9,460 research outputs found

    In vitro investigation of the effect of disulfiram on hypoxia induced NFκB, 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 NFκB 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 (NFκB-p65) subunit exhibited CSC and EMT markers indicating the essential role of NFκB in maintaining GSC phenotypes. The study also highlighted the significance of NFκB in driving chemoresistance, invasiveness, and the potential role of NFκB 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 NFκB 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

    On the Mechanism of Building Core Competencies: a Study of Chinese Multinational Port Enterprises

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    This study aims to explore how Chinese multinational port enterprises (MNPEs) build their core competencies. Core competencies are firms’special capabilities and sources to gain sustainable competitive advantage (SCA) in marketplace, and the concept led to extensive research and debates. However, few studies include inquiries about the mechanisms of building core competencies in the context of Chinese MNPEs. Accordingly, answers were sought to three research questions: 1. What are the core competencies of the Chinese MNPEs? 2. What are the mechanisms that the Chinese MNPEs use to build their core competencies? 3. What are the paths that the Chinese MNPEs pursue to build their resources bases? The study adopted a multiple-case study design, focusing on building mechanism of core competencies with RBV. It selected purposively five Chinese leading MNPEs and three industry associations as Case Companies. The study revealed three main findings. First, it identified three generic core competencies possessed by Case Companies, i.e., innovation in business models and operations, utilisation of technologies, and acquisition of strategic resources. Second, it developed the conceptual framework of the Mechanism of Building Core Competencies (MBCC), which is a process of change of collective learning in effective and efficient utilization of resources of a firm in response to critical events. Third, it proposed three paths to build core competencies, i.e., enhancing collective learning, selecting sustainable processes, and building resource base. The study contributes to the knowledge of core competencies and RBV in three ways: (1) presenting three generic core competencies of the Chinese MNPEs, (2) proposing a new conceptual framework to explain how Chinese MNPEs build their core competencies, (3) suggesting a solid anchor point (MBCC) to explain the links among resources, core competencies, and SCA. The findings set benchmarks for Chinese logistics industry and provide guidelines to build core competencies

