21684 research outputs found
Sort by
Interplay between AMP-activated protein kinase (AMPK) and The Sphingolipid System in Adipose Tissue Regulation
Get PDFIntroduction: Cardiovascular diseases represent a global health burden, with vascular dysfunction and chronic low-grade inflammation recognised as key pathological drivers. Published evidence highlights the crucial regulatory role of perivascular adipose tissue (PVAT) in maintaining vascular homeostasis. Dysfunctional PVAT with has been implicated in the development of vascular disease. Within this context, sphingosine kinase 1 (SphK1) and its bioactive lipid product, sphingosine-1-phosphate (S1P), is noted as a modulator of vascular tone and inflammation. Furthermore, AMP-activated protein kinase (AMPK) an enzyme which promotes cellular energy homeostasis, serves as a vascular function regulator. The interplay between AMPK signalling and the SphK1/S1P axis within PVAT represents a promising therapeutic target for ameliorating vascular dysfunction. This thesis investigates the functional interactions between AMPK, SphK1/S1P signalling within cultured adipocytes and aortic PVAT, advancing understanding of vascular biology in the hope of identifying novel therapeutic strategies for cardiovascular and metabolic diseases.
Methods and Materials: This chapter outlines the experimental methodologies and analytical techniques used to investigate the interplay between AMP-activated protein kinase (AMPK) and sphingosine-1-phosphate (S1P) in the regulation of adipose tissue, with a particular emphasis on the role of PVAT. Wild-type (WT) and AMPKα1 knockout (KO) mice were employed as experimental models. Vascular function was assessed using wire myography to measure relaxation responses of thoracic aortic rings following exposure to S1P, AMPK activators (AICAR, A-769662, and Compound 991), and their combinations. The contribution of PVAT-derived mediators was investigated by comparing vascular responses in rings with and without intact PVAT. Adipokine secretion was analysed using a proteome-based mouse adipokine array, while nitric oxide (NO) production was quantified using a Sievers 280 NO analyser. Quantitative real-time PCR and western blotting were used to assess gene and protein expression in PVAT, mouse embryonic fibroblasts (MEFs), and 3T3-L1 adipocytes. Additionally, immunofluorescence microscopy was employed to examine the localisation of sphingosine kinase 1 (SphK1). All experiments were conducted under standardised laboratory conditions, and data were analysed using appropriate statistical methods to ensure accuracy, reproducibility, and scientific validity.
Results: Chapter 3 explore the regulatory relationship between AMPK and SphK1 during adipocyte differentiation and in PVAT. Using 3T3-L1 adipocyte cells, mouse embryonic fibroblast (MEF) cells which lack AMPK, and mouse abdominal and thoracic PVAT, SphK1 expression was assessed in adipocytes and in cells lacking AMPK. SphK1 protein levels notably increased during adipocyte differentiation, highlighting a possible role in adipogenesis. In AMPKα1/α2 knockout MEFs, increased SphK1 protein levels were observed without corresponding changes in mRNA expression. Furthermore, tissue-specific differences were noted in PVAT, with distinct regulatory patterns observed between thoracic and abdominal PVAT.
Chapte r4 examine the roles of S1P and AMPK activation, using the activator AICAR, in modulating vascular function through PVAT in mouse thoracic aortic rings. S1P alone showed no vasorelaxant effects, while AICAR caused a significant vascular relaxation. S1P and AICAR combined substantially augmented this relaxation, particularly in endothelium-denuded aortic rings containing PVAT. This effect was significantly reduced in AMPKα1 knockout mice, suggesting a critical role for the AMPKα1 subunit. Further experiments suggest that increased secretion of PVAT-derived adiponectin and nitric oxide could be potential mechanisms. S1PR1, a vascular-expressed receptor for S1P was identified as a key mediator of these effects. Findings highlight the complex interplay between S1P signalling, AMPK activation, and PVAT-derived factors in vascular regulation.
Chapter 5 investigate the impact of S1P and different AMPK activators, namely Compound 991 (C991), and A-769662, on vascular relaxation mediated by PVAT in mouse thoracic aortic rings. As in Chapter 4, S1P alone showed no vasorelaxation effects, while each AMPK activator induced significant relaxation, particularly in PVAT-containing vessels. However, combined treatments with S1P and either C991 or A-769662 resulted in non-significant enhanced vascular relaxation, highlighting that the mechanism of AMPK activation may be crucial for this enhancement of relaxation.
