4,837 research outputs found

    Studying the interplay between ageing and Parkinson's disease using the zebrafish model

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    Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Ageing is the major risk factor for developing PD but the interplay between ageing and PD remains elusive. To investigate the effect of ageing on PD-relevant pathological mechanisms, zebrafish mutant lines harbouring mutations in ageing-associated genes (klotho-/-, sirt1-/-, satb1a-/-, satb1b-/- and satb1a-/-;satb1b-/-) were generated, using CRISPR/Cas9 gene editing. Likewise, a chemical model for SIRT1 deficiency was utilised. klotho-/- zebrafish displayed an accelerated ageing phenotype at 3mpf and reduced survival to 6mpf. Dopaminergic neuron number, MPP+ susceptibility and microglial number were unaffected in klotho-/- larvae. NAD+ levels were decreased in 6mpf klotho-/- brains. However, ATP levels and DNA damage were unaffected. sirt1-/- zebrafish did not display a phenotype through adulthood. il-1β and il-6 were not upregulated in sirt1-/- larvae, and chemical inhibition of sirt1 did not increase microglial number. cdkn1a, il-1β and il-6 were not upregulated in satb1a-/- and satb1b-/- larvae. Dopaminergic neuron number and MPP+ susceptibility were unaffected in satb1a-/- larvae. However, satb1b-/- larvae demonstrated a moderate decrease in dopaminergic neuron number but equal susceptibility to MPP+ as satb1b+/+ larvae. Adult satb1a-/- but not adult satb1b-/- zebrafish were emaciated. satb1a-/-;satb1b-/- zebrafish did not display a phenotype through adulthood. Transgenic zebrafish expressing human wildtype α-Synuclein (Tg(eno2:hsa.SNCA-ires-EGFP)) were crossed with klotho-/- and sirt1-/- zebrafish, and treated with a sirt1-specific inhibitor. Neither genetic cross affected survival. The klotho mutation did not increase microglial number in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. Likewise, sirt1 inhibition did not induce motor impairment or cell death in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. In conclusion, the suitability of zebrafish for studying ageing remains elusive, as only 1 ageing-associated mutant line displayed accelerated ageing. However, zebrafish remain an effective model for studying PD-relevant pathological mechanisms due to the availability of CRISPR/Cas9 gene editing, neuropathological and neurobehavioral tools

    An empirical investigation of the relationship between integration, dynamic capabilities and performance in supply chains

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    This research aimed to develop an empirical understanding of the relationships between integration, dynamic capabilities and performance in the supply chain domain, based on which, two conceptual frameworks were constructed to advance the field. The core motivation for the research was that, at the stage of writing the thesis, the combined relationship between the three concepts had not yet been examined, although their interrelationships have been studied individually. To achieve this aim, deductive and inductive reasoning logics were utilised to guide the qualitative study, which was undertaken via multiple case studies to investigate lines of enquiry that would address the research questions formulated. This is consistent with the author’s philosophical adoption of the ontology of relativism and the epistemology of constructionism, which was considered appropriate to address the research questions. Empirical data and evidence were collected, and various triangulation techniques were employed to ensure their credibility. Some key features of grounded theory coding techniques were drawn upon for data coding and analysis, generating two levels of findings. These revealed that whilst integration and dynamic capabilities were crucial in improving performance, the performance also informed the former. This reflects a cyclical and iterative approach rather than one purely based on linearity. Adopting a holistic approach towards the relationship was key in producing complementary strategies that can deliver sustainable supply chain performance. The research makes theoretical, methodological and practical contributions to the field of supply chain management. The theoretical contribution includes the development of two emerging conceptual frameworks at the micro and macro levels. The former provides greater specificity, as it allows meta-analytic evaluation of the three concepts and their dimensions, providing a detailed insight into their correlations. The latter gives a holistic view of their relationships and how they are connected, reflecting a middle-range theory that bridges theory and practice. The methodological contribution lies in presenting models that address gaps associated with the inconsistent use of terminologies in philosophical assumptions, and lack of rigor in deploying case study research methods. In terms of its practical contribution, this research offers insights that practitioners could adopt to enhance their performance. They can do so without necessarily having to forgo certain desired outcomes using targeted integrative strategies and drawing on their dynamic capabilities

