10,666 research outputs found

    In vitro investigation of the effect of disulfiram on hypoxia induced NFÎșB, epithelial to mesenchymal transition and cancer stem cells in glioblastoma cell lines

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    A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.Glioblastoma multiforme (GBM) is one of the most aggressive and lethal cancers with a poor prognosis. Advances in the treatment of GBM are limited due to several resistance mechanisms and limited drug delivery into the central nervous system (CNS) compartment by the blood-brain barrier (BBB) and by actions of the normal brain to counteract tumour-targeting medications. Hypoxia is common in malignant brain tumours such as GBM and plays a significant role in tumour pathobiology. It is widely accepted that hypoxia is a major driver of GBM malignancy. Although it has been confirmed that hypoxia induces GBM stem-like-cells (GSCs), which are highly invasive and resistant to all chemotherapeutic agents, the detailed molecular pathways linking hypoxia, GSC traits and chemoresistance remain obscure. Evidence shows that hypoxia induces cancer stem cell phenotypes via epithelial-to-mesenchymal transition (EMT), promoting therapeutic resistance in most cancers, including GBM. This study demonstrated that spheroid cultured GBM cells consist of a large population of hypoxic cells with CSC and EMT characteristics. GSCs are chemo-resistant and displayed increased levels of HIFs and NFÎșB activity. Similarly, the hypoxia cultured GBM cells manifested GSC traits, chemoresistance and invasiveness. These results suggest that hypoxia is responsible for GBM stemness, chemoresistance and invasiveness. GBM cells transfected with nuclear factor kappa B-p65 (NFÎșB-p65) subunit exhibited CSC and EMT markers indicating the essential role of NFÎșB in maintaining GSC phenotypes. The study also highlighted the significance of NFÎșB in driving chemoresistance, invasiveness, and the potential role of NFÎșB as the central regulator of hypoxia-induced stemness in GBM cells. GSC population has the ability of self-renewal, cancer initiation and development of secondary heterogeneous cancer. The very poor prognosis of GBM could largely be attributed to the existence of GSCs, which promote tumour propagation, maintenance, radio- and chemoresistance and local infiltration. In this study, we used Disulfiram (DS), a drug used for more than 65 years in alcoholism clinics, in combination with copper (Cu) to target the NFÎșB pathway, reverse chemoresistance and block invasion in GSCs. The obtained results showed that DS/Cu is highly cytotoxic to GBM cells and completely eradicated the resistant CSC population at low dose levels in vitro. DS/Cu inhibited the migration and invasion of hypoxia-induced CSC and EMT like GBM cells at low nanomolar concentrations. DS is an FDA approved drug with low toxicity to normal tissues and can pass through the BBB. Further research may lead to the quick translation of DS into cancer clinics and provide new therapeutic options to improve treatment outcomes in GBM patients

    Learning disentangled speech representations

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    A variety of informational factors are contained within the speech signal and a single short recording of speech reveals much more than the spoken words. The best method to extract and represent informational factors from the speech signal ultimately depends on which informational factors are desired and how they will be used. In addition, sometimes methods will capture more than one informational factor at the same time such as speaker identity, spoken content, and speaker prosody. The goal of this dissertation is to explore different ways to deconstruct the speech signal into abstract representations that can be learned and later reused in various speech technology tasks. This task of deconstructing, also known as disentanglement, is a form of distributed representation learning. As a general approach to disentanglement, there are some guiding principles that elaborate what a learned representation should contain as well as how it should function. In particular, learned representations should contain all of the requisite information in a more compact manner, be interpretable, remove nuisance factors of irrelevant information, be useful in downstream tasks, and independent of the task at hand. The learned representations should also be able to answer counter-factual questions. In some cases, learned speech representations can be re-assembled in different ways according to the requirements of downstream applications. For example, in a voice conversion task, the speech content is retained while the speaker identity is changed. And in a content-privacy task, some targeted content may be concealed without affecting how surrounding words sound. While there is no single-best method to disentangle all types of factors, some end-to-end approaches demonstrate a promising degree of generalization to diverse speech tasks. This thesis explores a variety of use-cases for disentangled representations including phone recognition, speaker diarization, linguistic code-switching, voice conversion, and content-based privacy masking. Speech representations can also be utilised for automatically assessing the quality and authenticity of speech, such as automatic MOS ratings or detecting deep fakes. The meaning of the term "disentanglement" is not well defined in previous work, and it has acquired several meanings depending on the domain (e.g. image vs. speech). Sometimes the term "disentanglement" is used interchangeably with the term "factorization". This thesis proposes that disentanglement of speech is distinct, and offers a viewpoint of disentanglement that can be considered both theoretically and practically