Discussion: Chapter 3 demonstrated that AMPKα1/α2 knockout (KO) leads to elevated SphK1 protein expression in MEFs without corresponding changes in mRNA levels, indicating post-transcriptional regulation. This deficiency also enhances ERK1/2 and JNK signalling, consistent with a shift toward a pro-inflammatory phenotype. Importantly, SphK1 was selectively upregulated in thoracic PVAT of AMPKα1 KO mice, but not in abdominal PVAT, underscoring a depot-specific regulatory role of AMPK.
Chapter 4 demonstrated that while S1P alone exerts limited vasorelaxant effects, its combination with AICAR, an AMPK activator, significantly enhances PVAT-mediated vascular relaxation through nitric oxide and adiponectin pathways. Chapter 5 explored the effects of direct AMPK activators, A-769662 and Compound 991, confirming their ability to induce vascular relaxation, although without the synergistic enhancement observed with AICAR and S1P. The pivotal role of AMPK signalling in integrating metabolic and inflammatory pathways is underscored and its potential as a therapeutic target for vascular dysfunction highlighted.
Conclusion: This thesis provides novel insights into the regulatory interplay between sphingosine-1-phosphate (S1P) signalling, AMPK activation via AICAR, and the functional role of perivascular adipose tissue (PVAT) in modulating vascular relaxation in the mouse thoracic aorta. The combination of AICAR and S1P enhanced vasorelaxation, highlighting the importance of indirect AMPK activation in promoting PVAT-derived adiponectin and nitric oxide. The selective upregulation of SphK1 in AMPK-deficient tissues suggests a shift toward a pro-inflammatory phenotype. These findings identify the SphK1/S1P–AMPK axis as a potential target for improving vascular health
Efficient and scalable algorithms for bigraph matching
Get PDFBigraph reactive systems provide an established approach to modelling large and dynamic systems which contain both spatial and non-spatial relationships between entities, and have been used for modelling in a wide variety of research areas such as biology, networking, sensors and security. Bigraph state rewriting operations which represent temporal evolution rely upon an underlying NP-complete matching algorithm to identify pattern components to substitute, but this limits the scale and scope of bigraphs due to the computational cost and frequency of rewriting. The bigraph matching tool BigraphER relies on a Boolean satisfiability (SAT) encoding to do this, which generates an impractically large number of clauses for larger models which limits scalability and is difficult to adapt for extensions to the bigraph structure.
We propose a novel and efficient algorithm for solving bigraph matching which encodes the problem as a subgraph isomorphism constraint satisfaction problem, applying additional constraints where required to model the added complexity of bigraph composition logic. This approach can be supported by any constraint programming toolkit as well as any graph solving tool which supports additional side-constraints. This approach also grants more flexibility in regards to modelling extensions to the bigraph formalism such as bigraphs with sharing and directed bigraphs.
We adapt the state of the art constraint-based Glasgow Subgraph Solver tool to implement the encoded matching problem, where we observe a greater solve time of over two orders of magnitude on a variety of different real-world matching instances performed within mixed reality, protocol and conference models. We also integrate the subgraph solver into the BigraphER framework and provide further evaluation metrics when used as a component for building full-scale models.
We build further upon this idea by proposing an adaptation for the McSplit algorithm for finding largest common subgraphs in order to obtain a maximum common bigraph between two agents, a novel definition which provides the means for supporting more rich and complex types of modelling in a bigraph toolkit such as performing contextual transitions for labelled transition systems and identifying bisimulations. This is implemented using a prototype solver to demonstrate the promise of this approach. These contributions substantially expand the scope of bigraph modelling tools and their applications for modeling large-scale systems
Applying optogenetics in Synechococcus sp. PCC 7002
Get PDFCyanobacteria can be utilised in biotechnology as environmentally sustainable cell machines to convert CO2 into a diverse range of biochemicals. However, a lack of molecular tools available for precise and dynamic control of gene expression hinders metabolic engineering and often contributes to low product titres. Optogenetic tools enable light-regulated control of gene expression with high tunability and reversibility, though their application in cyanobacteria species with high industrial potential is limited. In this study, two different optogenetic systems were characterised in Synechococcus sp. PCC 7002, applications for metabolic engineering were tested, and a transcriptomics study was performed to pinpoint novel optogenetic tools. Firstly, the green/red lightresponsive CcaS/CcaR optogenetic system originating from Synechocystis sp. PCC 6803 was expressed in Synechococcus sp. PCC 7002 and performance was monitored by measuring its regulation of Green Fluorescent Protein (GFP). Characterisation of activation and deactivation was performed under a range of different light wavelengths and intensities using both fluorescence spectrometry and qRT-PCR. The performance of the