21,976 research outputs found

    Trueing

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    Even in areas of philosophy of science that don’t involve formal treatments of truth, one’s background view of truth still centrally shapes views on other issues. I offer an informal way to think about truth as trueing, like trueing a bicycle wheel. This holist approach to truth provides a way to discuss knowledge products like models in terms of how well-trued they are to their target. Trueing emphasizes: the process by which models are brought into true; how the idealizations in models are not false but rather like spokes in appropriate tension to achieve a better-trued fit to target; and that this process is not accomplished once and done forever, but instead requires upkeep and ongoing fine-tuning. I conclude by emphasizing the social importance of being a pragmatist about truth in order to accurately answer questions about science such as, “but do we really know that…

    Testing the nomological network for the Personal Engagement Model

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    The study of employee engagement has been a key focus of management for over three decades. The academic literature on engagement has generated multiple definitions but there are two primary models of engagement: the Personal Engagement Model of Kahn (1990), and the Work Engagement Model (WEM) of Schaufeli et al., (2002). While the former is cited by most authors as the seminal work on engagement, research has tended to focus on elements of the model and most theoretical work on engagement has predominantly used the WEM to consider the topic. The purpose of this study was to test all the elements of the nomological network of the PEM to determine whether the complete model of personal engagement is viable. This was done using data from a large, complex public sector workforce. Survey questions were designed to test each element of the PEM and administered to a sample of the workforce (n = 3,103). The scales were tested and refined using confirmatory factor analysis and then the model was tested determine the structure of the nomological network. This was validated and the generalisability of the final model was tested across different work and organisational types. The results showed that the PEM is viable but there were differences from what was originally proposed by Kahn (1990). Specifically, of the three psychological conditions deemed necessary for engagement to occur, meaningfulness, safety, and availability, only meaningfulness was found to contribute to employee engagement. The model demonstrated that employees experience meaningfulness through both the nature of the work that they do and the organisation within which they do their work. Finally, the findings were replicated across employees in different work types and different organisational types. This thesis makes five contributions to the engagement paradigm. It advances engagement theory by testing the PEM and showing that it is an adequate representation of engagement. A model for testing the causal mechanism for engagement has been articulated, demonstrating that meaningfulness in work is a primary mechanism for engagement. The research has shown the key aspects of the workplace in which employees experience meaningfulness, the nature of the work that they do and the organisation within which they do it. It has demonstrated that this is consistent across organisations and the type of work. Finally, it has developed a reliable measure of the different elements of the PEM which will support future research in this area

    A Design Science Research Approach to Smart and Collaborative Urban Supply Networks

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    Urban supply networks are facing increasing demands and challenges and thus constitute a relevant field for research and practical development. Supply chain management holds enormous potential and relevance for society and everyday life as the flow of goods and information are important economic functions. Being a heterogeneous field, the literature base of supply chain management research is difficult to manage and navigate. Disruptive digital technologies and the implementation of cross-network information analysis and sharing drive the need for new organisational and technological approaches. Practical issues are manifold and include mega trends such as digital transformation, urbanisation, and environmental awareness. A promising approach to solving these problems is the realisation of smart and collaborative supply networks. The growth of artificial intelligence applications in recent years has led to a wide range of applications in a variety of domains. However, the potential of artificial intelligence utilisation in supply chain management has not yet been fully exploited. Similarly, value creation increasingly takes place in networked value creation cycles that have become continuously more collaborative, complex, and dynamic as interactions in business processes involving information technologies have become more intense. Following a design science research approach this cumulative thesis comprises the development and discussion of four artefacts for the analysis and advancement of smart and collaborative urban supply networks. This thesis aims to highlight the potential of artificial intelligence-based supply networks, to advance data-driven inter-organisational collaboration, and to improve last mile supply network sustainability. Based on thorough machine learning and systematic literature reviews, reference and system dynamics modelling, simulation, and qualitative empirical research, the artefacts provide a valuable contribution to research and practice

    Pollution-induced community tolerance in freshwater biofilms – from molecular mechanisms to loss of community functions