    Understanding the Code of Life: Holistic Conceptual Modeling of the Genome

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    [ES] En las últimas décadas, los avances en la tecnología de secuenciación han producido cantidades significativas de datos genómicos, hecho que ha revolucionado nuestra comprensión de la biología. Sin embargo, la cantidad de datos generados ha superado con creces nuestra capacidad para interpretarlos. Descifrar el código de la vida es un gran reto. A pesar de los numerosos avances realizados, nuestra comprensión del mismo sigue siendo mínima, y apenas estamos empezando a descubrir todo su potencial, por ejemplo, en áreas como la medicina de precisión o la farmacogenómica. El objetivo principal de esta tesis es avanzar en nuestra comprensión de la vida proponiendo una aproximación holística mediante un enfoque basado en modelos que consta de tres artefactos: i) un esquema conceptual del genoma, ii) un método para su aplicación en el mundo real, y iii) el uso de ontologías fundacionales para representar el conocimiento del dominio de una forma más precisa y explícita. Las dos primeras contribuciones se han validado mediante la implementación de sistemas de información genómicos basados en modelos conceptuales. La tercera contribución se ha validado mediante experimentos empíricos que han evaluado si el uso de ontologías fundacionales conduce a una mejor comprensión del dominio genómico. Los artefactos generados ofrecen importantes beneficios. En primer lugar, se han generado procesos de gestión de datos más eficientes, lo que ha permitido mejorar los procesos de extracción de conocimientos. En segundo lugar, se ha logrado una mejor comprensión y comunicación del dominio.[CA] En les últimes dècades, els avanços en la tecnologia de seqüenciació han produït quantitats significatives de dades genòmiques, fet que ha revolucionat la nostra comprensió de la biologia. No obstant això, la quantitat de dades generades ha superat amb escreix la nostra capacitat per a interpretar-los. Desxifrar el codi de la vida és un gran repte. Malgrat els nombrosos avanços realitzats, la nostra comprensió del mateix continua sent mínima, i a penes estem començant a descobrir tot el seu potencial, per exemple, en àrees com la medicina de precisió o la farmacogenómica. L'objectiu principal d'aquesta tesi és avançar en la nostra comprensió de la vida proposant una aproximació holística mitjançant un enfocament basat en models que consta de tres artefactes: i) un esquema conceptual del genoma, ii) un mètode per a la seua aplicació en el món real, i iii) l'ús d'ontologies fundacionals per a representar el coneixement del domini d'una forma més precisa i explícita. Les dues primeres contribucions s'han validat mitjançant la implementació de sistemes d'informació genòmics basats en models conceptuals. La tercera contribució s'ha validat mitjançant experiments empírics que han avaluat si l'ús d'ontologies fundacionals condueix a una millor comprensió del domini genòmic. Els artefactes generats ofereixen importants beneficis. En primer lloc, s'han generat processos de gestió de dades més eficients, la qual cosa ha permés millorar els processos d'extracció de coneixements. En segon lloc, s'ha aconseguit una millor comprensió i comunicació del domini.[EN] Over the last few decades, advances in sequencing technology have produced significant amounts of genomic data, which has revolutionised our understanding of biology. However, the amount of data generated has far exceeded our ability to interpret it. Deciphering the code of life is a grand challenge. Despite our progress, our understanding of it remains minimal, and we are just beginning to uncover its full potential, for instance, in areas such as precision medicine or pharmacogenomics. The main objective of this thesis is to advance our understanding of life by proposing a holistic approach, using a model-based approach, consisting of three artifacts: i) a conceptual schema of the genome, ii) a method for its application in the real-world, and iii) the use of foundational ontologies to represent domain knowledge in a more unambiguous and explicit way. The first two contributions have been validated by implementing genome information systems based on conceptual models. The third contribution has been validated by empirical experiments assessing whether using foundational ontologies leads to a better understanding of the genomic domain. The artifacts generated offer significant benefits. First, more efficient data management processes were produced, leading to better knowledge extraction processes. Second, a better understanding and communication of the domain was achieved.Las fructíferas discusiones y los resultados derivados de los proyectos INNEST2021 /57, MICIN/AEI/10.13039/501100011033, PID2021-123824OB-I00, CIPROM/2021/023 y PDC2021- 121243-I00 han contribuido en gran medida a la calidad final de este tesis.García Simón, A. (2022). Understanding the Code of Life: Holistic Conceptual Modeling of the Genome [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/19143