CcaS/CcaR system was further improved by making targeted genetic modifications to the pCpcG2 output promoter. Secondly, the blue light-regulated YF1/FixJ optogenetic system of noncyanobacterial origin was expressed in Synechococcus sp. PCC 7002. The system demonstrated poor performance with minimal increase in system output in response to blue light or darkness. To evaluate the use of optogenetics for metabolic engineering, the optimised CcaS/CcaR system was tested for lightcontrolled heterologous production of mannitol and L-alanine. While the former was successful, the latter failed despite careful troubleshooting. Finally, to identify new potential optogenetic tools from Synechococcus sp. PCC 7002, RNA sequencing was used to identify genes differentially expressed in blue and orange light. A variety of genes were identified, including transcriptional regulators and kinases which could have roles in wavelength-specific signalling pathways. Overall, this work lays a critical foundation for the use of optogenetics to increase control over metabolic pathways and improve the production of commercially valuable compounds in an industrially promising cyanobacteria species
Investigating the political economy of industry 4.0. A labour process analysis in the commercial aerospace sector
No full textAbstract not currently available
From metonymy to metaphor: A diachronic corpus-based comparison of metaphorical meanings of English and Chinese colour terms
Get PDFCross-cultural comparisons of metaphors mostly take the form of synchronic research (e.g. Kövecses 2005). However, diachronic research contributes not only to revealing cultural factors of one language (e.g. Gevaert 1995) but also to investigating universal trends (e.g. Trim 2014). Colour metaphors are appropriate subjects to investigate the interplay of similar conceptualisation (even potentially universal trends) and cultural specificity because of the common metonymic relationships to the universal natural world and culture-specific symbolism of colours. This thesis compares English and Chinese colour metaphors and analyses the similarities and differences in the metaphorical conceptualisation and ongoing development of metaphorical expression. It investigates five pairs of English and Chinese colour terms with the same etymological metonymies (green, orange, rose/rosy, purple, gold(en) and their Chinese counterparts qing/lv, cheng(se)/juse, meiguise, zi, jin(se)), and three pairs with different etymological metonymies (pink, peach(y), beige and their Chinese counterparts fen(hong)(se), tao(hua)se, mise), in order to investigate the interaction between metonymy and metaphor in the development of both English and Chinese colour metaphors.
This thesis uses a corpus-based method of collecting metaphorical senses of colour terms from historical corpora in four periods of English and Chinese respectively, to reveal and compare the routes taken during the course of their metaphorical development. The corpora are supplemented by other resources – dictionaries, the Historical Thesaurus of English, and Mapping Metaphor with the Historical Thesaurus.
The results show that colour metaphors develop from connotations of colour in a process that moves from metonymy to metaphor. The study suggests that the metaphorical conceptualisation of colour terms starts from an experiential scene that generates connotations associated with colour. The generation process has three main motivations: metonymic basis, cultural context and relationship with other colours. Then, the connotations are generalised to a distinct domain outside of the experiential scene and finally develop into metaphorical meanings. The similarities are motivated by the potentially universal patterns both in the generation process (which give rise to the same connotations of the same metonymic bases) and in the generalisation process (which trigger the shared generic conceptualisations of metaphorical mappings). The potentially universal pattern in colour metaphors also reveals another kind of potentially universal human experience relating to the environment other than embodiment as the experiential bases of potential universal metaphors. The differences are driven by culturally motivated patterns in the generation process and generalisation process, which give rise to culturally specific connotations and metaphorical mappings
New materials with optoelectronic and energy conversion properties
No full textAbstract not currently available
Soft-linked planning and operation of an integrated energy system in Great Britain
Get PDFThe National Energy System Operator (NESO) in Great Britain (GB) is now responsible for integrated planning of the electricity, natural gas and hydrogen systems, placing emphasis on spatial dependence and operational synergies among energy resources. In energy system planning models, operational bottlenecks including transmission congestion, renewable energy curtailment, and load shedding, are undervalued due to a lack of spatial, temporal, and technical resolution.
This thesis proposes, for the first time, the exchange of information between an energy system planning model, which determines the long-term development and investment pathway of energy technologies, and an integrated electricity, natural gas and hydrogen system optimal energy flow model. This soft-link between the models is shown to successfully identify operational challenges arising from longterm energy system planning, while also capturing interactions between individual energy systems by increasing modelling resolution.