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    Exposure to herbicides poses a threat to aquatic biofilms by affecting their community structure, physiology and function. These changes render biofilms to become more tolerant, but on the downside community tolerance has ecologic costs. A concept that addresses induced community tolerance to a pollutant (PICT) was introduced by Blanck and Wängberg (1988). The basic principle of the concept is that microbial communities undergo pollution-induced succession when exposed to a pollutant over a long period of time, which changes communities structurally and functionally and enhancing tolerance to the pollutant exposure. However, the mechanisms of tolerance and the ecologic consequences were hardly studied up to date. This thesis addresses the structural and functional changes in biofilm communities and applies modern molecular methods to unravel molecular tolerance mechanisms. Two different freshwater biofilm communities were cultivated for a period of five weeks, with one of the communities being contaminated with 4 μg L-1 diuron. Subsequently, the communities were characterized for structural and functional differences, especially focusing on their crucial role of photosynthesis. The community structure of the autotrophs was assessed using HPLC-based pigment analysis and their functional alterations were investigated using Imaging-PAM fluorometry to study photosynthesis and community oxygen profiling to determine net primary production. Then, the molecular fingerprints of the communities were measured with meta-transcriptomics (RNA-Seq) and GC-based community metabolomics approaches and analyzed with respect to changes in their molecular functions. The communities were acute exposed to diuron for one hour in a dose-response design, to reveal a potential PICT and uncover related adaptation to diuron exposure. The combination of apical and molecular methods in a dose-response design enabled the linkage of functional effects of diuron exposure and underlying molecular mechanisms based on a sensitivity analysis. Chronic exposure to diuron impaired freshwater biofilms in their biomass accrual. The contaminated communities particularly lost autotrophic biomass, reflected by the decrease in specific chlorophyll a content. This loss was associated with a change in the molecular fingerprint of the communities, which substantiates structural and physiological changes. The decline in autotrophic biomass could be due to a primary loss of sensitive autotrophic organisms caused by the selection of better adapted species in the course of chronic exposure. Related to this hypothesis, an increase in diuron tolerance has been detected in the contaminated communities and molecular mechanisms facilitating tolerance have been found. It was shown that genes of the photosystem, reductive-pentose phosphate cycle and arginine metabolism were differentially expressed among the communities and that an increased amount of potential antioxidant degradation products was found in the contaminated communities. This led to the hypothesis that contaminated communities may have adapted to oxidative stress, making them less sensitive to diuron exposure. Moreover, the photosynthetic light harvesting complex was altered and the photoprotective xanthophyll cycle was increased in the contaminated communities. Despite these adaptation strategies, the loss of autotrophic biomass has been shown to impair primary production. This impairment persisted even under repeated short-term exposure, so that the tolerance mechanisms cannot safeguard primary production as a key function in aquatic systems.:1. The effect of chemicals on organisms and their functions .............................. 1 1.1 Welcome to the anthropocene .......................................................................... 1 1.2 From cellular stress responses to ecosystem resilience ................................... 3 1.2.1 The individual pursuit for homeostasis ....................................................... 3 1.2.2 Stability from diversity ................................................................................. 5 1.3 Community ecotoxicology - a step forward in monitoring the effects of chemical pollution? ................................................................................................................. 6 1.4 Functional ecotoxicological assessment of microbial communities ................... 9 1.5 Molecular tools – the key to a mechanistic understanding of stressor effects from a functional perspective in microbial communities? ...................................... 12 2. Aims and Hypothesis ......................................................................................... 14 2.1 Research question .......................................................................................... 14 2.2 Hypothesis and outline .................................................................................... 15 2.3 Experimental approach & concept .................................................................. 16 2.3.1 Aquatic freshwater biofilms as model community ..................................... 16 2.3.2 Diuron as model herbicide ........................................................................ 17 2.3.3 Experimental design ................................................................................. 18 3. Structural and physiological changes in microbial communities after chronic exposure - PICT and altered functional capacity ................................................. 21 3.1 Introduction ..................................................................................................... 21 3.2 Methods .......................................................................................................... 23 3.2.1 Biofilm cultivation ...................................................................................... 23 3.2.2 Dry weight and autotrophic index ............................................................. 23 3.2.4 Pigment analysis of periphyton ................................................................. 23 3.2.4.1 In-vivo pigment analysis for community characterization ....................... 24 3.2.4.2 In-vivo pigment analysis based on Imaging-PAM fluorometry ............... 24 3.2.4.3 In-vivo pigment fluorescence for tolerance detection ............................. 26 3.2.4.4 Ex-vivo pigment analysis by high-pressure liquid-chromatography ....... 27 3.2.5 Community oxygen metabolism measurements ....................................... 28 3.3 Results and discussion ................................................................................... 29 3.3.1 Comparison of the structural community parameters ............................... 29 3.3.2 Photosynthetic activity and primary production of the communities after selection phase ................................................................................................. 33 3.3.3 Acquisition of photosynthetic tolerance .................................................... 34 3.3.4 Primary production at exposure conditions ............................................... 36 3.3.5 Tolerance detection in primary production ................................................ 37 3.4 Summary and Conclusion ........................................................................... 40 4. Community gene expression analysis by meta-transcriptomics ................... 41 4.1 Introduction to meta-transcriptomics ............................................................... 41 4.2. Methods ......................................................................................................... 43 4.2.1 Sampling and RNA extraction................................................................... 43 4.2.2 RNA sequencing analysis ......................................................................... 44 4.2.3 Data assembly and processing................................................................. 45 4.2.4 Prioritization of contigs and annotation ..................................................... 47 4.2.5 Sensitivity analysis of biological processes .............................................. 48 4.3 Results and discussion ................................................................................... 48 4.3.1 Characterization of the meta-transcriptomic fingerprints .......................... 49 4.3.2 Insights into community stress response mechanisms using trend analysis (DRomic’s) ......................................................................................................... 51 4.3.3 Response pattern in the isoform PS genes .............................................. 63 4.5 Summary and conclusion ................................................................................ 65 5. Community metabolome analysis ..................................................................... 66 5.1 Introduction to community metabolomics ........................................................ 66 5.2 Methods .......................................................................................................... 68 5.2.1 Sampling, metabolite extraction and derivatisation................................... 68 5.2.2 GC-TOF-MS analysis ............................................................................... 69 5.2.3 Data processing and statistical analysis ................................................... 69 5.3 Results and discussion ................................................................................... 70 5.3.1 Characterization of the metabolic fingerprints .......................................... 70 5.3.2 Difference in the metabolic fingerprints .................................................... 71 5.3.3 Differential metabolic responses of the communities to short-term exposure of diuron ............................................................................................................ 73 5.4 Summary and conclusion ................................................................................ 78 6. Synthesis ............................................................................................................. 79 6.1 Approaches and challenges for linking molecular data to functional measurements ...................................................................................................... 79 6.2 Methods .......................................................................................................... 83 6.2.1 Summary on the data ............................................................................... 83 6.2.2 Aggregation of molecular data to index values (TELI and MELI) .............. 83 6.2.3 Functional annotation of contigs and metabolites using KEGG ................ 83 6.3 Results and discussion ................................................................................... 85 6.3.1 Results of aggregation techniques ........................................................... 85 6.3.2 Sensitivity analysis of the different molecular approaches and endpoints 86 6.3.3 Mechanistic view of the molecular stress responses based on KEGG functions ............................................................................................................ 89 6.4 Consolidation of the results – holistic interpretation and discussion ............... 93 6.4.1 Adaptation to chronic diuron exposure - from molecular changes to community effects.............................................................................................. 93 6.4.2 Assessment of the ecological costs of Pollution-induced community tolerance based on primary production ............................................................. 94 6.5 Outlook ............................................................................................................ 9