    Gasificação direta de biomassa para produção de gás combustível

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    The excessive consumption of fossil fuels to satisfy the world necessities of energy and commodities led to the emission of large amounts of greenhouse gases in the last decades, contributing significantly to the greatest environmental threat of the 21st century: Climate Change. The answer to this man-made disaster is not simple and can only be made if distinct stakeholders and governments are brought to cooperate and work together. This is mandatory if we want to change our economy to one more sustainable and based in renewable materials, and whose energy is provided by the eternal nature energies (e.g., wind, solar). In this regard, biomass can have a main role as an adjustable and renewable feedstock that allows the replacement of fossil fuels in various applications, and the conversion by gasification allows the necessary flexibility for that purpose. In fact, fossil fuels are just biomass that underwent extreme pressures and heat for millions of years. Furthermore, biomass is a resource that, if not used or managed, increases wildfire risks. Consequently, we also have the obligation of valorizing and using this resource. In this work, it was obtained new scientific knowledge to support the development of direct (air) gasification of biomass in bubbling fluidized bed reactors to obtain a fuel gas with suitable properties to replace natural gas in industrial gas burners. This is the first step for the integration and development of gasification-based biorefineries, which will produce a diverse number of value-added products from biomass and compete with current petrochemical refineries in the future. In this regard, solutions for the improvement of the raw producer gas quality and process efficiency parameters were defined and analyzed. First, addition of superheated steam as primary measure allowed the increase of H2 concentration and H2/CO molar ratio in the producer gas without compromising the stability of the process. However, the measure mainly showed potential for the direct (air) gasification of high-density biomass (e.g., pellets), due to the necessity of having char accumulation in the reactor bottom bed for char-steam reforming reactions. Secondly, addition of refused derived fuel to the biomass feedstock led to enhanced gasification products, revealing itself as a highly promising strategy in terms of economic viability and environmental benefits of future gasification-based biorefineries, due to the high availability and low costs of wastes. Nevertheless, integrated techno economic and life cycle analyses must be performed to fully characterize the process. Thirdly, application of low-cost catalyst as primary measure revealed potential by allowing the improvement of the producer gas quality (e.g., H2 and CO concentration, lower heating value) and process efficiency parameters with distinct solid materials; particularly, the application of concrete, synthetic fayalite and wood pellets chars, showed promising results. Finally, the economic viability of the integration of direct (air) biomass gasification processes in the pulp and paper industry was also shown, despite still lacking interest to potential investors. In this context, the role of government policies and appropriate economic instruments are of major relevance to increase the implementation of these projects.O consumo excessivo de combustíveis fósseis para garantir as necessidades e interesses da sociedade conduziu à emissão de elevadas quantidades de gases com efeito de estufa nas últimas décadas, contribuindo significativamente para a maior ameaça ambiental do século XXI: Alterações Climáticas. A solução para este desastre de origem humana é de caráter complexo e só pode ser atingida através da cooperação de todos os governos e partes interessadas. Para isto, é obrigatória a criação de uma bioeconomia como base de um futuro mais sustentável, cujas necessidades energéticas e materiais sejam garantidas pelas eternas energias da natureza (e.g., vento, sol). Neste sentido, a biomassa pode ter um papel principal como uma matéria prima ajustável e renovável que permite a substituição de combustíveis fósseis num variado número de aplicações, e a sua conversão através da gasificação pode ser a chave para este propósito. Afinal, na prática, os combustíveis fósseis são apenas biomassa sujeita a elevada temperatura e pressão durante milhões de anos. Além do mais, a gestão eficaz da biomassa é fundamental para a redução dos riscos de incêndio florestal e, como tal, temos o dever de utilizar e valorizar este recurso. Neste trabalho, foi obtido novo conhecimento científico para suporte do desenvolvimento das tecnologias de gasificação direta (ar) de biomassa em leitos fluidizados borbulhantes para produção de gás combustível, com o objetivo da substituição de gás natural em queimadores industriais. Este é o primeiro passo para o desenvolvimento de biorrefinarias de gasificação, uma potencial futura indústria que irá providenciar um variado número de produtos de valor acrescentado através da biomassa e competir com a atual indústria petroquímica. Neste sentido, foram analisadas várias medidas para a melhoria da qualidade do gás produto bruto e dos parâmetros de eficiência do processo. Em primeiro, a adição de vapor sobreaquecido como medida primária permitiu o aumento da concentração de H2 e da razão molar H2/CO no gás produto sem comprometer a estabilidade do processo. No entanto, esta medida somente revelou potencial para a gasificação direta (ar) de biomassa de alta densidade (e.g., pellets) devido à necessidade da acumulação de carbonizados no leito do reator para a ocorrência de reações de reforma com vapor. Em segundo, a mistura de combustíveis derivados de resíduos e biomassa residual florestal permitiu a melhoria dos produtos de gasificação, constituindo desta forma uma estratégia bastante promissora a nível económico e ambiental, devido à elevada abundância e baixo custo dos resíduos urbanos. Contudo, devem ser efetuadas análises técnico-económicas e de ciclo de vida para a completa caraterização do processo. Em terceiro, a aplicação de catalisadores de baixo custo como medida primária demonstrou elevado potencial para a melhoria do gás produto (e.g., concentração de H2 e CO, poder calorífico inferior) e para o incremento dos parâmetros de eficiência do processo; em particular, a aplicação de betão, faialite sintética e carbonizados de pellets de madeira, demonstrou resultados promissores. Finalmente, foi demonstrada a viabilidade económica da integração do processo de gasificação direta (ar) de biomassa na indústria da pasta e papel, apesar dos parâmetros determinados não serem atrativos para potenciais investidores. Neste contexto, a intervenção dos governos e o desenvolvimento de instrumentos de apoio económico é de grande relevância para a implementação destes projetos.Este trabalho foi financiado pela The Navigator Company e por Fundos Nacionais através da Fundação para a Ciência e a Tecnologia (FCT).Programa Doutoral em Engenharia da Refinação, Petroquímica e Químic

    Transformation of the business model to establish sustainable value in the consumer durables super store industry of Sri Lanka