    The developing maternal-infant relationship: a qualitative longitudinal study

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    Aim The study aimed to explore maternal perceptions and the use of knowledge relating to their infant’s mental health over time using qualitative longitudinal research. Background There has been a growing interest in infant mental health over recent years. Much of this interest is directed through the lens of infant determinism, through knowledge regarding neurological development resulting in biological determinism. Research and policy in this field are directed toward individual parenting behaviours, usually focused on the mother. Despite this, there is little attention given to maternal perspectives of infant mental health, indicating that a more innovative approach to methodology is required. Methods This study took a qualitative longitudinal approach, and interviews were undertaken with seven mothers from the third trimester of pregnancy and then throughout the first year of the infant’s life. Interviews were conducted at 34 weeks of pregnancy, and then when the infant was 6 and 12 weeks, 6, 9, and 12 months, alongside the collection of researcher field notes—a total of 41 interviews. Data were analysed by creating case profiles, memos, and summaries, and then cross-comparison of the emerging narratives. A psycho-socially informed approach was taken to the analysis of data. Findings Three interrelated themes emerged from the data: evolving maternal identity, growing a person, and creating a safe space. The theme of evolving maternal identity dominated the other themes of growing a person and creating a safe space in a way that met perceived socio-cultural requirements for mothering and childcare practices. Participants’ personal stories give voice to their perceptions of the developing maternal-infant relationship in the context of their socio-cultural setting, relationships with others, and experiences over time. Conclusions This study adds new knowledge by giving mothers a voice to express how the maternal-infant relationship develops over time. The findings demonstrate how the developing maternal-infant relationship grows in response to their mutual needs as the mother works to create and sustain identities for herself and the infant that will fit within their socio-cultural context and individual situations. Additionally, the findings illustrate the importance of temporal considerations, social networks, and intergenerational relationships to this evolving process. Recommendations for practice, policy, and education are made that reflect the unique relationship between mother and infant and the need to conceptualise this using an ecological approach

    From wallet to mobile: exploring how mobile payments create customer value in the service experience

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    This study explores how mobile proximity payments (MPP) (e.g., Apple Pay) create customer value in the service experience compared to traditional payment methods (e.g. cash and card). The main objectives were firstly to understand how customer value manifests as an outcome in the MPP service experience, and secondly to understand how the customer activities in the process of using MPP create customer value. To achieve these objectives a conceptual framework is built upon the Grönroos-Voima Value Model (Grönroos and Voima, 2013), and uses the Theory of Consumption Value (Sheth et al., 1991) to determine the customer value constructs for MPP, which is complimented with Script theory (Abelson, 1981) to determine the value creating activities the consumer does in the process of paying with MPP. The study uses a sequential exploratory mixed methods design, wherein the first qualitative stage uses two methods, self-observations (n=200) and semi-structured interviews (n=18). The subsequent second quantitative stage uses an online survey (n=441) and Structural Equation Modelling analysis to further examine the relationships and effect between the value creating activities and customer value constructs identified in stage one. The academic contributions include the development of a model of mobile payment services value creation in the service experience, introducing the concept of in-use barriers which occur after adoption and constrains the consumers existing use of MPP, and revealing the importance of the mobile in-hand momentary condition as an antecedent state. Additionally, the customer value perspective of this thesis demonstrates an alternative to the dominant Information Technology approaches to researching mobile payments and broadens the view of technology from purely an object a user interacts with to an object that is immersed in consumers’ daily life

    Examining the Impact of Personal Social Media Use at Work on Workplace Outcomes

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    A noticable shift is underway in today’s multi-generational workforce. As younger employees propel digital workforce transformation and embrace technology adoption in the workplace, organisations need to show they are forward-thinking in their digital transformation strategies, and the emergent integration of social media in organisations is reshaping internal communication strategies, in a bid to improve corporate reputations and foster employee engagement. However, the impact of personal social media use on psychological and behavioural workplace outcomes is still debatebale with contrasting results in the literature identifying both positive and negative effects on workplace outcomes among organisational employees. This study seeks to examine this debate through the lens of social capital theory and study personal social media use at work using distinct variables of social use, cognitive use, and hedonic use. A quantitative analysis of data from 419 organisational employees in Jordan using SEM-PLS reveals that personal social media use at work is a double-edged sword as its impact differs by usage types. First, the social use of personal social media at work reduces job burnout, turnover intention, presenteeism, and absenteeism; it also increases job involvement and organisational citizen behaviour. Second, the cognitive use of personal social media at work increases job involvement, organisational citizen behaviour, employee adaptability, and decreases presenteeism and absenteeism; it also increases job burnout and turnover intention. Finally, the hedonic use of personal social media at work carries only negative effects by increasing job burnout and turnover intention. This study contributes to managerial understanding by showing the impact of different types of personal social media usage and recommends that organisations not limit employee access to personal social media within work time, but rather focus on raising awareness of the negative effects of excessive usage on employee well-being and encourage low to moderate use of personal social media at work and other personal and work-related online interaction associated with positive workplace outcomes. It also clarifies the need for further research in regions such as the Middle East with distinct cultural and socio-economic contexts