    Exploring the Training Factors that Influence the Role of Teaching Assistants to Teach to Students With SEND in a Mainstream Classroom in England

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    With the implementation of inclusive education having become increasingly valued over the years, the training of Teaching Assistants (TAs) is now more important than ever, given that they work alongside pupils with special educational needs and disabilities (hereinafter SEND) in mainstream education classrooms. The current study explored the training factors that influence the role of TAs when it comes to teaching SEND students in mainstream classrooms in England during their one-year training period. This work aimed to increase understanding of how the training of TAs is seen to influence the development of their personal knowledge and professional skills. The study has significance for our comprehension of the connection between the TAs’ training and the quality of education in the classroom. In addition, this work investigated whether there existed a correlation between the teaching experience of TAs and their background information, such as their gender, age, grade level taught, years of teaching experience, and qualification level. A critical realist theoretical approach was adopted for this two-phased study, which involved the mixing of adaptive and grounded theories respectively. The multi-method project featured 13 case studies, each of which involved a trainee TA, his/her college tutor, and the classroom teacher who was supervising the trainee TA. The analysis was based on using semi-structured interviews, various questionnaires, and non-participant observation methods for each of these case studies during the TA’s one-year training period. The primary analysis of the research was completed by comparing the various kinds of data collected from the participants in the first and second data collection stages of each case. Further analysis involved cross-case analysis using a grounded theory approach, which made it possible to draw conclusions and put forth several core propositions. Compared with previous research, the findings of the current study reveal many implications for the training and deployment conditions of TAs, while they also challenge the prevailing approaches in many aspects, in addition to offering more diversified, enriched, and comprehensive explanations of the critical pedagogical issues

    Integrative multi-omics analysis for the effect of genetic alterations in cancer xenograft and organoid models