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    The business model of an organization, operates as the fundamental blue print of the planning process, which shapes the nature of the strategies executed during the course of operation. These strategies in turn are responsible for the value creation or value erosion that takes place during the operation of the organization determining its sustainability, and in a broader context the sustainability of the industry. The research is done for the Consumer Durables Super Store (CDSS) industry of Sri Lanka concerning the existing business model, the value erosion occurring as a result of it and the risk it carries to the sustainability of the industry. The theoretical aspect of the research to develop a relationship based business model was anchored on the understanding of existing frameworks relating to sustainable value and extracting relevant areas of each of these frameworks (alignment of value, transforming current strategies and service offerings to create sustainable value) to develop a suitable hybrid framework with modifications to the literature to suite the research context.Ten in-depth interviews with CDSS organizational representatives holding leadership, sales and marketing management positions, and two focus group sessions with fifty selected customers were conducted in a virtual environment due to the prevailing pandemic situation. The data collected were analyzed with NVIVO 12, with themes relevant to the research utilized as codes, giving a clear understanding over the buyer and seller purview on the themes of the research. The findings surfaced the value erosion caused due to the financially driven strategies originated from the transactional orientation of the existing business model. The theories adopted to construct the relationship oriented business model to rectify the value erosion taking place, based on sustainable value, value alignment and service offerings, were modified to incorporate ‘quality of trade’ to bridge the gap, leading towards the creation and delivery of sustainable value to the buyer-seller eco system of the industry

    Embodying entrepreneurship: everyday practices, processes and routines in a technology incubator

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    The growing interest in the processes and practices of entrepreneurship has been dominated by a consideration of temporality. Through a thirty-six-month ethnography of a technology incubator, this thesis contributes to extant understanding by exploring the effect of space. The first paper explores how class structures from the surrounding city have appropriated entrepreneurship within the incubator. The second paper adopts a more explicitly spatial analysis to reveal how the use of space influences a common understanding of entrepreneurship. The final paper looks more closely at the entrepreneurs within the incubator and how they use visual symbols to develop their identity. Taken together, the three papers reject the notion of entrepreneurship as a primarily economic endeavour as articulated through commonly understood language and propose entrepreneuring as an enigmatic attractor that is accessed through the ambiguity of the non-verbal to develop the ‘new’. The thesis therefore contributes to the understanding of entrepreneurship and proposes a distinct role for the non-verbal in that understanding

    Development of in-vitro in-silico technologies for modelling and analysis of haematological malignancies

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    Worldwide, haematological malignancies are responsible for roughly 6% of all the cancer-related deaths. Leukaemias are one of the most severe types of cancer, as only about 40% of the patients have an overall survival of 10 years or more. Myelodysplastic Syndrome (MDS), a pre-leukaemic condition, is a blood disorder characterized by the presence of dysplastic, irregular, immature cells, or blasts, in the peripheral blood (PB) and in the bone marrow (BM), as well as multi-lineage cytopenias. We have created a detailed, lineage-specific, high-fidelity in-silico erythroid model that incorporates known biological stimuli (cytokines and hormones) and a competing diseased haematopoietic population, correctly capturing crucial biological checkpoints (EPO-dependent CFU-E differentiation) and replicating the in-vivo erythroid differentiation dynamics. In parallel, we have also proposed a long-term, cytokine-free 3D cell culture system for primary MDS cells, which was firstly optimized using easily-accessible healthy controls. This system enabled long-term (24-day) maintenance in culture with high (>75%) cell viability, promoting spontaneous expansion of erythroid phenotypes (CD71+/CD235a+) without the addition of any exogenous cytokines. Lastly, we have proposed a novel in-vitro in-silico framework using GC-MS metabolomics for the metabolic profiling of BM and PB plasma, aiming not only to discretize between haematological conditions but also to sub-classify MDS patients, potentially based on candidate biomarkers. Unsupervised multivariate statistical analysis showed clear intra- and inter-disease separation of samples of 5 distinct haematological malignancies, demonstrating the potential of this approach for disease characterization. The work herein presented paves the way for the development of in-vitro in-silico technologies to better, characterize, diagnose, model and target haematological malignancies such as MDS and AML.Open Acces

