13,640 research outputs found
Trueing
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…
Grasping nothing: a study of minimal ontologies and the sense of music
If music were to have a proper sense – one in which it is truly given – one might reasonably place this in sound and aurality. I contend, however, that no such sense exists; rather, the sense of music takes place, and it does so with the impossible. To this end, this thesis – which is a work of philosophy and music – advances an ontology of the impossible (i.e., it thinks the being of what, properly speaking, can have no being) and considers its implications for music, articulating how ontological aporias – of the event, of thinking the absolute, and of sovereignty’s dismemberment – imply senses of music that are anterior to sound. John Cage’s Silent Prayer, a nonwork he never composed, compels a rerethinking of silence on the basis of its contradictory status of existence; Florian Hecker et al.’s Speculative Solution offers a basis for thinking absolute music anew to the precise extent that it is a discourse of meaninglessness; and Manfred Werder’s [yearn] pieces exhibit exemplarily that music’s sense depends on the possibility of its counterfeiting. Inso-much as these accounts produce musical senses that take the place of sound, they are also understood to be performances of these pieces. Here, then, thought is music’s organon and its instrument
A Design Science Research Approach to Smart and Collaborative Urban Supply Networks
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
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
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
Animating potential for intensities and becoming in writing: challenging discursively constructed structures and writing conventions in academia through the use of storying and other post qualitative inquiries
Written for everyone ever denied the opportunity of fulfilling their academic potential, this is ‘Chloe’s story’. Using composite selves, a phrase chosen to indicate multiplicities and movement, to story both the initial event leading to ‘Chloe’s’ immediate withdrawal from a Further Education college and an imaginary second chance to support her whilst at university, this Deleuzo-Guattarian (2015a) ‘assemblage’ of post qualitative inquiries offers challenge to discursively constructed structures and writing conventions in academia. Adopting a posthuman approach to theorising to shift attention towards affects and intensities always relationally in action in multiple ‘assemblages’, these inquiries aim to decentre individual ‘lecturer’ and ‘student’ identities. Illuminating movements and moments quivering with potential for change, then, hoping thereby to generate second chances for all, different approaches to writing are exemplified which trouble those academic constraints by fostering inquiry and speculation: moving away from ‘what is’ towards ‘what if’.
With the formatting of this thesis itself also always troubling the rigid Deleuzo-Guattarian (2015a) ‘segmentary lines’ structuring orthodox academic practice, imbricated in these inquiries are attempts to exemplify Manning’s (2015; 2016) ‘artfulness’ through shifts in thinking within and around an emerging PhD thesis. As writing resists organising, the verb thesisising comes into play to describe the processes involved in creating this always-moving thesis. Using ‘landing sites’ (Arakawa and Gins, 2009) as a landscaping device, freely creating emerging ‘lines of flight’ (Deleuze and Guattari, 2015a) so often denied to students forced to adhere to strict academic conventions, this ‘movement-moving’ (Manning, 2014) opens up opportunities for change as in Manning’s (2016) ‘research-creation’. Arguing for a moving away from writing-representing towards writing-inquiring, towards a writing ‘that does’ (Wyatt and Gale, 2018: 127), and toward writing as immanent doing, it is hoped to animate potential for intensities and becoming in writing, offering opportunities and glimmerings of the not-yet-known
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do lÃquido pericárdico
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 benefÃcio hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardÃaca. 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 lÃquido pericárdico
foi seguida, tomando partido de biópsias e lÃquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteÃnas identificadas, respetivamente, no miocárdio
e no lÃquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteÃnas 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 sÃntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrÃnsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos especÃficos através de immunoblot e correlação
com dados clÃnicos 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 caseÃna cinase 2, a famÃlia 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 cardÃaca, 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 clÃnicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
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