    Modelling, Monitoring, Control and Optimization for Complex Industrial Processes

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    This reprint includes 22 research papers and an editorial, collected from the Special Issue "Modelling, Monitoring, Control and Optimization for Complex Industrial Processes", highlighting recent research advances and emerging research directions in complex industrial processes. This reprint aims to promote the research field and benefit the readers from both academic communities and industrial sectors

    Platform://Democracy: Perspectives on Platform Power, Public Values and the Potential of Social Media Councils

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    Social media platforms have created private communication orders which they rule through terms of service and algorithmic moderation practices. As their impact on public communication and human rights has grown, different models to increase the role of public interests and values in the design of their rules and their practices has, too. But who should speak for both the users and the public at large? Bodies of experts and/or selected user representatives, usually called Platform Councils of Social Media Councils (SMCs) have gained attention as a potential solution. Examples of Social Media Councils include Meta’s Oversight Board but most platforms companies have so far shied away from installing one. This survey of approaches to increasing the quality of platform decision-making and content governance involving more than 35 researchers from four continents brough to together in regional "research clinics" makes clear that trade-offs have to be carefully balanced. The larger the council, the less effective is its decision-making, even if its legitimacy might be increased. While there is no one-size-fits-all approach, the projects demonstrates that procedures matter, that multistakeholderism is a key concept for effective Social Media Councils, and that incorporating technical expertise and promoting inclusivity are important considerations in their design. As the Digital Services Act becomes effective in 2024, a Social Media Council for Germany’s Digital Services Coordinator (overseeing platforms) can serve as test case and should be closely monitored. Beyond national councils, there is strong case for a commission focused on ensuring human rights online can be modeled after the Venice Commission and can provide expertise and guidelines on policy questions related to platform governance, particularly those that affect public interests like special treatment for public figures, for mass media and algorithmic diversity. The commission can be staffed by a diverse set of experts from selected organizations and institutions established in the platform governance field

    Strategies to Reduce the Impact of Disruptions in Manufacturing Transportation Supply Chains

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    Abstract Supply chain managers in the manufacturing transportation industry grapple with reducing the impact of disruptions in transportation supply chains since 50% of U.S. companies have experienced between six to 20 disruptions per year. Ineffective transportation disruption strategies negatively impact the performance and profitability of manufacturing organizations resulting in losses and business failure. Grounded in Goldratt’s philosophy and thinking process of the Theory of Constraints (TOC), the purpose of this qualitative multiple case study was to explore successful strategies supply chain managers in the manufacturing transportation industry used to reduce the impact of disruptions in transportation supply chains. The participants were three supply chain managers from three different manufacturing industries doing business in the Commonwealth of Massachusetts, who successfully implemented strategies that reduced the impact of disruptions in manufacturing transportation in their organizations. Data were collected through face-to-face semistructured interviews, archival records, and social media websites. Through thematic analysis, three themes emerged: (a) technology and innovative solutions, (b) supply chain collaborative efforts, and (d) logistics and transportation innovative strategies. A key recommendation is for supply chain managers to create multi-vendor transportation ecosystems to work together rather than working by themselves. The implication for positive social change includes the potential to create employment and increase local communities’ tax revenues that could be used to provide the most needed social services
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