the type of surfactant used to stabilise the AuNPs. Furthermore, the negatively charged Au.RuPhenL2 and Au.RuDppzL2 conjugates demonstrated to have a high binding affinity with DNA, with binding constants comparable to known intercalators (Ka= 106 M-1). Unsurprisingly, Au.RuDppzL2 had the strongest interaction with DNA. For the first time, the interaction of the Au.RuPhenL2 and Au.RuDppzL2 conjugates is visualised by Transmission Electron Microscopy (TEM) and Energy Dispersed X-ray Spectroscopy (EDX). Intercalation and electrostatic interactions with an uncoiling of DNA, are the suggested modes of binding between AuNP.Ru conjugates and DNA. The luminescent nanoparticles (Au.RuPhenL1, Au.RuPhenL2 and Au.RuDppzL2) accumulated in the cytoplasm and in the nucleus of A549 cells just after 4 hours incubation. The larger 25 nm AuNPs showed higher cellular uptake than the 13 nm ones for Au.RuPhenL1 and Au.RuPhenL2. However, in the case of Au.RuDppzL2 there was high uptake for both 13 nm and 25 nm sized nanoparticles. All the AuNP.Ru conjugates showed phototoxicity in the nanomolar range for A549 cells upon visible light irradiation at 535 nm, whereas no toxicity was found in the dark. Overall, novel AuNP.Ru conjugates demonstrated promising results as DNA probes for imaging and as pro-drugs for photodynamic therapy for an effective theranostics strategy against cancer
How can the BBC deploy personalised media content recommendations responsibly?
Get PDFIt is well observed that recommender systems are one of the main success stories in the development of algorithmically driven technologies, and they are now adopted by many digital media companies for the personalisation of their content. The BBC is also in the process of deploying recommender systems to personalise the distribution of their media content. However, it is important that we ask how the BBC is able to deliver personalised media content recommendations responsibly, because unlike other media companies also deploying recommender systems, the BBC has a unique body of responsibilities. In this study we set out to identify what these responsibilities are and by defining responsibly as a combination of role responsibility, grounded on the BBC’s role as the nation’s primary public service broadcaster established by Parliament and accountable to the public, and legal responsibility, the sum of relevant laws and regulations, we are able to gather a clear list of the BBC’s responsibilities. I distil this list down to four core responsibilities, derived from two sources: a) political philosophy, and b) jurisprudence about the importance of speech in a democratic society, and ground them in a liberal democracy under the rule of law. These core responsibilities are to
support the place of democratic deliberation, our need for epistemic trust, our recognition of difference, and the protection of our human rights and the development of our human capabilities. By applying this framework, I am able to articulate what it means for the BBC to deploy recommender systems responsibly. In turn I will also use this framework as a tool to assess and evaluate the current BBC’s practices and operations in deploying recommenders, and ultimately to propose suggestions as to how the BBC can deploy recommenders more in line with its responsibilities
Effects of permitted forms of performance enhancement on determinants of doping in UK student-athletes
Get PDFElaborating psychosocial mechanisms that influence doping in sport is important considering societal concerns around health harms and fairness in sport. A key influence identified in the literature is the use of dietary and ergogenic supplements (Backhouse et al., 2013; Ntoumanis et al., 2014). Despite the associated risks of supplement use, evidence shows a high prevalence of use amongst athletes (Daher et al., 2022) but limited knowledge of the risks (Daher et al., 2021; Trakman et al., 2016). This is of particular concern given evidence to show possible ‘gateway effects’ of supplement use on doping (Backhouse et al., 2013; Hurst, 2023). A related theoretical model is the Incremental Model of Doping Behaviour that builds on the underlying concept of the gateway model, with two alterations; firstly, it frames progression to doping in terms of performance gains, rather than a desire to cheat. Secondly, it incorporates, and distinguished between, explicit functional and moral attitudes to performance enhancement. However, research to date has not investigated gateway effects over time, and the IMDB remains largely untested, thus limiting conclusions that can be drawn.
Motivations for supplement use by athletes have been widely studied, but to date, no research has qualitatively examined athlete’s perceptions of possible gateway effects of supplement use. Related, findings from research on educational interventions with athletes are equivocal (Bates et al., 2019; Hauw, 2016) and no research has qualitatively examined athlete’s views on optimal educational modalities in relation to supplement use. In particular, research has not yet explored whether the use of supplements could be positioned as an alternative, rather than precursor, to doping.
The present thesis sought to address these gaps in the literature. Chapter 2 provides a narrative review of relevant literature on athlete nutrition and supplement use, attitude research and its relevance to doping, methodological issues in extant literature, the rationale for exploring these issues in adolescent athletes and the choice of reflexive thematic analysis. Chapter 3 describes the development of the two scale instruments used in the quantitative chapter. Evidence to support distinctions between functional and moral attitudes is presented alongside evidence to show validity and stability of the measures.
Further empirical support is shown for a novel taxonomy of supplements and medication grouping supplements into conceptually sound categories based on factor analysis.