    Neural Natural Language Generation: A Survey on Multilinguality, Multimodality, Controllability and Learning

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    Developing artificial learning systems that can understand and generate natural language has been one of the long-standing goals of artificial intelligence. Recent decades have witnessed an impressive progress on both of these problems, giving rise to a new family of approaches. Especially, the advances in deep learning over the past couple of years have led to neural approaches to natural language generation (NLG). These methods combine generative language learning techniques with neural-networks based frameworks. With a wide range of applications in natural language processing, neural NLG (NNLG) is a new and fast growing field of research. In this state-of-the-art report, we investigate the recent developments and applications of NNLG in its full extent from a multidimensional view, covering critical perspectives such as multimodality, multilinguality, controllability and learning strategies. We summarize the fundamental building blocks of NNLG approaches from these aspects and provide detailed reviews of commonly used preprocessing steps and basic neural architectures. This report also focuses on the seminal applications of these NNLG models such as machine translation, description generation, automatic speech recognition, abstractive summarization, text simplification, question answering and generation, and dialogue generation. Finally, we conclude with a thorough discussion of the described frameworks by pointing out some open research directions.This work has been partially supported by the European Commission ICT COST Action “Multi-task, Multilingual, Multi-modal Language Generation” (CA18231). AE was supported by BAGEP 2021 Award of the Science Academy. EE was supported in part by TUBA GEBIP 2018 Award. BP is in in part funded by Independent Research Fund Denmark (DFF) grant 9063-00077B. IC has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838188. EL is partly funded by Generalitat Valenciana and the Spanish Government throught projects PROMETEU/2018/089 and RTI2018-094649-B-I00, respectively. SMI is partly funded by UNIRI project uniri-drustv-18-20. GB is partly supported by the Ministry of Innovation and the National Research, Development and Innovation Office within the framework of the Hungarian Artificial Intelligence National Laboratory Programme. COT is partially funded by the Romanian Ministry of European Investments and Projects through the Competitiveness Operational Program (POC) project “HOLOTRAIN” (grant no. 29/221 ap2/07.04.2020, SMIS code: 129077) and by the German Academic Exchange Service (DAAD) through the project “AWAKEN: content-Aware and netWork-Aware faKE News mitigation” (grant no. 91809005). ESA is partially funded by the German Academic Exchange Service (DAAD) through the project “Deep-Learning Anomaly Detection for Human and Automated Users Behavior” (grant no. 91809358)

    Freelance subtitlers in a subtitle production network in the OTT industry in Thailand: a longitudinal study

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    The present study sets out to investigate a subtitle production network in the over-the-top (OTT) industry in Thailand through the perspective of freelance subtitlers. A qualitative longitudinal research design was adopted to gain insights into (1) the way the work practices of freelance subtitlers are influenced by both human and non-human actors in the network, (2) the evolution of the network, and (3) how the freelance subtitlers’ perception of quality is influenced by changes occurring in the network. Eleven subtitlers were interviewed every six months over a period of two years, contributing to over 60 hours of interview data. The data analysis was informed by selected concepts from Actor-Network Theory (ANT) (Law 1992, 2009; Latour 1996, 2005; Mol 2010), and complemented by the three-dimensional quality model proposed by Abdallah (2016, 2017). Reflexive thematic analysis (Braun and Clarke 2019a, 2020b) was used to generate themes and sub-themes which address the research questions and tell compelling stories about the actor-network. It was found that from July 2017 to September 2019, the subtitle production network, which was sustained by complex interrelationships between actors, underwent a number of changes. The changes affected the work practices of freelance subtitlers in a more negative than positive way, demonstrating their precarious position in an industry that has widely adopted the vendor model (Moorkens 2017). Moreover, as perceived by the research participants, under increasingly undesirable working conditions, it became more challenging to maintain a quality process and to produce quality subtitles. Finally, translation technology and tools, including machine translation, were found to be key non-human actors that catalyse the changes in the network under study

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms
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