    Foundations for programming and implementing effect handlers

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    First-class control operators provide programmers with an expressive and efficient means for manipulating control through reification of the current control state as a first-class object, enabling programmers to implement their own computational effects and control idioms as shareable libraries. Effect handlers provide a particularly structured approach to programming with first-class control by naming control reifying operations and separating from their handling. This thesis is composed of three strands of work in which I develop operational foundations for programming and implementing effect handlers as well as exploring the expressive power of effect handlers. The first strand develops a fine-grain call-by-value core calculus of a statically typed programming language with a structural notion of effect types, as opposed to the nominal notion of effect types that dominates the literature. With the structural approach, effects need not be declared before use. The usual safety properties of statically typed programming are retained by making crucial use of row polymorphism to build and track effect signatures. The calculus features three forms of handlers: deep, shallow, and parameterised. They each offer a different approach to manipulate the control state of programs. Traditional deep handlers are defined by folds over computation trees, and are the original con-struct proposed by Plotkin and Pretnar. Shallow handlers are defined by case splits (rather than folds) over computation trees. Parameterised handlers are deep handlers extended with a state value that is threaded through the folds over computation trees. To demonstrate the usefulness of effects and handlers as a practical programming abstraction I implement the essence of a small UNIX-style operating system complete with multi-user environment, time-sharing, and file I/O. The second strand studies continuation passing style (CPS) and abstract machine semantics, which are foundational techniques that admit a unified basis for implementing deep, shallow, and parameterised effect handlers in the same environment. The CPS translation is obtained through a series of refinements of a basic first-order CPS translation for a fine-grain call-by-value language into an untyped language. Each refinement moves toward a more intensional representation of continuations eventually arriving at the notion of generalised continuation, which admit simultaneous support for deep, shallow, and parameterised handlers. The initial refinement adds support for deep handlers by representing stacks of continuations and handlers as a curried sequence of arguments. The image of the resulting translation is not properly tail-recursive, meaning some function application terms do not appear in tail position. To rectify this the CPS translation is refined once more to obtain an uncurried representation of stacks of continuations and handlers. Finally, the translation is made higher-order in order to contract administrative redexes at translation time. The generalised continuation representation is used to construct an abstract machine that provide simultaneous support for deep, shallow, and parameterised effect handlers. kinds of effect handlers. The third strand explores the expressiveness of effect handlers. First, I show that deep, shallow, and parameterised notions of handlers are interdefinable by way of typed macro-expressiveness, which provides a syntactic notion of expressiveness that affirms the existence of encodings between handlers, but it provides no information about the computational content of the encodings. Second, using the semantic notion of expressiveness I show that for a class of programs a programming language with first-class control (e.g. effect handlers) admits asymptotically faster implementations than possible in a language without first-class control

    Digital asset management via distributed ledgers

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    Distributed ledgers rose to prominence with the advent of Bitcoin, the first provably secure protocol to solve consensus in an open-participation setting. Following, active research and engineering efforts have proposed a multitude of applications and alternative designs, the most prominent being Proof-of-Stake (PoS). This thesis expands the scope of secure and efficient asset management over a distributed ledger around three axes: i) cryptography; ii) distributed systems; iii) game theory and economics. First, we analyze the security of various wallets. We start with a formal model of hardware wallets, followed by an analytical framework of PoS wallets, each outlining the unique properties of Proof-of-Work (PoW) and PoS respectively. The latter also provides a rigorous design to form collaborative participating entities, called stake pools. We then propose Conclave, a stake pool design which enables a group of parties to participate in a PoS system in a collaborative manner, without a central operator. Second, we focus on efficiency. Decentralized systems are aimed at thousands of users across the globe, so a rigorous design for minimizing memory and storage consumption is a prerequisite for scalability. To that end, we frame ledger maintenance as an optimization problem and design a multi-tier framework for designing wallets which ensure that updates increase the ledger’s global state only to a minimal extent, while preserving the security guarantees outlined in the security analysis. Third, we explore incentive-compatibility and analyze blockchain systems from a micro and a macroeconomic perspective. We enrich our cryptographic and systems' results by analyzing the incentives of collective pools and designing a state efficient Bitcoin fee function. We then analyze the Nash dynamics of distributed ledgers, introducing a formal model that evaluates whether rational, utility-maximizing participants are disincentivized from exhibiting undesirable infractions, and highlighting the differences between PoW and PoS-based ledgers, both in a standalone setting and under external parameters, like market price fluctuations. We conclude by introducing a macroeconomic principle, cryptocurrency egalitarianism, and then describing two mechanisms for enabling taxation in blockchain-based currency systems
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