Chapter 4 presents the results of two-wave (Study 1) and three-wave (Study 2) cross-lagged panel analyses. The findings show strong support for the stability of the novel attitude variables over time and limited cross-lagged effects between muscle building supplements and functional doping attitudes. Results are somewhat inconsistent and methodological issues that may have affected the results are discussed.
Chapter 5 presents qualitative work exploring athlete’s approach to nutrition and supplement use and their views on optimal nutrition education, in individual interviews (Study 3) and focus groups (Study 4). Data analyses reveal a complex pattern of influences that reflect disparate strands of extant literature, previously largely unconnected. Athletes had poor knowledge of nutrition and supplements but many used supplements frequently. Drivers for this are discussed, including convenience, poor food skills and multiple influences (e.g. peers, coaches, lifestyle). Discussions on educational interventions, alongside reviews of the literature, highlighted the need for personally relevant, multi-faceted approaches that encompassed both knowledge and skill acquisition. The implications of this thesis for policy and practice are discussed in Chapter 6
Search for decays of the Higgs Boson into a Z Boson and a light hadronically decaying resonance
Get PDFThe work for this thesis was conducted within the ATLAS experiment. Initially, a noise study of the trigger system of ATLAS experiment was undertaken. This included the searching for noisy trigger towers and adjusting the noise thresholds for the new trigger component eFEX.
Subsequently, a search for Higgs boson decays to a Z boson and a light resonance a is performed, using 140~fb^{-1} \sqrt{s}=13 TeV pp collision data collected by the ATLAS experiment. a is considered to be a beyond standard model particle or a standard model charmonium state. The mass of a is less than 4 GeV and it is required to decay to quarks or gluons, while Z boson decays to two leptons. No significant excess above the expected background is observed. The observed 95% confidence-level upper limits are set on the branching ratio of Higgs boson decays to a Z boson and the a resonance, with values starting from 13.9% for a decays to gluons, and from 9.2% for a decays to a pair of quarks for different a masses.
The search also considers the axion-like particle models. 95% confidence-level upper limits are set on the strength of the effective coupling C_{Zh}^{eff} with 2.0 TeV^{-1} for 0.5 GeV axion-like particle a, and 0.9 TeV^{-1} for 1.0 GeV a
The vocabulary growth of EFL learners in Saudi Arabia: The role of individual differences, digital flashcard learning and quiz frequency
Get PDFDespite the substantial expansion in vocabulary research since the 1980s (Laufer, 2009; Meara, 2002), we still know very little about how vocabulary develops over time and what factors influence this development (Pellicer-Sánchez, 2019; Webb & Nation, 2017). The first study of the thesis aimed to address this by examining the vocabulary breadth growth of EFL learners over a school semester (12 weeks). It measured the vocabulary growth (meaning recognition and meaning recall) of 141 Saudi intermediate school (aged 15) and secondary school (aged 16) students using the Updated Vocabulary Levels Test (Webb et al., 2017). To explain the expected variation in vocabulary growth, the study examined the role of individual differences focusing on three key factors: out-of-class exposure (e.g., watching TV and playing video games), self-regulation and motivation. The main finding from this study is that vocabulary growth in an EFL context can be low and slow (Nurweni & Read, 1999; Siyanova-Chanturia & Webb, 2016; Webb & Chang, 2012), and after many years of school instruction, students might still not develop a good knowledge of even the highest frequency vocabulary (i.e., the most frequent 1000 word-families). Additionally, out-of-class exposure and motivation were significant predictors of vocabulary learning.
The second study aimed to address the low knowledge of high frequency vocabulary found in the first study. Given the limited time of many EFL classes, it employed digital flashcard learning in out-of-class settings and included in-class quizzes to make sure that students genuinely engage with vocabulary learning and potentially benefit from the testing effect (Karpicke & Roediger, 2007). However, it was unclear based on the previous research how frequently quizzes should occur for optimal vocabulary learning. The second study aimed to address this gap by first examining the effect of quizzing (quiz vs. no-quiz) followed by an examination of the effect of quiz frequency (weekly, biweekly and monthly) on vocabulary learning over a school semester (eight weeks). Secondary school students (n = 76, age = 16-17) learned 120 target words using digital flashcards in naturalistic out-of- class settings using their personal devices. The second study had two main findings. First, the groups who received quizzes showed significant vocabulary improvement on the posttest while the group who did not receive quizzes did not make any significant vocabulary gains. This finding suggests that supplementing out-of-class vocabulary learning with in-class quizzes can be an effective vocabulary learning approach. It also suggests that students’ willingness to engage in out-of-class language learning (i.e., extra- curricular learning) should not be taken for granted when there is no source of external motivation (Seibert Hanson & Brown, 2019). Second, there were no significant differences in the learning gains between the three quiz frequency groups (weekly, biweekly and monthly), suggesting that more frequent quizzes do not necessarily lead to more vocabulary learning.
The thesis overall makes valuable contributions to both vocabulary theory and practice. The first study enhances our understanding of the nature of vocabulary knowledge by examining vocabulary growth longitudinally while taking into account the role of individual differences. The second study offers practical recommendations to help language learners learn vocabulary more effectively. The two studies combined make important strides in advancing L2 vocabulary learning, instruction and research
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