The proposed modelling framework is applied to a case study of future energy plans for GB, to assess the operational viability of system expansion plans. Results find insufficient electricity transmission capacity in 2030 to avoid congestion, with curtailment increasing six-fold, and electrical load shed due to lack of supply in the West Midlands of England. Thus, 14 transmission upgrades are recommended to eliminate electricity transmission congestion in 2030, which are effective in avoiding congestion-induced curtailment in 2050. Further analysis of 2050 highlights the need for additional supply in the West Midlands to avoid load shedding as residential and transportation demands are electrified.
The government funded hydrogen clusters are successful in providing early adopters of hydrogen demands and production in 2030, however clusters become net consumers of hydrogen in 2050. Natural gas demand is sustained in 2050 through energy conversion, resulting in overlap of critical natural gas and hydrogen transmission infrastructure, increasing the difficulty of infrastructure conversion.
Ultimately, the soft-link framework proposed here has successfully illuminated the operational impacts of long-term energy system planning, while endogenising the impacts of individual system interactions within the integrated energy system. Additionally, major operational challenges were unearthed from existing long-term plans for the GB energy system, highlighting the critical need for operationally aware integrated energy system planning
As you wish: why there is no moral duty to come out
Get PDFThe goal of this dissertation is to examine the possibility that queer people have a duty to come out of the closet. This duty to come out has an impact on the morality of whether or not it is permissible for queer people to keep their identities to themselves. If it is the case that queer people have a duty to come out, then by hiding their identity, they would be acting immorally, and this affects their ability to protect their identities from individuals that may harm or discriminate against them.
This dissertation explores this question in five chapters. Chapter One focuses on defining queer identities. Furthermore, Chapter One also focuses on how queer people come out, why queer people come out, and why some queer individuals choose to remain in the closet. Chapter Two focuses on Dennis Cooley’s argument for why queer people ought to come out. His argument focuses on the immorality of deception and the inability for queer people to flourish when they are in the closet. Both of these arguments fail to hold up to scrutiny.
Chapters Three and Four focus on addressing opposing reasons for coming out that stems from Cooley’s initial position. These reasons are the internal drive to come out and an external drive to come out. Chapter Three examines how authenticity might serve as a potential internal drive to come out. I demonstrate that there are numerous hurdles that prevent us from grounding a potential duty to come out in the concept of authenticity. In contrast, Chapter Four examines how queer erasure can motivate a moral duty to come out. This stems from an external drive to help other queer people who are negatively affected by queer erasure. This chapter examines both historical and modern examples of queer erasure to reinforce this position, and argues that this external drive is more promising as a potential basis for a duty to come out.
Finally, Chapter Five explores whether there is a duty to come out in order to combat this problem of queer erasure. I identify a method of combatting this problem that I call “Lighthousing”, which is the act of queer people acting as a visible representation of queerness to help closeted queer people understand their identity. While the impetus to engage in Lighthousing does not create a moral duty to come out, it does show that coming out for this reason (i.e. specifically to help other queer people) is supererogatory. Overall, there is no duty to come out, but coming out is a praiseworthy act in many cases
Fabrication and characterisation of sub-50 nm gate using single-step EBL InP HEMT with Au/Ge/Ni/Au ultra-low contact resistance for next-generation communication
No full textAbstract not currently available
Housing and labour market interactions
Get PDFAs workers switch jobs, they also often choose to move residences to be closer to their new place of work. This thesis investigates the dynamic interactions between housing and labour markets, showing that when housing is scarce, it acts as a barrier to job market transitions and aggregate employment.
While previous research has explored these markets independently, this study contributes to the literature by developing a Dynamic Stochastic General Equilibrium (DSGE) model treating the markets jointly. Chapter 1 introduces the theoretical framework, demonstrating how search frictions and spillover effects between housing and labour markets allow the model to replicate key stylized facts.
The second chapter empirically estimates the model using Bayesian methods and UK timeseries data from 1971Q2 to 2020Q1. It quantifies spillover elasticities, monetary policy parameters, and shock decompositions, shedding light on the effects of major housing and labour policy interventions during the Thatcher era. Counterfactual simulations reveal how policy reforms shaped market flexibility and economic resilience. The third chapter extends the analysis to the US economy using data from 1965Q2 to 2020Q1. Comparative analysis highlights structural differences in labour market flexibility between the UK and the US. A counterfactual experiment explores the macroeconomic consequences of a more flexible labour market in the United Kingdom, drawing lessons from the experience of the United States
Data sources:
Access Repository Dashboard
Do you manage Open Research Online? Become a CORE Member to access insider analytics, issue reports and manage access to outputs from your repository in the CORE Repository Dashboard! 👇