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    Department of Biomedical EngineeringDNA damage is a well-recognized factor in the development and progression of cancer. Numerous studies on genetic changes associated with cancer or the DNA repair pathway have been conducted, however, there is still a need for additional research on their function. The establishment of patient-derived xenografts or organoids for the purpose of testing functional genomic approaches is the subject of ongoing research. According to model-specific characteristics, it is not fully understood how these attempts to simulate patient cancer differ from original cancer. To comprehend the distinction between genuine patient cancer and these patient-derived disease models in more depth, multi-omics analysis is required to comprehend the overall genotypes, phenotypes, and environmental variables. Depending on the characteristics of each disease model, distinct omics analysis approaches and factors must be considered. In addition, care must be taken to avoid technical errors when integrating omics data generated by different sequencing equipment. There is currently no golden rule for data integration, but several approaches are being developed. It is crucial to determine the function of genes linked with the DNA repair pathway because these genes contribute to the induction or prevention of cancer. In chapter 1, I identified the interaction between MRE11 and TRIP13 through proximity labeling combined with the SILAC method which is quantitative proteomics using metabolic labeling. TRIP13 depletion doesn???t affect the nuclease activity and conformation of the MRN complex but directly inhibits the interaction of MDC1 with MRN complex and MDC1 recruitment on the DNA damage site. TRIP13 degradation with mirin treatment shows additive effects on ATM signaling activation. In conclusion, TRIP13 regulates immediate-early DNA damage sensing through MRE11 and ATM signaling independently of mirin. When assessing the functional genomic approach using patient-derived disease models, it is essential to determine which aspects of the models' correlation to actual cancer should be properly considered. In chapter 2, I found there are a few overlapped deleterious somatic mutations of the PDX model and their original tumor. I suspected novel mutagen exposure during PDX establishment or sample contamination. However, germline mutations of PDX models are well conserved from original tumors, and their mutational signatures of PDX also mimic that of their tumor. Though the number of overlapped mutations between the PDX model and their tumor was few, brain tumor-specific mutations are found in PDX samples. Especially, histone methylation- and cilia-related gene mutations are enriched in PDX samples. While it suggested these mutated genes are needed for maintaining the stemness of brain tumor PDX model or PDX model would be more appropriate for the samples with high heterogeneity, I have presented precautions and considerations in PDX model genome analysis. Multi-omics analysis that takes into consideration genetic, expressive, and clinical aspects can provide important information for the study of diseases with complicated etiologies, such as cancer, and can contribute to the development of diagnosis and treatment. To utilize colorectal cancer organoids for Companion Diagnostics (CDx), in chapter 3, I characterized patient-derived colorectal cancer (CRC) organoids through well-known genomic markers such as Tumor mutation burden (TMB), Microsatellite instability (MSI) and propose a novel grouping method using sharing same mutation site. The classification of CRC patients was more detailed combined with consensus molecular subtype (CMS) classifications. Additionally, I extract the expression features of the patients who experience recurrence or metastasis after first-line chemotherapy treatment with reference to clinical data. Drug response of CRC organoids by patient group and knockdown of the extracted features in the selected organoids would be validated in further study. In summary, with this dissertation, I conducted functional research on the DNA repair pathway of cancer-related genes, as well as the genetic analysis between patient-derived xenograft and original tumors, and introduced a novel perspective on the diagnosis and treatment of colorectal cancer patients using patient-derived organoids through multi-omics analysis.ope

    Categories and foundational ontology: A medieval tutorial

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    Foundational ontologies, central constructs in ontological investigations and engineering alike, are based on ontological categories. Firstly proposed by Aristotle as the very ur- elements from which the whole of reality can be derived, they are not easy to identify, let alone partition and/or hierarchize; in particular, the question of their number poses serious challenges. The late medieval philosopher Dietrich of Freiberg wrote around 1286 a tutorial that can help us today with this exceedingly difficult task. In this paper, I discuss ontological categories and their importance for foundational ontologies from both the contemporary perspective and the original Aristotelian viewpoint, I provide the translation from the Latin into English of Dietrich's De origine II with an introductory elaboration, and I extract a foundational ontology–that is in fact a single-category one–from this text rooted in Dietrich's specification of types of subjecthood and his conception of intentionality as causal operation

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 β chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IκB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de referência para doentes com estenose aórtica e visa a eliminação da sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica. Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os mecanismos biológicos subjacentes a uma remodelagem reversa incompleta ainda não são claros. Além disso, não dispomos de ferramentas de prognóstico definitivos nem de terapias auxiliares para melhorar a condição dos pacientes indicados para substituição da válvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica para a caracterização, respetivamente, do miocárdio e do líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas desreguladas foram detetadas. As análises de anotação de genes, de enriquecimento de vias celulares e discriminativa corroboram um cenário de aumento da expressão de genes pro-hipertróficos e de síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos apontou para a cadeia β do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma, sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição dos pacientes indicados para intervenção. Em particular, a avaliação funcional de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver força (tensão ativa). Este estudo levanta várias hipóteses na investigação da remodelagem reversa. No futuro, estudos de ganho e/ou perda de função realizados em cardiomiócitos isolados ou em modelos animais de banding-debanding da aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos encontrados. Além disso, estudos clínicos em coortes de maior dimensão trarão conclusões definitivas quanto ao valor de prognóstico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    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
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